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Sample records for small-for-size fatty liver

  1. Small-for-size graft in liver transplantation.

    PubMed

    Kiuchi, Tetsuya; Oike, Fumitaka; Yamamoto, Hidekazu

    2003-11-01

    Controversies on small-for-size (SFS) graft in liver transplantation have evolved in parallel with the history of living donor liver transplantation for adults. It is true that the liver regenerates rapidly within a limited threshold. But 'normal' liver weight itself is variable and the influences of variable liver graft and extrahepatic factors are not negligible in pathological condition. Clinical features of 'SFS syndrome' are neither specific nor inevitable in low-weight liver and many other factors than actual graft weight contribute to their occurrence. Among them, early elevation of portal venous pressure highly probably plays a key role. In the clinical trials of surgical modification and local pharmacological manipulation targeting portal hemodynamics and tissue congestion, it may be the time to discard an excessive fear for SFS grafts and to minimize unnecessary withdrawal from the opportunity of transplantation.

  2. Protective effect of eNOS overexpression against ischemia/reperfusion injury in small-for-size liver transplantation

    PubMed Central

    Zhang, Bo; Liu, Qiu-Hua; Zhou, Cui-Jie; Hu, Ming-Zheng; Qian, Hai-Xin

    2016-01-01

    Ischemia/reperfusion (I/R) injury can occur during small-for-size liver transplantation, resulting in delayed graft function and decreased long-term graft survival. The aim of the present study was to evaluate the effects of genetic overexpression of endothelial nitric oxide synthase (eNOS) in protecting hepatocytes against I/R injury in a rat model of small-for-size liver transplantation. L02 liver cells were transfected with the eNOS gene using an adenovirus (Ad-eNOS). eNOS expression was detected using quantitative polymerase chain reaction and western blot analysis. To evaluate the effect of eNOS overexpression, L02 cells were placed in a hypoxic environment for 12 h and immediately transferred to an oxygen-enriched atmosphere. For in vivo testing, rats pretreated with Ad-eNOS or control underwent small-for-size liver transplantation. At 6 h after reperfusion, the bile quantity, serum transaminase and nitric oxide (NO) levels, and histological outcomes were evaluated. Cell apoptosis was assessed by flow cytometry or TUNEL assay. In vitro, Ad-eNOS prevented apoptosis in L02 cells with an increase in the level of NO in culture supernatant. In vivo, Ad-eNOS pre-treatment significantly increased bile production, improved abnormal transaminase levels, diminished apoptosis among liver cells, and decreased hepatocellular damage at 6 h after I/R injury. The eNOS-mediated renal protective effects might be associated with the downregulation of tumor necrosis factor-α and a reduction in macrophage activation in the early stage of reperfusion in small-for-size liver allografts. eNOS-derived NO production significantly attenuates hepatic I/R injury. Thus, eNOS overexpression constitutes a promising therapeutic approach to prevent liver I/R injury following small-for-size liver transplantation. PMID:27882135

  3. The outcomes of pediatric living donor liver transplantation using small-for-size grafts: experience of a single institute.

    PubMed

    Yamada, Naoya; Sanada, Yukihiro; Hirata, Yuta; Okada, Noriki; Ihara, Yoshiyuki; Sasanuma, Hideki; Urahashi, Taizen; Sakuma, Yasunaru; Yasuda, Yoshikazu; Mizuta, Koichi

    2016-04-01

    We aimed to evaluate patients who had undergone pediatric LDLT with small-for-size graft (SFSG) and identify risk factors of graft failure to establish a preoperative graft selection strategy. The data was collected retrospectively. SFSG was used in 14LDLTs (5.7%) of 245 LDLTs performed between May 2001 and March 2014. The mean patient age and body weight at LDLT were 12.6 ± 2.0 years and 40.5 ± 9.9 kg, respectively. The graft type was left lobe in six patients, left + caudate lobe in seven patients, and posterior segment in one patient. The graft survival rates in SFSG and non-SFSG groups were 78.9 and 93.1%, respectively (p = 0.045). In the univariate analysis, bleeding volume during LDLT were an independent risk factors for graft failure (p = 0.011). Graft failure was caused by sepsis in all three patients and occurred at a median of 70 postoperative days 70 (range 14-88 days). Among them, two cases showed high preoperative PELD/MELD score (PELD; 19.4 and MELD; 22, respectively). Pediatric LDLT using SFSG had poor outcome and prognosis, especially when it accompanies the surgical infectious complications with preoperative high PELD/MELD scores.

  4. Fatty Liver

    MedlinePlus

    ... and Throat Disorders Eye Disorders Fundamentals Heart and Blood Vessel Disorders Hormonal and Metabolic Disorders Immune Disorders Infections Injuries and Poisoning Kidney and Urinary Tract Disorders Liver ...

  5. Hypoxia and fatty liver.

    PubMed

    Suzuki, Tomohiro; Shinjo, Satoko; Arai, Takatomo; Kanai, Mai; Goda, Nobuhito

    2014-11-07

    The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

  6. Nonalcoholic fatty liver disease.

    PubMed

    Krawczyk, Marcin; Bonfrate, Leonilde; Portincasa, Piero

    2010-10-01

    Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. Nonalcoholic Fatty Liver Disease.

    PubMed

    Thrasher, Tyler; Abdelmalek, Manal F

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is the leading cause of chronic liver disease. Treatments target lifestyle modification and improvement of underlying risk factors. Noninvasive biomarkers for diagnosis and staging of NAFLD and safe, cost-effective treatments for patients with nonalcoholic steatohepatitis (NASH) and/or NASH-related cirrhosis are currently under investigation. ©2016 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.

  8. Obesity, fatty liver and liver cancer.

    PubMed

    Qian, Yan; Fan, Jian-Gao

    2005-05-01

    It has been suggested that obesity and fatty liver may be associated with the morbidity and mortality of liver cancer, and the early diagnosis and effective treatment of fatty liver coupled with liver cancer are supposed to improve the prognosis of obese patients. This review was attempted to understand the relationship between obesity, fatty liver and liver cancer. An English-language literature search using PUBMED (1990-2004) on obesity, fatty liver and liver cancer and other related articles in Chinese. Obesity is associated with the risk of death from all cancers and from cancers at individual sites including liver cancer, and it is an independent risk factor for hepatocellular carcinoma (HCC) in patients with alcoholic cirrhosis and cryptogenic cirrhosis. Because nonalcoholic steatohepatitis has been implicated as a major cause of cryptogenic cirrhosis, the development of HCC may be part of progressive nature of this condition. Obesity is associated with the incidence and mortality of HCC. More frequent surveillance for HCC may be warranted in obese patients with fatty liver and attempts should be made to interrupt the progression from simple hepatic steatosis to steatohepatitis, cirrhosis and ultimately HCC.

  9. Acute fatty liver of pregnancy.

    PubMed

    Papafragkakis, Haris; Singhal, Shashideep; Anand, Sury

    2013-10-01

    Acute fatty liver of pregnancy is a rare but serious and potentially fatal complication of pregnancy. It typically presents in the third trimester with microvesicular fatty infiltration of the liver and can lead to multiorgan failure and death. Differentiation from hemolysis-elevated liver enzymes-low platelets syndrome can guide management. A high index of suspicion is necessary in the appropriate clinical setting to identify clinical manifestations and complications and manage them appropriately. In severe cases, prompt delivery can be lifesaving for the mother and fetus. Liver transplantation remains controversial and must be considered individually. Defects in fatty acid oxidation secondary to various enzymatic deficiencies have been associated with acute fatty liver of pregnancy. Women or couples with known defects in fatty acid oxidation and women with a history of previous liver disease during pregnancy or sudden death of a child within the first 2 years of life should be assessed for a defect in fatty acid oxidation and monitored carefully. Our review summarizes the current knowledge in pathophysiology, diagnostic approach and management of this disorder.

  10. Pediatric nonalcoholic fatty liver disease.

    PubMed

    Bozic, Molly A; Subbarao, Girish; Molleston, Jean P

    2013-08-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population. Increased recognition of this form of liver disease parallels the dramatic rise in childhood and adolescent obesity over the past 2 decades. Like adults, most children with NAFLD are obese, and comorbidities include insulin resistance, hypertension, and dyslipidemia. Unfortunately, pediatric NAFLD is not always a benign condition, with some children progressing to hepatic fibrosis and even cirrhosis in severe cases. The etiology of nonalcoholic steatohepatitis is not yet fully understood; however, hepatic steatosis in the context of insulin resistance and increased oxidative stress may lead to progressive disease. Although physical examination, laboratory evaluation, and radiographic findings provide clues to the potential presence of fatty liver disease, liver biopsy remains the gold standard for diagnosis. Lifestyle modification, including slow and steady weight loss, improved dietary habits, and increased daily, aerobic physical activity, remains the first-line approach in treating pediatric fatty liver disease. Antioxidant pharmacologic therapy such as use of vitamin E has shown some benefit in patients with biopsy-proven steatohepatitis. Nutrition plays an essential role not only in the development of fatty liver disease but also potentially in the treatment and prevention of progression to more severe disease.

  11. Pathophysiology of Non Alcoholic Fatty Liver Disease.

    PubMed

    Petta, Salvatore; Gastaldelli, Amalia; Rebelos, Eleni; Bugianesi, Elisabetta; Messa, Piergiorgio; Miele, Luca; Svegliati-Baroni, Gianluca; Valenti, Luca; Bonino, Ferruccio

    2016-12-11

    The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.

  12. Pathophysiology of Non Alcoholic Fatty Liver Disease

    PubMed Central

    Petta, Salvatore; Gastaldelli, Amalia; Rebelos, Eleni; Bugianesi, Elisabetta; Messa, Piergiorgio; Miele, Luca; Svegliati-Baroni, Gianluca; Valenti, Luca; Bonino, Ferruccio

    2016-01-01

    The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation. PMID:27973438

  13. Role of bioactive fatty acids in nonalcoholic fatty liver disease.

    PubMed

    Juárez-Hernández, Eva; Chávez-Tapia, Norberto C; Uribe, Misael; Barbero-Becerra, Varenka J

    2016-08-02

    Nonalcoholic fatty liver disease (NAFLD) is characterized by fat deposition in hepatocytes, and a strong association with nutritional factors. Dietary fatty acids are classified according to their biochemical properties, which confer their bioactive roles. Monounsaturated fatty acids have a dual role in various human and murine models. In contrast, polyunsaturated fatty acids exhibit antiobesity, anti steatosic and anti-inflammatory effects. The combination of these forms of fatty acids-according to dietary type, daily intake and the proportion of n-6 to n-3 fats-can compromise hepatic lipid metabolism. A chemosensory rather than a nutritional role makes bioactive fatty acids possible biomarkers for NAFLD. Bioactive fatty acids provide health benefits through modification of fatty acid composition and modulating the activity of liver cells during liver fibrosis. More and better evidence is necessary to elucidate the role of bioactive fatty acids in nutritional and clinical treatment strategies for patients with NAFLD.

  14. Non-alcoholic fatty liver disease.

    PubMed

    Pearce, Lynne

    2016-08-24

    Essential facts Non-alcoholic fatty liver disease (NAFLD) is an excess of fat in the liver that is not the result of excessive alcohol consumption or other secondary causes, such as hepatitis C. According to the National Institute for Health and Care Excellence, fatty liver - steatosis - affects between 20% and 30% of the population and its prevalence is increasing.

  15. Acute fatty liver of pregnancy.

    PubMed Central

    Korula, J.; Malatjalian, D. A.; Badley, B. W.

    1982-01-01

    Acute fatty liver of pregnancy (AFLP) is rare and is peculiar to the latter half of pregnancy. Despite the high rates of death among affected mothers and their fetuses, early recognition of the disease and immediate delivery of the infant may improve the chances of survival. This paper describes a case of AFLP, characterized by a rapid decrease in the size of the liver, a greatly prolonged prothrombin time and minimal increases in the serum transaminase levels, in which an immediate cesarean section followed by vigorous supportive care led to survival of both mother and infant. It is clear that guidelines on treatment are necessary if the management of such cases is to be successful. Images FIG. 2 PMID:6751513

  16. CKD and nonalcoholic fatty liver disease.

    PubMed

    Targher, Giovanni; Chonchol, Michel B; Byrne, Christopher D

    2014-10-01

    The possible link between nonalcoholic fatty liver disease and chronic kidney disease (CKD) recently has attracted considerable scientific interest. Accumulating clinical evidence indicates that the presence and severity of nonalcoholic fatty liver disease is associated significantly with CKD (defined as decreased estimated glomerular filtration rate and/or proteinuria) and that nonalcoholic fatty liver disease predicts the development and progression of CKD, independently of traditional cardiorenal risk factors. Experimental evidence also suggests that nonalcoholic fatty liver disease itself may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory, procoagulant, pro-oxidant, and profibrogenic mediators that play important roles in the development and progression of CKD. However, despite the growing evidence linking nonalcoholic fatty liver disease with CKD, it has not been definitively established whether a causal association exists. The clinical implication for these findings is that patients with nonalcoholic fatty liver disease may benefit from more intensive surveillance or early treatment interventions to decrease the risk of CKD. In this review, we discuss the evidence linking nonalcoholic fatty liver disease with CKD and the putative mechanisms by which nonalcoholic fatty liver disease contributes to kidney damage. We also briefly discuss current treatment options for this increasingly prevalent disease that is likely to have an important future impact on the global burden of disease.

  17. Molecular mechanisms of alcoholic fatty liver.

    PubMed

    Purohit, Vishnudutt; Gao, Bin; Song, Byoung-Joon

    2009-02-01

    Alcoholic fatty liver is a potentially pathologic condition which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. Alcohol exposure may induce fatty liver by increasing NADH/NAD(+) ratio, increasing sterol regulatory element-binding protein-1 (SREBP-1) activity, decreasing peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity, and increasing complement C3 hepatic levels. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-alpha (TNF-alpha) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity, whereas betaine and pioglitazone may attenuate fatty liver by down-regulating SREBP-1 activity. PPAR-alpha agonists have potentials to attenuate alcoholic fatty liver. Adiponectin and interleukin-6 may attenuate alcoholic fatty liver by up-regulating PPAR-alpha and insulin signaling pathways while down-regulating SREBP-1 activity and suppressing TNF-alpha production. Recent studies show that paracrine activation of hepatic cannabinoid receptor 1 by hepatic stellate cell-derived endocannabinoids also contributes to the development of alcoholic fatty liver. Furthermore, oxidative modifications and inactivation of the enzymes involved in the mitochondrial and/or peroxisomal beta-oxidation of fatty acids could contribute to fat accumulation in the liver.

  18. Nonalcoholic fatty liver disease: diagnosis and management.

    PubMed

    Wilkins, Thad; Tadkod, Altaf; Hepburn, Iryna; Schade, Robert R

    2013-07-01

    Nonalcoholic fatty liver disease is characterized by excessive fat accumulation in the liver (hepatic steatosis). Nonalcoholic steatohepatitis is characterized by steatosis, liver cell injury, and inflammation. The mechanism of nonalcoholic fatty liver disease is unknown but involves the development of insulin resistance, steatosis, inflammatory cytokines, and oxidative stress. Nonalcoholic fatty liver disease is associated with physical inactivity, obesity, and metabolic syndrome. Screening is not recommended in the general population. The diagnosis is usually made after an incidental discovery of unexplained elevation of liver enzyme levels or when steatosis is noted on imaging (e.g., ultrasonography). Patients are often asymptomatic and the physical examination is often unremarkable. No single laboratory test is diagnostic, but tests of liver function, tests for metabolic syndrome, and tests to exclude other causes of abnormal liver enzyme levels are routinely performed. Imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging, can assess hepatic fat, measure liver and spleen size, and exclude other diseases. Liver biopsy remains the criterion standard for the diagnosis of nonalcoholic steatohepatitis. Noninvasive tests are available and may reduce the need for liver biopsy. A healthy diet, weight loss, and exercise are first-line therapeutic measures to reduce insulin resistance. There is insufficient evidence to support bariatric surgery, metformin, thiazolidinediones, bile acids, or antioxidant supplements for the treatment of nonalcoholic fatty liver disease. The long-term prognosis is not associated with an increased risk of all-cause mortality, cardiovascular disease, cancer, or liver disease.

  19. [Acute fatty liver of pregnancy].

    PubMed

    Bacq, Y; Constans, T; Body, G; Choutet, P; Lamisse, F

    1986-01-01

    The authors analyse 115 cases of acute fatty liver of pregnancy, proven histologically. Characteristics of the condition is the finding of central nuclei in the hepatocytes containing microvesicular droplets. The disease occurs more frequently in primiparous women (54 per cent) and usually occurs in the third trimester of the pregnancy. A pre-icteric phase usually precedes the jaundice and during that time there is usually vomiting and/or nausa with abdominal pain or anarexia. In 92 per cent of case there is transient loss of consciousness with hepatic encephalopathy. Further tests show that there is more defective liver function than would be expected from the extent of cell lysis; and there is defective renal function. The worst complications are intestinal haemorrhages (48 per cent of cases)--genital bleeding (43 per cent of cases)--shock--diffuse intravascular coagulation and complications associated with coma. Maternal mortality at present runs at 25 per cent and fetal mortality at 60 per cent. The condition does not recur. Early evacuation of the uterus is recommended by most authors and does probably improve the outlook. The various hypotheses concerning the aetiology are discussed.

  20. Heritability of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Schwimmer, Jeffrey B.; Celedon, Manuel A.; Lavine, Joel E.; Salem, Rany; Campbell, Nzali; Schork, Nicholas J.; Shiehmorteza, Masoud; Yokoo, Takeshi; Chavez, Alyssa; Middleton, Michael S.; Sirlin, Claude B.

    2010-01-01

    Background & Aims Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The etiology is believed to be multi-factorial with a substantial genetic component; however, the heritability of NAFLD is undetermined. Therefore, a familial aggregation study was performed to test the hypothesis that NAFLD is highly heritable. Methods Overweight children with biopsy-proven NAFLD and overweight children without NAFLD served as probands. Family members were studied including magnetic resonance imaging to quantify liver fat fraction. Fatty liver was defined as a liver fat fraction ≥ 5%. Etiologies for fatty liver other than NAFLD were excluded. Narrow-sense heritability estimates for fatty liver (dichotomous) and fat fraction (continuous) were calculated using variance components analysis adjusted for covariate effects. Results Fatty liver was present in 17% of siblings and 37% of parents of overweight children without NAFLD. Fatty liver was significantly more common in siblings (59%) and parents (78%) of children with NAFLD. Liver fat fraction was correlated with body mass index (BMI), although the correlation was significantly stronger for families of children with NAFLD than those without NAFLD. Adjusted for age, sex, race, and BMI, heritability of fatty liver was 1.000 and of liver fat fraction 0.386. Conclusion Family members of children with NAFLD should be considered at high risk for NAFLD. These data suggest that familial factors are a major determinant of whether an individual has NAFLD. Studies examining the complex relations between genes and environment in the development and progression of NAFLD are warranted. PMID:19208353

  1. Uridine Prevents Fenofibrate-Induced Fatty Liver

    PubMed Central

    Le, Thuc T.; Urasaki, Yasuyo; Pizzorno, Giuseppe

    2014-01-01

    Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD+/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD) and acyl-CoA oxidase 1 (ACOX1), and induces excessive accumulation of long chain fatty acids (LCFA) and very long chain fatty acids (VLCFA). Uridine co-administration at a daily dosage of 400 mg/kg raises NAD+/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver. PMID:24475249

  2. Advances in Pediatric Nonalcoholic Fatty Liver Disease

    PubMed Central

    Loomba, Rohit; Sirlin, Claude B.; Schwimmer, Jeffrey B.; Lavine, Joel E.

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in children and adolescents in the United States. A two- to three-fold rise in the rates of obesity and overweight in children over the last 2 decades is probably responsible for the epidemic of NAFLD. Emerging data suggest that children with NASH progress to cirrhosis which may ultimately increase liver-related mortality. More worrisome is the recognition that cardiovascular risk and morbidity in children and adolescents is associated with fatty liver. Pediatric fatty liver disease often displays a histologic pattern distinct from that found in adults. Liver biopsy remains the gold standard for diagnosis of NASH. Non-invasive biomarkers are needed to identify individuals with progressive liver injury. Targeted therapies to improve liver histology and metabolic abnormalities associated with fatty liver are needed. Currently, randomized-controlled trials are underway in the pediatric population to define pharmacologic therapy for NAFLD. Public health awareness and intervention are needed to promote healthy diet, exercise, and lifestyle modifications to prevent and reduce the burden of disease in the community. PMID:19637286

  3. Non-alcoholic fatty liver disease.

    PubMed

    Neuschwander-Tetri, Brent A

    2017-02-28

    Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. As the burden of hepatitis C abates over the next decade, non-alcoholic fatty liver disease will become the major form of chronic liver disease in adults and children and could become the leading indication for liver transplantation. This overview briefly summarizes the most recent data on the pathophysiology, diagnosis, and treatment of non-alcoholic fatty liver disease. Ongoing clinical trials are focused on an array of disease mechanisms and reviewed here are how these treatments fit into the current paradigm of substrate overload lipotoxic liver injury. Many of the approaches are directed at downstream events such as inflammation, injury and fibrogenesis. Addressing more proximal processes such as dysfunctional satiety mechanisms and inappropriately parsimonious energy dissipation are potential therapeutic opportunities that if successfully understood and exploited would not only address fatty liver disease but also the other components of the metabolic syndrome such as obesity, diabetes and dyslipidemia.

  4. Nonalcoholic Fatty Liver Disease & NASH

    MedlinePlus

    ... liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Weight loss can reduce fat in the liver, inflammation, and fibrosis. No medicines have been approved to treat NAFLD and NASH. Eating, ... Clinical Trials The National Institute ...

  5. Nonalcoholic fatty liver disease: a systematic review.

    PubMed

    Rinella, Mary E

    2015-06-09

    Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. PubMed was queried for published articles through February 28, 2015, using the search terms NAFLD and cirrhosis, mortality, biomarkers, and treatment. A total of 88 references were selected, including 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses. Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest (<50%) and none is approved by the US Food and Drug Administration. The association between nonalcoholic steatohepatitis and cardiovascular disease is clear, though causality remains to be proven in well-controlled prospective studies. The

  6. Fluorescing fatty acids in rat fatty liver models.

    PubMed

    Croce, Anna C; Ferrigno, Andrea; Di Pasqua, Laura G; Berardo, Clarissa; Mannucci, Barbara; Bottiroli, Giovanni; Vairetti, Mariapia

    2017-06-01

    The autofluorescence (AF) of NAD(P)H and flavins has been at the basis of many in-situ studies of liver energy metabolism and functionality. Conversely, few data have been so far reported on fluorescing lipids. In this work we investigated the AF of liver lipid extracts from two fatty liver models, Wistar rats fed with MCD diet for 12 days (Wi-MCD), and obese (fa/fa) Zucker rats. Among the most abundant fatty acids in the lipid extracts, indicated by mass spectrometry, arachidonic acid (AA) exhibited higher quantum yield than the other fluorescing fatty acids (FLFA), and red shifted AF spectrum. This allowed to estimate the AA contribution to the overall emission of lipid extracts by curve fitting analysis. AA prevailed in obese Zucker livers, accounting for the different AF spectral profiles between the two models. AF and mass spectrometry indicated also a different balance between the fluorescing fraction and the overall amount of AA in the two models. The ability of AF to detect directly AA and FLFA was demonstrated, suggesting its supportive role as tool in wide-ranging applications, from the control of animal origin food, to experimental investigations on liver fat accumulation, lipotoxicity and disease progression, with potential translation to the clinics. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Pediatric Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Delvin, Edgard; Patey, Natasha; Dubois, Josée; Henderson, Melanie; Lévy, Émile

    2015-01-01

    Summary The rapidly increasing prevalence of childhood obesity and its associated co-morbidities such as hypertriglyceridemia, hyper-insulinemia, hypertension, early atherosclerosis, metabolic syndrome, and non-alcoholic fatty liver disease are major public health concerns in many countries. Therefore the trends in child and adolescent obesity should be closely monitored over time, as in the near future, we may anticipate a major increase of young adults with the stigmata of the metabolic syndrome, and of the related non-alcoholic fatty liver disease (NAFLD), that may lead to non-alcoholic steatohepatitis. PMID:28356817

  8. Acute liver failure due to acute fatty liver of pregnancy.

    PubMed

    Wand, S; Waeschle, R M; Von Ahsen, N; Hawighorst, T; Bräuer, A; Quintel, M

    2012-04-01

    Acute fatty liver of pregnancy (AFLP) is a rare but serious liver disease and typically occurs during the third trimester. It carries the risk for significant perinatal and maternal mortality. Therefore an early diagnosis and delivery, followed by close monitoring and optimized management of the impaired liver function with all associated problems are necessary to prevent maternal and foetal death. This case report focuses on the management of acute liver failure due to AFLP in a 31 year old women treated in our intensive care unit (ICU) after an emergency C-section.

  9. Pediatric Non-alcoholic Fatty Liver Disease.

    PubMed

    Uppal, Vikas; Mansoor, Sana; Furuya, Katryn N

    2016-05-01

    Childhood obesity has reached epidemic proportions, and by 2012, more than one third of American children were overweight or obese. As a result, increasingly, children are developing complications of obesity including liver disease. In fact, non-alcoholic fatty liver disease is the most common form of chronic liver disease seen in children today. Recently, there has been a burgeoning literature examining the pathogenesis, genetic markers, and role of the microbiome in this disease. On the clinical front, new modalities of diagnosing hepatic steatosis and hepatic fibrosis are being developed to provide non-invasive methods of surveillance in children. Lastly, the mainstay of treatment of pediatric non-alcoholic fatty liver disease (NAFLD) has been largely through lifestyle interventions, namely, dieting and exercise. Currently, there are a number of clinical trials examining novel lifestyle and drug therapies for NAFLD that are registered with the US National Institutes of Health ClinicalTrials.gov website.

  10. Lipoprotein metabolism in nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Zhenghui Gordon; Robson, Simon C.; Yao, Zemin

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD. PMID:23554788

  11. [Non-alcoholic fatty liver disease (NAFLD)].

    PubMed

    Rau, Monika; Weiss, Johannes; Geier, Andreas

    2015-07-01

    Non-alcoholic fatty liver disease is the most common chronic liver disease in Europe and in the USA with rising prevalence. Patients with a metabolic syndrome (diabetes mellitus, obesity, dyslipidemia) are patients at risk with the highest prevalence for NAFLD. Progression from a non-alcoholic fatty liver (NAFL) to a non-alcoholic steatohepatitis (NASH) occurs in 5-20% of patients with the potential to develop a liver fibrosis/cirrhosis. NASH patients and NAFLD patients with higher fibrosis should be identified because they are at risk of a higher mortality. A specific treatment for NASH is not available at the moment. Therefore, the treatment of risk factors and metabolic syndrome has high priority.

  12. Extrahepatic Complications of Nonalcoholic Fatty Liver Disease.

    PubMed

    Chacko, Kristina R; Reinus, John

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is an important cause of liver disease that is often associated with the metabolic syndrome. There is a growing awareness that extrahepatic complications occur in individuals with NAFLD, especially an increased risk of cardiovascular disease. Development of diabetes mellitus, chronic kidney disease, colorectal cancer, and endocrinopathies has been linked to NAFLD. This article reviews the extrahepatic complications affecting individuals with NAFLD and the pathogenesis underlying their development. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Durability of small-for-size living donor allografts.

    PubMed

    Au, Kin Pan; Chan, See Ching; Chok, Kenneth Siu Ho; Chan, Albert Chi Yan; Wong, Tiffany Cho Lam; Sharr, William Wei; Lo, Chung Mau

    2015-11-01

    Our aim was to study the long-term outcomes of living donor liver transplantation using small-for-size (SFS) grafts. From July 2002 to July 2009, 233 patients received a right liver graft with a middle hepatic vein from a living donor in our center. Recipients were stratified according to the graft weight to recipient standard liver volume (GW/SLV) ratio into 4 groups: >50% (n = 89), >40% to 50% (n = 85), >35% to 40% (n = 38), and ≤ 35% (n = 21). They were compared in terms of graft survivals, biliary stricture rates, renal function in terms of estimated glomerular filtration rate (eGFR), platelet counts, and graft function in terms of serum bilirubin and international normalized ratio (INR). The 5-year graft survivals for patients with GW/SLV of >50%, >40% to 50%, >35% to 40% and ≤ 35% were 88.8%, 88.2%, 81.5%, and 81.0%, respectively. Transplantation for hepatocellular carcinoma affected graft survivals (P = 0.02), but graft size did not (P = 0.66). There were no differences in frequency of biliary stricture (21.3% versus 17.1% versus 21.1% versus 28.6%; P = 0.75). At each year after transplant, their platelet counts (P = 0.12-0.65), eGFR (P = 0.49-0.91), bilirubin (P = 0.14-0.51), and INR (P = 0.20-0.98) remained comparable. SFS grafts with GW/SLV ≤ 35% and >35% to 40% had comparable long-term outcomes with larger liver grafts. Graft size did not affect long-term graft survivals.

  14. Genetics Home Reference: non-alcoholic fatty liver disease

    MedlinePlus

    ... Genetics Home Health Conditions NAFLD non-alcoholic fatty liver disease Enable Javascript to view the expand/collapse ... Open All Close All Description Non-alcoholic fatty liver disease ( NAFLD ) is a buildup of excessive fat ...

  15. Resveratrol alleviates alcoholic fatty liver in mice.

    PubMed

    Ajmo, Joanne M; Liang, Xiaomei; Rogers, Christopher Q; Pennock, Brandi; You, Min

    2008-10-01

    Alcoholic fatty liver is associated with inhibition of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), two critical signaling molecules regulating the pathways of hepatic lipid metabolism in animals. Resveratrol, a dietary polyphenol, has been identified as a potent activator for both SIRT1 and AMPK. In the present study, we have carried out in vivo animal experiments that test the ability of resveratrol to reverse the inhibitory effects of chronic ethanol feeding on hepatic SIRT1-AMPK signaling system and to prevent the development of alcoholic liver steatosis. Resveratrol treatment increased SIRT1 expression levels and stimulated AMPK activity in livers of ethanol-fed mice. The resveratrol-mediated increase in activities of SIRT1 and AMPK was associated with suppression of sterol regulatory element binding protein 1 (SREBP-1) and activation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha). In parallel, in ethanol-fed mice, resveratrol administration markedly increased circulating adiponectin levels and enhanced mRNA expression of hepatic adiponectin receptors (AdipoR1/R2). In conclusion, resveratrol treatment led to reduced lipid synthesis and increased rates of fatty acid oxidation and prevented alcoholic liver steatosis. The protective action of resveratrol is in whole or in part mediated through the upregulation of a SIRT1-AMPK signaling system in the livers of ethanol-fed mice. Our study suggests that resveratrol may serve as a promising agent for preventing or treating human alcoholic fatty liver disease.

  16. Managing non-alcoholic fatty liver disease

    PubMed Central

    Ngu, Jing Hieng; Goh, George Boon Bee; Poh, Zhongxian; Soetikno, Roy

    2016-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly with the obesity and diabetes mellitus epidemics. It is rapidly becoming the most common cause of liver disease worldwide. NAFLD can progress to serious complications such as cirrhosis, hepatocellular carcinoma and death. Therefore, it is important to recognise this condition so that early intervention can be implemented. Lifestyle modifications and strict control of metabolic risk factors are the mainstay of treatment. As disease progression is slow in the majority of NAFLD patients, most can be managed well by primary care physicians. NAFLD patients with advanced liver fibrosis should be referred to specialist care for further assessment. PMID:27439352

  17. Non-alcoholic fatty liver disease in children.

    PubMed

    Chaturvedi, Kanupriya; Vohra, Pankaj

    2012-09-01

    A cross sectional study was conducted in 100 children, aged 5 to 12 years, to find the prevalence of non-alcoholic fatty liver diseases (NAFLD), at New Delhi. Those with fatty liver on ultrasonography with no apparent etiology, were labeled as NAFLD. Three (3%) children had evidence of fatty liver on ultrasonography.

  18. Developmental origins of nonalcoholic fatty liver disease.

    PubMed

    Brumbaugh, David E; Friedman, Jacob E

    2014-01-01

    Obese pregnant women may transmit their metabolic phenotype to offspring, leading to a cycle of obesity and diabetes over generations. Early childhood obesity predicts nonalcoholic fatty liver disease (NAFLD), the most common chronic human liver disease. The fetus may be vulnerable to steatosis because immature fetal adipose depots are not available to buffer the excess transplacental lipid delivery in maternal obesity. In animal models, in utero high-fat diet exposure results in an increase in the accumulation of liver triglycerides in offspring and increased hepatic oxidative stress and apoptosis, perhaps priming the liver for later development of NAFLD. Innate immune dysfunction and necroinflammatory changes have been observed in postnatal offspring liver of animals born to high-fat-fed dams. Postweaning, livers of offspring exposed to maternal high-fat feeding in utero share pathophysiologic features with human NAFLD, including increased de novo lipogenesis and decreased free fatty acid oxidation. Human studies using magnetic resonance imaging have shown that maternal BMI predicts infant intrahepatocellular lipid storage, as seen in animal models. The generational transfer of NAFLD may occur via epigenetic changes in offspring liver. Transmission of microbiota from mother to infant may impact energy retention and immune function that contribute to a predisposition to NAFLD.

  19. Expression of fatty acid synthase in nonalcoholic fatty liver disease.

    PubMed

    Dorn, Christoph; Riener, Marc-Oliver; Kirovski, Georgi; Saugspier, Michael; Steib, Kathrin; Weiss, Thomas S; Gäbele, Erwin; Kristiansen, Glen; Hartmann, Arndt; Hellerbrand, Claus

    2010-03-25

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an experimental model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and experimental NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD.

  20. CT appearance of focal fatty infiltration of the liver

    SciTech Connect

    Halvorsen, R.A.; Korobkin, M.; Ram, P.C.; Thompson, W.M.

    1982-08-01

    Focal fatty infiltration of the liver is an entity that may be confused with liver metastasis on computed tomography (CT). The imaging results and medical records of 16 patients with CT appearance suggestive of focal fatty liver were reviewed, three of whom had the simultaneous presence of metastitic liver disease. Focal fatty liver often has a distinctive appearance with CT, usually with a nonspherical shape, absence of mass effect, and density close to water. Liver metastases are usually round or oval, and unless cystic or necrotic, they have CT attenuation values closer to normal liver parenchyma than water. A radionuclide liver scan almost always resolves any confusion about the differential diagnosis of focal fatty liver: a well defined focus of photon deficiency is due to neoplasm rather than focal fatty infiltration. Sonography sometimes helps to confirm the CT impression, but may be misleading if the diagnosis of focal or diffuse fatty infiltration is not suspected before the examination.

  1. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis.

    PubMed

    Marengo, Andrea; Rosso, Chiara; Bugianesi, Elisabetta

    2016-01-01

    The burden of hepatocellular carcinoma (HCC), the most common form of liver cancer, is steadily growing because obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) are replacing viral- and alcohol-related liver disease as major pathogenic promoters. The most worrisome aspects of these new risk factors are their large spread in the general population and their link with HCC arising in noncirrhotic livers. HCC may be the presenting feature of an asymptomatic nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. The HCC risk connected to metabolic factors has been underestimated so far, and a poorer surveillance has prevented an adequate treatment. Systemic and hepatic molecular mechanisms involved in obesity- and NAFLD-induced hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review summarizes current evidence linking obesity, NAFLD and liver cancer, discusses its clinical impact and describes the main mechanisms underlying this complex relationship.

  2. Nonalcoholic Fatty Liver Disease in Pediatrics.

    PubMed

    Duncan, Martin; Zong, Wenjing; Biank, Vincent F; Hageman, Joseph R

    2016-02-01

    A 16-year-old Hispanic girl with an elevated body mass index in an otherwise normal state of health presented for her well-child examination. She had signs of metabolic syndrome and insulin resistance including increased waist circumference and acanthosis nigricans. Laboratory results revealed elevated transaminases with otherwise normal hepatic function. Based on the physical examination and laboratory results, she was diagnosed with nonalcoholic fatty liver disease (NAFLD). After further evaluation, she eventually underwent a liver biopsy. The biopsy revealed nonalcoholic steatohepatitis (NASH) with stage 2 fibrosis. This article reviews the definition of NAFLD and NASH, an increasingly prevalent cause of pediatric chronic liver disease associated with obesity and metabolic syndrome. The article also outlines the epidemiology, risk factors, and natural history of NAFLD, which may help identify and prevent high-risk pediatric patients from progressing to irreversible liver disease. Understanding the diagnostic and treatment options offers the best chance at preventing and reversing the early stages of this disease.

  3. Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease.

    PubMed

    Chen, Guanliang; Ni, Yinhua; Nagata, Naoto; Xu, Liang; Ota, Tsuguhito

    2016-08-23

    Nonalcoholic fatty liver disease (NAFLD) is one of the most important chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The blurred pathogenesis of NAFLD is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. NAFLD is closely associated with complications such as obesity, diabetes, steatohepatitis, and liver fibrosis. During the progression of NAFLD, reactive oxygen species (ROS) are activated and induce oxidative stress. Recent attempts at establishing effective NAFLD therapy have identified potential micronutrient antioxidants that may reduce the accumulation of ROS and finally ameliorate the disease. In this review, we present the molecular mechanisms involved in the pathogenesis of NAFLD and introduce some dietary antioxidants that may be used to prevent or cure NAFLD, such as vitamin D, E, and astaxanthin.

  4. Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Chen, Guanliang; Ni, Yinhua; Nagata, Naoto; Xu, Liang; Ota, Tsuguhito

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most important chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The blurred pathogenesis of NAFLD is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. NAFLD is closely associated with complications such as obesity, diabetes, steatohepatitis, and liver fibrosis. During the progression of NAFLD, reactive oxygen species (ROS) are activated and induce oxidative stress. Recent attempts at establishing effective NAFLD therapy have identified potential micronutrient antioxidants that may reduce the accumulation of ROS and finally ameliorate the disease. In this review, we present the molecular mechanisms involved in the pathogenesis of NAFLD and introduce some dietary antioxidants that may be used to prevent or cure NAFLD, such as vitamin D, E, and astaxanthin. PMID:27563875

  5. Clinicopathological evaluation of downer dairy cows with fatty liver

    PubMed Central

    Kalaitzakis, Emmanouil; Panousis, Nikolaos; Roubies, Nikolaos; Giadinis, Nektarios; Kaldrymidou, Eleni; Georgiadis, Marios; Karatzias, Harilaos

    2010-01-01

    This study evaluated the relationship between severity of fatty liver and macromineral status in downer dairy cows and determined the usefulness of selected biochemical analytes for assessing prognosis. Blood and liver biopsy specimens were obtained from 36 Holstein downer cows shortly after the cows became recumbent and before they were treated. Liver tissue was examined histologically and serum activity of liver-derived enzymes and concentration of total lipids, triglycerides, bile acids, glucose, β-hydroxybutyrate, acetoacetic acid, total bilirubin, non-esterified fatty acids (NEFA), cholesterol and macrominerals (Ca, Mg, K, Na, P) were determined. Fatty liver infiltration was severe in 44% of the cows and moderate in 44%. Serum activities of ornithine carbamoyltransferase and glutamate dehydrogenase, and NEFA/cholesterol ratio were good indicators of fatty liver. Cows with severe fatty liver had the lowest mean K values. The prognosis is guarded for downer cows with moderate and severe fatty liver and when total bilirubin concentration is high. PMID:20808573

  6. Curcumin improves alcoholic fatty liver by inhibiting fatty acid biosynthesis.

    PubMed

    Guo, Chang; Ma, Jingfan; Zhong, Qionghong; Zhao, Mengyuan; Hu, Tianxing; Chen, Tong; Qiu, Longxin; Wen, Longping

    2017-08-01

    Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy. Copyright © 2017. Published by Elsevier Inc.

  7. Biomarkers in nonalcoholic fatty liver disease

    PubMed Central

    Neuman, Manuela G; Cohen, Lawrence B; Nanau, Radu M

    2014-01-01

    BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers. AIM: To review the biomarkers used to diagnose and define the severity of NAFLD and NASH. METHODS: A comprehensive PubMed and Google Scholar literature search was performed using the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed. RESULTS: Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity. CONCLUSIONS: The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical

  8. Metabolic Syndrome: Nonalcoholic Fatty Liver Disease.

    PubMed

    Williams, Tracy

    2015-08-01

    Although nonalcoholic fatty liver disease (NAFLD) is not one of the defining criteria for metabolic syndrome, it is a common hepatic manifestation. NAFLD includes a spectrum of histologic findings ranging from simple steatosis, known as nonalcoholic fatty liver, to nonalcoholic steatohepatitis (NASH). To make the diagnosis of NAFLD, other etiologies of steatosis or hepatitis, such as hepatotoxic drugs, excessive alcohol intake, congenital errors of metabolism, or viral hepatitis, must be ruled out. After ruling out other conditions, the diagnosis of NAFLD often is made clinically, but a definitive diagnosis of NASH requires liver biopsy. As with other complications of metabolic syndrome, insulin resistance is thought to be an underlying etiology of NAFLD. Management strategies attempt to reverse or improve insulin resistance while minimizing liver damage. The strongest evidence supports lifestyle modifications with weight loss, but there is some evidence to support bariatric surgery, medical therapy with insulin-sensitizing agents, and/or pharmacotherapy to promote weight loss. Cardiovascular disease is the major cause of mortality in patients with NAFLD, so management must include modification of cardiovascular risk factors. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

  9. Fatty liver disease and obesity in youth.

    PubMed

    Della Corte, Claudia; Mazzotta, Anna Rita; Nobili, Valerio

    2016-02-01

    The purpose of this short review is to summarize recent developments in the understanding of pediatric nonalcoholic fatty liver disease (NAFLD), focusing on novel findings in pathogenetic mechanisms and the therapeutic armamentarium. As a result of the increasing prevalence of pediatric obesity, NAFLD has rapidly become the most common cause of chronic hepatopathies in children. Lifestyle modification and diet remain the mainstay of treatment of pediatric obesity and NAFLD, but with disappointing results because of the difficulty in obtaining sustained long-term results. Considering the risk of progression of liver damage to cirrhosis and end-stage liver disease, in the last decades scientific research in this field has been directed to the identification of pathogenetic mechanisms and possible therapeutic strategies for NAFLD. We describe the therapeutic options for the management of pediatric NAFLD, focusing on emerging alternative strategies, including surgical approaches and new drugs directed against novel potential molecular targets.

  10. Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease.

    PubMed

    VanWagner, Lisa B; Rinella, Mary E

    2016-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with an increased prevalence of metabolic, macro- and microvascular complications. The primary causes of mortality in NAFLD are cardiovascular disease (CVD), malignancy and liver disease. NAFLD is a multisystem disease that affects a variety of extra-hepatic organ systems. The main focus of this review is to summarize the reported extra-hepatic associations, which include CVD, chronic kidney disease, obstructive sleep apnea, osteoporosis, psoriasis, colorectal cancer, iron overload and various endocrinopathies (e.g. type 2 diabetes mellitus, thyroid dysfunction, and polycystic ovarian syndrome). Due to the systemic manifestations of NAFLD patients require a multidisciplinary assessment and may benefit from more rigorous surveillance and early treatment interventions to decrease mortality related to malignancy or cardiometabolic diseases.

  11. Treatment of nonalcoholic fatty liver disease

    PubMed Central

    Siebler, Juergen; Galle, Peter R

    2006-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer pioglitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective. PMID:16610015

  12. [Nonalcoholic fatty liver disease in children].

    PubMed

    Bojórquez-Ramos, María del Carmen

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of liver disease in children and adolescents in the United States of America (USA) and probably in the entire western hemisphere, due to the increase in the prevalence of overweight and obesity. Steatosis can progress to inflammation, fibrosis and even cirrhosis, which increases the morbidity and mortality associated to liver disease. In every overweight and obese child a thorough analysis should be performed including liver function tests and liver ultrasound, in order to establish a timely diagnosis. The liver biopsy is the most specific study to rule out other potentially treatable entities. It is necessary to count on non-invasive methods to detect children with NAFLD and identify those in risk of progression. Biomarkers related to inflammation, oxidative stress, apoptosis and fibrosis have been reported. The main goal of the treatment is to modify the life style, starting with a healthy diet and an increase of physical activity. Regarding pharmacological treatment, there is evidence of histological improvement with vitamin E use, as opposed to metformin, but more conclusive studies regarding this subject are needed.

  13. Nonalcoholic fatty liver disease - A multisystem disease?

    PubMed Central

    Mikolasevic, Ivana; Milic, Sandra; Turk Wensveen, Tamara; Grgic, Ivana; Jakopcic, Ivan; Stimac, Davor; Wensveen, Felix; Orlic, Lidija

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome (MetS). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of MetS. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease (CVD), diabetes mellitus type 2 (T2DM) and chronic kidney disease (CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with MetS, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both (sub-) specialists and primary care physicians. PMID:27920470

  14. Quantitative evaluation of fatty liver by computed tomography in rabbits

    SciTech Connect

    Kawata, R.; Sakata, K.; Kunieda, T.; Saji, S.; Doi, H.; Nozawa, Y.

    1984-04-01

    Biochemical, histologic, and computed tomographic (CT) examinations of the liver were performed in 32 rabbits in which fatty liver was induced by prolonged intravenous fat infusion. In two groups of rabbits, in which 2 and 4 g/kg/day of fat emulsion was administered, respectively, posttreatment reduction in CT value of mild degree was observed. In the group that received 8 g/kg/day of fat emulsion, posttreatment change in CT value was sufficient for a diagnosis of fatty liver of moderate degree. Reduction in CT value in fatty liver might be due largely to accumulation of triglyceride and cholesterol in the liver cells. Significant correlation was found between changes in CT value of the liver and degrees of histological fat accumulation in the liver cells. Consecutive measurement of CT values of the liver during prolonged intravenous hyperalimentation is a nonagressive method of diagnosing fatty liver.

  15. Lipid content in the liver of fatty metamorphosis of pregnancy.

    PubMed Central

    Eisele, J. W.; Barker, E. A.; Smuckler, E. A.

    1975-01-01

    Lipid analyses were performed on the liver of a patient who died during an episode of acute fatty liver of pregnancy, and on livers from normal subjects and from subjects suffering from nutritional fatty livers. Comparison of these data indicates that in fatty liver of pregnancy the increased hepatic lipids consist primarily of free fatty acids. The recognized toxicity of fatty acids suggests a pathogenic mechanism for the disease. Nutritional fatty liver is associated predominantly with an increase in triglyceride. These changes are not the result of postmortem change, and they confirm and extend the previous data concerning the fat accumulation in human hepatic illness. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 1 PMID:1239955

  16. Role of liver biopsy in nonalcoholic fatty liver disease

    PubMed Central

    Nalbantoglu, ILKe; Brunt, Elizabeth M

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), defined as abnormal accumulation (> 5%) of hepatic triglyceride without excess alcohol intake, is the most common form of chronic liver disease in adults and children in the United States. NAFLD encompasses a spectrum of histologic findings including uncomplicated steatosis, steatosis with inflammation and steatohepatitis [nonalcoholic steatohepatitis (NASH)]; the latter can advance to cirrhosis and hepatocellular carcinoma. NASH is currently accepted as the hepatic manifestation of the set of cardiovascular risk factors collectively known as metabolic syndrome. In 1999 a system for histologic grading and staging for NASH was proposed; this was revised by the NASH Clinical Research Network in 2005 for the entire spectrum of lesions in NAFLD, including the lesions and patterns of pediatric NAFLD, and for application in clinical research trials. Diagnosis remains distinct from grade and stage. A recent European proposal separates steatosis from activity to derive a numeric diagnosis of NASH. Even though there have been promising advancements in non-invasive testing, these tests are not yet detailed enough to replace the full range of findings provided by liver biopsy evaluation. Limitations of biopsy are acknowledged, but liver biopsy remains the “gold standard” for diagnosis and determination of amounts of necroinflammatory activity, and location of fibrosis, as well as remodeling of the parenchyma in NASH. This review focuses on the specific histologic lesions of NAFLD and NASH, grading and staging, differential diagnoses to be considered, and the continuing role of the liver biopsy in this important liver disease. PMID:25083076

  17. Pediatric Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Bush, Haley; Golabi, Pegah; Younossi, Zobair M.

    2017-01-01

    With the increase in the prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become among the leading causes of chronic liver disease in the pediatric age group. Once believed to be a “two-hit process”, it is now clear that the actual pathophysiology of NAFLD is complex and involves multiple pathways. Moreover, NAFLD is not always benign, and patients with non-alcoholic steatohepatitis (NASH) are at increased risk of developing advanced stages of liver disease. It has also been shown that NAFLD is not only a liver disease, but is also associated with multiple extrahepatic manifestations, including cardiovascular diseases, type 2 diabetes, and low bone mineral density. Although the data is scarce in the pediatric population, some studies have suggested that long-term mortality and the requirement of liver transplantation will continue to increase in patients with NAFLD. More studies are needed to better understand the natural history of NAFLD, especially in the pediatric age group. PMID:28598410

  18. Obesity, fatty liver disease and intestinal microbiota

    PubMed Central

    Arslan, Nur

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota (dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations. PMID:25469013

  19. Obesity, fatty liver disease and intestinal microbiota.

    PubMed

    Arslan, Nur

    2014-11-28

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota (dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations.

  20. Radiologic evaluation of nonalcoholic fatty liver disease

    PubMed Central

    Lee, Seung Soo; Park, Seong Ho

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a frequent cause of chronic liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH)-related liver cirrhosis. Although liver biopsy is still the gold standard for the diagnosis of NAFLD, especially for the diagnosis of NASH, imaging methods have been increasingly accepted as noninvasive alternatives to liver biopsy. Ultrasonography is a well-established and cost-effective imaging technique for the diagnosis of hepatic steatosis, especially for screening a large population at risk of NAFLD. Ultrasonography has a reasonable accuracy in detecting moderate-to-severe hepatic steatosis although it is less accurate for detecting mild hepatic steatosis, operator-dependent, and rather qualitative. Computed tomography is not appropriate for general population assessment of hepatic steatosis given its inaccuracy in detecting mild hepatic steatosis and potential radiation hazard. However, computed tomography may be effective in specific clinical situations, such as evaluation of donor candidates for hepatic transplantation. Magnetic resonance spectroscopy and magnetic resonance imaging are now regarded as the most accurate practical methods of measuring liver fat in clinical practice, especially for longitudinal follow-up of patients with NAFLD. Ultrasound elastography and magnetic resonance elastography are increasingly used to evaluate the degree of liver fibrosis in patients with NAFLD and to differentiate NASH from simple steatosis. This article will review current imaging methods used to evaluate hepatic steatosis, including the diagnostic accuracy, limitations, and practical applicability of each method. It will also briefly describe the potential role of elastography techniques in the evaluation of patients with NAFLD. PMID:24966609

  1. Liver Fatty Acid Binding Protein and Obesity

    PubMed Central

    Atshaves, B.P.; Martin, G.G.; Hostetler, H.A.; McIntosh, A.L.; Kier, A.B.; Schroeder, F.

    2010-01-01

    While low levels of unesterified long chain fatty acids (LCFAs) are normal metabolic intermediates of dietary and endogenous fat, LCFAs are also potent regulators of key receptors/enzymes, and at high levels become toxic detergents within the cell. Elevated levels of LCFAs are associated with diabetes, obesity, and metabolic syndrome. Consequently, mammals evolved fatty acid binding proteins (FABPs) that bind/sequester these potentially toxic free fatty acids in the cytosol and present them for rapid removal in oxidative (mitochondria, peroxisomes) or storage (endoplasmic reticulum, lipid droplets) organelles. Mammals have a large (15 member) family of FABPs with multiple members occurring within a single cell type. The first described FABP, liver-FABP (L-FABP, or FABP1), is expressed in very high levels (2-5% of cytosolic protein) in liver as well as intestine and kidney. Since L-FABP facilitates uptake and metabolism of LCFAs in vitro and in cultured cells, it was expected that abnormal function or loss of L-FABP would reduce hepatic LCFA uptake/oxidation and thereby increase LCFAs available for oxidation in muscle and/or storage in adipose. This prediction was confirmed in vitro with isolated liver slices and cultured primary hepatocytes from L-FABP gene-ablated mice. Despite unaltered food consumption when fed a control diet ad libitum, the L-FABP null mice exhibited age- and sex-dependent weight gain and increased fat tissue mass. The obese phenotype was exacerbated in L-FABP null mice pair-fed a high fat diet. Taken together with other findings, these data suggest that L-FABP could have an important role in preventing age- or diet-induced obesity. PMID:20537520

  2. Epidemiology of fatty liver: An update

    PubMed Central

    Bedogni, Giorgio; Nobili, Valerio; Tiribelli, Claudio

    2014-01-01

    We provide a concise review of the main epidemiological literature on fatty liver (FL) published between January 2011 and October 2013. The findings from the literature will be considered in light of the already available knowledge. We discuss the limitations inherent in the categorization of FL into non-alcoholic and alcoholic FL, the potential relevance of FL as an independent predictor of cardiometabolic disease, and recent research addressing the role of FL as an independent predictor of mortality. This review is organized as a series of answers to relevant questions about the epidemiology of FL. PMID:25083078

  3. Herbal medicines and nonalcoholic fatty liver disease.

    PubMed

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-08-14

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future.

  4. Herbal medicines and nonalcoholic fatty liver disease

    PubMed Central

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future. PMID:27570425

  5. Genetic predisposition in nonalcoholic fatty liver disease

    PubMed Central

    Sookoian, Silvia; Pirola, Carlos J.

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed. PMID:28268262

  6. Bariatric surgery and nonalcoholic fatty liver disease.

    PubMed

    Bower, Guy; Athanasiou, Thanos; Isla, Alberto M; Harling, Leanne; Li, Jia V; Holmes, Elaine; Efthimiou, Evangelos; Darzi, Ara; Ashrafian, Hutan

    2015-07-01

    The rising prevalence of nonalcoholic fatty liver disease (NAFLD) is associated with the increasing global pandemic of obesity. These conditions cluster with type II diabetes mellitus and the metabolic syndrome to result in obesity-associated liver disease. The benefits of bariatric procedures on diabetes and the metabolic syndrome have been recognized for some time, and there is now mounting evidence to suggest that bariatric procedures improve liver histology and contribute to the beneficial resolution of NAFLD in obese patients. These beneficial effects derive from a number of weight-dependent and weight-independent mechanisms including surgical BRAVE actions (bile flow changes, restriction of stomach size, anatomical gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) and subsequent effects such as reduced lipid intake, adipocytokine secretion, modulation of gut flora, improvements in insulin resistance and reduced inflammation. Here, we review the clinical investigations on bariatric procedures for NAFLD, in addition to the mounting mechanistic data supporting these findings. Elucidating the mechanisms by which bariatric procedures may resolve NAFLD can help enhance surgical approaches for metabolic hepatic dysfunction and also contribute toward developing the next generation of therapies aimed at reducing the burden of obesity-associated liver disease.

  7. Nonmedicinal interventions in nonalcoholic fatty liver disease

    PubMed Central

    Neuman, Manuela G; Nanau, Radu M; Cohen, Lawrence B

    2015-01-01

    Unhealthy diet and lack of physical exercise are responsible for fat accumulation in the liver, which may lead to liver disease. Histologically, the severity of the disease has two stages: nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NAFLD is defined by the presence of steatosis with no evidence of cellular injury such as hepatocyte ballooning. NASH is a distinct entity from NAFLD, and is characterized by the presence of inflammation with hepatocytes damage, with or without fibrosis. While several therapeutic strategies have been proposed to improve this condition, the present review aims to discuss nonmedicinal interventions used to reduce liver involvement or to prevent the disease altogether. The authors investigated dietary patterns and vitamin deficiencies associated with NAFLD, and their role in enhancing disease severity. Additionally, they reviewed the role of exercise and the use of interventions, such as as intragastric balloon and bariatric surgery, for improving disease progression. The authors propose monitoring disease progression or repair by following changes in cytoadipokine levels. PMID:26076224

  8. Psoriasis and Nonalcoholic Fatty Liver Disease.

    PubMed

    Carrascosa, J M; Bonanad, C; Dauden, E; Botella, R; Olveira-Martín, A

    2017-03-16

    Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver condition in the West. The prevalence and severity of NAFLD is higher and the prognosis worse in patients with psoriasis. The pathogenic link between psoriasis and NAFLD is chronic inflammation and peripheral insulin resistance, a common finding in diseases associated with psoriasis. NAFLD should therefore be ruled out during the initial evaluation of patients with psoriasis, in particular if they show signs of metabolic syndrome and require systemic treatment. Concomitant psoriasis and NAFLD and the likelihood of synergy between them place limitations on general recommendations and treatment for these patients given the potential for liver toxicity. As hepatotoxic risk is associated with some of the conventional drugs used in this setting (e.g., acitretin, methotrexate, and ciclosporin), patients prescribed these treatments should be monitored as appropriate. Anti-tumor necrosis factor agents hold the promise of potential benefits based on their effects on the inflammatory process and improving peripheral insulin resistance. However, cases of liver toxicity have also been reported in relation to these biologics. No evidence has emerged to suggest that anti-p40 or anti-interleukin 17 agents provide benefits or have adverse effects.

  9. Nuclear receptors and nonalcoholic fatty liver disease.

    PubMed

    Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E; Falkner, K Cameron; Feng, Wenke; Clark, Barbara J; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A; McClain, Craig J; Prough, Russell A

    2016-09-01

    Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

  10. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome.

    PubMed

    Lonardo, Amedeo; Ballestri, Stefano; Marchesini, Giulio; Angulo, Paul; Loria, Paola

    2015-03-01

    The conventional paradigm of nonalcoholic fatty liver disease representing the "hepatic manifestation of the metabolic syndrome" is outdated. We identified and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions. Online Medical databases were searched, relevant articles were identified, their references were further assessed and tabulated data were checked. Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes. Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk factor for the future development of the metabolic syndrome. Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not associated with insulin resistance and metabolic syndrome. Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome.

  11. Endocrine causes of nonalcoholic fatty liver disease.

    PubMed

    Marino, Laura; Jornayvaz, François R

    2015-10-21

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.

  12. Endocrine causes of nonalcoholic fatty liver disease

    PubMed Central

    Marino, Laura; Jornayvaz, François R

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed. PMID:26494962

  13. Nonalcoholic fatty liver disease and statins.

    PubMed

    Tziomalos, Konstantinos; Athyros, Vasilios G; Paschos, Paschalis; Karagiannis, Asterios

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of elevated transaminase levels and affects approximately one third of the general population. Patients with NAFLD are at increased risk for cardiovascular events, which represent the leading cause of death in this population. We discuss the safety and efficacy of statins in this population. We reviewed the most recent literature on the safety of statins in patients with NAFLD and on their effects on liver histology and cardiovascular events. It appears that statins can be safely administered to patients with NAFLD, including those with elevated transaminase levels (<3 times the upper limit of normal). Post-hoc analyses of randomized controlled trials also suggest that statins might reduce cardiovascular morbidity in this population. On the other hand, there are few and controversial data on the effects of statins on liver histology in patients with NAFLD. Statins appear to be safe and might also reduce cardiovascular events in patients with NAFLD. Ongoing and future studies will clarify whether statins might also have a role in the treatment of NAFLD. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Evaluation of fatty proportion in fatty liver using least squares method with constraints.

    PubMed

    Li, Xingsong; Deng, Yinhui; Yu, Jinhua; Wang, Yuanyuan; Shamdasani, Vijay

    2014-01-01

    Backscatter and attenuation parameters are not easily measured in clinical applications due to tissue inhomogeneity in the region of interest (ROI). A least squares method(LSM) that fits the echo signal power spectra from a ROI to a 3-parameter tissue model was used to get attenuation coefficient imaging in fatty liver. Since fat's attenuation value is higher than normal liver parenchyma, a reasonable threshold was chosen to evaluate the fatty proportion in fatty liver. Experimental results using clinical data of fatty liver illustrate that the least squares method can get accurate attenuation estimates. It is proved that the attenuation values have a positive correlation with the fatty proportion, which can be used to evaluate the syndrome of fatty liver.

  15. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease.

    PubMed

    Choi, Steve S; Diehl, Anna Mae

    2008-06-01

    Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese

  16. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis.

    PubMed

    Koo, Seung-Hoi

    2013-09-01

    Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.

  17. Fatty liver in birds at the Zoological Society of London.

    PubMed

    Wadsworth, P F; Jones, D M; Pugsley, S L

    1984-04-01

    The livers of 531 captive wild birds necropsied at the Zoological Society of London were examined histologically. Marked fatty infiltration of the liver was found in 13 cases. Seven of the 13 cases were from the order Psittaciformes indicating that some species (cockatoos, parakeets and parrots) in this order may be particularly susceptible to fatty infiltration of the liver. Affected livers were commonly swollen or enlarged, pale, white or yellow in colour and soft, friable or fatty at post mortem examination. Histologically, marked fatty infiltration of the liver was characterised by the presence of intracytoplasmic fat vacuoles within hepatocytes without zonal or lobular distribution throughout the sections examined. Reticulolysis and fibrosis of the hepatic parenchyma were found in association with marked fatty liver in a proportion of cases. Macroscopic or histological evidence of hepatic haemorrhages was not found in affected birds. In psittacine birds, obesity was frequently seen at post mortem examination and it was considered that nutritional and/or metabolic factors were important causes of fatty liver in this group. Fatty liver was found in association with chronic wasting diseases caused by mycotic infection in two cases.

  18. Thyroid dysfunction and nonalcoholic fatty liver disease.

    PubMed

    Efstathiadou, Zoe A; Kita, Marina D; Polyzos, Stergios A

    2017-02-09

    Thyroid hormones are crucial for hepatic lipid and glucose metabolism. Nonalcoholic fatty liver disease (NAFLD), a very common and potentially serious disease of modern society, shares common clinical features with hypothyroidism, such as obesity, insulin resistance and dyslipidemia. Furthermore, in certain studies, increased prevalence of hypothyroidism was observed in patients with NAFLD. However, whether there is a linear relationship between thyroid hormone levels and NAFLD incidence and severity, including values within or in proximity to the reference range remains a contradictory subject in the literature. On the other hand, attempts to treat NAFLD with thyromimetic drugs remain at an early stage. In this review, data derived from observational studies along with evidence on possible treatment with thyroid hormone analogues are presented.

  19. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

    PubMed Central

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K.; Mukherjee, Rathin; Reddy, Duvvur N.; Rao, Padaki N.

    2015-01-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. PMID:26155043

  20. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    PubMed

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

  1. Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice.

    PubMed

    Ritze, Yvonne; Böhle, Maureen; Haub, Synia; Hubert, Astrid; Enck, Paul; Zipfel, Stephan; Bischoff, Stephan C

    2013-12-09

    Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system. C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4 g/(kg.d), 8 weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey's post hoc test and Bartlett's test for equal variances was used. Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease. In conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely

  2. Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice

    PubMed Central

    2013-01-01

    Background Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system. Methods C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4 g/(kg.d), 8 weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey’s post hoc test and Bartlett’s test for equal variances was used. Results Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease. Conclusion In conclusion, diets rich in saturated or monounsaturated fatty acids promote the

  3. The epidemiology, pathogenesis and histopathology of fatty liver disease.

    PubMed

    Levene, Adam P; Goldin, Robert D

    2012-08-01

    Fatty liver disease includes non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), each of which is increasing in prevalence. Each represents a histological spectrum that extends from isolated steatosis to steatohepatitis and cirrhosis. NAFLD is associated with obesity, diabetes, and insulin resistance, and is considered to be the liver manifestation of the metabolic syndrome. The pathogenesis of NAFLD and ALD involves cytokines, adipokines, oxidative stress, and apoptosis. Histopathology is the gold standard for assessing the severity of liver damage in NAFLD and ALD. We have reviewed the literature, and described and compared the epidemiology, natural disease history, pathogenesis and histopathology of NAFLD and ALD. © 2012 Blackwell Publishing Ltd.

  4. Sirtuins and nonalcoholic fatty liver disease

    PubMed Central

    Nassir, Fatiha; Ibdah, Jamal A

    2016-01-01

    Mammalian sirtuins are seven members belonging to the silent information regulator 2 family, a group of Class III histone/protein deacetylases. Sirtuins (SIRT 1-7) have different subcellular localization and function and they regulate cellular protein function through various posttranslational modifications. SIRT1 and 3, the most studied sirtuins, use the product of cellular metabolism nicotinamide adenine dinucleotide as a cofactor to post-translationally deacetylate cellular proteins and consequently link the metabolic status of the cell to protein function. Sirtuins have been shown to play a key role in the development and rescue of various metabolic diseases including non-alcoholic fatty liver disease (NAFLD). NAFLD is currently the most chronic liver disease due mainly to high-calorie consumption and lower physical activity. No pharmacological approach is available to treat NAFLD, the current recommended treatment are lifestyle modification such as weight loss through calorie restriction and exercise. Recent studies have shown downregulation of sirtuins in human as well as animal models of NAFLD indicating an important role of sirtuins in the dynamic pathophysiology of NAFLD. In this review, we highlight the recent knowledge on sirtuins, their role in NAFLD and their unique potential role as novel therapeutic target for NAFLD treatment. PMID:28028356

  5. Role of Kupffer cells in failure of fatty livers following liver transplantation and alcoholic liver injury.

    PubMed

    Thurman, R G; Gao, W; Connor, H D; Adachi, Y; Stachlewitz, R F; Zhong, Z; Knecht, K T; Bradford, B U; Mason, R P; Lemasters, J J

    1995-01-01

    Kupffer cells have been implicated in mechanisms of pathophysiology following liver transplantation. Recently, postoperative injury in ethanol-induced fatty liver has been evaluated because fatty livers often fail following transplantation. The low-flow, reflow liver perfusion model was used to study the role of Kupffer cells (KC) in reperfusion injury to fatty livers from rats fed a diet containing ethanol for 4-5 weeks. Treatment with GdCl3, which selectively destroys KC, decreased cell death significantly. Thus, destruction of KC minimized hepatic reperfusion injury, most likely by inhibiting free radical formation and improving microcirculation. Since it was demonstrated recently that destruction of KC prevented the hypermetabolic state observed with acute alcohol exposure, their involvement in events leading to alcohol-induced liver disease was investigated. In rats exposed to ethanol continuously via intragastric feeding for up to 4 weeks, GdCl3 treatment prevented elevation of aspartate aminotransferase (AST) and dramatically reduced the average hepatic pathological score. These results indicate that KC participate in the early phases of alcohol-induced liver injury. Endotoxaemia occurs in alcoholics and activates KC; therefore, we evaluated the effect of minimizing bacterial endotoxin by intestinal sterilization with the antibiotics polymyxin B and neomycin. Antibiotics diminished plasma endotoxin levels significantly and prevented ethanol-induced increases in AST values. These results indicate that endotoxin is involved in the mechanism of ethanol-induced liver injury. A six-line radical spectrum was detected with electron paramagnetic resonance spectroscopy in bile from alcohol-treated rats which was blocked by GdCl3. The free radical adducts had hyperfine coupling constants characteristic of lipid-derived free radical products. In conclusion, these studies demonstrate that KC are involved in reperfusion injury to ethanol-induced fatty livers and hepatic

  6. Risk assessment chart for predicting fatty liver in Japanese subjects.

    PubMed

    Inabe, Fumiyo; Takahashi, Eiko; Moriyama, Kengo; Negami, Masako; Otsuka, Hiroki

    2012-12-20

    The diagnosis of fatty liver is done mainly by ultrasonography, which it is not included in the usual health checkup examinations. The aim of this study was to develop an index to predict the existence of fatty liver using tests that are part of specific health examinations. A total of 7,305 Japanese (4,042 men; 3,263 women) who underwent annual health checks were enrolled. Body mass index (BMI), Waist circumference (WC), blood pressure, and levels of triglyceride (TG), high-density lipoprotein cholesterol, fasting plasma glucose (FPG), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase were used to predict fatty liver, and a stepwise procedure was used to select an optimal subset of dummy regressors. The probabilities for predicting fatty liver were calculated from the logistic regression equation using the constant and coefficients for each variable. Risk assessment charts for predicting the probability of fatty liver were developed. These probabilities were displayed in a color-coded manner by combining BMI, TG, FPG, ALT, and WC. Our fatty liver-predicting index consisted of the components of metabolic syndrome (MetS) and ALT, thus indicating a close relationship of fatty liver and MetS. The use of this index enables quantitative assessments of the severity of MetS.

  7. Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ur Rahman, Zia; Hurairah, Abu

    2016-01-01

    Our objective was to study nonalcoholic fatty liver disease (NAFLD) as a relevant risk factor associated with hepatocellular carcinoma (HCC) in patients with and without cirrhosis. HCC is a common cancer worldwide that predominantly involves patients with hepatic cirrhosis. HCC has recently been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders. This association is alarming due to the high prevalence of NAFLD globally, which may contribute to the rising incidence of HCC. A 31-year-old female with a history of dyslipidemia, hypertension, and diabetes mellitus presented with abdominal pain that persisted for six months. The pain was associated with gastrointestinal symptoms and weight loss. She was drug-free and a nonalcoholic and a nonsmoker. The physical examination was unremarkable. The abdominal exam showed a soft and non-tender abdomen, with no organomegaly or ascites. The laboratory evaluation was unremarkable. The imaging studies showed a hypodense lesion in the right hepatic lobe with strong arterial enhancement. Subsequently, the patient underwent a liver biopsy. The histopathology results were consistent with HCC. The patient underwent an uneventful segment VI liver resection and tumor-free margins were achieved. In our patient, NAFLD was designated as an independent etiology for HCC, without cirrhosis. Our patient recovered well and has been disease free for over a year. HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk of HCC. These results provide new targets for surveillance, prevention, early recognition, and effective treatment of HCC associated with NAFLD. PMID:27733959

  8. The Differentiation of Intestinal-Failure-Associated Liver Disease from Nonalcoholic Fatty Liver and Nonalcoholic Steatohepatitis.

    PubMed

    Buchman, Alan L; Naini, Bita V; Spilker, Bert

    2017-02-01

    Intestinal failure-associated liver disease (IFALD), formerly known as parenteral nutrition-associated liver disease has often been listed in textbooks as an example of nonalcoholic fatty liver disease (NAFLD). However, the etiology, pathophysiology, epidemiology, histology, and progression differ substantially between the conditions defined as NAFLD and the disease, IFALD. Therefore, IFALD should not be defined or considered as a type or a cause of nonalcoholic fatty liver or nonalcoholic steatohepatitis, but rather as a distinct disease.

  9. Continuous positive airway pressure improves sleep apnea associated fatty liver.

    PubMed

    Shpirer, Isaac; Copel, Laurian; Broide, Efrat; Elizur, Arnon

    2010-08-01

    Treatment of sleep apnea can improve liver enzyme abnormalities in patients with nonalcoholic fatty liver disease. However, the effect of continuous positive airway pressure therapy for sleep apnea on liver fat accumulation was not assessed. Liver biopsy is the "gold standard" for determining and quantifying liver fat accumulation; however, obtaining two separate liver biopsies is challenging. We examined, using a newly described computerized tomography method to quantify liver fat accumulation, whether treatment of sleep apnea improves liver steatosis. In a prospective cohort study, patients diagnosed with obstructive sleep apnea, at Assaf Harofeh Medical Center's sleep laboratory, were identified. Patients completed a questionnaire and underwent blood tests for liver enzymes and lipid profile, and computed tomography scans to determine the liver attenuation index. Patients with liver attenuation index or=30%) were treated with continuous positive airway pressure for 2-3 years. Subsequently, patients underwent repeat blood tests and tomography scans. Of 47 patients who were analyzed, 16 had a low liver attenuation index (liver attenuation index compared with patients with mild sleep apnea despite comparable body mass index and triglycerides levels. Patients who were compliant with 2-3 years of continuous positive airway pressure treatment demonstrated significant improvement in the mean liver attenuation index, whereas noncompliant patients did not. Patients with nonalcoholic fatty-liver disease may benefit from identification and treatment for obstructive sleep apnea because treatment may improve liver steatosis.

  10. Vitamin E reduces liver stiffness in nonalcoholic fatty liver disease

    PubMed Central

    Fukui, Aiko; Kawabe, Naoto; Hashimoto, Senju; Murao, Michihito; Nakano, Takuji; Shimazaki, Hiroaki; Kan, Toshiki; Nakaoka, Kazunori; Ohki, Masashi; Takagawa, Yuka; Takamura, Tomoki; Kamei, Hiroyuki; Yoshioka, Kentaro

    2015-01-01

    AIM: To evaluate the efficacy of vitamin E treatment on liver stiffness in nonalcoholic fatty liver disease (NAFLD). METHODS: Thirty-eight NAFLD patients were administered vitamin E for > 1 year. The doses of vitamin E were 150, 300, or 600 mg; three times per day after each meal. Responses were assessed by liver enzyme levels [aspartate aminotransferase (AST), alanine aminotranferease (ALT), and γ-glutamyl transpeptidase (γ-GTP)], noninvasive scoring systems of hepatic fibrosis-4 [FIB-4 index and aspartate aminotransferase-to-platelet index (APRI)], and liver stiffness [velocity of shear wave (Vs)] measured by acoustic radiation force impulse elastography. Vs measurements were performed at baseline and 12 mo after baseline. The patients were genotyped for the patatin-like phospholipase domain containing 3 (PNPLA3) polymorphisms and then divided into either the CC/CG or GG group to examine each group’s responses to vitamin E treatment. RESULTS: We found marked differences in the platelet count, serum albumin levels, alkaline phosphatase levels, FIB-4 index, APRI, and Vs at baseline depending on the PNPLA3 polymorphism. AST, ALT, and γ-GTP levels (all P < 0.001); FIB-4 index (P = 0.035); APRI (P < 0.001); and Vs (P < 0.001) significantly decreased from baseline to 12 mo in the analysis of all patients. In the subset analyses of PNPLA3 genotypes, AST levels (P = 0.011), ALT levels (P < 0.001), γ-GTP levels (P = 0.005), APRI (P = 0.036), and Vs (P = 0.029) in genotype GG patients significantly improved, and AST and ALT levels (both P < 0.001), γ-GTP levels (P = 0.003), FIB-4 index (P = 0.017), and APRI (P < 0.001) in genotype CC/CG patients. CONCLUSION: One year of vitamin E treatment improved noninvasive fibrosis scores and liver stiffness in NAFLD patients. The responses were similar between different PNPLA3 genotypes. PMID:26644818

  11. Fatty acids and the Endoplasmic Reticulum in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Gentile, Christopher L.; Frye, Melinda A.; Pagliassotti, Michael J.

    2011-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning public health concernin westernized nations. The obesity-related disorder is associated with an increased risk of cardiovascular disease, type 2 diabetes and liver failure. Although the underlying pathogenesis of NAFLD is unclear, increasing evidence suggests that excess saturated fatty acids presented to or stored within the liver may play a role in both the development and progression of the disorder. Aputative mechanism linking saturated fatty acids to NAFLD may been doplasmic reticulum (ER) stress. Specifically, excess saturated fatty acids may induce an ER stress response that, if left unabated, can activate stress signaling pathways, cause hepatocyte cell death, and eventually lead to liver dysfunction. In the current review we discuss the involvement of saturated fatty acids in the pathogenesis of NAFLD with particular emphasis on the role of ER stress. PMID:21328622

  12. Fatty Acid–Regulated Transcription Factors in the Liver

    PubMed Central

    Jump, Donald B.; Tripathy, Sasmita; Depner, Christopher M.

    2014-01-01

    Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. PMID:23528177

  13. Non-fatal acute fatty liver of pregnancy.

    PubMed Central

    Bernuau, J; Degott, C; Nouel, O; Rueff, B; Benhamou, J P

    1983-01-01

    Four patients are described, admitted during a three-year period, who recovered from acute fatty liver of pregnancy; vomiting and jaundice were the main manifestations of the disease; coma and anuria were absent. During the same period, we observed one patient who died of acute fatty liver of pregnancy. This experience suggests that the non-fatal form of the disorder may be much commoner than the fatal form. Images Fig. 1 Fig. 2 PMID:6832629

  14. Fatty acid composition in serum correlates with that in the liver and non-alcoholic fatty liver disease activity scores in mice fed a high-fat diet.

    PubMed

    Wang, Xing-He; Li, Chun-Yan; Muhammad, Ishfaq; Zhang, Xiu-Ying

    2016-06-01

    In this study, we investigated the correlation between the serum fatty acid composition and hepatic steatosis, inflammation, hepatocellular ballooning scores, and liver fatty acids composition in mice fed a high-fat diet. Livers were collected for non-alcoholic fatty liver disease score analysis. Fatty acid compositions were analysed by gas chromatography. Correlations were determined by Pearson correlation coefficient. Exposed to a high-fat diet, mice developed fatty liver disease with varying severity without fibrosis. The serum fatty acid variation became more severe with prolonged exposure to a high-fat diet. This variation also correlated significantly with the variation in livers, with the types of fatty acids corresponding to liver steatosis, inflammation, and hepatocellular ballooning scores. Results of this study lead to the following hypothesis: the extent of serum fatty acid variation may be a preliminary biomarker of fatty liver disease caused by high-fat intake.

  15. Fatty Liver Index and Lipid Accumulation Product Can Predict Metabolic Syndrome in Subjects without Fatty Liver Disease

    PubMed Central

    Cheng, Yuan-Lung; Wang, Yuan-Jen; Lan, Keng-Hsin; Huo, Teh-Ia; Hsieh, Wei-Yao; Hou, Ming-Chih; Lee, Fa-Yauh; Wu, Jaw-Ching; Lee, Shou-Dong

    2017-01-01

    Background. Fatty liver index (FLI) and lipid accumulation product (LAP) are indexes originally designed to assess the risk of fatty liver and cardiovascular disease, respectively. Both indexes have been proven to be reliable markers of subsequent metabolic syndrome; however, their ability to predict metabolic syndrome in subjects without fatty liver disease has not been clarified. Methods. We enrolled consecutive subjects who received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Fatty liver disease was diagnosed by abdominal ultrasonography. The ability of the FLI and LAP to predict metabolic syndrome was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. Results. Male sex was strongly associated with metabolic syndrome, and the LAP and FLI were better than other variables to predict metabolic syndrome among the 29,797 subjects. Both indexes were also better than other variables to detect metabolic syndrome in subjects without fatty liver disease (AUROC: 0.871 and 0.879, resp.), and the predictive power was greater among women. Conclusion. Metabolic syndrome increases the cardiovascular disease risk. The FLI and LAP could be used to recognize the syndrome in both subjects with and without fatty liver disease who require lifestyle modifications and counseling. PMID:28194177

  16. [Non-alcoholic fatty liver disease in children and adolescents].

    PubMed

    Björklund, Jessica; Laursen, Tea Lund; Kazankov, Konstantin; Thomsen, Karen Louise; Hamilton-Dutoit, Stephen; Stenbøg, Elisabeth; Grønbæk, Henning

    2017-07-03

    Non-alcoholic fatty liver disease (NAFLD) is characterized by liver fat accumulation and non-alcoholic steatohepatitis (NASH) with inflammation and fibrosis, which may lead to cirrhosis also in childhood. NAFLD/NASH in children are related to obesity and the metabolic syndrome, and incidence and prevalence are expected to increase. Children having liver steatosis and elevated liver enzymes are most often asymptomatic, and a liver biopsy is necessary for correct diagnosis and staging. The treatment should focus on lifestyle changes, as pharmacological therapy needs further evaluation.

  17. Pediatric fatty liver disease: Role of ethnicity and genetics

    PubMed Central

    Marzuillo, Pierluigi; Miraglia del Giudice, Emanuele; Santoro, Nicola

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver. PMID:24966605

  18. Low vitamin D status is associated with advanced liver fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Yang, Bing-Bing; Chen, Yuan-Hua; Zhang, Cheng; Shi, Chang-E; Hu, Kai-Feng; Zhou, Ju; Xu, De-Xiang; Chen, Xi

    2017-02-01

    Several studies explored the association between vitamin D status and nonalcoholic fatty liver disease with contradictory results. We aimed to investigate the association between vitamin D status, inflammatory cytokines and liver fibrosis in nonalcoholic fatty liver disease patients. Two hundred nineteen nonalcoholic fatty liver disease patients and 166 age- and gender- matched healthy controls were recruited for this study. Serum 25(OH)D was measured by radioimmunoassay. Serum interleukin-8 and transforming growth factor-β1 were measured using ELISA. Serum 25(OH)D was only marginally decreased in nonalcoholic fatty liver disease patients. Interestingly, serum 25(OH)D was markedly reduced in nonalcoholic fatty liver disease patients with advanced liver fibrosis compared to nonalcoholic fatty liver disease patients with indeterminate liver fibrosis and no advanced fibrosis. Logistic regression analysis showed that there was an inverse association between serum 25(OH)D and severity of liver fibrosis in nonalcoholic fatty liver disease patients. Further analysis showed that serum interleukin-8 was elevated in nonalcoholic fatty liver disease patients, the highest interleukin-8 in patients with advanced fibrosis. An inverse correlation between serum 25(OH)D and interleukin-8 was observed in nonalcoholic fatty liver disease patients with and without liver fibrosis. Although serum transforming growth factor-β1 was slightly elevated in nonalcoholic fatty liver disease patients, serum transforming growth factor-β1 was reduced in nonalcoholic fatty liver disease patients with advanced fibrosis. Unexpectedly, a positive correlation between serum 25(OH)D and transforming growth factor-β1 was observed in nonalcoholic fatty liver disease patients with advanced fibrosis. In conclusion, low vitamin D status is associated with advanced liver fibrosis in nonalcoholic fatty liver disease patients. Interleukin-8 may be an important mediator for hepatic fibrosis in nonalcoholic

  19. NONALCOHOLIC FATTY LIVER DISEASE BRAZILIAN SOCIETY OF HEPATOLOGY CONSENSUS.

    PubMed

    Cotrim, Helma P; Parise, Edison R; Figueiredo-Mendes, Cláudio; Galizzi-Filho, João; Porta, Gilda; Oliveira, Claudia P

    2016-01-01

    The prevalence of obesity-related metabolic syndrome has rapidly increased in Brazil, resulting in a high frequency of nonalcoholic fatty liver disease, that didn't receive much attention in the past. However, it has received increased attention since this disease was identified to progress to end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma. Clinical practice guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease have not been established in Brazil. The Brazilian Society of Hepatology held an event with specialists' members from all over Brazil with the purpose of producing guideline for Nonalcoholic Fatty Liver Disease based on a systematic approach that reflects evidence-based medicine and expert opinions. The guideline discussed the following subjects: 1-Concepts and recommendations; 2-Diagnosis; 3-Non-medical treatment; 4-Medical treatment; 5-Pediatrics - Diagnosis; 6-Pediatrics - Non-medical treatment; 7-Pediatrics - Medical treatment; 8-Surgical treatment.

  20. Nonalcoholic fatty liver disease in overweight children and adolescents.

    PubMed

    Sagi, R; Reif, S; Neuman, G; Webb, M; Phillip, M; Shalitin, S

    2007-08-01

    To investigate the prevalence and characteristics of non-alcoholic fatty liver disease (NAFLD) and identify predictors for NAFLD in an overweight paediatric population. The study group included 58 overweight (BMI-SDS 3.37 +/- 1) patients aged 8-18 years attending the paediatric obesity clinic. They underwent a clinical and biochemical work-up and liver ultrasonography. Grading of liver steatosis severity was done according to discrepancy in ultrasonographic liver-kidney densities. The prevalence of NAFLD was 60.3%. There was a highly significant (p = 0.004) association between severity of obesity and the presence or absence of liver steatosis. The study cohort was divided into three groups: group 1 (patients with normal ultrasonographic liver structure and normal liver enzymes), group 2 (patients with ultrasonographic fatty liver and normal liver enzymes) and group 3 (patients with ultrasonographic fatty liver and elevated liver enzymes). The BMI-SDS was significantly higher in group 3 compared to group 1 (4.2 +/- 1.1 vs. 2.8 +/- 0.9, p < 0.001). The rate of obesity complications was more prevalent in group 3 compared to groups 1 and 2 (p < 0.001). The insulin resistance index was higher in group 3 compared to group 1 (0.75 +/- 0.2 vs. 0.47 +/- 0.3, p < 0.05). The prevalence of NAFLD in our study cohort was high (60.3%). Patients with steatosis and elevated liver enzymes had a higher risk for obesity complications. Measurements of liver enzymes alone are insufficient, and liver ultrasonography is required for early identification of NAFLD.

  1. ω-3 Fatty acids reverse lipotoxity through induction of autophagy in nonalcoholic fatty liver disease.

    PubMed

    Chen, Yi; Xu, Chengfu; Yan, Tianlian; Yu, Chaohui; Li, Youming

    2015-01-01

    The aim of this study was to evaluate the effect of ω-3 fatty acids on nonalcoholic fatty liver disease concerning hepatocyte lipid accumulation as well as apoptosis induced by free fatty acids (FFAs) and to explore the underlying mechanism involving autophagy. Hepatocytes were incubated with a mixture of free fatty acids (FFAs) to mimic in vitro lipotoxicity in the pathogenesis of nonalcoholic fatty liver disease, presented by lipid accumulation and cellular apoptosis. Chemical inhibitor or inducer of autophagy and genetic deficit cells, as well as ω-3 fatty acids were used as intervention. The autophagic role of ω-3 fatty acids was investigated using Western blot and immunofluorescence. The underlying mechanism of ω-3 fatty acids involving autophagy was preliminarily explored by quantitative real-time polymerase chain reaction and Western blot. FFAs induce lipid accumulation and apoptosis in hepatocytes. Inhibition or genetic defect of autophagy increases lipid accumulation induced by FFA, whereas induction acts inversely. ω-3 Fatty acids reduced lipid accumulation and inhibited apoptosis induced by FFA. ω-3 Fatty acids induced autophagy by downregulating stearoyl-CoA desaturase 1 expression in hepatocytes. ω-3 Fatty acids exert protective effects on hepatocytes against lipotoxicity through induction of autophagy, as demonstrated by inhibition of lipid accumulation and apoptosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Targeting nuclear receptors for the treatment of fatty liver disease.

    PubMed

    Tanaka, Naoki; Aoyama, Toshifumi; Kimura, Shioko; Gonzalez, Frank J

    2017-05-23

    Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis. Recently, disorders associated with disrupted nutrient/energy homeostasis, e.g., obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), are increasing worldwide. Notably, in NAFLD, a progressive subtype exists, designated as non-alcoholic steatohepatitis (NASH) that is characterized by typical histological features resembling alcoholic steatohepatitis (ASH), and NASH/ASH are recognized as major causes of hepatitis virus-unrelated liver cirrhosis and hepatocellular carcinoma. Since hepatic steatosis is basically caused by an imbalance between fat/energy influx and utilization, abnormal signaling of these nuclear receptors contribute to the pathogenesis of fatty liver disease. Standard therapeutic interventions have not been fully established for fatty liver disease, but some new agents that activate or inhibit nuclear receptor signaling have shown promise as possible therapeutic targets. In this review, we summarize recent findings on the roles of nuclear receptors in fatty liver disease and discuss future perspectives to develop promising pharmacological strategies targeting nuclear receptors for NAFLD/NASH. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Olive oil consumption and non-alcoholic fatty liver disease.

    PubMed

    Assy, Nimer; Nassar, Faris; Nasser, Gattas; Grosovski, Maria

    2009-04-21

    The clinical implications of non-alcoholic fatty liver diseases (NAFLD) derive from their potential to progress to fibrosis and cirrhosis. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride (TG) accumulation. An olive oil-rich diet decreases accumulation of TGs in the liver, improves postprandial TGs, glucose and glucagon-like peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver. The principal mechanisms include: decreased nuclear factor-kappaB activation, decreased low-density lipoprotein oxidation, and improved insulin resistance by reduced production of inflammatory cytokines (tumor necrosis factor, interleukin-6) and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1. The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids, mainly from olive oil. In this review, we describe the dietary sources of the monounsaturated fatty acids, the composition of olive oil, dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis, clinical and experimental studies that assess the relationship between olive oil and NAFLD, and the mechanism by which olive oil ameliorates fatty liver, and we discuss future perspectives.

  4. [Role of probiotics in treatment of nonalcoholic fatty liver disease].

    PubMed

    Chen, M; Wang, M C; Ni, R; Wang, J; Wang, L; Wang, G N; Zhang, L Y

    2017-01-20

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in China and manifests as simple fatty liver, non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies have shown that intestinal flora can affect the development and progression of NAFLD via the "gut-liver axis" . Probiotics are active microorganisms with beneficial effects on the host, and more and more studies have found that probiotics play a positive role in improving NAFLD. They are cheaper, less harmful, and safer compared with antibiotics and surgery, and therefore, it may become a new method for the prevention and treatment of NAFLD. This article reviews the research advances in probiotics in the treatment of NAFLD, in order to provide a basis for the treatment of NAFLD using probiotics.

  5. Nutritional and metabolic aspects of fatty liver disease in poultry.

    PubMed

    Whitehead, C C

    1979-07-01

    Summary There are two metabolic disorders of major commercial importance in poultry that involve the occurrence of fatty deposits in the liver. Fatty Liver and Kidney Syndrome (FLKS) affects young birds and the main manifestations, lipid infiltrations into liver and many other organs, are apparently secondary effects of the primary lesion that lies in carbohydrate metabolism. Although several nutritional and environmental factors influence FLKS, the main factor is the vitamin, biotin. In the absence of an adequate supply of biotin, the hepatic activity of pyruvate carboxylase, a biotin-dependent enzyme, becomes so low that gluconeogenesis in the liver via pyruvate becomes negligible. When the bird is then subject to a mild stress and 1or short term fasting, liver glycogen reserves become rapidly depleted and a progressive hypoglycaemia develops that ultimately proves fatal. Supplementing diets with adequate amounts of biotin can prevent the syndrome. Fatty Liver Haemorrhagic Syndrome (FLHS) is brought about by an excessive accumulation of fat in the livers of adult hens which weakens the cellular structure of the liver and allows fatal haemorrhaging to occur. The aetiology of the syndrome is not clear, but a major factor is an excessive intake of dietary energy. However, Me involvement of hormonal and toxicological factors, as well as other nutritional factors, is also possible.

  6. Nutritional and metabolic aspects of fatty liver disease in poultry.

    PubMed

    Whitehead, C C

    1979-07-15

    There are two metabolic disorders of major commercial importance in poultry that involve the occurrence of fatty deposits in the liver. Fatty Liver and Kidney Syndrome (FLKS) affects young birds and the main manifestations, lipid infiltrations into liver and many other organs, are apparently secondary effects of the primary lesion that lies in carbohydrate metabolism. Although several nutritional and environmental factors influence FLKS, the main factor is the vitamin, biotin. In the absence of an adequate supply of biotin, the hepatic activity of pyruvate carboxylase, a biotin-dependent enzyme, becomes so low that gluconeogenesis in the liver via pyruvate becomes negligible. When the bird is then subject to a mild stress and/or short term fasting, liver glycogen reserves become rapidly depleted and a progressive hypoglycaemia develops that ultimatley proves fatal. Supplementing diets with adequate amounts of biotin can prevent the syndrome. Fatty Liver Haemorrhagic Syndrome (FLHS) is brought about by an excessive accumulation of fat in the livers of adult hens which weakens the cellular structure of the liver and allows fatal haemorrhaging to occur. The aetiology of the syndrome is not clear, but a major factor is an excessive intake of dietary energy. However, the involvement of hormonal and toxicological factors, as well as other nutritional factors, is also possible.

  7. Obstructive sleep apnea is associated with fatty liver index, the index of nonalcoholic fatty liver disease.

    PubMed

    Chen, Xiao; Lin, Xian; Chen, Li-Da; Lin, Qi-Chang; Chen, Gong-Ping; Yu, Yao-Hua; Huang, Jian-Chai; Zhao, Jian-Ming

    2016-06-01

    The relationship between obstructive sleep apnea (OSA) and nonalcoholic fatty liver disease (NAFLD) is gaining increased attention. The aim of the present study was to examine the relationship of OSA with NAFLD defined by an elevated fatty liver index (FLI). A total of 319 consecutive patients who underwent standard polysomnography were enrolled. Fasting blood samples were obtained from all patients for biological profile measurements, and demographic data were collected. Values of FLI were determined and assessed as predictors of the presence of NAFLD, as measured by ultrasound. The discriminative ability of FLI was estimated on the basis of the area under the receiver operator characteristic curve. An FLI of 60 achieved the highest diagnostic accuracy and yielded an area under the receiver operator characteristic curve of 0.822 (95% confidence interval: 0.729-0.916) in the detection of NAFLD. Patients with an FLI of 60 or higher had a significantly lower lowest O2 saturation (73 vs. 83%, P<0.001), a lower mean nocturnal oxygen saturation (93 vs. 95%, P<0.001), a higher apnea-hypopnea index (39.7 vs. 18.4, P<0.001), a higher oxygen desaturation index (39 vs. 10.6, P<0.001), and a higher percentage of sleep time spent with SpO2 less than 90% (4.63 vs. 0.92%, P<0.001) compared with those with FLI less than 60. In multivariate analysis, the presence of OSA was independently associated with elevated FLI after adjusting for confounding factors (odds ratio: 5.141, 95% confidence interval: 1.414-18.696, P=0.013). Our results suggest a positive association between the severity of OSA and NAFLD defined by an elevated FLI, which may serve as a good biomarker for detecting NAFLD in OSA patients.

  8. [Non-alcoholic fatty liver disease and steatohepatitis].

    PubMed

    Pár, Gabriella; Horváth, Gábor; Pár, Alajos

    2013-07-21

    Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, the hepatic manifestations of metabolic syndrome with close association with inzulin resistance and obesity, are the most common liver diseases, affecting up to a third of the population worldwide. They confer increased risk for hepatocellular carcinoma as well as cardiovascular diseases. The review aims to summarize advances in epidemiology, pathogenesis and clinical management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Besides liver biopsy and biomarkers, a novel non-invasive diagnostic tool the called "controlled attenuation parameter" measuring the attenuation of ultrasound generated by the transient elastography transducer, can quantitatively assess the hepatic fat content and differentiate between steatosis grades. At the same time, liver stiffness (fibrosis) can also be evaluated. The authors present their own results obtained with the latter procedure. In non-alcoholic fatty liver disease, the lifestyle intervention, weight loss, diet and exercise supported by cognitive behavioural therapy represent the basis of management. Components of metabolic syndrome (obesity, dyslipidaemia, diabetes and arterial hypertension) have to be treated. Although there is no approved pharmacological therapy for NASH, it seems that long lasting administration of vitamin E in association with high dose ursodeoxycholic acid may be beneficial. In addition, omega-3 polyunsaturated fatty acid substitution can also decrease liver fat, however, the optimal dose is not known yet. Further controlled clinical studies are warranted to establish the real value of any suggested treatment modalities for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, although these are in experimental phase yet.

  9. [Fatty liver and its clinical management in obese adolescents].

    PubMed

    González Jiménez, Emilio; Schmidt Río-Valle, Jacqueline; Álvarez Ferre, Judit

    2011-01-01

    Liver steatosis, also called non-alcoholic fatty liver, is characterized by a pathological fat accumulation in the liver, leading to liver damage in the form of inflammation and fibrosis. These histological features are similar to those in alcoholic hepatitis. Obesity is known to be the most common cause of simple steatosis in the preadolescent and adolescent population with a consequent serious health risk. The aim of this study was to provide an update on the concepts, pathophysiology and clinical management of hepatic steatosis secondary to obesity at an early age.

  10. Experimentally induced "fatty liver syndrome" condition in laying hens.

    PubMed

    Harms, R H; Roland, D A; Simpson, C F

    1977-03-01

    Two experiments were conducted with aged laying hens to determine the influence of feeding 5,000 p.p.m. of iodine as potassium iodine (KI) and/or injecting 12 mg. of estradiol upon fat accumulation in the liver and serum cholesterol levels. The KI was fed for 8 days before making liver and blood determinations, and the estradiol was injected 3 days prior to making the determinations. The feeding of KI or injection of estradiol resulted in significantly increased liver weight. When the two treatments were combined a further significant increase in liver weights was obtained. The percent of fat in the liver was significantly increased by the injection of estradiol. However, the feeding of KI in the presence or absence of estradiol did not affect the percentage of fat in the liver. Neither of the treatments significantly affected the fatty acid composition of the liver fat. Feeding of KI or injection of estradiol significantly increased total serum cholesterol levels. When the two treatments were combined a further increase in serum cholesterol level was observed. Histological changes of the livers of hens treated with KI and estradiol were similar to those previously described for the "fatty liver syndrome."

  11. Emerging roles of SIRT1 in fatty liver diseases

    PubMed Central

    Ding, Ren-Bo; Bao, Jiaolin; Deng, Chu-Xia

    2017-01-01

    Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD+) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases. PMID:28808418

  12. Caring for the woman with acute fatty liver of pregnancy.

    PubMed

    Holub, Karen; Camune, Barbara

    2015-01-01

    Acute fatty liver of pregnancy, although rare, is usually a third trimester of pregnancy occurrence that may be life threatening for both the pregnant woman and the fetus. Often, the onset resembles gastroenteritis or cholecystitis and correct diagnosis is delayed. Because it can also present with preeclampsia and eclampsia, it may be mistakenly diagnosed as hemolysis, elevated liver enzymes, low platelet syndrome. This article presents diagnostic differences between liver conditions that can complicate pregnancy and management strategies for treating and maintaining the well-being of pregnant women, fetuses, and infants who are affected by acute fatty liver of pregnancy. Early recognition and rapid intervention from antepartum diagnosis through delivery and the postpartum period are required by the nursing team and medical providers to reduce maternal and neonatal morbidity and mortality.

  13. [Non-alcoholic fatty liver disease and hepatocellular carcinoma - 2016].

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease.

  14. Non-alcoholic fatty liver disease and childhood obesity.

    PubMed

    Mathur, Prashant; Das, Manoja K; Arora, Narendra K

    2007-04-01

    Obesity has emerged as a significant global health problem in the pediatric population. Pediatric liver disease is a serious complication of childhood obesity. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver--simple steatosis, NASH/ steatohepatitis--fat with in.ammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. The important message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.

  15. Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

    PubMed

    Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

    2015-10-01

    Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem.

  16. [Fatty liver syndrome in laying hens].

    PubMed

    Dimitrov, A; Antonov, S; Stoianov, P; Petrova, L; Aleksandrova, E

    1980-01-01

    Pathomorphological and biochemical investigations on liver and blood serum laying hens affected by the liver obesity syndrome were carried out. It was established that the mortality due to the liver obesity syndrome varies within the range of 3.1 and 3.7% for the entire period of exploitation. A rise in mortality is observed in case fodder mixtures with higher peroxide and aldehyde number are prepared. Besides the typical changes in the liver, the pathologo-anatomical investigation established varying in its expression duodenitis of rupture of the liver and hemorrhage. In hens suffering from advanced liver obesity an increased content of total protein in the blood serum was observed. The relative and absolute content of prealbumens and albumens was also higher, while the content of globulins was relatively lower. The content of beta-lipoproteins was raised and total lipids in the blood serum were considerably increased. The investigation on total lipids and lipid fractions in the liver established a correlation between the extent of obesity and the content of total lipids. A trend toward increasing the total and particularly the esterificated holesterin was evident in affected birds. The chemical investigation of various lots of fodder mixtures established often cases of rancid fats, which was manifested by high values of the peroxide and aldehyde number. The aminoacid composition of fodder also varied too much. It is assumed that besides the genetic control of liver obesity rancid fats and insufficient content of essential amino acids in the fodder mixtures also lead to an increased mortality percentage in the affected birds.

  17. Fatty liver index vs waist circumference for predicting non-alcoholic fatty liver disease.

    PubMed

    Motamed, Nima; Sohrabi, Masoudreza; Ajdarkosh, Hossein; Hemmasi, Gholamreza; Maadi, Mansooreh; Sayeedian, Fatemeh Sima; Pirzad, Reza; Abedi, Khadijeh; Aghapour, Sivil; Fallahnezhad, Mojtaba; Zamani, Farhad

    2016-03-14

    To determine the discriminatory performance of fatty liver index (FLI) for non-alcoholic fatty liver disease (NAFLD). The data of 5052 subjects aged over 18 years were analyzed. FLI was calculated from body mass index, waist circumference (WC), triglyceride, and gamma glutamyl transferase data. Logistic regression analysis was conducted to determine the association between FLI and NAFLD. The discriminatory performance of FLI in the diagnosis of NAFLD was evaluated by receiver operating characteristic analysis. Area under the curves (AUCs) and related confidence intervals were estimated. Optimal cutoff points of FLI in the diagnosis of NAFLD were determined based on the maximum values of Youden's index. The mean age of men and women in the study population were 44.8 ± 16.8 and 43.78 ± 15.43, respectively (P = 0.0216). The prevalence of NAFLD was 40.1% in men and 44.2% in women (P < 0.0017). FLI was strongly associated with NAFLD, so that even a one unit increase in FLI increased the chance of developing NAFLD by 5.8% (OR = 1.058, 95%CI: 1.054-1.063, P < 0.0001). Although FLI showed good performance in the diagnosis of NAFLD (AUC = 0.8656 (95%CI: 0.8548-0.8764), there was no significant difference with regards to WC (AUC = 0.8533, 95%CI: 0.8419-0.8646). The performance of FLI was not significantly different between men (AUC = 0.8648, 95%CI: 0.8505-0.8791) and women (AUC = 0.8682, 95%CI: 0.8513-0.8851). The highest performance with regards to age was related to the 18-39 age group (AUC = 0.8930, 95%CI: 0.8766-0.9093). The optimal cutoff points of FLI were 46.9 in men (sensitivity = 0.8242, specificity = 0.7687, Youden's index = 0.5929) and 53.8 in women (sensitivity = 0.8233, specificity = 0.7655, Youden's index = 0.5888). Although FLI had acceptable discriminatory power in the diagnosis of NAFLD, WC was a simpler and more accessible index with a similar performance.

  18. Fatty liver index, gamma-glutamyltransferase, and early carotid plaques.

    PubMed

    Kozakova, Michaela; Palombo, Carlo; Eng, Marco Paterni; Dekker, Jacqueline; Flyvbjerg, Allan; Mitrakou, Asimina; Gastaldelli, Amalia; Ferrannini, Ele

    2012-05-01

    An association between fatty liver and carotid atherosclerosis has been established; however, it is not clear whether this relationship is a consequence of shared conventional risk factors or whether it is determined by specific circulating factors originating from liver or adipose tissue. To identify the factors possibly linking fatty liver and atherosclerosis, we assessed, in 1,012 subjects free of confounding diseases (e.g., hypertension, diabetes, cardiovascular diseases, and dyslipidemia) and metabolic syndrome, the relationship between the presence of early plaques at carotid bifurcation and fatty liver index (FLI; a validated surrogate marker of fatty liver), as well as the associations between carotid plaque presence and established atherosclerotic risk factors, family history of cardiovascular disease (FH-CVD) or diabetes, insulin sensitivity, serum liver enzymes, adipokines, fatty free acids, and high-sensitivity C-reactive protein (hsCRP). A total of 55 of 1,012 subjects (5.4%) had small plaque at carotid bifurcation. Subjects with plaque were older and had higher prevalence of FLI ≥60 and FH-CVD, higher blood pressure, plasma low-density lipoprotein cholesterol, glucose, gamma-glutamyltransferase (GGT), and hsCRP, as compared to subjects without plaques (P < 0.05). In a logistic regression model, adjusted for sex, liver transaminase, and alcohol consumption, the independent predictors of plaque presence were age (P < 0.0005), FLI ≥60 (P < 0.0005), and current smoking (P < 0.05). When FLI in the model was replaced by variables used in its equation (e.g., body mass index, waist circumference, plasma triglycerides, and GGT), the independent determinants of plaque presence were age (P < 0.001), GGT (P = 0.001), and current smoking (P < 0.05). Our cross-sectional study suggests that subjects with FLI ≥60 are at higher risk of atherosclerotic lesions, independently of established risk factors, and that serum GGT may represent a link between fatty liver

  19. Focally spared area of fatty liver caused by arterioportal shunt

    SciTech Connect

    Arita, Takeshi; Matsunaga, Naofumi; Honma, Yutaka

    1996-05-01

    We describe a case with a focally spared area in fatty liver caused by arterioportal shunt. Furthermore, we discuss the cause of the focally spared area related to a localized dilution or reduction in portal blood flow. 13 refs., 1 fig.

  20. Audio-Visual Aid in Teaching "Fatty Liver"

    ERIC Educational Resources Information Center

    Dash, Sambit; Kamath, Ullas; Rao, Guruprasad; Prakash, Jay; Mishra, Snigdha

    2016-01-01

    Use of audio visual tools to aid in medical education is ever on a rise. Our study intends to find the efficacy of a video prepared on "fatty liver," a topic that is often a challenge for pre-clinical teachers, in enhancing cognitive processing and ultimately learning. We prepared a video presentation of 11:36 min, incorporating various…

  1. Audio-Visual Aid in Teaching "Fatty Liver"

    ERIC Educational Resources Information Center

    Dash, Sambit; Kamath, Ullas; Rao, Guruprasad; Prakash, Jay; Mishra, Snigdha

    2016-01-01

    Use of audio visual tools to aid in medical education is ever on a rise. Our study intends to find the efficacy of a video prepared on "fatty liver," a topic that is often a challenge for pre-clinical teachers, in enhancing cognitive processing and ultimately learning. We prepared a video presentation of 11:36 min, incorporating various…

  2. Clinical Presentation and Patient Evaluation in Nonalcoholic Fatty Liver Disease.

    PubMed

    Patel, Vaishali; Sanyal, Arun J; Sterling, Richard

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a diagnosis of exclusion. Most patients are asymptomatic and diagnosed incidentally. Most patients remain undiagnosed. A high index of suspicion and serologic work-up to rule out alternative causes of liver disease is required. In NALFD, fibrosis correlates with outcomes, including mortality. To diagnose, assess severity, and monitor fibrosis, 2 noninvasive methods can be used. However, noninvasive tests are more helpful at extremes of fibrosis: excluding it or diagnosing advanced fibrosis. Liver biopsy is usually reserved for cases whereby noninvasive tests fail to accurately determine the degree of fibrosis or the diagnosis is unclear.

  3. Non-alcoholic fatty liver disease in children.

    PubMed

    Janczyk, Wojciech; Socha, Piotr

    2012-06-01

    Non-alcoholic fatty liver disease is increasingly prevalent in children, together with obesity. Transaminases, tests for insulin resistance, ultrasonography and MRI are variably used as surrogates markers of steatosis. Other liver diseases, such as Wilson disease, should be excluded. A liver biopsy is performed in selected cases: young children, familial history of severe disease, inconclusive tests for other pathologies, suspected advanced fibrosis, hypertransaminasemia despite weight loss and in clinical trials. Weight reduction, and changes in lifestyle, are the front-line treatment. Drug therapy is under evaluation. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  4. Rapid lipid enrichment in omega3 fatty acids: liver data.

    PubMed

    Carpentier, Yvon A; Peltier, Sebastien; Portois, Laurence; Sener, Abdullah; Malaisse, Willy J

    2008-03-01

    The bolus intravenous injection of a novel medium-chain triglyceride:fish oil emulsion to normal subjects was recently reported to enrich within 60 min the phospholipid content of leucocytes and platelets in long-chain polyunsaturated omega3 fatty acids. The present study, conducted in second generation omega3-depleted rats, aims at investigating whether such a procedure may also increase within 60 min the phospholipid content of omega3 fatty acids in cells located outwards of the bloodstream, in this case liver cells, and whether this coincides with correction of the perturbation in the liver triglyceride fatty acid content and profile otherwise prevailing in these rats. The results indicate that such is indeed the case and further suggest a cause-to-effect relationship between the two events.

  5. Probiotics in Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Cirrhosis.

    PubMed

    Qamar, Amir A

    2015-01-01

    With the growing epidemic of obesity, the incidence of both nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH) is increasing. The intestinal microbiota differs between individuals who are obese or have normal body mass indices. Animal studies have shown increased intestinal permeability in NAFL, NASH, and cirrhosis. This increases the risk of oxidative and inflammatory injury to the liver from intestinal microbacteria. It may also increase the risk of fatty acid injury and fatty deposition. Bacterial translocation is associated with increased portal hypertension and hepatic encephalopathy in cirrhosis. By preventing bacterial adhesion and translocation, probiotics may have a role in the management of patients with NAFL, NASH, and cirrhosis. Multiple small studies have suggested that probiotics improve some of the clinical markers of activity in patients with NAFL and NASH. Controlled studies have also shown improved outcomes in patients with cirrhosis who were treated with probiotics.

  6. Estimation of fish and omega-3 fatty acid intake in pediatric nonalcoholic fatty liver disease

    PubMed Central

    St-Jules, David E; Watters, Corilee A; Brunt, Elizabeth M; Wilkens, Lynne R; Novotny, Rachel; Belt, Patricia; Lavine, Joel E

    2013-01-01

    Introduction Fish and omega-3 fatty acids are reported to be beneficial in pediatric nonalcoholic fatty liver disease (NAFLD), but no studies have assessed their relation to histological severity. The objectives of this study were to evaluate the dietary intake of fish and omega-3 fatty acids in children with biopsy-proven NAFLD, and examine their association with serological and histological indicators of disease. Materials and Methods This was a cross-sectional analysis of 223 children (6–18 years) that participated in the Treatment of Nonalcoholic Fatty Liver Disease in Children trial or the NAFLD Database study conducted by the Nonalcoholic Steatohepatitis Clinical Research Network. The distribution of fish and omega-3 fatty acid intake were determined from responses to the Block Brief 2000 Food Frequency Questionnaire, and analyzed for associations with serum alanine aminotransferase, histological features of fatty liver disease, and diagnosis of steatohepatitis after adjusting for demographic, anthropometric and dietary variables. Results The minority of subjects consumed the recommended eight ounces of fish per week (22/223 (10%)) and 200 mg of long-chain omega-3 fatty acids per day (12/223 (5%)). Lack of fish and long-chain omega-3 fatty acid intake was associated with greater portal (p=0.03 and p=0.10, respectively) and lobular inflammation (p=0.09 and p=0.004, respectively) after controlling for potential confounders. Discussion Fish and omega-3 fatty acid intake were insufficient in children with NAFLD, which may increase susceptibility to hepatic inflammation. Patients with pediatric NAFLD should be encouraged to consume the recommended amount of fish per week. PMID:24177784

  7. Clinical approaches to non-alcoholic fatty liver disease

    PubMed Central

    Schwenger, Katherine JP; Allard, Johane P

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients. PMID:24587650

  8. Non-alcoholic fatty liver disease: A poorly known pandemic.

    PubMed

    Augustin, Salvador; Graupera, Isabel; Caballeria, Juan

    2017-07-24

    Non-alcoholic fatty liver disease (NAFLD) consists of an excessive depositing of fat in the liver, which can end up by causing inflammation, fibrosis and also cirrhosis with the corresponding complications including liver cancer. NAFLD has become the most common liver disease worldwide. The incidence has increased in parallel with the obesity, diabetes and metabolic syndrome epidemic, thus resulting in becoming one of the main indications for liver transplant. The diagnosis has principally been through histology but with the development of non-invasive methods, these have helped in simplifying the management of these patients in clinical practice. The only therapeutic strategies currently available are focused on weight loss (lifestyle changes or bariatric surgery). There is still no approved pharmacological option for the treatment of NAFLD, however there are a number of molecular studies in advanced stages of development. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  9. Therapeutic potential of green tea in nonalcoholic fatty liver disease.

    PubMed

    Masterjohn, Christopher; Bruno, Richard S

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a constellation of progressive liver disorders that are closely related to obesity, diabetes, and insulin resistance and may afflict over 70 million Americans. NAFLD may occur as relatively benign, nonprogressive liver steatosis, but in many individuals it may progress in severity to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure or hepatocellular carcinoma. No validated treatments currently exist for NAFLD except for weight loss, which has a poor long-term success rate. Thus, dietary strategies that prevent the development of liver steatosis or its progression to nonalcoholic steatohepatitis are critically needed. Green tea is rich in polyphenolic catechins that have hypolipidemic, thermogenic, antioxidant, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD. This review presents the experimental evidence demonstrating the hepatoprotective properties of green tea and its catechins and the proposed mechanisms by which these targeted dietary agents protect against NAFLD.

  10. Non alcoholic fatty liver disease and metabolic syndrome

    PubMed Central

    Paschos, P; Paletas, K

    2009-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic entity increasingly recognized as a major health burden in developed countries. It includes a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and rarely, progression to cirrhosis. Recent studies emphasize the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction in the development and progression of NAFLD. Furthermore, accumulating evidence supports an association between NAFLD and metabolic syndrome. Although the data are mainly epidemiological, the pathogenesis of NAFLD and metabolic syndrome seems to have common pathophysiological mechanisms, with focus on insulin resistance as a key factor. This review summarizes the current knowledge on the epidemiology, pathophysiology and diagnosis of both NAFLD and metabolic syndrome and the findings that strongly support the association of nonalcoholic fatty liver disease as a possible component in the cluster of metabolic syndrome. PMID:19240815

  11. Nonalcoholic fatty liver disease: the concept and confusion.

    PubMed

    Sanal, M G

    2011-12-01

    Nonalcoholic fatty liver disease (NAFLD) is generally considered as a disease associated with diabetes mellitus type 2. But on a closer evaluation we realize a host of confusion associated with this from the nomenclature, diagnosis to pathogenesis. The term refers to a spectrum ranging from steatosis to steatosis with inflammation (NASH) to cirrhosis in the absence of alcohol abuse. But in fact NAFLD is a vague term for a spectrum of diseases which differ not only in the clinical presentation but also in the etiology. NAFLD is loose to incorporate so many etiologies excluding alcoholism and few other "known" etiologies, presenting as fat in liver. Considering the diverse etiologies there is a need for personalized management in NAFLD, which at present is difficult. Currently fatty liver disease could be considered as an added Hepato-cardiovascular-renal and cancer risk factor rather than a specific diagnosis.

  12. Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan.

    PubMed

    Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

    2017-06-01

    Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females.

  13. Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice.

    PubMed

    Yamazaki, Tomomi; Nakamori, Akiko; Sasaki, Eriko; Wada, Satoshi; Ezaki, Osamu

    2007-12-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oil-induced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma.

  14. Human germline hedgehog pathway mutations predispose to fatty liver.

    PubMed

    Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu; Kruszka, Paul; Weiss, Karin; Everson, Joshua L; Bataller, Ramon; Kleiner, David E; Ward, Jerrold M; Sulik, Kathleen K; Lipinski, Robert J; Solomon, Benjamin D; Muenke, Maximilian

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2(+/-)) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2(+/-) mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2(+/-) mice exposed to a high-fat diet. Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous

  15. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

    USDA-ARS?s Scientific Manuscript database

    Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...

  16. Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease.

    PubMed

    Komatsu, Michiharu; Yazaki, Masahide; Tanaka, Naoki; Sano, Kenji; Hashimoto, Etsuko; Takei, Yo-ichi; Song, Yuan-Zong; Tanaka, Eiji; Kiyosawa, Kendo; Saheki, Takeyori; Aoyama, Toshifumi; Kobayashi, Keiko

    2008-11-01

    Citrin deficiency caused by SLC25A13 gene mutations develops into adult-onset type II citrullinemia (CTLN2) and may be accompanied with hepatic steatosis and steatohepatitis. As its clinical features remain unclear, we aimed to explore the characteristics of fatty liver disease associated with citrin deficiency. The prevalence of hepatic steatosis in 19 CTLN2 patients was examined, and clinical features were compared with those of non-alcoholic fatty liver disease (NAFLD) patients without known SLC25A13 gene mutations. Seventeen (89%) CTLN2 patients had steatosis, and 4 (21%) had been diagnosed as having NAFLD before appearance of neuropsychological symptoms. One patient had steatohepatitis. Citrin deficiency-associated fatty livers showed a considerably lower prevalence of accompanying obesity and metabolic syndrome, higher prevalence of history of pancreatitis, and higher serum levels of pancreatic secretory trypsin inhibitor (PSTI) than fatty livers without the mutations. Receiver operating characteristic curve analyses revealed that a body mass index < 20kg/m(2) and serum PSTI>29ng/mL were associated with citrin deficiency. Patients presenting with non-alcoholic fatty liver unrelated to obesity and metabolic syndrome might have citrin deficiency, and serum PSTI may be a useful indicator for distinguishing this from conventional NAFLD.

  17. Nonalcoholic fatty liver disease, association with cardiovascular disease and treatment (II). The treatment of nonalcoholic fatty liver disease.

    PubMed

    Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández-Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan

    Disease nonalcoholic fatty liver disease (NAFLD) comprises a series of histologically similar to those induced by alcohol consumption in people with very little or no liver damage same. The importance of NAFLD is its high prevalence in our Western societies, from the point of view liver in its progressive evolution from steatosis to steatohepatitis, cirrhosis and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with accelerated atherosclerosis and cardiovascular events, the leading cause of morbidity and mortality. This updated January 2016 revision consists of two parts. In this second part, the treatment of NAFLD and its influence on cardiovascular disease and drugs used in the control of cardiovascular risk factors showing a beneficial effect on the liver disease will be reviewed. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Fenretinide ameliorates insulin resistance and fatty liver in obese mice.

    PubMed

    Koh, In-uk; Jun, Hye-Seung; Choi, Joo Sun; Lim, Joo Hyun; Kim, Won Ho; Yoon, Jong Bok; Song, Jihyun

    2012-01-01

    Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.

  19. [Acute fatty liver in pregnancy: revealing fetal fatty acid oxidation disorders].

    PubMed

    Lamireau, D; Feghali, H; Redonnet-Vernhet, I; Mesli, S; Carles, D; Brissaud, O

    2012-03-01

    Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome are serious maternal illnesses occurring in the third trimester of pregnancy with significant perinatal and maternal mortality. AFLP may result from mitochondrial defects in the beta-oxidation of fatty acids, in particular a deficiency of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the fetus. Clinical findings in AFLP vary and its diagnosis is complicated by a significant overlap in clinical and biochemical features with HELLP syndrome. We report the case of 2 siblings who died, the first one in the neonatal period of asphyxia with multivisceral presentation and the second one from sudden death at 7 months. Autopsy of the latter infant revealed hepatic steatosis associated with cardiomyopathy, which led to suspicion of a fatty acid oxidation deficiency. Mutation analysis demonstrated that both children were homozygous for the common mutation c.1528G>C and the parents were heterozygous for this same mutation. This case demonstrates the importance of screening mothers with acute fatty liver disease of pregnancy and their children at birth for a metabolic disease. This article proposes several metabolic tests for mother and child suspected of having beta-oxidation of a fatty acid disorder.

  20. Peroxisomes compensate hepatic lipid overflow in mice with fatty liver.

    PubMed

    Knebel, Birgit; Hartwig, Sonja; Haas, Jutta; Lehr, Stefan; Goeddeke, Simon; Susanto, Franciscus; Bohne, Lothar; Jacob, Sylvia; Koellmer, Cornelia; Nitzgen, Ulrike; Müller-Wieland, Dirk; Kotzka, Jorg

    2015-07-01

    Major causes of lipid accumulation in liver are increased import or synthesis or decreased catabolism of fatty acids. The latter is caused by dysfunction of cellular organelles controlling energy homeostasis, i.e., mitochondria. Peroxisomes also appear to be an important organelle in lipid metabolism of hepatocytes, but little is known about their role in the development of non-alcoholic fatty liver disease (NAFLD). To investigate the role of peroxisomes alongside mitochondria in excessive hepatic lipid accumulation, we used leptin-resistant db/db mice on C57BLKS background, a mouse model that develops hyperphagia-induced diabetes with obesity and NAFLD. Proteome and gene expression analyses along with lipid analyses in the liver revealed differential expression of genes related to lipid metabolism and β-oxidation, whereas genes for peroxisomal proteins were predominantly regulated. Our investigations show that in fatty liver disease in combination with obesity and diabetes, the hepatocyte-protecting organelle peroxisome is altered. Hence, peroxisomes might indicate a stage of pre-NAFLD, play a role in the early development of NAFLD and appear to be a potential target for treatment and prevention of NAFLD. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Fatty liver in H63D homozygotes with hyperferritinemia

    PubMed Central

    Sebastiani, Giada; Wallace, Daniel F; Davies, Susan E; Kulhalli, Vasu; Walker, Ann P; Dooley, James S

    2006-01-01

    To study the clinical correlates of the H63D mu-tation we have analysed the phenotype of H63D homo-zygotes identified through mutation analysis in a referral laboratory. A total of 366 blood samples referred for HFE analysis were screened for C282Y and H63D mutations. Four H63D homozygotes were identified. All had raised serum ferritin but normal transferrin saturation. They were negative for hepatitis B and C and only one patient consumed excess alcohol. In all 4 cases ultrasonography revealed fatty liver. In two patients a liver biopsy was done and showed mild siderosis with an unusual distribution and macrovesicular steatosis. These data confirm the association between fatty liver, hyperferritinemia and increased hepatic iron, but do not clarify whether siderosis was related to steatosis rather than homozygosity for the H63D mutation. Patients with fatty liver may complicate the interpretation of data in population studies of the expression of H63D homozygosity. PMID:16586555

  2. Sleep Apnea and Fatty Liver Are Coupled Via Energy Metabolism

    PubMed Central

    Arısoy, Ahmet; Sertoğullarından, Bunyamin; Ekin, Selami; Özgökçe, Mesut; Bulut, Mehmet Deniz; Huyut, Mehmet Tahir; Ölmez, Şehmus; Turan, Mahfuz

    2016-01-01

    Background Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by intermittent hypoxia. Non-alcoholic fatty liver disease is the most common cause of chronic liver disease worldwide. We aimed to evaluate the relationship between OSA and fatty liver. Material/Methods We enrolled 176 subjects to this study who underwent polysomnography (PSG) for suspected OSA. The control group included 42 simple snoring subjects. PSG, biochemical tests, and ultrasonographic examination were performed all subjects. Results The simple snoring and mild, moderate, and severe OSA groups included 18/42 (42.86%), 33/52 (63.5%), 27/34 (79.4%), and 28/48 (79.2%) subjects with hepatosteatosis, respectively. There were significant differences in hepatosteatosis and hepatosteatosis grade between the simple snoring and the moderate and severe OSA groups. Logistic regression analysis showed that BMI and average desaturation were independently and significantly related to hepatic steatosis. Conclusions Our study shows that BMI and the average desaturation contribute to non-alcoholic fatty liver in subjects with OSA. In this regard, sleep apnea may trigger metabolic mitochondrial energy associated processes thereby altering lipid metabolism and obesity as well. PMID:26993969

  3. Soft drinks consumption and nonalcoholic fatty liver disease.

    PubMed

    Nseir, William; Nassar, Fares; Assy, Nimer

    2010-06-07

    Nonalcoholic fatty liver disease (NAFLD) is a common clinical condition which is associated with metabolic syndrome in 70% of cases. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress combine to increase free fatty acid delivery to the liver, and increased hepatic triglyceride accumulation contributes to fatty liver. Regular soft drinks have high fructose corn syrup which contains basic sugar building blocks, fructose 55% and glucose 45%. Soft drinks are the leading source of added sugar worldwide, and have been linked to obesity, diabetes, and metabolic syndrome. The consumption of soft drinks can increase the prevalence of NAFLD independently of metabolic syndrome. During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. This review emphasizes some hard facts about soft drinks, reviews fructose metabolism, and explains how fructose contributes to the development of obesity, diabetes, metabolic syndrome, and NAFLD.

  4. Management of non-alcoholic fatty liver disease in 2015

    PubMed Central

    Malhotra, Neel; Beaton, Melanie D

    2015-01-01

    There is no single pharmacologic therapy that has been approved to treat nonalcoholic fatty liver disease in the general population. The backbone of therapy currently includes intensive lifestyle modification with established targets for diet and weight loss. The use of unsweetened, unfiltered coffee along with limiting high fructose corn syrup have emerged as beneficial dietary recommendations. The use of empiric oral hypoglycemic agents and vitamin E, however, has not been widely accepted. Developing bariatric surgical techniques are promising, but additional studies with long-term follow up are needed before it can be widely recommended. Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage disease have developed. The future treatment of those with nonalcoholic fatty liver disease will likely involve a personalized approach. The importance of the gut microbiome in mediating hepatocyte inflammation and intestinal permeability is emerging and may offer avenues for novel treatment. The study of anti-fibrotic agents such as pentoxifylline and FXR agonists hold promise and new pathways, such as hepatocyte cannabinoid receptor antagonists are being studied. With the incidence of obesity and the metabolic syndrome increasing throughout the developed world, the future will continue to focus on finding novel agents and new applications of existing therapies to help prevent and to mediate the progression of nonalcoholic fatty liver disease. PMID:26730275

  5. Sleep Apnea and Fatty Liver Are Coupled Via Energy Metabolism.

    PubMed

    Arısoy, Ahmet; Sertoğullarından, Bunyamin; Ekin, Selami; Özgökçe, Mesut; Bulut, Mehmet Deniz; Huyut, Mehmet Tahir; Ölmez, Şehmus; Turan, Mahfuz

    2016-03-19

    Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by intermittent hypoxia. Non-alcoholic fatty liver disease is the most common cause of chronic liver disease worldwide. We aimed to evaluate the relationship between OSA and fatty liver. We enrolled 176 subjects to this study who underwent polysomnography (PSG) for suspected OSA. The control group included 42 simple snoring subjects. PSG, biochemical tests, and ultrasonographic examination were performed all subjects. The simple snoring and mild, moderate, and severe OSA groups included 18/42 (42.86%), 33/52 (63.5%), 27/34 (79.4%), and 28/48 (79.2%) subjects with hepatosteatosis, respectively. There were significant differences in hepatosteatosis and hepatosteatosis grade between the simple snoring and the moderate and severe OSA groups. Logistic regression analysis showed that BMI and average desaturation were independently and significantly related to hepatic steatosis. Our study shows that BMI and the average desaturation contribute to non-alcoholic fatty liver in subjects with OSA. In this regard, sleep apnea may trigger metabolic mitochondrial energy associated processes thereby altering lipid metabolism and obesity as well.

  6. Soft drinks consumption and nonalcoholic fatty liver disease

    PubMed Central

    Nseir, William; Nassar, Fares; Assy, Nimer

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a common clinical condition which is associated with metabolic syndrome in 70% of cases. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress combine to increase free fatty acid delivery to the liver, and increased hepatic triglyceride accumulation contributes to fatty liver. Regular soft drinks have high fructose corn syrup which contains basic sugar building blocks, fructose 55% and glucose 45%. Soft drinks are the leading source of added sugar worldwide, and have been linked to obesity, diabetes, and metabolic syndrome. The consumption of soft drinks can increase the prevalence of NAFLD independently of metabolic syndrome. During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. This review emphasizes some hard facts about soft drinks, reviews fructose metabolism, and explains how fructose contributes to the development of obesity, diabetes, metabolic syndrome, and NAFLD. PMID:20518077

  7. Nuclear Transport Modulation Reduces Hypercholesterolemia, Atherosclerosis, and Fatty Liver

    PubMed Central

    Liu, Yan; Major, Amy S.; Zienkiewicz, Jozef; Gabriel, Curtis L.; Veach, Ruth Ann; Moore, Daniel J.; Collins, Robert D.; Hawiger, Jacek

    2013-01-01

    Background Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide. Methods and Results A cell‐penetrating nuclear transport modifier (NTM) reduced hyperlipidemia, atherosclerosis, and fatty liver in low‐density lipoprotein receptor‐deficient mice fed a Western diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P<0.005) and liver (41% and 34%, respectively; P<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (P<0.0005), and liver function improved compared with saline‐treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (P<0.005), and body weight gain was ameliorated (P<0.005) in NTM‐treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress‐responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element‐binding protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM‐modulated translocation of SREBPs to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia. Conclusions Two‐pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications. PMID:23563994

  8. [Non-alcoholic fatty liver disease--new view].

    PubMed

    Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

    2008-06-01

    Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others

  9. The Natural Course of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-05-20

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from "bland steatosis" to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death.

  10. Non-alcoholic fatty liver disease in 2015

    PubMed Central

    Ahmed, Monjur

    2015-01-01

    There is worldwide epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase. PMID:26085906

  11. Nonalcoholic fatty liver disease as a multi-systemic disease.

    PubMed

    Fotbolcu, Hakan; Zorlu, Elçin

    2016-04-28

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD includes a wide spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis and advanced hepatic fibrosis. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic diseases. Therefore, NAFLD is usually associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia. NAFLD is highly prevalent in the general population and is associated with increased cardiovascular morbidity and mortality. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. This review focuses on pathogenesis of NAFLD and its relation with other systemic diseases.

  12. Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes.

    PubMed

    Ahmed, Aijaz; Wong, Robert J; Harrison, Stephen A

    2015-11-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal serum aminotransferase levels in both developed and developing countries. Patients with nonalcoholic steatohepatitis (NASH), a subset of NAFLD, are at risk for progressive liver disease and in need of effective treatment options. A practical approach may be pursued by identifying patients with NAFLD with the highest likelihood for histologic evidence of NASH. Despite decades of clinical trials, no single treatment can be recommended to all patients with NASH. Importantly, there is no evidence that pioglitazone or vitamin E improves fibrosis. Bariatric surgeries may improve hepatic histology in morbidly obese patients with NASH, although randomized clinical trials are lacking. Currently, NASH is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. The primary and secondary prevention of NAFLD may require aggressive strategies for managing obesity, diabetes, and metabolic syndrome.

  13. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler.

    PubMed

    Perry, Rachel J; Kim, Taehan; Zhang, Xian-Man; Lee, Hui-Young; Pesta, Dominik; Popov, Violeta B; Zhang, Dongyan; Rahimi, Yasmeen; Jurczak, Michael J; Cline, Gary W; Spiegel, David A; Shulman, Gerald I

    2013-11-05

    Nonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D.

  14. Functional pitch of a liver: fatty liver disease diagnosis with photoacoustic spectrum analysis

    NASA Astrophysics Data System (ADS)

    Xu, Guan; Meng, Zhuoxian; Lin, Jiandie; Carson, Paul; Wang, Xueding

    2014-03-01

    To provide more information for classification and assessment of biological tissues, photoacoustic spectrum analysis (PASA) moves beyond the quantification of the intensities of the photoacoustic (PA) signals by the use of the frequency-domain power distribution, namely power spectrum, of broadband PA signals. The method of PASA quantifies the linear-fit to the power spectrum of the PA signals from a biological tissue with 3 parameters, including intercept, midband-fit and slope. Intercept and midband-fit reflect the total optical absorption of the tissues whereas slope reflects the heterogeneity of the tissue structure. Taking advantage of the optical absorption contrasts contributed by lipid and blood at 1200 and 532 nm, respectively and the heterogeneous tissue microstructure in fatty liver due to the lipid infiltration, we investigate the capability of PASA in identifying histological changes of fatty livers in mouse model. 6 and 9 pairs of normal and fatty liver tissues from rat models were examined by ex vivo experiment with a conventional rotational PA measurement system. One pair of rat models with normal and fatty livers was examined non-invasively and in situ with our recently developed ultrasound and PA parallel imaging system. The results support our hypotheses that the spectrum analysis of PA signals can provide quantitative measures of the differences between the normal and fatty liver tissues and that part of the PA power spectrum can suffice for characterization of microstructures in biological tissues. Experimental results also indicate that the vibrational absorption peak of lipid at 1200nm could facilitate fatty liver diagnosis.

  15. Non-alcoholic fatty liver disease: An expanded review

    PubMed Central

    Benedict, Mark; Zhang, Xuchen

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the “magic bullet” in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients. PMID:28652891

  16. Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.

    PubMed

    Noureddin, Mazen; Rinella, Mary E

    2015-05-01

    Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Nonalcoholic Fatty Liver Disease in Children: Hepatic and Extrahepatic Complications.

    PubMed

    Selvakumar, Praveen Kumar Conjeevaram; Kabbany, Mohammad Nasser; Nobili, Valerio; Alkhouri, Naim

    2017-06-01

    Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the most common form of chronic liver disease in children and adolescents. The histologic spectrum of NAFLD is broad ranging, from the relatively benign form of simple steatosis to the aggressive form of nonalcoholic steatohepatitis, eventually leading to fibrosis and cirrhosis. NAFLD has also been recognized as an independent risk factor for extrahepatic complications, such as cardiovascular disease, type 2 diabetes mellitus, sleep disorders, and osteoporosis. In this review, we discuss both the hepatic and extrahepatic complications of NAFLD in children. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Effect of hens fed dietary flaxseed with and without a fatty liver supplement on hepatic, plasma and production characteristics relevant to fatty liver haemorrhagic syndrome in laying hens.

    PubMed

    Schumann, B E; Squires, E J; Leeson, S; Hunter, B

    2003-05-01

    1. Two long-term experiments were conducted with Single Comb White Leghorn (SCWL) hens (line UCD-003) predisposed to fatty liver haemorrhagic syndrome (FLHS). The first investigated the effect of adding a fatty liver supplement to the diet of laying hens prior to the onset of lay, and continuing either until peak production or throughout 39 weeks into lay. The second experiment, lasting 9 months into lay, investigated the effect of adding a fatty liver supplement, with or without 100 g/kg dietary ground flaxseed, to the diet. Body weight, feed intake, plasma triglycerides (in experiment 2) and egg production were measured throughout the experiment. Liver weight, liver fat content, liver malondialdehyde (MDA) content and liver haemorrhage score and fatty acid content of liver fat (in experiment 2) were measured at the end of each experiment. 2. In experiment 1, hens given diets containing the fatty liver supplement had higher egg production and eggshell strength, but there was no difference in liver parameters including MDA content or haemorrhage score compared with controls. 3. At the end of experiment 2, hens on 100 g/kg flaxseed diets had lower body weight, liver weight, liver dry matter and fat content, and plasma triglyceride concentrations than hens given the control diets. 4. Liver haemorrhage score was positively correlated with liver weight, but not with liver fat content, plasma triglyceride concentration or liver MDA content. This suggests that reducing the liver lipid content or feeding fatty liver supplements may not be as effective in controlling FLHS as controlling the size of the liver.

  19. Plasma phospholipids and fatty acid composition differ between liver biopsy-proven nonalcoholic fatty liver disease and healthy subjects

    PubMed Central

    Ma, D W L; Arendt, B M; Hillyer, L M; Fung, S K; McGilvray, I; Guindi, M; Allard, J P

    2016-01-01

    Background: There is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with perturbations in liver lipid metabolism. Liver phospholipid and fatty acid composition have been shown to be altered in NAFLD. However, detailed profiles of circulating lipids in the pathogenesis of NAFLD are lacking. Objective: Therefore, the objective of the present study was to examine circulating lipids and potential mechanisms related to hepatic gene expression between liver biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH) and healthy subjects. Subjects: Plasma phospholipid and fatty acid composition were determined in 31 healthy living liver donors as healthy controls (HC), 26 patients with simple hepatic steatosis (SS) and 20 with progressive NASH. Hepatic gene expression was analyzed by Illumina microarray in a subset of 22 HC, 16 SS and 14 NASH. Results: Concentrations of phosphatidylethanolamine (PE) increased relative to disease progression, HCFatty acid composition of phospholipids was also remodeled. In particular, docosahexaenoic and arachidonic acid were higher (P<0.05) in SS and NASH relative to HC in PS. Differentially expressed hepatic genes included ETNK1 and PLSCR1 that are involved in PE synthesis and PS transport, respectively. Conclusions: The present study demonstrates that there is a disruption in phospholipid metabolism that is present in SS, but more pronounced in NASH. Intervention studies targeted at lipid metabolism could benefit SS and NASH. PMID:27428872

  20. Nonalcoholic fatty liver disease: molecular pathways and therapeutic strategies

    PubMed Central

    2013-01-01

    Along with rising numbers of patients with metabolic syndrome, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased in proportion with the obesity epidemic. While there are no established treatments for NAFLD, current research is targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD. The basic research that has identified potential molecular targets for pharmacotherapy will be outlined. PMID:24209497

  1. Dietary approach in the treatment of nonalcoholic fatty liver disease

    PubMed Central

    Ferolla, Silvia Marinho; Silva, Luciana Costa; Ferrari, Maria de Lourdes Abreu; da Cunha, Aloísio Sales; Martins, Flaviano dos Santos; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome (MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis (NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition. PMID:26523205

  2. Gender-based differences in the relationship between fatty liver disease and atherosclerosis

    PubMed Central

    Kim, Hyun-Jin; Lim, Chae-Wan; Lee, Jae hyuk; Park, Hyung-Bok; Suh, Yongsung; Cho, Yoon-Hyeong; Choi, Tae-Young; Hwang, Eui-Seok; Cho, Deok-Kyu; Kim, Hyun-Jin

    2016-01-01

    Summary Background Carotid intima–media thickness (CIMT) is a surrogate of subclinical atherosclerosis. Fatty liver disease is also linked to increased risk of cardiovascular events. The aim of this study was to evaluate the association between fatty liver disease and CIMT according to gender. Methods Patients who had undergone carotid and abdominal ultrasound between June 2011 and December 2013 were retrospectively evaluated. The differences between the CIMT values measured in the common carotid artery and the prevalence of carotid plaque in patients with fatty liver disease and those with normal livers were investigated. Results Out of a total of 1 121 patients, the men had more fatty liver disease than the women. The mean CIMT of the men was significantly higher than that of the women, and the men had more plaque than the women. The women with fatty liver disease had a significantly higher mean CIMT value and more plaque than the women with normal livers. The differences between the men with fatty liver and those with normal livers in mean CIMT values and in the prevalence of plaque were not significant. In the women, multivariate analysis showed that fatty liver disease was independently associated with subclinical atherosclerosis [adjusted hazards ratio (HR) 1.65, 95% confidence interval (CI) 1.007–2.697, p = 0.047]. Conclusions The men had more fatty liver disease, carotid plaque and higher CIMT values than the women. Fatty liver disease was a useful predictor of atherosclerosis, especially for the female study patients. PMID:26972662

  3. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

    PubMed Central

    Satapati, Santhosh; Kucejova, Blanka; Duarte, Joao A.G.; Fletcher, Justin A.; Reynolds, Lacy; Sunny, Nishanth E.; He, Tianteng; Nair, L. Arya; Livingston, Kenneth; Fu, Xiaorong; Merritt, Matthew E.; Sherry, A. Dean; Malloy, Craig R.; Shelton, John M.; Lambert, Jennifer; Parks, Elizabeth J.; Corbin, Ian; Magnuson, Mark A.; Browning, Jeffrey D.; Burgess, Shawn C.

    2015-01-01

    Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid–induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways. PMID:26571396

  4. Nonalcoholic fatty liver may increase the risk of operation in patients with fatty liver and the frequency of cancer in their first-degree relatives.

    PubMed

    Basaranoglu, Metin; Canbakan, Billur; Yildiz, Kemal; Ceylan, Bahadir; Baysal, Birol; Uysal, Omer; Senturk, Hakan

    2016-10-01

    Fatty liver is a common disease in developed countries. We investigated the frequency of operation in patients with fatty liver and the frequency of cancer in their first-degree relatives. In this study, we evaluated 105 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), 121 patients with hepatitis C (61 patients with fatty liver and 60 patients without fatty liver), 50 patients with inflammatory bowel disease (IBD), and 109 patients with dyspepsia as a control group. There was no difference for sex, mean age, and marital status among the groups, except that patients with IBD were younger than others (p < 0.001). The frequency of cancer in family was as follows: 18 % in IBD, 9 % in dyspepsia, 28 % in hepatitis C with hepatic steatosis, 21.5 % in hepatitis C without steatosis, and 27 % in NAFLD (p = 0.006). Then, we divided the study group into two groups-group 1: IBD + dyspepsia + hepatitis C without hepatic steatosis, and group 2: hepatitis C with hepatic steatosis + NAFLD-and performed the same analysis. We found that the frequency of cancer in family was 16 % in group 1 (the patients without fatty liver) vs. 24.4 % in group 2 (those with fatty liver; p = 0.037). We also investigated the rate of operation in patients. The results were as follows: 33 % in group 1 vs. 43 % in group 2 (p = 0.043). Independently of the underlying chronic diseases, occurrence of fat in the liver increased the frequency of operation in patients with fatty liver and the rate of cancer in their first-degree relatives. Understanding the underlying causes of fatty liver forms might decrease the cancer frequency in the population and number of operation in patients with fatty liver.

  5. Liver histology according to the presence of metabolic syndrome in nonalcoholic fatty liver disease cases

    PubMed Central

    Uslusoy, Hüseyin Saadettin; Nak, Selim Giray; Gülten, Macit; Bıyıklı, Zeynep

    2009-01-01

    AIM: To investigate the histologic features of the liver in nonalcoholic fatty liver disease (NAFLD) cases according to the presence of metabolic syndrome or its individual components. METHODS: We enrolled 81 patients (40 male, 41 female) who were diagnosed with fatty liver by ultrasonographic scan and fulfilled the inclusion criteria. First anamnesis, anthropometric, clinical, laboratory and imaging features of all participants were recorded and then liver biopsy was performed after gaining consent from patients. Diagnosis of metabolic syndrome was dependent on patients having 3 or more out of 5 risk criteria defined by the WHO. Biopsy specimens were assessed according to Brunt et al’s classification. RESULTS: Sixty-nine of the 81 patients had nonalcoholic steatohepatitis (NASH), 11 had simple fatty liver and 1 had cirrhosis according to histologic evaluation. Comparisons were made between two groups of NASH patients, those with and without metabolic syndrome. We did not detect statistically significant differences in liver histology between NASH patients with and without metabolic syndrome. CONCLUSION: NASH can progress without metabolic risk factors or the presence of metabolic syndrome. PMID:19266602

  6. Liver histology according to the presence of metabolic syndrome in nonalcoholic fatty liver disease cases.

    PubMed

    Uslusoy, Hüseyin Saadettin; Nak, Selim-Giray; Gülten, Macit; Biyikli, Zeynep

    2009-03-07

    To investigate the histologic features of the liver in nonalcoholic fatty liver disease (NAFLD) cases according to the presence of metabolic syndrome or its individual components. We enrolled 81 patients (40 male, 41 female) who were diagnosed with fatty liver by ultrasonographic scan and fulfilled the inclusion criteria. First anamnesis, anthropometric, clinical, laboratory and imaging features of all participants were recorded and then liver biopsy was performed after gaining consent from patients. Diagnosis of metabolic syndrome was dependent on patients having 3 or more out of 5 risk criteria defined by the WHO. Biopsy specimens were assessed according to Brunt et al's classification. Sixty-nine of the 81 patients had nonalcoholic steatohepatitis (NASH), 11 had simple fatty liver and 1 had cirrhosis according to histologic evaluation. Comparisons were made between two groups of NASH patients, those with and without metabolic syndrome. We did not detect statistically significant differences in liver histology between NASH patients with and without metabolic syndrome. NASH can progress without metabolic risk factors or the presence of metabolic syndrome.

  7. Obstructive sleep apnea and non-alcoholic Fatty liver disease: is the liver another target?

    PubMed

    Mirrakhimov, Aibek E; Polotsky, Vsevolod Y

    2012-01-01

    Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

  8. Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease

    PubMed Central

    Hussain, Mazhar; Majeed Babar, Muhammad Zafar; Hussain, Muhammad Shahbaz; Akhtar, Lubna

    2016-01-01

    Objective: To determine the effect of Vildagliptin in non-alcoholic, fatty liver disease patients with dyslipidemia. Methods: A randomized placebo controlled trial was conducted at outpatient clinic of Medical Unit-I of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which fifty eight patients of NAFLD with dyslipidemia were divided in to two, case and control groups. The case group was given tablet Vildagliptin 50mg twice a day for twelve weeks and control group was given placebo in same way. Body weight, body mass index (BMI), lipid profile, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. Results: After 12 weeks treatment of vildagliptin there was significant improvement in following parameters. Body weight and BMI decreased significantly from 88 ± 11 to79 ± 12 kg (p0.036) and 30±4to 27±5 kg/m2 (p 0.005) respectively. Notable reduction in the value of TC, TG and LDL-C (TC:252±24 to 220±20mg/dl (p 0.031); TG: 190±24 to115±22 mg/dl (p 0.005); LDL-C 160±15 to 145±13mg/dl (p 0.004). HDL-C level increased significantly from 29±5to45±4 mg/dl (p 0.001). There was remarkable reduction in aminotransferases level (ALT: 78± 17 to 48±14IU/L (p 0.036). AST: 63.3±13 to41±11IU/L (p 0.002). There was overall 65.5% improvement in fatty liver grading on ultrasound with vildagliptin while non significant effects were seen in placebo group in all of the above parameters. Conclusion: Vildagliptin exhibited beneficial effects in non-alcoholic fatty liver disease, Non-diabetic patients with dyslipidemia. PMID:28083033

  9. Rice endosperm protein slows progression of fatty liver and diabetic nephropathy in Zucker diabetic fatty rats.

    PubMed

    Kubota, Masatoshi; Watanabe, Reiko; Yamaguchi, Miki; Hosojima, Michihiro; Saito, Akihiko; Fujii, Mikio; Fujimura, Shinobu; Kadowaki, Motoni

    2016-10-01

    We previously reported that rice endosperm protein (REP) has renoprotective effects in Goto-Kakizaki rats, a non-obese diabetic model. However, whether these effects occur in obese diabetes remains unclear. This study aimed to clarify the effects of REP on obese diabetes, especially on fatty liver and diabetic nephropathy, using the obese diabetic model Zucker diabetic fatty (ZDF) rats. In total, 7-week-old male ZDF rats were fed diets containing 20 % REP or casein (C) for 8 weeks. Changes in fasting blood glucose levels and urinary markers were monitored during the experimental period. Hepatic lipids and metabolites were measured and renal glomeruli were observed morphologically. HbA1c levels were significantly lower in rats fed REP, compared with C (P<0·05). Compared with C in the liver, REP prevented lipid accumulation (total lipid, TAG and total cholesterol, P<0·01). Liver metabolome analysis indicated that levels of metabolites associated with glycolysis, the pentose phosphate pathway and carnitine metabolism were significantly greater in the REP group than in the C group (P<0·05), suggesting activation of both glucose catabolism and fatty acid oxidation. The metabolite increases promoted by REP may contribute to suppression of liver lipid accumulation. Urinary excretion of albumin and N-acetyl-β-d-glucosaminidase was significantly reduced in rats fed REP for 8 weeks (P<0·01). In addition, there was a distinct suppression of mesangial matrix expansion and glomerular hypertrophy in response to REP (P<0·01). Thus, REP had preventive effects on obese diabetes, fatty liver and diabetic nephropathy.

  10. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

    PubMed Central

    Cotter, David G.; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M.; d’Avignon, D. André; Graham, Mark J.; Dietzen, Dennis J.; Brunt, Elizabeth M.; Patti, Gary J.; Crawford, Peter A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease. PMID:25347470

  11. Glucocorticoids and non-alcoholic fatty liver disease.

    PubMed

    Woods, Conor P; Hazlehurst, Jonathon M; Tomlinson, Jeremy W

    2015-11-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the global obesity and metabolic disease epidemic and is rapidly becoming the leading cause of liver cirrhosis and indication for liver transplantation worldwide. The hallmark pathological finding in NAFLD is excess lipid accumulation within hepatocytes, but it is a spectrum of disease ranging from benign hepatic steatosis to steatohepatitis through to fibrosis, cirrhosis and risk of hepatocellular carcinoma. The exact pathophysiology remains unclear with a multi-hit hypothesis generally accepted as being required for inflammation and fibrosis to develop after initial steatosis. Glucocorticoids have been implicated in the pathogenesis of NAFLD across all stages. They have a diverse array of metabolic functions that have the potential to drive NAFLD acting on both liver and adipose tissue. In the fasting state, they are able to mobilize lipid, increasing fatty acid delivery and in the fed state can promote lipid accumulation. Their action is controlled at multiple levels and in this review will outline the evidence base for the role of GCs in the pathogenesis of NAFLD from cell systems, rodent models and clinical studies and describe interventional strategies that have been employed to modulate glucocorticoid action as a potential therapeutic strategy.

  12. Translational approaches: from fatty liver to non-alcoholic steatohepatitis.

    PubMed

    Rosso, Natalia; Chavez-Tapia, Norberto C; Tiribelli, Claudio; Bellentani, Stefano

    2014-07-21

    Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis.

  13. Non-alcoholic fatty liver disease: The diagnosis and management

    PubMed Central

    Abd El-Kader, Shehab M; El-Den Ashmawy, Eman M Salah

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease that occurs across all age groups and is recognized to occur in 14%-30% of the general population, representing a serious and growing clinical problem due to the growing prevalence of obesity and overweight. Histologically, it resembles alcoholic liver injury but occurs in patients who deny significant alcohol consumption. NAFLD encompasses a spectrum of conditions, ranging from benign hepatocellular steatosis to inflammatory nonalcoholic steatohepatitis, fibrosis, and cirrhosis. The majority of hepatocellular lipids are stored as triglycerides, but other lipid metabolites, such as free fatty acids, cholesterol, and phospholipids, may also be present and play a role in disease progression. NAFLD is associated with obesity and insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies; however, staging the disease requires a liver biopsy. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and medications appear promising. The aim of this review is to highlight the current information regarding epidemiology, diagnosis, and management of NAFLD as well as new information about pathogenesis, diagnosis and management of this disease. PMID:25937862

  14. Translational approaches: From fatty liver to non-alcoholic steatohepatitis

    PubMed Central

    Rosso, Natalia; Chavez-Tapia, Norberto C; Tiribelli, Claudio; Bellentani, Stefano

    2014-01-01

    Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis. PMID:25083077

  15. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

    PubMed Central

    Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L’Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

    2015-01-01

    Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development. PMID:25621497

  16. Mitochondrial genome architecture in non-alcoholic fatty liver disease.

    PubMed

    Sookoian, Silvia; Flichman, Diego; Scian, Romina; Rohr, Cristian; Dopazo, Hernán; Gianotti, Tomas Fernández; Martino, Julio San; Castaño, Gustavo O; Pirola, Carlos J

    2016-12-01

    Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the 'missing heritability

  17. Non-alcoholic Fatty Liver Disease: East Versus West

    PubMed Central

    Agrawal, Swastik; Duseja, Ajay K

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West. PMID:25755421

  18. [Acute fatty liver of pregnancy--case report].

    PubMed

    Gruber, Katarzyna; Skoczyńska, Anna; Belowska-Bień, Kinga; Poreba, Rafał; Podgórski, Maciej; Szuba, Andrzej; Andrzejak, Ryszard

    2008-03-01

    Severe liver function disorders in late pregnancy are relatively rare but extremely dangerous, as they may quickly develop into a fulminant disease and become a life-threatening disorder for the mother and the fetus. In the following study we have reported a case of a previously healthy woman with severe liver disorder in the third trimester of pregnancy. On the basis of anamnesis, differential diagnosis, typical course and complications of the disease, and proper response to intensive supportive medical therapy, we diagnosed an acute fatty liver of pregnancy. The diagnosis was based on clinical presentation and laboratory abnormalities. Owing to timely intervention and adequate supportive care management, this severe complication of a pregnancy has had a successful outcome for both the mother and the child.

  19. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Takahashi, Yoshihisa; Soejima, Yurie; Fukusato, Toshio

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages. PMID:22654421

  20. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Takahashi, Yoshihisa; Soejima, Yurie; Fukusato, Toshio

    2012-05-21

    Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

  1. Circulating microRNAs in nonalcoholic fatty liver disease.

    PubMed

    DiStefano, Johanna K; Gerhard, Glenn S

    2016-01-01

    Liver biopsy is currently recognized as the most accurate method for diagnosing and staging nonalcoholic fatty liver disease (NAFLD). However, this procedure is typically performed when disease has progressed to clinically significant stages, thereby limiting early diagnosis of patients who are at high risk for development of liver- and cardiovascular-related morbidity and mortality. Recently, microRNAs (miRNAs), short, noncoding RNAs that regulate gene expression, have been associated with histological features of NAFLD and are readily detected in the circulation. As such, miRNAs are emerging as potentially useful noninvasive markers with which to follow the progression of NAFLD. In this article, we present the evidence linking circulating miRNAs with NAFLD and discuss the potential value of circulating miRNA profiles in the development of improved methods for NAFLD diagnosis and clinical monitoring of disease progression.

  2. Circulating microRNAs in nonalcoholic fatty liver disease

    PubMed Central

    Gerhard, Glenn S.

    2016-01-01

    Summary Liver biopsy is currently recognized as the most accurate method for diagnosing and staging nonalcoholic fatty liver disease (NAFLD). However, this procedure is typically performed when disease has progressed to clinically significant stages, thereby limiting early diagnosis of patients who are at high risk for development of liver- and cardiovascular-related morbidity and mortality. Recently, microRNAs (miRNAs), short, noncoding RNAs that regulate gene expression, have been associated with histological features of NAFLD and are readily detected in the circulation. As such, miRNAs are emerging as potentially useful noninvasive markers with which to follow the progression of NAFLD. In this article, we present the evidence linking circulating miRNAs with NAFLD and discuss the potential value of circulating miRNA profiles in the development of improved methods for NAFLD diagnosis and clinical monitoring of disease progression. PMID:26606259

  3. Nonalcoholic fatty liver disease and polycystic ovary syndrome

    PubMed Central

    Vassilatou, Evangeline

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world comprising a spectrum of liver damage from fatty liver infiltration to end-stage liver disease, in patients without significant alcohol consumption. Increased prevalence of NAFLD has been reported in patients with polycystic ovary syndrome (PCOS), one of the most common endocrinopathies in premenopausal women, which has been redefined as a reproductive and metabolic disorder after the recognition of the important role of insulin resistance in the pathophysiology of the syndrome. Obesity, in particular central adiposity and insulin resistance are considered as the main factors related to NAFLD in PCOS. Moreover, existing data support that androgen excess, which is the main feature of PCOS and is interrelated to insulin resistance, may be an additional contributing factor to the development of NAFLD. Although the natural history of NAFLD remains unclear and hepatic steatosis seems to be a relatively benign condition in most patients, limited data imply that advanced stage of liver disease is possibly more frequent in obese PCOS patients with NAFLD. PCOS patients, particularly obese patients with features of the metabolic syndrome, should be submitted to screening for NAFLD comprising assessment of serum aminotransferase levels and of hepatic steatosis by abdominal ultrasound. Lifestyle modifications including diet, weight loss and exercise are the most appropriate initial therapeutic interventions for PCOS patients with NAFLD. When pharmacologic therapy is considered, metformin may be used, although currently there is no medical therapy of proven benefit for NAFLD. Long-term follow up studies are needed to clarify clinical implications and guide appropriate diagnostic evaluation, follow-up protocol and optimal treatment for PCOS patients with NAFLD. PMID:25024594

  4. From fatty liver to fibrosis: a tale of "second hit".

    PubMed

    Basaranoglu, Metin; Basaranoglu, Gökcen; Sentürk, Hakan

    2013-02-28

    Although much is known about how fat accumulates in the liver, much remains unknown about how this causes sustained hepatocellular injury. The consequences of injury are recognized as nonalcoholic steatohepatitis (NASH) and progressive fibrosis. The accumulation of fat within the hepatocytes sensitizes the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired. An additional stressor is sometimes referred to as a "second hit" in a paradigm that identifies the accumulation of fat as the "first hit". Possible candidates for the second hit include increased oxidative stress, lipid peroxidation and release of toxic products such as malondialdehyde and 4-hydroxynonenal, decreased antioxidants, adipocytokines, transforming growth factor (TGF)-β, Fas ligand, mitochondrial dysfunction, fatty acid oxidation by CYPs (CYP 2E1, 4A10 and 4A14), and peroxisomes, excess iron, small intestinal bacterial overgrowth, and the generation of gut-derived toxins such as lipopolysaccharide and ethanol. Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury. Previous studies have specifically observed increased plasma and tissue levels of oxidative stress markers and lipid peroxidation products, with reduced hepatic and plasma levels of antioxidants. There is also some indirect evidence of the benefit of antioxidants such as vitamin E, S-adenosylmethionine, betaine, phlebotomy to remove iron, and N-acetylcysteine in NASH. However, a causal relationship or a pathogenic link between NASH and oxidative stress has not been established so far. A number of sources of increased reactive oxygen species production have been established in NASH that include proinflammatory cytokines such as tumor necrosis factor (TNF)-α, iron overload, overburdened and dysfunctional mitochondria, CYPs, and peroxisomes. Briefly, the pathogenesis of NASH is multifactorial and excess intracellular fatty acids, oxidant stress, ATP depletion

  5. Nonalcoholic fatty liver disease: Synopsis of current developments.

    PubMed

    Onyekwere, C A; Ogbera, A O; Samaila, A A; Balogun, B O; Abdulkareem, F B

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) which is defined as the accumulation of fat>5% of liver weight is increasingly becoming an important cause of chronic liver disease. This article tries to chronicle advances that have occurred in the understanding of the pathogenesis, pathology as well as the management of this disease. We have done a Medline search on published work on the subject and reviewed major conference proceedings in the preceding years. The Pathogenesis involves a multi-hit process in which increased accumulation of triglycerides in face of insulin resistance results in increased susceptibility to inflammatory damage mediated by increased expression of inflammatory cytokines and adipokines, oxidative stress and mitochondrial dysfunction, endoplasmic reticulum stress and gut derived endotoxemia. An interplay of multiple metabolic genetic expression and environmental factors however determine which patient with NAFLD will progress from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver cirrhosis. The minimum criteria for diagnosis of NASH are steatosis, ballooning and lobular inflammation; fibrosis is not required. The NASH Clinical Research Network (CRN), histological scoring system is used to grade and stage the disease for standardization. The management of NAFLD consists of treating liver disease as well as associated metabolic co-morbidities such as obesity, hyperlipidaemia, insulin resistance and type 2 diabetes mellitus (T2DM). Patient education is important as their insight and commitment is pivotal, and lifestyle modification is the first line of treatment. Improvement in liver histology in non-diabetic NASH patients has been reported with use of Vitamin E. Other liver-related therapies under investigations include pentoxyfiylins, Caspar inhibitors, Resveratrol as well as probiotics. The prognosis (both overall and liver-related mortality) for simple steatosis is not different from that of the general population however.

  6. Imaging patterns and focal lesions in fatty liver: a pictorial review.

    PubMed

    Venkatesh, Sudhakar K; Hennedige, Tiffany; Johnson, Geoffrey B; Hough, David M; Fletcher, Joel G

    2016-12-20

    Non-alcoholic fatty liver disease is the most common cause of chronic liver disease and affects nearly one-third of US population. With the increasing trend of obesity in the population, associated fatty change in the liver will be a common feature observed in imaging studies. Fatty liver causes changes in liver parenchyma appearance on imaging modalities including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) and may affect the imaging characteristics of focal liver lesions (FLLs). The imaging characteristics of FLLs were classically described in a non-fatty liver. In addition, focal fatty change and focal fat sparing may also simulate FLLs. Knowledge of characteristic patterns of fatty change in the liver (diffuse, geographical, focal, subcapsular, and perivascular) and their impact on the detection and characterization of FLL is therefore important. In general, fatty change may improve detection of FLLs on MRI using fat suppression sequences, but may reduce sensitivity on a single-phase (portal venous) CT and conventional ultrasound. In patients with fatty liver, MRI is generally superior to ultrasound and CT for detection and characterization of FLL. In this pictorial essay, we describe the imaging patterns of fatty change in the liver and its effect on detection and characterization of FLLs on ultrasound, CT, MRI, and PET.

  7. Exercise and the liver: implications for therapy in fatty liver disorders.

    PubMed

    Johnson, Nathan A; Keating, Shelley E; George, Jacob

    2012-02-01

    The increasing recognition that fatty liver plays a direct role in the pathogenesis of cardiovascular and metabolic disease has resulted in significant research enquiry into the efficacy of lifestyle therapy in modulating liver fat. Recently, this has extended to the specific investigation of a possible independent benefit of physical activity/exercise in nonalcoholic fatty liver disease (NAFLD). In this article we review the effect of acute and regular exercise (training) on metabolism, including liver glucose and lipid metabolism, and the available human trials that have compared the benefit of regular exercise versus a nonexercise control on liver fat. The limited human research suggests that exercise can reduce liver fat and that this benefit may be mediated, in part, by a reduction in hepatic lipogenesis. The relative importance of extrahepatic adaptations and acute versus regular exercise in explaining this benefit are discussed. From a clinical perspective, the revelation of a benefit of exercise per se offers a novel approach for liver fat reduction, and highlights the importance of incorporating fitness assessment and prescription in the management of patients with fatty liver disorders. Implementation of exercise therapy in a clinical setting is arguably the biggest challenge because evidence shows that mere provision of information about the benefits of exercise and/or exercise prescription to the patient does not translate to positive outcomes. Rather, the focus should be on implementing strategies to promote behavior change including regular contact and assessment with a health care professional, self-monitoring, and personalization of goals that focus on changing physical activity behavior.

  8. Fractionation of gamma-glutamyltransferase in patients with nonalcoholic fatty liver disease and alcoholic liver disease

    PubMed Central

    Sueyoshi, Shigeo; Sawai, Setsu; Satoh, Mamoru; Seimiya, Masanori; Sogawa, Kazuyuki; Fukumura, Atsushi; Tsutsumi, Mikihiro; Nomura, Fumio

    2016-01-01

    AIM To assess how serum gamma-glutamyltransferase (GGT) fractions vary in patients with alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). METHODS Serum samples were obtained from 14 patients with biopsy-proven alcoholic liver diseases and 9 patients with biopsy proven non-alcoholic fatty liver disease. In addition to these biopsy-proven cases, 16 obese (body mass index > 25) patients without any history of alcohol consumption but with a fatty liver on ultrasound examination and with elevated GGT were included for an additional analysis. Serum GGT fractionation was conducted by high-performance gel filtration liquid chromatography and was separated into the four fractions, big-GGT, medium-GGT, small-GGT (s-GGT), and free-GGT (f-GGT). RESULTS The results were expressed as a ratio of each fraction including the total GGT (t-GGT). The s-GGT/t-GGT ratios were lowest for the control group and highest for the ALD group. The differences between the control and NAFLD groups and also between the NAFLD and ALD groups were statistically significant. In contrast, the f-GGT/t-GGT ratios were highest in the control group and lowest in the ALD group, with the differences being statistically significant. As a result, the s-GGT/f-GGT ratios were markedly increased in the NAFLD group as compared with the control group. The increase of the s-GGT/t-GGT ratios, the decrease of the f-GGT/t-GGT ratios, and the increase of s-GGT/F-GGT ratios as compared with the control group subjects were also found in obese patients with clinically diagnosed fatty change of the liver. CONCLUSION Serum GGT fractionation by high-performance gel filtration liquid chromatography is potentially useful for the differential diagnosis of ALD and NAFLD. PMID:28083083

  9. Nonalcoholic Fatty Liver Disease Management: Dietary and Lifestyle Modifications.

    PubMed

    Nguyen, Vi; George, Jacob

    2015-08-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of abnormalities that can range from bland liver fat (steatosis), to hepatic inflammation and liver injury (steatohepatitis). It is estimated that NAFLD will become the principal cause of liver disease in Western nations and the leading indication for liver transplantation. Advancements in disease recognition and management are therefore paramount. Although the development of new, reliable drug therapies is vital, lifestyle interventions remain the most effective treatment modality. In addition to weight loss as a primary measure of treatment success, there is growing recognition that other endpoints, including the prevention or delay of diabetes onset, reduced cardiovascular events, prevention of cancer, and improved overall mortality, are equally important outcomes that can be independently modified by lifestyle change. Moreover, NAFLD is inextricably part of a complex, systemic disease process that is linked with deeply entrenched maladaptive lifestyle behaviors. Thus, a holistic, multidisciplinary, and individualized approach to disease management will be the key to achieving any realistic population-level change.

  10. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

    PubMed Central

    Le, Thuy-Anh; Loomba, Rohit

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations. PMID:25755424

  11. Pediatric nonalcoholic fatty liver disease: A clinical and laboratory challenge

    PubMed Central

    Pacifico, Lucia; Poggiogalle, Eleonora; Cantisani, Vito; Menichini, Guendalina; Ricci, Paolo; Ferraro, Flavia; Chiesa, Claudio

    2010-01-01

    The true prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is unknown. Challenges in determining the population prevalence of NAFLD include the type of test (and the reference intervals used to define normal and abnormal), the type of population (general population, hospital series), the demographic characteristics of the population sampled, and the nature of the study design. The natural history of pediatric NAFLD remains uncertain. The issue of when to perform a liver biopsy in children with suspected NAFLD remains controversial. Children with NAFLD but normal alanine aminotransferase are rarely investigated. However, evidence of alterations in glucose metabolism parameters should prompt a better understanding of the natural history of pediatric NAFLD not only in terms of the progression of liver disease but also regarding its potential relationship with other health outcomes such as type 2 diabetes mellitus and cardiovascular disease. This evidence could make liver biopsy mandatory in the majority of cases at risk of progressive and severe hepatic and extrahepatic disease. This conclusion, however, raises the question of the feasibility of liver biopsy assessment in an extremely large at risk population, and of the cost/effectiveness of this policy. There is a considerable, continuous interest in reliable, noninvasive alternatives that will allow the prognosis of pediatric NAFLD to be followed in large community or population-based studies. PMID:21161009

  12. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis.

    PubMed

    Le, Thuy-Anh; Loomba, Rohit

    2012-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations.

  13. Pharmacologic therapy for nonalcoholic fatty liver disease in adults.

    PubMed

    Malinowski, Scott S; Byrd, Jennifer S; Bell, Allison M; Wofford, Marion R; Riche, Daniel M

    2013-02-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in hepatocytes in the absence of excessive alcohol intake, ranging in severity from simple steatosis to nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis can ultimately progress to cirrhosis and hepatocellular carcinoma. NAFLD is associated with cardiometabolic risk factors and is the most common chronic liver disease among adults in the Western Hemisphere. Although simple steatosis is generally considered a self-limiting disease, evidence suggests an increased risk of cardiovascular disease, and, less conclusively, mortality, among individuals with NAFLD and/or NASH. The current standard of care for the treatment of patients with NAFLD focuses on lifestyle interventions, particularly diet and exercise. There is a lack of consensus regarding the most effective and appropriate pharmacologic therapy. A PubMed search was conducted using the medical subject heading terms "fatty liver" and "steatohepatitis." This review focuses on the current pharmacologic options available for treating adults with NAFLD and/or NASH. Continued investigation of drugs or combinations that improve NAFLD progression is crucial. Clinicians, particularly pharmacists, must take an active role in identification and appropriate selection of pharmacotherapy for NAFLD. © 2013 Pharmacotherapy Publications, Inc.

  14. Genetic background in nonalcoholic fatty liver disease: A comprehensive review.

    PubMed

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-10-21

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.

  15. Genetic background in nonalcoholic fatty liver disease: A comprehensive review

    PubMed Central

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-01-01

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

  16. Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

    PubMed Central

    Nakajima, Kei

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are multidisciplinary liver diseases that often accompany type 2 diabetes or metabolic syndrome, which are characterized by insulin resistance. Therefore, effective treatment of type 2 diabetes and metabolic syndrome should target not only the cardiometabolic abnormalities, but also the associated liver disorders. In the last decade, it has been shown that metformin, thiazolidinediones, vitamin E, ezetimibe, n-3 polyunsaturated fatty acids, renin-angiotensin system (RAS) blockers, and antiobesity drugs may improve hepatic pathophysiological disorders as well as clinical parameters. Accordingly, insulin sensitizers, antioxidative agents, Niemann-Pick C1-like 1 (NPC1L1) inhibitors, RAS blockers, and drugs that target the central nervous system may represent candidate pharmacotherapies for NAFLD and possibly NASH. However, the efficacy, safety, and tolerability of long-term treatment (potentially for many years) with these drugs have not been fully established. Furthermore, clinical trials have not comprehensively examined the efficacy of lipid-lowering drugs (i.e., statins, fibrates, and NPC1L1 inhibitors) for the treatment of NAFLD. Although clinical evidence for RAS blockers and incretin-based agents (GLP-1 analogs and dipeptidyl peptidase-4 inhibitors) is also lacking, these agents are promising in terms of their insulin-sensitizing and anti-inflammatory effects without causing weight gain. PMID:23304532

  17. Biotin deficiency and liver metabolism in relation to fatty liver and kidney syndrome.

    PubMed

    Pearce, J; Balnave, D

    1978-07-01

    Varying degrees of biotin deficiency were induced by adding freeze-dried, raw egg white to the diet of broiler chicks. Aspects of liver metabolism were studied with reference to fatty liver and kidney syndrome. Mortality was low with 11.8 g egg white/kg diet, or less, but with 17.7 g/kg or more, mortality was very high. High mortality was observed with less than 0.33 microgram biotin/g liver. Associated with low concentrations of liver biotin were substantial increases in liver weight and lipid content in starved birds. The increased liver lipid content was not observed in birds fed ad libitum. The increased liver lipid content in biotin-deficient, starved birds was not reflected in the specific activities of hepatic lipogenic enzymes or hepatic lipogenesis in vivo measured by the incorporation of tritium from 3H-labelled water into liver lipid. Biotin deficiency affected the specific activities of the biotin-requiring enzymes, pyruvate carboxylase and acetyl CoA carboxylase, differently; the latter was unaffected whereas the former decreased concomitantly with liver biotin concentration.

  18. Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation

    PubMed Central

    Patel, Yuval A.; Berg, Carl L.

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for transplantation, including its increasing prevalence, unique patient demographics, outcomes related to liver transplantation, development of post-liver transplantation NAFLD, and NAFLD in the liver donor population. It also highlights exciting areas where further research is needed, such as the role of bariatric surgery and preconditioning of marginal donor grafts. PMID:26815171

  19. Role of Mitochondria in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Nassir, Fatiha; Ibdah, Jamal A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) affects about 30% of the general population in the United States and includes a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Significant insight has been gained into our understanding of the pathogenesis of NALFD; however the key metabolic aberrations underlying lipid accumulation in hepatocytes and the progression of NAFLD remain to be elucidated. Accumulating and emerging evidence indicate that hepatic mitochondria play a critical role in the development and pathogenesis of steatosis and NAFLD. Here, we review studies that document a link between the pathogenesis of NAFLD and hepatic mitochondrial dysfunction with particular focus on new insights into the role of impaired fatty acid oxidation, the transcription factor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuins in development and progression of NAFLD. PMID:24837835

  20. Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis.

    PubMed

    Sookoian, Silvia; Pirola, Carlos J

    2013-11-01

    Obstructive sleep apnea (OSA) is associated with the cluster of clinical conditions that comprise the metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD). Our primary purpose was to estimate the effect of OSA on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Our secondary purpose was to investigate the potential influence of OSA on histological severity of NAFLD to explore whether chronic intermittent hypoxia is associated with inflammation and fibrosis. Our literature search identified 11 studies, from which we extracted information about numbers of control subjects and OSA patients, and ALT, AST, and NAFLD. From a total of 668 OSA patients and 404 controls, we found that the standardized difference in mean values of ALT and AST levels in patients with OSA was significantly different from that in the controls. Meta-regression showed that the association was independent of body mass index and type 2 diabetes. Fatty liver was associated with OSA in five studies with 400 subjects. OSA was significantly associated with liver fibrosis in 208 subjects, but not with lobular inflammation. Routine assessment of liver enzymes and liver damage should be implemented in OSA patients because they have an increase of 13.3% of ALT and 4.4% of AST levels, and a 2.6-fold higher risk of liver fibrosis when they have NAFLD, which is 2.6 times more frequent in OSA patients.

  1. Altered Arsenic Disposition in Experimental Nonalcoholic Fatty Liver Disease

    PubMed Central

    Canet, Mark J.; Hardwick, Rhiannon N.; Lake, April D.; Kopplin, Michael J.; Scheffer, George L.; Klimecki, Walter T.; Gandolfi, A. Jay

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH. PMID:22699396

  2. Tissue lipid composition in fatty liver and kidney syndrome in chicks.

    PubMed

    Whitehead, C C

    1975-01-01

    The lipid composition of the liver, kidneys, heart and adipose tissue of chicks affected by the fatty liver and kidney syndrome were analysed. Livers and kidneys showed 400 to 500 per cent increases in heart lipid levels. Liver and kidney triglycerides contained increased proportions of mono-unsaturated fatty acids, mainly palmitoleic acid, at the expense of the saturated fatty acids, mainly stearic acid. Phospholipid and adipose tissue fatty acid composition were not markedly altered. The abnormalities were regressing in birds recovering from the syndrome.

  3. Fatty infiltration of the liver: demonstration by proton spectroscopic imaging: preliminary observations

    SciTech Connect

    Lee, J.K.T.; Dixon, W.T.; Ling, D.; Levitt, R.G.; Murphy, W.A. Jr.

    1984-10-01

    Two normal volunteers and three patients with CT evidence of fatty infiltration of the liver were studied to determine whether magnetic resonance imaging using a pulse sequence designed to differentiate fat and water could be used to detect fatty infiltration of the liver in human being. The magnetic resonance technique used a modified spin echo technique (simple proton spectroscopic imaging). Quantitative data showed that fatty liver can be separated from normal liver using the spin echo technique, and that the opposed image of the proton spectroscopic technique is more sensitive to small changes in hepatic fatty content than in-phase images with any echo time.

  4. Current Pharmacologic Therapy for Nonalcoholic Fatty Liver Disease.

    PubMed

    Ganesh, Swaytha; Rustgi, Vinod K

    2016-05-01

    Weight loss, regular exercise, and diet composition modification seem to improve biochemical and histologic abnormalities. Other therapies directed at insulin resistance, oxidative stress, cytoprotection, and fibrosis may also offer benefits. Insulin sensitizers and vitamin E seem to be the most promising; however, they cause side effects. A multifaceted approach of lifestyle modifications, weight loss, and pharmacotherapy can be used in combination, but no single treatment approach has proved universally applicable to the general population with nonalcoholic steatohepatitis (NASH). Continuous clinical and preclinical studies on existing and potential drugs are needed to improve treatment of nonalcoholic fatty liver disease/NASH.

  5. Non-alcoholic Fatty liver disease in children.

    PubMed

    Singer, Cristina; Stancu, Polixenia; Coşoveanu, Simona; Botu, Alina

    2014-01-01

    In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children.

  6. Non-Alcoholic Fatty Liver Disease in Children

    PubMed Central

    SINGER, CRISTINA; STANCU, POLIXENIA; COŞOVEANU, SIMONA; BOTU, ALINA

    2014-01-01

    In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children. PMID:25729601

  7. [Consequences of non-alcoholic fatty liver disease still unclear].

    PubMed

    Jansen, Peter L M

    2012-01-01

    There is still a lack of clarity concerning the long-term outcome and severity of non-alcoholic fatty liver disease (NAFLD). Results of a study recently conducted by the National Health and Nutrition Examination Survey (NHANES) showed that patients with NAFLD diagnosed 30 years ago did not experience decreased survival when compared with persons without NAFLD. But questions arise about the diagnostic methods in this study and the consequences for daily practice. Is NAFLD really a disease, and what is the diagnostic method of choice?

  8. Update on Berberine in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Liu, Yang; Zhang, Li; Song, Haiyan

    2013-01-01

    Berberine (BBR), an active ingredient from nature plants, has demonstrated multiple biological activities and pharmacological effects in a series of metabolic diseases including nonalcoholic fatty liver disease (NAFLD). The recent literature points out that BBR may be a potential drug for NAFLD in both experimental models and clinical trials. This review highlights important discoveries of BBR in this increasing disease and addresses the relevant targets of BBR on NAFLD which links to insulin pathway, adenosine monophosphate-activated protein kinase (AMPK) signaling, gut environment, hepatic lipid transportation, among others. Developing nuanced understanding of the mechanisms will help to optimize more targeted and effective clinical application of BBR for NAFLD. PMID:23843872

  9.  Most overweight and obese Indian children have nonalcoholic fatty liver disease.

    PubMed

    Pawar, Sunil V; Zanwar, Vinay G; Choksey, Ajay S; Mohite, Ashok R; Jain, Samit S; Surude, Ravindra G; Contractor, Qais Q; Rathi, Pravin M; Verma, Ravi U; Varthakavi, Premlata K

     Background and rationale. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of pediatric liver disease in western countries. Its prevalence in Indian subcontinent is not well studied.

  10. A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C.

    PubMed

    Charlotte, Fréderic; Le Naour, Gilles; Bernhardt, Carole; Poynard, Thierry; Ratziu, Vlad

    2010-08-01

    In nonalcoholic fatty liver disease the amount of fibrosis for individual histologic stages is unknown. To better understand the fibrotic potential of nonalcoholic fatty liver disease, we compared the amount of fibrosis in nonalcoholic fatty liver disease versus chronic hepatitis C virus patients. The area of fibrosis for equivalent fibrosis stages was measured by micromorphometry in 70 nonalcoholic fatty liver disease and 70 matched, untreated, chronic hepatitis C virus controls. The area of fibrosis correlated with Brunt stage (r = 0.71; P < .001) in nonalcoholic fatty liver disease and METAVIR stage (r = 0.58; P < .001) in chronic hepatitis C virus. Mean area of fibrosis was similar in nonalcoholic fatty liver disease and chronic hepatitis C virus patients (7.77% versus 7.70%). Although chronic hepatitis C virus patients displayed higher area of fibrosis in early disease (no or mild fibrosis), nonalcoholic fatty liver disease and chronic hepatitis C virus patients had similar area of fibrosis in more advanced disease (7.83% versus 8.06%, respectively; P = .86 for bridging fibrosis; and 16.62% versus 12.98%, respectively; P = .29 for cirrhosis). The area of fibrosis was similar in Brunt stage 3 nonalcoholic fatty liver disease and METAVIR stage 2 chronic hepatitis C virus, the usual threshold for initiating therapy. The area of steatosis declined with increasing fibrosis stages confirming the early loss of liver fat with progressive fibrosis in nonalcoholic fatty liver disease. Fibrosis is as abundant in nonalcoholic fatty liver disease as in chronic hepatitis C virus, especially in the advanced stages of the disease. The fibrotic potential of nonalcoholic fatty liver disease is as severe as that of chronic hepatitis C virus.

  11. Nonalcoholic fatty liver disease and metabolic syndrome in postmenopausal women.

    PubMed

    Rodrigues, Marcio H; Bruno, Anderson S; Nahas-Neto, Jorge; Santos, Maria Emilia S; Nahas, Eliana A P

    2014-05-01

    Nonalcoholic fatty liver disease (NAFLD) is considered the most common cause of chronic liver disease in the Western countries. NAFLD includes a spectrum ranging from a simple steatosis to a nonalcoholic steatohepatitis (NASH) which is defined by the presence of inflammatory infiltrate, cellular necrosis, hepatocyte ballooning, and fibrosis and cirrhosis that can eventually develop into hepatocellular carcinoma. Studies emphasize the role of insulin resistance, oxidative stress, pro-inflammatory cytokines, adipokines in the development and progression of NAFLD. It seems to be independently associated with type II diabetes mellitus, increased triglycerides, decreased HDL-cholesterol, abdominal obesity and insulin resistance. These findings are in accordance with the criteria used in the diagnosis of metabolic syndrome (MetS). Here, we will discuss the current knowledge on the epidemiology, pathophysiology and diagnosis of NAFLD and the association of metabolic syndrome in postmenopausal women.

  12. A concise review of non-alcoholic fatty liver disease.

    PubMed

    Than, Nwe Ni; Newsome, Philip N

    2015-03-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and the incidence of which is rising rapidly due to the increasing epidemic of obesity in both adults and children. The initial accumulation of fat followed by subsequent inflammation is central to the development of liver damage, and is critically influenced by host factors including age, gender, presence of diabetes, genetic polymorphisms and more recently by the gut microbiome. An increasing body of data suggest that NAFLD is also an independent risk factor of cardiovascular disease, which remains the commonest cause of mortality in such patients. This review focusses on the pathogenesis of NAFLD, and the evolution of new approaches to the management and treatment of NAFLD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Glycosyltransferases and non-alcoholic fatty liver disease

    PubMed Central

    Zhan, Yu-Tao; Su, Hai-Ying; An, Wei

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized. PMID:26937136

  14. Glycosyltransferases and non-alcoholic fatty liver disease.

    PubMed

    Zhan, Yu-Tao; Su, Hai-Ying; An, Wei

    2016-02-28

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized.

  15. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Oliveira, Claudia P.; de Lima Sanches, Priscila; de Abreu-Silva, Erlon Oliveira; Marcadenti, Aline

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID:26770987

  16. Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review.

    PubMed

    Nseir, William; Mahamid, Mahmud

    2013-03-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that refers to the presence of hepatic steatosis without significant intake of alcohol. NAFLD is an asymptomatic disease that can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The most common cause of mortality in patients with NAFLD or NASH is cardiovascular disease (CVD). Currently, the treatment of NAFLD focuses on gradual weight loss and life style modifications. However, multifactorial treatment of NAFLD or NASH risk factors may be needed to reduce the likelihood of these patients developing CVD. This review discusses the mechanisms that link hyperlipidemia and NAFLD. In addition, the review focuses on the safety and efficacy of statins in patients with NAFLD or NASH, and their effect on the extent of hepatic steatosis and fibrosis based on human studies.

  17. [Pediatric nonalcoholic fatty liver disease/nonalcoholic steatohepatitis].

    PubMed

    Takahashi, Yoshihisa; Fukusato, Toshio; Inui, Ayano; Fujisawa, Tomoo

    2012-10-01

    Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is a hepatic disease associated with metabolic syndrome. In recent years, pediatric NAFLD has increased in line with the increased prevalence of pediatric obesity. The estimated prevalence of pediatric NAFLD is 2.6-9.6%. With regard to the pathogenesis of NAFLD/ NASH, the "two-hit" or "multiple-hit" hypothesis is widely accepted, and many genetic and environmental factors are associated with the development of NAFLD/NASH. Liver biopsy is regarded as the gold standard for the diagnosis of NAFLD/NASH. Pediatric NAFLD has different histopathological characteristics from those of adult NAFLD. Although pharmacotherapy has been studied in clinical trials, lifestyle modification by diet and exercise remains the mainstay of treatment for NAFLD/NASH.

  18. Nonalcoholic fatty liver disease and low-carbohydrate diets.

    PubMed

    York, Linda Wasserbach; Puthalapattu, Swathy; Wu, George Y

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance, obesity, and other features of metabolic syndrome and is known to be the most common cause for abnormal liver enzymes. The recent surge in the number of patients with NAFLD has been accompanied by an increase in research on potential treatment options, particularly weight loss and dietary interventions. Given the growing interest on the role of carbohydrates in the prevention and treatment of NAFLD, this review discusses the relationship between the amount of carbohydrates in the diet and effects on NAFLD, with special emphasis on a low-carbohydrate diet. We discuss the role of insulin resistance in the pathophysiology of NAFLD and provide an overview of various popular diets and their role as a treatment option for NAFLD. Additional large, longer-duration trials studying the efficacy of a low-carbohydrate diet in the treatment and prevention of NAFLD are eagerly awaited.

  19. Sirtuin 1 signaling and alcoholic fatty liver disease

    PubMed Central

    Jogasuria, Alvin; Taylor, Charles; Wu, Jiashin

    2015-01-01

    Alcoholic fatty liver disease (AFLD) is one of the most prevalent forms of liver disease worldwide and can progress to inflammation (hepatitis), fibrosis/cirrhosis, and ultimately lead to end stage liver injury. The mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. Nevertheless, understanding its pathogenesis will facilitate the development of effective pharmacological or nutritional therapies for treating human AFLD. Chronic ethanol consumption causes steatosis and inflammation in rodents or humans by disturbing several important hepatic transcriptional regulators, including AMP-activated kinase (AMPK), lipin-1, sterol regulatory element binding protein 1 (SREBP-1), PPARγ co-activator-1α (PGC-1α), and nuclear transcription factor-κB (NF-κB). Remarkably, the effects of ethanol on these regulators are mediated in whole or in part by inhibition of a central signaling molecule, sirtuin 1 (SIRT1), which is a nicotinamide adenine dinucleotide (NAD+, NADH)-dependent class III protein deacetylase. In recent years, SIRT1 has emerged as a pivotal molecule controlling the pathways of hepatic lipid metabolism, inflammatory responses and in the development of AFLD in rodents and in humans. Ethanol-mediated SIRT1 inhibition suppresses or stimulates the activities of above described transcriptional regulators and co-regulators, thereby deregulating diverse lipid metabolism and inflammatory response pathways including lipogenesis, fatty acid β-oxidation, lipoprotein uptake and secretion and expression of pro-inflammatory cytokines in the liver. This review aims to highlight our current understanding of SIRT1 regulatory mechanisms and its response to ethanol-induced toxicity, thus, affirming significant role of SIRT1 signaling in the development of AFLD. PMID:26005675

  20. Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease

    PubMed Central

    Trautwein, Christian

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and covers a disease spectrum ranging from steatosis to inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The innate immune response in the liver plays an important role during NAFLD progression. In addition, changes in the intestinal microbial balance and bacterial translocation can further affect disease progression. Immune cells in the liver recognize cell damage or pathogen invasion with intracellular or surface-expressed pattern recognition receptors (PRRs), subsequently initiating signaling cascades that trigger the release of factors promoting the inflammatory response during NAFLD progression. Therefore, mechanisms by which cells of the immune system are activated and recruited into the liver and how these cells cause injury and stress are important for understanding the inflammatory response during NAFLD. PMID:25568861

  1. Autophagy and non-alcoholic fatty liver disease.

    PubMed

    Lavallard, Vanessa J; Gual, Philippe

    2014-01-01

    Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non-alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma.

  2. Current Status of Therapy in Nonalcoholic Fatty Liver Disease

    PubMed Central

    McNear, Scott

    2009-01-01

    The obesity epidemic has now spread worldwide. With increase in weight, there is an increase in dysregulated energy metabolism ultimately leading to dysfunction of multiple organ systems recognized as the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide, and is thought to be the hepatic manifestation of metabolic syndrome. It is a nondiscriminating disease affecting both children and adults and no socioeconomic class is spared. There is a well-defined increase in both liver-related and all-cause mortality. Current projections foresee a continued worsening in prevalence, especially with the increased rate of childhood obesity. Prevention would be the ultimate goal, but with continued trends in obesity, therapeutic options are needed to manage this chronic liver disease and prevent its complications of cirrhosis and even hepatocellular carcinoma. Therapies will need to be affordable, tolerable, and safe to be useful on such a large scale. This article will discuss some of the basic understanding of NAFLD, as well as review the currently tested therapies, some novel therapies, and potential future therapeutic options. PMID:21180532

  3. Autophagy and Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Lavallard, Vanessa J.

    2014-01-01

    Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non-alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma. PMID:25295245

  4. Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease.

    PubMed

    Viglino, Damien; Jullian-Desayes, Ingrid; Minoves, Mélanie; Aron-Wisnewsky, Judith; Leroy, Vincent; Zarski, Jean-Pierre; Tamisier, Renaud; Joyeux-Faure, Marie; Pépin, Jean-Louis

    2017-06-01

    Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities. Copyright ©ERS 2017.

  5. Drug metabolism alterations in nonalcoholic fatty liver disease

    PubMed Central

    Merrell, Matthew D.; Cherrington, Nathan J.

    2013-01-01

    Drug-metabolizing enzymes play a vital role in the elimination of the majority of therapeutic drugs. The major organ involved in drug metabolism is the liver. Chronic liver diseases have been identified as a potential source of significant interindividual variation in metabolism. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting between 60 and 90 million Americans, yet the vast majority of NAFLD patients are undiagnosed. NAFLD encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis and fibrosis. Numerous animal studies have investigated the effects of NAFLD on hepatic gene expression, observing significant alterations in mRNA, protein, and activity levels. Information on the effects of NAFLD in human patients is limited, though several significant investigations have recently been published. Significant alterations in the activity of drug-metabolizing enzymes may affect the clearance of therapeutic drugs, with the potential to result in adverse drug reactions. With the enormous prevalence of NAFLD, it is conceivable that every drug currently on the market is being given to patients with NAFLD. The current review is intended to present the results from both animal models and human patients, summarizing the observed alterations in the expression and activity of the phase I and II drug-metabolizing enzymes. PMID:21612324

  6. Validation of the Fatty Liver Index for Nonalcoholic Fatty Liver Disease in Middle-Aged and Elderly Chinese.

    PubMed

    Huang, Xiaolin; Xu, Min; Chen, Ying; Peng, Kui; Huang, Ya; Wang, Po; Ding, Lin; Lin, Lin; Xu, Yu; Chen, Yuhong; Lu, Jieli; Wang, Weiqing; Bi, Yufang; Ning, Guang

    2015-10-01

    The fatty liver index (FLI), which is an algorithm based on waist circumference, body mass index (BMI), triglyceride, and gamma-glutamyl-transferase (GGT), was initially developed to detect fatty liver in Western countries. Our study aimed to evaluate the accuracy and optimal cut-off point of the FLI for predicting nonalcoholic fatty liver disease (NAFLD) in middle-aged and elderly Chinese. This cross-sectional study included 8626 Chinese adults aged 40 years or above recruited from Jiading District, Shanghai, China. Anthropometric and biochemical features were collected by a standard protocol. NAFLD was diagnosed by hepatic ultrasonography. The accuracy and cut-off point of the FLI to detect NAFLD were evaluated by area under the receiver operator characteristic curve (AUROC) and the maximum Youden index analysis, respectively. The AUROC of the FLI for NAFLD was 0.834 (95% confidence interval: 0.825-0.842), and larger than that of its each individual component [0.786 (0.776-0.796), 0.783 (0.773-0.793), 0.727 (0.716-0.739), and 0.707 (0.695-0.719) for waist circumference, BMI, triglyceride, and GGT, respectively] (all P < 0.001). The optimal cut-off point of the FLI for diagnosing NAFLD was 30 with the maximum Youden Index of 0.51, achieving a high sensitivity of 79.89% and a specificity of 71.51%. The FLI-diagnosed NAFLD individuals were in worse metabolic characteristics (waist circumference, BMI, blood pressure, serum lipids, and aminotransferases) than ultrasonography-diagnosed NAFLD patients (all P < 0.05).The FLI could accurately identify NAFLD and the optimal cut-off point was 30 in middle-aged and elderly Chinese. As FLI-diagnosed NAFLD patients were in worse metabolism, much attention should be paid to the metabolic controls and managements of NAFLD.

  7. Tissue distribution comparison between healthy and fatty liver rats after oral administration of hawthorn leaf extract.

    PubMed

    Yin, Jingjing; Qu, Jianguo; Zhang, Wenjie; Lu, Dongrui; Gao, Yucong; Ying, Xixiang; Kang, Tingguo

    2014-05-01

    Hawthorn leaves, a well-known traditional Chinese medicine, have been widely used for treating cardiovascular and fatty liver diseases. The present study aimed to investigate the therapeutic basis treating fatty liver disease by comparing the tissue distribution of six compounds of hawthorn leaf extract (HLE) in fatty liver rats and healthy rats after oral administration at first day, half month and one month, separately. Therefore, a sensitive and specific HPLC method with internal standard was developed and validated to determine chlorogenic acid, vitexin-4''-O-glucoside, vitexin-2''-O-rhamnoside, vitexin, rutin and hyperoside in the tissues including heart, liver, spleen, kidney, stomach and intestine. The results indicated that the six compounds in HLE presented some bioactivity in treating rat fatty liver as the concentrations of the six compounds varied significantly in inter- and intragroup comparisons (healthy and/or fatty liver group).

  8. Assessment of Liver Viscoelasticity for the Diagnosis of Early Stage Fatty Liver Disease Using Transient Elastography

    NASA Astrophysics Data System (ADS)

    Remenieras, Jean-Pierre; Dejobert, Maelle; Bastard, Cécile; Miette, Véronique; Perarnau, Jean-Marc; Patat, Frédéric

    Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of fat within the Liver. The main objective of this work is (1) to evaluate the feasibility of measuring in vivo in the liver the shear wave phase velocity dispersion cs(ω) between 20 Hz and 90 Hz using vibration-controlled transient elastography (VCTE); (2) to estimate through the rheological Kelvin-Voigt model the shear elastic μ and shear viscosity η modulus; (3) to correlate the evolution of these viscoelastic parameters on two patients at Tours Hospital with the hepatic fat percentage measured with T1-weighted gradient-echo in-and out-phase MRI sequence. For the first volunteer who has 2% of fat in the liver, we obtained μ = 1233 ± 133 Pa and η = 0.5 ± 0.4 Pa.s. For the patient with 22% of fat, we measure μ = 964 ± 91 Pa and η = 1.77 ± 0.3 Pa.s. In conclusion, this novel method showed to be sensitive in characterizing the visco-elastic properties of fatty liver.

  9. Epidemiology and risk factors of nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Duseja, Ajay; Chalasani, Naga

    2013-12-01

    The nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis, determined by either imaging or histology, in the absence of secondary causes of hepatic fat accumulation. Nonalcoholic fatty liver is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes or fibrosis. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. Although initial epidemiological studies have focused on its prevalence in the Western countries, it is becoming increasingly clear that NAFLD is highly prevalent in the Asia Pacific region, and there may be important distinctions in its phenotype between Asia Pacific and Western countries. Of particular interest are "lean NAFLD" and the "urban-rural divide," which will be discussed in this review article. Obesity, dyslipidemia, type 2 diabetes and metabolic syndrome are established risk factors for developing NAFLD. Many other risk factors (e.g., hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, hypopituitarism and hypogonadism) for NAFLD have been described in the Western countries, but these associations are yet to be investigated adequately in the Asia Pacific region.

  10. Current concepts and management approaches in nonalcoholic fatty liver disease.

    PubMed

    Attar, Bashar M; Van Thiel, David H

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction worldwide. NAFLD may progress to nonalcoholic steatohepatitis (NASH) and in turn cirrhosis. Importantly, hepatic cancer can occur in NASH in the absence of cirrhosis. The cardinal histologic feature of NAFLD is the presence of an excessive accumulation of triacylglycerols and diacylglycerols in hepatocytes. The presence of obesity and insulin resistance lead to an increased hepatic-free fatty acid (FFA) flux creating an environment appropriate for the development of NAFLD. The generation of toxic reactive oxygen species with the production of hepatic injury and inflammation as a consequence of FFA oxidation will ultimately lead to the initiation and progression of fibrosis. Lifestyle modifications specifically weight loss, physical exercise, and cognitive behavior therapy have been recommended as treatments for NASH. Dietary fructose is an independent risk factor for the development of NAFLD. Pioglitazone can be used to treat biopsy-proven NASH; however, its safety risks should be considered carefully. Greater consumption for coffee, independent of its caffeine component, has been associated with a significant reduced risk of advanced fibrosis in NASH. Additional data are needed before recommending bariatric surgery as an established option for the specific treatment of NASH.

  11. Transcriptional networks implicated in human nonalcoholic fatty liver disease.

    PubMed

    Ye, Hua; Liu, Wei

    2015-10-01

    The transcriptome of nonalcoholic fatty liver disease (NAFLD) was investigated in several studies. However, the implications of transcriptional networks in progressive NAFLD are not clear and mechanisms inducing transition from nonalcoholic simple fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are still elusive. The aims of this study were to (1) construct networks for progressive NAFLD, (2) identify hub genes and functional modules in these networks and (3) infer potential linkages among hub genes, transcription factors and microRNAs (miRNA) for NAFLD progression. A systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) was utilized to dissect transcriptional profiles in 19 normal, 10 NAFL and 16 NASH patients. Based on this framework, 3 modules related to chromosome organization, proteasomal ubiquitin-dependent protein degradation and immune response were identified in NASH network. Furthermore, 9 modules of co-expressed genes associated with NAFL/NASH transition were found. Further characterization of these modules defined 13 highly connected hub genes in NAFLD progression network. Interestingly, 11 significantly changed miRNAs were predicted to target 10 of the 13 hub genes. Characterization of modules and hub genes that may be regulated by miRNAs could facilitate the identification of candidate genes and pathways responsible for NAFL/NASH transition and lead to a better understanding of NAFLD pathogenesis. The identified modules and hub genes may point to potential targets for therapeutic interventions.

  12. Interaction of type 2 diabetes and nonalcoholic fatty liver disease.

    PubMed

    Verderese, John Paul; Younossi, Zobair

    2013-07-01

    Evauation of: Kasturiratne A, Weerasinghe S, Dassanayake A et al. Influence of non-alcoholic fatty liver disease on the development of diabetes mellitus. J. Gastroenterol. Hepatol. 28(1), 142-147 (2013). It has been a few decades that Type 2 diabetes has been clearly linked to the development and progression of nonalcoholic fatty liver disease (NAFLD). In a recent study reported by Kastuiratne et al., the reverse scenario is also reported. In this study, a cohort of Sri Lankan adults were evaluated for NAFLD by ultrasound and for the presence of Type 2 diabetes. Those without diabetes at baseline were followed prospectively for 3 years and assessed for incident diabetes. On multivariate analysis, after adjustment for a number of factors (age, impaired fasting glucose, BMI, waist circumference, elevated ALT, family history of diabetes and presence of hypertension and hyperlipidemia), NAFLD was the only predictor of incident diabetes in those with and without impaired fasting glucose at baseline. This study adds to the growing evidence connecting NAFLD to Type 2 diabetes and highlights the importance of its recognition in an effort to target those at the highest risk of diabetes for lifestyle and pharmacologic intervention.

  13. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.

    PubMed

    Stål, Per

    2015-10-21

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.

  14. Effects of Phlebotomy on Liver Enzymes and Histology of Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Khodadoostan, Mahsa; Zamanidoost, Maryam; Shavakhi, Ahmad; Sanei, Hosein; Shahbazi, Masood; Ahmadian, Mehdi

    2017-01-01

    Background: Nonalcoholic fatty liver disease (NAFLD), defined as excessive liver fat deposition and one of end-stage liver disease causes. Increased ferritin levels are associated with insulin resistance and a higher hepatic iron and fat content. Hyperferritinemia has been associated with severity of liver damage in NAFLD. The study aimed to evaluate the effects of phlebotomy on liver enzymes and histology in such patients. Materials and Methods: Thirty-two eligible patients who had NAFLD and after 6 months of lifestyle modification still had NAFLD, and whose ferritin serum was above 250 mg/dl, were enrolled in this clinical trial study. After written informed consent was obtained, each patient's blood serum was taken for aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK-P), complete blood count (CBC), total iron-binding capacity (TIBC), iron, and ferritin. Then the patients underwent liver biopsy. After that patients underwent phlebotomy, giving 350 cc blood monthly. Before every phlebotomy, hemoglobin and ferritin were checked. If they were in the goal range, phlebotomy was discontinued and the patient underwent liver biopsy. A serum sample was taken for testing at the beginning of the study. The results before and after phlebotomy were compared. The maximum duration of the study was 6 months. Results: Thirty-two patients (26 males and 6 females) were enrolled, and the mean average age was 33.7 ± 6.74 years. Phlebotomy improved liver enzymes and histology of liver significantly (P < 0.001) and induced reduction of ferritin. Conclusion: Phlebotomy is effective for the improvement of liver enzymes and histology in patients with NAFLD and hyperferritinemia. PMID:28299304

  15. Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk.

    PubMed

    Pacifico, Lucia; Nobili, Valerio; Anania, Caterina; Verdecchia, Paola; Chiesa, Claudio

    2011-07-14

    Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

  16. Nuclear receptors and nonalcoholic fatty liver disease1

    PubMed Central

    Cave, Matthew C.; Clair, Heather B.; Hardesty, Josiah E.; Falkner, K. Cameron; Feng, Wenke; Clark, Barbara J.; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A.; McClain, Craig J.; Prough, Russell A.

    2016-01-01

    Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

  17. IDENTIFICATION OF ENVIRONMENTAL CHEMICALS ASSOCIATED WITH THE DEVELOPMENT OF TOXICANT ASSOCIATED FATTY LIVER DISEASE IN RODENTS

    PubMed Central

    Al-Eryani, Laila; Wahlang, Banrida; Falkner, K.C.; Guardiola, J. J.; Clair, H.B.; Prough, R.A.; Cave, M.

    2014-01-01

    Background Toxicant associated fatty liver disease (TAFLD) is a recently identified form of non-alcoholic fatty liver disease (NAFLD) associated with exposure to industrial chemicals and environmental pollutants. Numerous studies have been conducted to test the association between industrial chemicals/ environmental pollutants and fatty liver disease both in vivo and in vitro. Objectives The objective of the paper is to report a list of chemicals associated with TAFLD. Methods Two federal databases of rodent toxicology studies– ToxRefDB (Environmental Protection Agency) and Chemical Effects in Biological Systems (CEBS, National Toxicology Program) were searched for liver endpoints. Combined, these two databases archive nearly 2000 rodent studies. TASH descriptors including fatty change, fatty necrosis, Oil red O positive staining, steatosis and lipid deposition were queried. Results Using these search terms, 123 chemicals associated with fatty liver were identified. Pesticides and solvents were the most frequently identified chemicals, while PCBs/dioxins were the most potent. About 44% of identified compounds were pesticides or their intermediates, and nearly 10% of pesticide registration studies in ToxRefDB were associated with fatty liver. Fungicides and herbicides were more frequently associated with fatty liver than insecticides. Conclusions More research on pesticides, solvents, metals and PCBs/dioxins in NAFLD/TAFLD is warranted due to their association with liver damage. PMID:25326588

  18. Experimentally induced fatty liver and kidney syndrome in the young turkey.

    PubMed

    Whitehead, C C; Siller, W G

    1983-01-01

    Turkeys were fed up to four weeks of age on diets of low biotin content and then fasted for 18 hours. Three birds developed clinical signs of fatty liver and kidney syndrome (FLKS) and on autopsy had pale and swollen livers and kidneys. Morphological studies showed fatty accumulations in liver, kidney, heart and proventriculus but no signs of inflammatory or degenerative changes. The infiltrated lipid had an abnormal fatty acid composition, with an increased proportion of monounsaturated fatty acids. Affected birds suffered from severe hypoglycaemia and hepatic glycogen was depleted. These findings demonstrate that FLKS can be induced experimentally in turkeys.

  19. Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease.

    PubMed

    Ter Horst, Kasper W; Serlie, Mireille J

    2017-09-06

    Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases.

  20. Paediatric non-alcoholic fatty liver disease: an overview.

    PubMed

    AlKhater, S A

    2015-05-01

    Non-alcoholic fatty liver disease (NAFLD) is a progressive disease that encompasses a spectrum of liver diseases, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Data related to survival in children are scarce, but these data firmly associate NAFLD with higher risks of hepatic and non-hepatic morbidities and mortalities compared with the general population. More recently, the association between NAFLD and cardiovascular disease among children has increasingly been recognized. Given that obesity is a major risk factor for the disease, paediatric NAFLD is becoming a global issue, paralleling the dramatic rise in obesity worldwide. NASH, which is more common in obese children, has the potential to advance to liver fibrosis and failure. It is unclear why certain patients undergo such transformation but this susceptibility is likely related to an interaction between a genetically susceptible host and the surrounding environment. Currently, treatment is largely conservative and includes lifestyle modification, attainable through healthy weight reduction via diet and exercise. In this review, current knowledge about NAFLD in children is summarized. This review aims to increase the awareness of the medical community about a hidden public health issue and to identify current gaps in the literature while providing directions for future research. © 2015 World Obesity.

  1. The histopathology of fatty liver and kidney syndrome in chicks.

    PubMed

    Wight, P A; Siller, W G

    1975-09-01

    Studies of the general histopathology of the fatty liver and kidney syndrome in chickens have shown abnormal accumulations of the lipid in a variety of organs but no degenerative or inflammatory reactions. Lipid was found in some skeletal muscles, alimentary tract, autonomic ganglia, central nervous system and pineal gland as well as in the liver, kidney and heart. Small amounts of lipid were sometimes seen in the exocrine pancreas, adrenal medulla and epithelium of the thyroid follicles. Lipid deposits in the liver were primarily associated with the hepatic structural unit. The glycogen content of the hepatic cell was reduced. The lipid-metabolising gastrocnemius muscle contained abnormal amounts of lipid but this did not apply to the carbohydrate-metabolising pectoralis major muscle. The thymus did not contain excessive lipid but was significantly smaller in affected than in control birds of similar ages. There was loss of tinctorial distinction between the cortex and medulla of the adrenal gland associated with decreased basophilia of the latter region. Many of these morphological changes can be correlated with previously reported biochemical findings and they are discussed in relation to the hyperlipaemia and hypoglycaemia which characterise the disease.

  2. Low Hepatic Tissue Copper in Pediatric Nonalcoholic Fatty Liver Disease.

    PubMed

    Mendoza, Michael; Caltharp, Shelley; Song, Ming; Collin, Lindsay; Konomi, Juna V; McClain, Craig J; Vos, Miriam B

    2017-07-01

    Animal models and studies in adults have demonstrated that copper restriction increases severity of liver injury in nonalcoholic fatty liver disease (NAFLD). This has not been studied in children. We aimed to determine if lower tissue copper is associated with increased NAFLD severity in children. This was a retrospective study of pediatric patients who had a liver biopsy including a hepatic copper quantitation. The primary outcome compared hepatic copper concentration in NAFLD versus non-NAFLD. Secondary outcomes compared hepatic copper levels against steatosis, fibrosis, lobular inflammation, balloon degeneration, and NAFLD activity score (NAS). The study analysis included 150 pediatric subjects (102 with NAFLD and 48 non-NAFLD). After adjusting for age, body mass index z score, gamma glutamyl transferase, alanine aminotransferase, and total bilirubin, NAFLD subjects had lower levels of hepatic copper than non-NAFLD (P = 0.005). In addition, tissue copper concentration decreased as steatosis severity increased (P < 0.001). Copper levels were not associated with degree of fibrosis, lobular inflammation, portal inflammation, or balloon degeneration. In this cohort of pediatric subjects with NAFLD, we observed decreased tissue copper levels in subjects with NAFLD when compared with non-NAFLD subjects. In addition, tissue copper levels were lower in subjects with nonalcoholic steatohepatitis, a more severe form of the disease, when compared with steatosis alone. Further studies are needed to explore the relationship between copper levels and NAFLD progression.

  3. Bile acid receptors and nonalcoholic fatty liver disease

    PubMed Central

    Yuan, Liyun; Bambha, Kiran

    2015-01-01

    With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH. PMID:26668692

  4. Epigenetics in non-alcoholic fatty liver disease.

    PubMed

    Lee, Jooho; Kim, Yuri; Friso, Simonetta; Choi, Sang-Woon

    2017-04-01

    Non-alcoholic fatty liver disease (NAFLD), a common hepatic disorder ranging from simple steatosis through steatohepatitis to fibrosis and cirrhosis, is an emerging health concern. NAFLD is a pathologic condition characterized by the buildup of extra fat in liver cells that is not caused by alcohol consumption. Excess hepatic fat accumulation results from increased delivery of triglycerides (TG) to the liver or conversion of surplus carbohydrates to TG. Importantly, a subgroup of NAFLD results in hepatocellular injury and inflammation, which is referred to as non-alcoholic steatohepatitis (NASH), and may progress to irreversible cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares, in part, the common pathogenesis of metabolic syndrome including obesity, hyperlipidemia, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines. Epigenetics, an inheritable phenomenon that affects gene expression without altering the DNA sequence, provides a new perspective on the pathogenesis of NAFLD. Reversible epigenetic changes take place at the transcriptional level and provide a phenotypic connection between the host and environment. An accumulating body of evidence suggests the importance of epigenetic roles in NAFLD, which in turn can be identified as potential therapeutic targets and non-invasive biomarkers of NAFLD. It is anticipated that the epigenetic modifiers in NAFLD may provide novel molecular indicators that can determine not only the initial risk but also the disease progression and prognosis. In the present review, we update the roles of epigenetics as pathologic mechanisms, therapeutic targets and biomarkers in NAFLD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

    PubMed Central

    Aigner, Elmar; Weiss, Günter; Datz, Christian

    2015-01-01

    Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID:25729473

  6. Nonalcoholic fatty liver disease and obstructive sleep apnea.

    PubMed

    Aron-Wisnewsky, Judith; Clement, Karine; Pépin, Jean-Louis

    2016-08-01

    Obstructive sleep apnea (OSA) and more importantly its hallmark, chronic intermittent hypoxia (CIH), are established factors in the pathogenesis and exacerbation of nonalcoholic fatty liver disease (NAFLD). This has been clearly demonstrated in rodent models exposed to intermittent hypoxia, and strong evidence now also exists in both paediatric and adult human populations. OSA and CIH induce insulin-resistance and dyslipidemia which are involved in NAFLD physiopathogenesis. CIH increases the expression of the hypoxia inducible transcription factor HIF1α and that of downstream genes involved in lipogenesis, thereby increasing β-oxidation and consequently exacerbating liver oxidative stress. OSA also disrupts the gut liver axis, increasing intestinal permeability and with a possible role of gut microbiota in the link between OSA and NAFLD. OSA patients should be screened for NAFLD and vice versa those with NAFLD for OSA. To date there is no evidence that treating OSA with continuous positive airway pressure (CPAP) will improve NAFLD but it might at least stabilize and slow its progression. Nevertheless, these multimorbid patients should be efficiently treated for all their metabolic co-morbidities and be encouraged to follow weight stabilization or weight loss programs and physical activity life style interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Takahashi, Yoshihisa; Fukusato, Toshio

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH. PMID:25400438

  8. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Takahashi, Yoshihisa; Fukusato, Toshio

    2014-11-14

    Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.

  9. Rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Imajo, Kento; Yoneda, Masato; Kessoku, Takaomi; Ogawa, Yuji; Maeda, Shin; Sumida, Yoshio; Hyogo, Hideyuki; Eguchi, Yuichiro; Wada, Koichiro; Nakajima, Atsushi

    2013-11-04

    Research in nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), has been limited by the availability of suitable models for this disease. A number of rodent models have been described in which the relevant liver pathology develops in an appropriate metabolic context. These models are promising tools for researchers investigating one of the key issues of NASH: not so much why steatosis occurs, but what causes the transition from simple steatosis to the inflammatory, progressive fibrosing condition of steatohepatitis. The different rodent models can be classified into two large groups. The first includes models in which the disease is acquired after dietary or pharmacological manipulation, and the second, genetically modified models in which liver disease develops spontaneously. To date, no single rodent model has encompassed the full spectrum of human disease progression, but individual models can imitate particular characteristics of human disease. Therefore, it is important that researchers choose the appropriate rodent models. The purpose of the present review is to discuss the metabolic abnormalities present in the currently available rodent models of NAFLD, summarizing the strengths and weaknesses of the established models and the key findings that have furthered our understanding of the disease's pathogenesis.

  10. Nonalcoholic fatty liver disease and cholesterol gallstones: which comes first?

    PubMed

    Ahmed, Mohamed H; Ali, Asif

    2014-05-01

    Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are both highly prevalent in the general population and are associated with obesity, insulin resistance, dyslipidemia, and high dietary cholesterol intake. Insulin resistance is a key feature of both NAFLD and GD. Hepatic insulin resistance provides a crucial link between the metabolic syndrome, NAFLD, and increased cholesterol gallstone susceptibility. Hepatic insulin resistance is not only associated with accumulation of hepatic fat but also has a crucial role in supersaturation and excessive production of bile salts. It is not yet clear whether NAFLD is a precursor of GD or whether the presence of GD possibly indicates the presence of long-standing features of metabolic syndrome that accelerates the progression of NAFLD. Recent reports suggested the association between gallstones and nonalcoholic steatohepatitis and liver fibrosis. Importantly, both NAFLD and GD are both associated with high incidence of cardiovascular disease (CVD) and mortality. Emerging evidence suggests a potential benefit of statin therapy in NAFLD and GD. Further research is needed to determine (i) how the presence of NAFLD and GD is associated with CVD (ii) and whether the presence of GD in association with NAFLD increases the risk of liver fibrosis, and (iii) the impact of therapy of NAFLD in the incidence of GD.

  11. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease.

    PubMed

    Kirpich, Irina A; Marsano, Luis S; McClain, Craig J

    2015-09-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called "gut-liver axis", play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The dietary factors may alter the gut microbiota and intestinal barrier function, favoring the occurrence of metabolic endotoxemia and low grade inflammation, thereby contributing to the development of obesity and obesity-associated fatty liver disease. Therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management. This review summarizes the current knowledge regarding the complex interplay between the gut microbiota, intestinal barrier, and dietary factors in NAFLD pathogenesis. The concepts addressed in this review have important clinical implications, although more work needs to be done to understand how dietary factors affect the gut barrier and microbiota, and to comprehend how microbe-derived components may interfere with the host's metabolism contributing to NAFLD development.

  12. Gut-Liver Axis, Nutrition, and Non Alcoholic Fatty Liver Disease

    PubMed Central

    Kirpich, Irina A.; Marsano, Luis S.; McClain, Craig J.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called ”gut-liver axis”, play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The dietary factors may alter the gut microbiota and intestinal barrier function, favoring the occurrence of metabolic endotoxemia and low grade inflammation, thereby contributing to the development of obesity and obesity-associated fatty liver disease. Therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management. This review summarizes the current knowledge regarding the complex interplay between the gut microbiota, intestinal barrier, and dietary factors in NAFLD pathogenesis. The concepts addressed in this review have important clinical implications, although more work needs to be done to understand how dietary factors affect the gut barrier and microbiota, and to comprehend how microbe-derived components may interfere with the host’s metabolism contributing to NAFLD development. PMID:26151226

  13. Ethanol and liver: recent insights into the mechanisms of ethanol-induced fatty liver.

    PubMed

    Liu, Jinyao

    2014-10-28

    Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease.

  14. Nuclear receptors and transcription factors in the development of fatty liver disease.

    PubMed

    Vluggens, Aurore; Reddy, Janardan K

    2012-12-01

    Liver regulates certain key aspects of lipid metabolism including de novo lipogenesis, fatty acid oxidation, and lipoprotein uptake and secretion. Disturbances in these hepatic functions can contribute to the development of fatty liver disease. An understanding of the regulatory mechanisms influencing hepatic lipid homeostasis and systemic energy balance is therefore of paramount importance in gaining insights that might be useful in the management of fatty liver disease. In this regard, emerging evidence indicates that certain members of the nuclear receptor superfamily and some key transcription coactivators function as intracellular sensors to orchestrate hepatic lipid metabolism. Dysregulation of nuclear receptor-mediated transcriptional signaling and perturbations in the levels of their cognate endogenous ligands play a prominent role in the development of fatty liver disease. The potential of nuclear receptors, transcription coactivators as well as enzymes that participate in the synthesis and degradation of endogenous nuclear receptor ligands, as effective therapeutic targets for fatty liver disease needs evaluation.

  15. Sulfur amino acids in diet-induced fatty liver: a new perspective based on recent findings.

    PubMed

    Toohey, John I

    2014-06-19

    The relationship of sulfur amino acids to diet-induced fatty liver was established 80 years ago, with cystine promoting the condition and methionine preventing it. This relationship has renewed importance today because diet-induced fatty liver is relevant to the current epidemics of obesity, non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes. Two recent papers provide the first evidence linking sulfane sulfur to diet-induced fatty liver opening a new perspective on the problem. This review summarizes the early data on sulfur amino acids in fatty liver and correlates that data with current knowledge of sulfur metabolism. Evidence is reviewed showing that the lipotropic effect of methionine may be mediated by sulfane sulfur and that the hepatosteatogenic effect of cystine may be related to the removal of sulfane sulfur by cysteine catabolites. Possible preventive and therapeutic strategies are discussed.

  16. Liver transplantation for nonalcoholic fatty liver disease: new challenges and new opportunities.

    PubMed

    Shaker, Mina; Tabbaa, Adam; Albeldawi, Mazen; Alkhouri, Naim

    2014-05-14

    Nonalcoholic fatty liver disease (NAFLD) is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world. Development of graft steatosis is a significant problem during the post-transplant course, which may happen as a recurrence of pre-existing disease or de novo NAFLD. There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome, immune-suppressive medications, genetics and others. There are few studies that assessed the effects of NAFLD on graft and patient survival; most of them were limited by the duration of follow up or by the number of patients. With this review article we will try to shed light on post-liver transplantation NAFLD, significance of the disease, how it develops, risk factors, clinical course and treatment options.

  17. Acute Fatty Liver of Pregnancy and its Differentiation from Other Liver Diseases in Pregnancy.

    PubMed

    Maier, J T; Schalinski, E; Häberlein, C; Gottschalk, U; Hellmeyer, L

    2015-08-01

    Background: There are a number of threatening liver diseases that occur during pregnancy. Acute fatty liver of pregnancy is a rare disease associated with high maternal and foetal mortality. Case Report: We report on a young gravida 1 woman who presented to our level 1 perinatal centre in the 36 + 5 week of pregnancy with an isolated elevation of transaminases together with diffuse upper abdominal complaints. After comprehensive diagnostic work-up we performed an emergency delivery by Caesarean section. This was followed by interdisciplinary management. Discussion: The differentiation from other liver diseases seems not to be obvious in all cases. Here we consider the following differential diagnoses: hyperemesis gravidarum, intrahepatic gestational cholestasis, preeclampsia, HELLP syndrome. Conclusion: Rapid diagnosis and delivery as well as interdisciplinary aftercare are necessary in order to reduce maternal and foetal mortality.

  18. Acute fatty liver of pregnancy: analysis of five consecutive cases from a tertiary centre.

    PubMed

    Barber, M A; Eguiluz, I; Martín, A; Plasencia, W; Valle, L; García, J A

    2010-04-01

    Acute fatty liver of pregnancy is a rare cause of jaundice and liver failure associated with high maternal and fetal mortality. We analysed five consecutive cases of acute fatty liver of pregnancy, along with the associated morbidity, mortality and complications. Between January 1999 and January 2008, a total of 68,524 deliveries were assisted at the Obstetrics and Gynaecology Department of the Hospital Universitario Materno-Infantil de Canarias (Canaries University Hospital Maternity Ward); among them, five cases of acute fatty liver of pregnancy were identified.

  19. Docosahexaenoic acid and non-alcoholic fatty liver disease in obese children: a novel approach?

    PubMed

    Verduci, Elvira; Lassandro, Carlotta; Radaelli, Giovanni; Soldati, Laura

    2015-04-02

    Non-alcoholic fatty liver disease represents the most common chronic liver disease in obese children of industrialized countries. Nowadays the first line of treatment of pediatric non-alcoholic fatty liver disease is based on dietary and lifestyle intervention; however compliance to these interventions is very difficult to maintain in long term period. This editorial discusses about docosahexaenoic acid treatment as possible novel approach for non-alcoholic fatty liver disease in obese children. Docosahexaenoic acid may modulate the inflammatory response, improve insulin sensitivity and could be effective in enhancing intestinal barrier integrity, essential to protect a healthy gut-liver axis. Indeed alteration of gut microbiota composition and increased intestinal permeability may rise the exposure of liver to gut-derived bacterial products, causing activation of signalling pathways implicated in liver inflammation and fibrogenesis. This mechanism has been observed in vitro and animal models of non-alcoholic fatty liver disease but also in a clinical study in adults. While evidence suggests that n-3 long-chain polyunsaturated fatty acids supplementation may decrease liver fat in adults, in pediatric population only a study examined this topic. In obese children with non-alcoholic fatty liver disease well designed randomized controlled trials are needed to better clarify the possible efficacy of docosahexaenoic acid treatment, and underlying mechanisms, to identify the optimal required dose and to evaluate if the docosahexaenoic acid effect is limited to the duration of the treatment or it may continue after the end of treatment.

  20. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research.

    PubMed

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Crespo Yanguas, Sara; Colle, Isabelle; Van Den Bossche, Bert; Da Silva, Tereza Cristina; de Oliveira, Cláudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini; Cogliati, Bruno; Vinken, Mathieu

    2015-07-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and '-omics'-based read-outs are still in their infancy, but show great promise. In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed.

  1. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

    PubMed Central

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

    2015-01-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

  2. From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease.

    PubMed

    Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia Del Giudice, Emanuele; Santoro, Nicola

    2017-01-18

    In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction.

  3. From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease

    PubMed Central

    Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia del Giudice, Emanuele; Santoro, Nicola

    2017-01-01

    In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction. PMID:28144387

  4. Review article: Drug therapy for non-alcoholic fatty liver disease.

    PubMed

    Comar, K M; Sterling, R K

    2006-01-15

    Non-alcoholic fatty liver disease represents a spectrum of liver diseases, characterized mainly by macrovesicular steatosis in the absence of significant alcohol ingestion. Non-alcoholic fatty liver disease includes both non-alcoholic fatty liver and non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis once considered a benign process is now known to lead to progressive fibrosis and cirrhosis. Histologically indistinguishable from alcoholic liver disease, the exact aetiology of non-alcoholic fatty liver disease remains unknown, but the fundamental pathophysiological process appears to be insulin resistance and oxidative stress related to the metabolic syndrome. Therapy has focused on risk factors, weight reduction and pharmacological intervention. Promising pharmacological treatments have been demonstrated with antioxidants, insulin sensitizers, hepatoprotectants and lipid-lowering agents. However, without larger randomized studies, no pharmacological treatments can be recommended at this time.

  5. Epidemiological survey and risk factor analysis of fatty liver disease of adult residents, Beijing, China.

    PubMed

    Yan, Jie; Xie, Wen; Ou, Wei-ni; Zhao, Hong; Wang, Su-yun; Wang, Jian-hui; Wang, Qi; Yang, Yu-ying; Feng, Xin; Cheng, Jun

    2013-10-01

    With the changes in diet structure and lifestyle, the incidence of fatty liver disease is increasing in China, especially in cities. The goal of the present study was to accurately determine the prevalence and risk factors of fatty liver disease in Beijing residents, China. By using random multistage stratification and cluster sampling, residents aged > 20 years in Dongcheng District and Tongzhou District were recruited, and questionnaire survey, physical examination, detection of fasting glucose, blood lipids and liver biochemistry, and ultrasonography of the liver, gallbladder, and spleen were carried out. Database EpiData 3.0 was employed for data input, followed by statistical analysis with SPSS version 11.0. A total of 3762 residents were included in the present study including 2328 males and 1434 females with a mean age of 46.37 ± 14.28 years (range 20-92 years). Ultrasonography revealed fatty liver in 1486 residents with a prevalence of 39.5%. Moreover, non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease were found in 1177 (31.3%) and 309 (8.2%) residents, respectively. After adjustment of prevalence based on the age and gender constituents of Beijing residents, the standardized prevalence of overall fatty liver disease, NAFLD, and alcoholic fatty liver disease was 35.1%, 31.0%, and 4.1%, respectively. Binary logistic regression analysis revealed waist-to-hip ratio, diastolic pressure, fasting blood glucose, triglyceride, high-density lipoprotein cholesterol, and low density lipoprotein cholesterol were closely related to NAFLD. The Beijing residents have a high prevalence of fatty liver disease as much as 35.1%, which is characterized by NAFLD. Obesity, and glucose and lipid metabolism disorders are the main risk factors of fatty liver disease. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  6. Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.

    PubMed

    Spengler, Erin K; Loomba, Rohit

    2015-09-01

    Nonalcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease in the United States, afflicting an estimated 80 to 100 million Americans. Nonalcoholic fatty liver disease is a spectrum of liver diseases composed of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Although nonalcoholic fatty liver has a negligible risk of progression, patients with NASH often develop cirrhosis or hepatocellular carcinoma. Although liver biopsy is required to diagnose NASH, only patients with a high risk of NASH or advanced fibrosis require this evaluation. Despite the high prevalence of NAFLD, well-defined screening recommendations are currently lacking. In this review, suggestions for screening, diagnosis, and initial work-up of NAFLD are given on the basis of established guidelines and recent publications. Proposed drug treatments of NASH are also discussed, highlighting the study outcomes, as well as proposed uses and limitations of these drugs. The literature was searched in PubMed using search terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, with filters of "English language." A date range of January 1, 2000, to May 1, 2015, was used for the search. The bibliographies of key references were also searched manually, and seminal publications before the year 2000 were included.

  7. Metabolic profiling of an alcoholic fatty liver in zebrafish (Danio rerio).

    PubMed

    Jang, Zi-Hey; Chung, Hee-Chung; Ahn, Yun Gyong; Kwon, Yong-Kook; Kim, Jin-Sup; Ryu, Jae-Ho; Ryu, Do Hyun; Kim, Cheol-Hee; Hwang, Geum-Sook

    2012-07-06

    Zebrafish (Danio rerio) is becoming a popular developmental biology model to study diseases and for drug discovery. In this study, we performed proton nuclear magnetic resonance spectroscopy ((1)H-NMR)- and gas chromatography-mass spectrometry (GC/MS)-based metabolic profiling of an alcoholic fatty liver using a zebrafish disease model. We examined metabolic differences between the control and alcoholic fatty liver groups in zebrafish to determine how metabolism in an alcoholic fatty liver is regulated. Multivariate statistical analysis showed a significant difference between the control and alcoholic fatty liver groups. The alcoholic fatty liver group showed increased excretion of isoleucine, acetate, succinate, choline, creatine, acetoacetate, 3-hydroxybutyrate (3HB), ethyl glucuronide (EtG), lactate/pyruvate ratio, fatty acids, and cholesterol, and decreased excretion of citrate, aspartate, tyrosine, glycine, glucose, alanine, betaine, and maltose. Metabolites identified in the fatty liver groups were associated with long-term alcohol consumption, which causes both oxidation-reduction (redox) changes and oxidative stress. This study suggests that global metabolite profiling in a zebrafish model can provide insights into the metabolic changes in an alcoholic fatty liver.

  8. Current status of liver disease in Korea: nonalcoholic fatty liver disease.

    PubMed

    Park, Sang Hoon

    2009-12-01

    Recently, obesity (BMI>or=25 kg/m2) and type II diabetes mellitus have reached epidemic proportions in Korea, and rates of nonalcoholic fatty liver disease (NAFLD) are between 10% and 25% of the general population. NAFLD in Korea is as closely associated with several components of metabolic syndrome including, obesity, hypertension, diabetes and dyslipidemia as it is in Western countries. Insulin resistance and hyperinsulinemia may play a role in the pathogenesis of fatty liver in patients with normal body weight as well as in patients with obesity. And, obesity induced accumulation of fat in the adipose tissue leads to an imbalance in the regulation of adipokines, such as downregulation of adiponectin and upregulation of retinol-binding protein 4 (RBP4) and ghrelin. High BMI, the AST/ALT ratio, and ALT levels could be used to distinguish NASH from simple steatosis in Korean patients. In large number of NAFLD patients who underwent a voluntary medical checkup, even a small weight reduction was associated with improvements in their hepatic steatosis grade on ultrasonography, serum aminotransferase levels, and related metabolic abnormalities. Subjects with fatty liver disease should be advised to lose weight through lifestyle modifications. Small animal and human studies of treatment with PPAR agonists and betaine have been reported in the Korean literature. It is now acknowledged that NAFLD is the most common liver disease in Korea, largely due to the considerable increase in metabolic abnormalities such as obesity and diabetes. Future studies should continue to focus both on the pathogenesis and the treatment of NAFLD in order to accumulate more of our own data.

  9. Relationship between ultrasound backscattered statistics and the concentration of fatty droplets in livers: an animal study.

    PubMed

    Ho, Ming-Chih; Lee, Yu-Hsin; Jeng, Yung-Ming; Chen, Chiung-Nien; Chang, King-Jen; Tsui, Po-Hsiang

    2013-01-01

    Ultrasound grayscale B-mode imaging is the most frequently used modality for examining fatty liver. Different concentrations and arrangements of fatty droplets in the liver may produce different statistical distributions of ultrasound backscatter signals, which may be treated as a useful clue for assessing the stage of fatty liver. To verify this point, we investigate the relationship between changes in backscattered statistics and the concentration of fatty droplets in the liver. Fatty liver was induced in rats fed a methionine-choline-deficient diet. Livers were excised from rats for in vitro ultrasound scanning using a single-element transducer. The envelopes of the acquired raw ultrasound signals were used for the analysis of the backscattered statistics by ultrasound Nakagami parametric imaging, which has been shown as a reliable tool to model the statistical distribution of ultrasound backscatter signals. Histological analyses and the measurements of triglyceride and cholesterol in the rat liver were conducted for comparison with the Nakagami parameter. Results show that the ultrasound Nakagami parameter has an excellent correlation with the concentration of fatty droplets, demonstrating that ultrasound backscatter statistics depend on the degree of fatty liver in rats.

  10. Lipoprotein Metabolism, Dyslipidemia and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Cohen, David E.; Fisher, Edward A.

    2014-01-01

    Cardiovascular disease represents the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). NAFLD patients exhibit an atherogenic dyslipidemia that is characterized by an increased plasma concentration of triglycerides, reduced concentration of high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) particles that are smaller and more dense than normal. The pathogenesis of NAFLD-associated atherogenic dyslipidemia is multifaceted, but many aspects are attributable to manifestations of insulin resistance. Here we review the structure, function and metabolism of lipoproteins, which are macromolecular particles of lipids and proteins that transport otherwise insoluble triglyceride and cholesterol molecules within the plasma. We provide a current explanation of the metabolic perturbations that are observed in the setting of insulin resistance. An improved understanding of the pathophysiology of atherogenic dyslipidemia would be expected to guide therapies aimed at reducing morbidity and mortality in NAFLD patients. PMID:24222095

  11. Intrauterine Growth Retardation and Nonalcoholic Fatty Liver Disease in Children

    PubMed Central

    Alisi, Anna; Panera, Nadia; Agostoni, Carlo; Nobili, Valerio

    2011-01-01

    Intrauterine growth retardation (IUGR), the most important cause of perinatal mortality and morbidity, is defined as a foetal growth less than normal for the population, often used as synonym of small for gestational age (SGA). Studies demonstrated the relationships between metabolic syndrome (MS) and birthweight. This study suggested that, in children, adolescents, and adults born SGA, insulin resistance could lead to other metabolic disorders: type 2 diabetes (DM2), dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). NAFLD may evolve to nonalcoholic steatohepatitis (NASH), and it is related to the development of MS. Lifestyle intervention, physical activity, and weight reduction represent the mainstay of NAFLD therapy. In particular, a catch-up growth reduction could decrease the risk to develop MS and NAFLD. In this paper, we outline clinical and experimental evidences of the association between IUGR, metabolic syndrome, insulin resistance, and NAFLD and discuss on a possible management to avoid the risk of MS in adulthood. PMID:22190925

  12. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease.

    PubMed

    Pastori, Daniele; Polimeni, Licia; Baratta, Francesco; Pani, Arianna; Del Ben, Maria; Angelico, Francesco

    2015-01-01

    Non-alcoholic fatty liver disease is an emerging liver disease in Western countries and the most frequent cause of incidental elevation of serum liver enzymes. Dyslipidaemia is frequently observed in patients with non-alcoholic fatty liver disease, and treatment of dyslipidaemia plays a critical role in the overall management of these patients. Moreover, coronary artery disease remains the most common cause of death. Statins are effective lipid-lowering agents, associated with a lowering the risk of cardiovascular events in several interventional randomized clinical trials. However, statins are often underused in patients with non-alcoholic fatty liver disease and many physicians are concerned about the prescription of statins to patients with unexplained persistent elevation of liver enzymes or active liver disease. Based on currently available data, statin therapy, at low-to-moderate doses, seems to be safe and has low liver toxicity. Treatment of dyslipidaemia in patients with non-alcoholic fatty liver disease is recommended and may also improve liver function tests. In these patients, the risks of not taking statins could outweigh the risks of taking the drug. Conversely, the usefulness of statins for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis is still a matter of debate and randomized clinical trials of adequate size and duration are required.

  13. Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease.

    PubMed

    von Loeffelholz, C; Horn, P; Birkenfeld, A L; Claus, R A; Metzing, B U; Döcke, S; Jahreis, G; Heller, R; Hoppe, S; Stockmann, M; Lock, J F; Rieger, A; Weickert, M O; Settmacher, U; Rauchfuß, F; Pfeiffer, A F H; Bauer, M; Sponholz, C

    2016-10-01

    Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. To study fetuin A as predictor of NAFLD/NASH in preoperative patients. 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings.

  14. Association between nonalcoholic fatty liver disease and coronary artery disease.

    PubMed

    Arslan, Uğur; Türkoğlu, Sedat; Balcioğlu, Serhat; Tavil, Yusuf; Karakan, Tarkan; Cengel, Atiye

    2007-09-01

    To demonstrate whether there is a relationship between the presence of nonalcoholic fatty liver disease (NAFLD) and the presence and extent of coronary artery disease (CAD). Ninety-two consecutive patients who planned to undergo coronary angiographies (CAG) without known CAD, other than findings of acute coronary syndrome, were enrolled in this study. Abdominal ultrasonography was performed before the CAG to detect NAFLD. CAD was defined as a stenosis of at least 50% in at least one major coronary artery. The extent of CAD was measured according to the number of major coronary artery/arteries affected by CAD. All the risk factors for CAD were included in a binary logistic regression model. Forward, backward, or step-wise selections were not used. P<0.05 was accepted as being significant. Sixty-five of the 92 patients (70.7%) were detected, by abdominal ultrasonography, to have fatty liver and 43 patients out of 92 (46.7%) were detected, by CAG, to have significant CAD. According to the results of logistic regression analysis, the presence of NAFLD independently increased the risk for CAD, as seen in CAG [odds ratio (OR), 95% confidence interval (CI): 6.73 (1.14-39.61); P=0.035]; this was despite factoring in the other risk factors for CAD and the components of metabolic syndrome. NAFLD was more commonly found in patients as the extent of CAD increased (P=0.001). The presence of NAFLD is independently associated with the presence and extent of CAD. Future studies are needed to explain the mechanisms of this relationship.

  15. Acute fatty liver of pregnancy -- an underlying condition for herpes simplex type 2 fulminant hepatitis necessitating liver transplantation.

    PubMed

    Luzar, B; Ferlan-Marolt, V; Poljak, M; Sojar, V; Stanisavljević, D; Bukovac, T; Markovic, S

    2005-05-01

    The infrequent occurrence of herpes simplex virus (HSV) hepatitis in healthy women in comparison with the high prevalence of HSV infections suggests that, in addition to deranged immunity, an underlying condition in the liver might be necessary to develop HSV hepatitis. We report the case of a 28-year-old pregnant woman in the 28 (th) week of gestation. Following HSV type 2 infection of the uterine cervix, acute liver failure developed, necessitating urgent liver transplantation. In addition to fulminant HSV type 2 hepatitis, the explanted liver also showed the histological features of acute fatty liver of pregnancy. The presented case suggests a possible pathogenetic role of acute fatty liver of pregnancy in the development of fulminant HSV hepatitis following recurrent infection with HSV in healthy pregnant women. We believe that early histopathological diagnosis, followed by specific antiviral treatment and liver transplantation in selected patients may improve the clinical outcome of otherwise almost uniformly fatal HSV hepatitis.

  16. Non-Alcoholic Fatty Liver Disease: Lipids and Insulin Resistance

    PubMed Central

    Berk, Paul D; Verna, Elizabeth C

    2016-01-01

    Abstract/Synopsis Obesity and its major co-morbidities, including type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), obesity cardiomyopathy, and certain cancers, are major public health problems worldwide. They are responsible for substantial morbidity and mortality, to a degree that life expectancy in the United States has actually declined in recent years because of it. Obesity is the increased accumulation of fat, i.e. triglycerides (TG), which are synthesized from glycerol and long chain fatty acids (LCFA), throughout the body. Although long believed to enter cells solely by passive diffusion, it has been established over the past 30 years that LCFA enter adipocytes, hepatocytes and cardiomyocytes via specific, facilitated transport processes, and that these processes are hormonally up-regulated in obesity. Metabolism of increased cellular TG content in obesity may lead to cell-specific lipotoxicity, contributing to co-morbidities such as NAFLD and cardiomyopathy. In contrast to the popular perception, dietary control and bariatric surgery can each achieve major initial weight loss in many patients. However several mechanisms, including persistent up-regulation of LCFA transport, contribute to weight regain in the large majority of patients. Better understanding of these transport processes and their regulation may be a key to successful future strategies to treat obesity and NAFLD. PMID:27063267

  17. Dietary habits and behaviors associated with nonalcoholic fatty liver disease

    PubMed Central

    Yasutake, Kenichiro; Kohjima, Motoyuki; Kotoh, Kazuhiro; Nakashima, Manabu; Nakamuta, Makoto; Enjoji, Munechika

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of health problems in Western (industrialized) countries. Moreover, the incidence of infantile NAFLD is increasing, with some of these patients progressing to nonalcoholic steatohepatitis. These trends depend on dietary habits and life-style. In particular, overeating and its associated obesity affect the development of NAFLD. Nutritional problems in patients with NAFLD include excess intake of energy, carbohydrates, and lipids, and shortages of polyunsaturated fatty acids, vitamins, and minerals. Although nutritional therapeutic approaches are required for prophylaxis and treatment of NAFLD, continuous nutrition therapy is difficult for many patients because of their dietary habits and lifestyle, and because the motivation for treatment differs among patients. Thus, it is necessary to assess the nutritional background and to identify nutritional problems in each patient with NAFLD. When assessing dietary habits, it is important to individually evaluate those that are consumed excessively or insufficiently, as well as inappropriate eating behaviors. Successful nutrition therapy requires patient education, based on assessments of individual nutrients, and continuing the treatment. In this article, we update knowledge about NAFLD, review the important aspects of nutritional assessment targeting treatment success, and present some concrete nutritional care plans which can be applied generally. PMID:24587653

  18. Investigating Nonalcoholic Fatty Liver Disease in a Liver-on-a-Chip Microfluidic Device

    PubMed Central

    Simonelli, Maria Chiara; Giannitelli, Sara Maria; Businaro, Luca; Trombetta, Marcella; Rainer, Alberto

    2016-01-01

    Background and Aim Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease worldwide, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to cirrhosis, eventually leading to hepatocellular carcinoma (HCC). HCC ranks as the third highest cause of cancer-related death globally, requiring an early diagnosis of NAFLD as a potential risk factor. However, the molecular mechanisms underlying NAFLD are still under investigation. So far, many in vitro studies on NAFLD have been hampered by the limitations of 2D culture systems, in which cells rapidly lose tissue-specific functions. The present liver-on-a-chip approach aims at filling the gap between conventional in vitro models, often scarcely predictive of in vivo conditions, and animal models, potentially biased by their xenogeneic nature. Methods HepG2 cells were cultured into a microfluidically perfused device under free fatty acid (FFA) supplementation, namely palmitic and oleic acid, for 24h and 48h. The device mimicked the endothelial-parenchymal interface of a liver sinusoid, allowing the diffusion of nutrients and removal of waste products similar to the hepatic microvasculature. Assessment of intracellular lipid accumulation, cell viability/cytotoxicity and oxidative stress due to the FFA overload, was performed by high-content analysis methodologies using fluorescence-based functional probes. Results The chip enables gradual and lower intracellular lipid accumulation, higher hepatic cell viability and minimal oxidative stress in microfluidic dynamic vs. 2D static cultures, thus mimicking the chronic condition of steatosis observed in vivo more closely. Conclusions Overall, the liver-on-a-chip system provides a suitable culture microenvironment, representing a more reliable model compared to 2D cultures for investigating NAFLD pathogenesis. Hence, our system is amongst the first in vitro models of human NAFLD developed within a microfluidic device in a sinusoid

  19. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis.

    PubMed

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-06-24

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis.

  20. Fenofibrate treatment attenuated chronic endoplasmic reticulum stress in the liver of nonalcoholic fatty liver disease mice.

    PubMed

    Zhang, Nan; Lu, Yunxia; Shen, Xinru; Bao, Yingying; Cheng, Jingjing; Chen, Li; Li, Bao; Zhang, Qiu

    2015-01-01

    Fenofibrate is widely used in clinical practice, but its influence on chronic endoplasmic reticulum (ER) stress induced by feeding a high-calorie and high-cholesterol diet (HCD) has still not been studied. We thus investigated its effects on the liver of the nonalcoholic fatty liver disease (NAFLD) mouse model. Male C57BL/6 mice fed an HCD for 3 months were treated with fenofibrate (HCD + FF, 40 mg/kg, once daily) via gavage for 4 weeks. Insulin sensitivity, serum lipid and inflammatory cytokines were measured. Liver tissues were procured for histological examination as well as analysis of hepatic triglyceride levels, distribution of inflammatory cytokines and genes involved in ER stress. Our results showed that chronic feeding of an HCD successfully induced an NAFLD model accompanied by inflammatory activation, apoptosis and severe ER stress in the liver. Fenofibrate administration significantly improved symptoms of NAFLD and decreased apoptosis, expression of inflammatory cytokines and genes involved in ER stress, such as inositol-requiring enzyme 1α (IRE1α), X-box binding protein 1 (XBP1) and JNK phosphorylation. Thus, our study suggests that fenofibrate protected against inflammatory injury and apoptosis, maybe alleviating ER stress through the IRE1α-XBP1-JNK pathway in the liver of NAFLD mice. © 2015 S. Karger AG, Basel

  1. Postpartum Acute Liver Dysfunction: A Case of Acute Fatty Liver of Pregnancy Developing Massive Intrahepatic Calcification.

    PubMed

    Bhat, Khalid Javid; Shovkat, Rabia; Samoon, Hamad Jeelani

    2015-12-01

    The function of the liver is particularly affected by the unique physiologic milieu of the pregnancy. Pregnancy-related liver diseases encompass a spectrum of different etiologies that are related to gestation or one of its complications. Hepatic calcification, a rare entity, is usually associated with infectious, vascular, or neoplastic lesions in the liver. To the best of our knowledge, only one case of rapidly occurring pregnancy-related intrahepatic calcification has been documented in a patient with severe eclampsia or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Here we present a case of immediate "postpartum" acute fatty liver of pregnancy (AFLP) in a 23-year-old hypertensive primigravida, complicated by acute renal dysfunction who developed dense intrahepatic calcification in less than a month after the initial diagnosis. A multidisciplinary approach for the management was used, to which the patient responded aptly. This case illustrates the first description of intrahepatic calcification in AFLP syndrome and highlights some of the challenges met in making the final diagnosis.

  2. Gut–Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Poeta, Marco; Pierri, Luca; Vajro, Pietro

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A “multiple-hit” hypothesis has been invoked to explain its pathogenesis. The “first hit” is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as “second hits” implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut–liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising. PMID:28767077

  3. NHE1 deficiency in liver: implications for non-alcoholic fatty liver disease.

    PubMed

    Prasad, Vikram; Chirra, Shivani; Kohli, Rohit; Shull, Gary E

    2014-07-25

    Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na(+)/H(+) exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.

  4. OSAS-related inflammatory mechanisms of liver injury in nonalcoholic fatty liver disease.

    PubMed

    Paschetta, Elena; Belci, Paola; Alisi, Anna; Liccardo, Daniela; Cutrera, Renato; Musso, Giovanni; Nobili, Valerio

    2015-01-01

    Obstructive sleep apnoea syndrome (OSAS) is a common sleep disorder, affecting over 4% of the general population, and is associated with metabolic syndrome and cardiovascular disease, independent of obesity and traditional risk factors. OSAS has been recently connected to nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world, which can be found in 30% of the general adult population. Several studies suggest that the chronic intermittent hypoxia (CIH) of OSAS patients may per se trigger liver injury, inflammation, and fibrogenesis, promoting NAFLD development and the progression from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In NAFLD patients, liver disease may be caused by hypoxia both indirectly by promoting inflammation and insulin resistance and directly by enhancing proinflammatory cytokine production and metabolic dysregulation in liver cells. In this review, we focus on molecular mechanisms linking OSAS to NAFLD, including hypoxia inducible factor (HIF), nuclear factor kappa B (NF-κB), YKL-40, unfolded protein response, and hypoxic adipose tissue inflammation, which all could provide novel potential therapeutic approaches for the management of NAFLD patients with OSAS.

  5. Noninvasive investigations for non alcoholic fatty liver disease and liver fibrosis

    PubMed Central

    Fierbinteanu-Braticevici, Carmen; Dina, Ion; Petrisor, Ana; Tribus, Laura; Negreanu, Lucian; Carstoiu, Catalin

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that have insulin resistance in common and are associated with metabolic conditions such as obesity, type 2 diabetes mellitus, and dyslipidemia. NAFLD ranges from simple liver steatosis, which follows a benign course, to nonalcoholic steatohepatitis (NASH), a more severe entity, with necroinflammation and fibrosis, which can progress to cryptogenic cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several noninvasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. These markers are currently neither available in all centers nor validated in extensive studies. Examples include high-sensitivity C reactive protein and plasma pentraxin 3, which are associated with extensive liver fibrosis in NASH. Interleukin-6 correlates with inflammation, and cytokeratin-18 represents a marker of hepatocyte apoptosis (prominent in NASH and absent in simple steatosis). Tissue polypeptide specific antigen seems to have a clinical utility in the follow-up of obese patients with NASH. PMID:20939106

  6. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis

    PubMed Central

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis. PMID:27347998

  7. Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver[S

    PubMed Central

    Moffat, Cynthia; Bhatia, Lavesh; Nguyen, Teresa; Lynch, Peter; Wang, Miao; Wang, Dongning; Ilkayeva, Olga R.; Han, Xianlin; Hirschey, Matthew D.; Claypool, Steven M.; Seifert, Erin L.

    2014-01-01

    Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi­dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O2 consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix. PMID:25114170

  8. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease.

    PubMed

    Paolella, Giulia; Mandato, Claudia; Pierri, Luca; Poeta, Marco; Di Stasi, Martina; Vajro, Pietro

    2014-11-14

    The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a "low bacterial richness" may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier ("leaky gut"), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy.

  9. Gut-liver axis and probiotics: Their role in non-alcoholic fatty liver disease

    PubMed Central

    Paolella, Giulia; Mandato, Claudia; Pierri, Luca; Poeta, Marco; Di Stasi, Martina; Vajro, Pietro

    2014-01-01

    The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a “low bacterial richness” may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier (“leaky gut”), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy. PMID:25400436

  10. Sex Steroid Modulation of Fatty Acid Utilization and Fatty Acid Binding Protein Concentration in Rat Liver

    PubMed Central

    Ockner, Robert K.; Lysenko, Nina; Manning, Joan A.; Monroe, Scott E.; Burnett, David A.

    1980-01-01

    The mechanism by which sex steroids influence very low density hepatic lipoprotein triglyceride production has not been fully elucidated. In previous studies we showed that [14C]oleate utilization and incorporation into triglycerides were greater in hepatocyte suspensions from adult female rats than from males. The sex differences were not related to activities of the enzymes of triglyceride biosynthesis, whereas fatty acid binding protein (FABP) concentration in liver cytosol was greater in females. These findings suggested that sex differences in lipoprotein could reflect a sex steroid influence on the availability of fatty acids for hepatocellular triglyceride biosynthesis. In the present studies, sex steroid effects on hepatocyte [14C]oleate utilization and FABP concentration were investigated directly. Hepatocytes from immature (30-d-old) rats exhibited no sex differences in [14C]oleate utilization. With maturation, total [14C]oleate utilization and triglyceride biosynthesis increased moderately in female cells and decreased markedly in male cells; the profound sex differences in adults were maximal by age 60 d. Fatty acid oxidation was little affected. Rats were castrated at age 30 d, and received estradiol, testosterone, or no hormone until age 60 d, when hepatocyte [14C]oleate utilization was studied. Castration virtually eliminated maturational changes and blunted the sex differences in adults. Estradiol or testosterone largely reproduced the appropriate adult pattern of [14C]oleate utilization regardless of the genotypic sex of the treated animal. In immature females and males, total cytosolic FABP concentrations were similar. In 60-d-old animals, there was a striking correlation among all groups (females, males, castrates, and hormone-treated) between mean cytosolic FABP concentration on the one hand, and mean total [14C]oleate utilization (r = 0.91) and incorporation into triglycerides (r = 0.94) on the other. In 30-d-old animals rates of [14C

  11. Nonalcoholic fatty liver disease increases risk for gastroesophageal reflux symptoms.

    PubMed

    Catanzaro, Roberto; Calabrese, Federica; Occhipinti, Sergio; Anzalone, Maria Grazia; Italia, Angelo; Milazzo, Michele; Marotta, Francesco

    2014-08-01

    Nonalcoholic fatty liver disease (NAFLD) is now recognized as a leading cause of liver dysfunction. Gastroesophageal reflux disease (GERD) is a common disorder causing symptoms that often impair patients' quality of life. In recent years, the prevalence of both these diseases has increased, partially overlapping the rise of metabolic disorders. We investigated whether a relation does exist between NAFLD and GERD symptoms. Cross-sectional study among 206 outpatients diagnosed with NAFLD and 183 controls. We collected clinical and laboratory data, assessed severity and frequency of GERD symptoms and the esophageal endoscopic pattern. The prevalence of GERD symptoms was higher in NAFLD patients than controls (61.2 vs. 27.9%, p < 0.001). We found a positive association between NAFLD and the experiencing of heartburn, regurgitation and belching. GERD symptoms were related to body mass index (BMI) and metabolic syndrome (MetS); a strong association persisted after adjustment for all the covariates (adjusted OR 3.49, 95 CI% 2.24-5.44, p < 0.001). Our data show that the prevalence of GERD typical symptoms is higher in patients with NAFLD. GERD was associated with higher BMI and MetS, but not with age and diabetes type 2. NAFLD remained strongly associated with GERD, independently of a coexisting MetS status. Consistent with these findings, MetS can be considered a shared background, but cannot completely explain this correlation. We suggest NAFLD as an independent risk factor for GERD symptoms.

  12. Potential Epigenetic Mechanism in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Sun, Chao; Fan, Jian-Gao; Qiao, Liang

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epigenetic mechanism of NAFLD. Elucidation of epigenetic factors may facilitate the identification of early diagnositic biomarkers and development of therapeutic strategies for NAFLD. PMID:25751727

  13. Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach.

    PubMed

    Alisi, Anna; Feldstein, Ariel E; Villani, Alberto; Raponi, Massimiliano; Nobili, Valerio

    2012-01-17

    Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis. NAFLD affects both adults and children who present with particular risk factors, including obesity, sedentary lifestyle and/or a predisposing genetic background. The escalation of the prevalence of NAFLD in children worldwide is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. The etiopathogenesis of primary NAFLD in children is unknown; however, considerable knowledge about the mechanisms of liver damage that occur during disease progression has been gathered over the past 30 years. Understanding the pathogenetic mechanisms, together with the histological pattern, provide the basis to characterize potential early predictors of the disease, suitable noninvasive diagnostic tools and design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD that showed encouraging results, to date, no treatment guidelines exist for children with NAFLD. In this Review, we provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis and treatment of NAFLD in children and adolescents.

  14. Non-alcoholic fatty liver disease, diet and gut microbiota

    PubMed Central

    Finelli, Carmine; Tarantino, Giovanni

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may advantageously affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are fervently awaited. PMID:26417275

  15. MicroRNAs in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Baffy, György

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD. PMID:26690233

  16. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  17. The prevalence of nonalcoholic fatty liver disease in the Americas.

    PubMed

    López-Velázquez, Jorge A; Silva-Vidal, Karen V; Ponciano-Rodríguez, Guadalupe; Chávez-Tapia, Norberto C; Arrese, Marco; Uribe, Misael; Méndez-Sánchez, Nahum

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an alarming public health problem. The disease is one of the main causes of chronic liver disease worldwide and is directly linked to the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) in the general population. The worldwide prevalence of NAFLD has been estimated at 20-30%, but the prevalence is unknown in the Americas because of a lack of epidemiological studies. However, given the trends in the prevalence of diabetes and obesity, the prevalence of NAFLD and its consequences are expected to increase in the near future. The aim of the present study is to present the current data on the prevalence of NAFLD in the Americas. We performed an electronic search of the main databases from January 2000 to September 2013 and identified 356 reports that were reviewed. We focused on the epidemiology and prevalence of known NAFLD risk factors including obesity, T2DM, and the metabolic syndrome (MS). The prevalence of the MS was highest in the United States, Mexico, Costa Rica, Puerto Rico, Chile, and Venezuela. In addition, Puerto Rico, Guyana, and Mexico have the highest prevalence of T2DM in the Americas, while USA has the most people with T2DM. In conclusion, the prevalence rates of NAFLD and obesity were highest in the United States, Belize, Barbados, and Mexico.

  18. Ultrasound image texture processing for evaluating fatty liver in peripartal dairy cows

    NASA Astrophysics Data System (ADS)

    Amin, Viren R.; Bobe, Gerd; Young, Jerry; Ametaj, Burim; Beitz, Donald

    2001-07-01

    The objective of this work is to characterize the liver ultrasound texture as it changes in diffuse disease of fatty liver. This technology could allow non-invasive diagnosis of fatty liver, a major metabolic disorder in early lactation dairy cows. More than 100 liver biopsies were taken from fourteen dairy cows, as a part of the USDA-funded study for effects of glucagon on prevention and treatment of fatty liver. Up to nine liver biopsies were taken from each cow during peripartal period of seven weeks and total lipid content was determined chemically. Just before each liver biopsy was taken, ultrasonic B-mode images were digitally captured using a 3.5 or 5 MHz transducer. Effort was made to capture images that were non-blurred, void of large blood vessels and multiple echoes, and of consistent texture. From each image, a region-of-interest of size 100-by-100 pixels was processed. Texture parameters were calculated using algorithms such as first and second order statistics, 2D Fourier transformation, co-occurrence matrix, and gradient analysis. Many cows had normal liver (3% to 6% total lipid) and a few had developed fatty liver with total lipid up to 15%. The selected texture parameters showed consistent change with changing lipid content and could potentially be used to diagnose early fatty liver non-invasively. The approach of texture analysis algorithms and initial results on their potential in evaluating total lipid percentage is presented here.

  19. Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease.

    PubMed

    Michaut, Anaïs; Moreau, Caroline; Robin, Marie-Anne; Fromenty, Bernard

    2014-08-01

    Although acetaminophen (APAP) is usually considered as a safe drug, this painkiller can lead to acute liver failure after overdoses. Moreover, there is evidence that the maximum recommended dosage can induce hepatic cytolysis in some individuals. Several predisposing factors appear to enhance the risk and severity of APAP-induced liver injury including chronic alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions linked to obesity. In contrast, obesity by itself does not seem to be associated with a higher risk of APAP-induced liver injury. Since 1987, seven studies dealt with APAP-induced hepatotoxicity in rodent models of NAFLD and five of them found that this liver disease was associated with higher APAP toxicity. Unfortunately, these studies did not unequivocally established the mechanism(s) whereby NAFLD could favour APAP hepatotoxicity, although some investigations suggested that pre-existent induction of hepatic cytochrome P450 2E1 (CYP2E1) could play a significant role by increasing the generation of N-acetyl-p-benzoquinone imine (NAPQI), the toxic metabolite of APAP. Moreover, pre-existent mitochondrial dysfunction associated with NAFLD could also be involved. In contrast, some investigations suggested that factors that could reduce the risk and severity of APAP hepatotoxicity in obesity and NAFLD include higher hepatic APAP glucuronidation, reduced CYP3A4 activity and increased volume of body distribution. Thus, the occurrence and the outcome of APAP-induced liver injury in an obese individual with NAFLD might depend on a delicate balance between metabolic factors that can be protective and others that favour large hepatic levels of NAPQI. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease

    SciTech Connect

    Prasad, Vikram; Chirra, Shivani; Kohli, Rohit; Shull, Gary E.

    2014-07-25

    Highlights: • FXR, PGC1α and PPARγ levels are upregulated in NHE1 deficient livers. • NHE1 deficiency downregulates expression of pro-lipogenic genes in liver. • Chronic exposure to high-fat diet upregulates hepatic NHE1 expression. • Loss of NHE1 better preserves hepatic insulin signaling in high-fat diet-fed mice. - Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na{sup +}/H{sup +} exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.

  1. [Acute fatty liver in pregnancy. Experience of 7 years].

    PubMed

    Cejudo Carranza, E; Helguera Martínez, A; García Cáceres, E

    2000-05-01

    The purpose of this clinical investigation was to evaluate the frequency, clinical presentation, evolution, and maternal-fetal morbimortality of Acute Fatty Liver of Pregnancy (AFL). Over a period of 7 years from January 1990 to December 1996 the charts of patients with diagnosis of Gestational Acute Fatty Liver released from the Adult Intensive Care Unit of the Hospital Luis Castelazo Ayala of the Instituto Mexicano del Seguro Social were examined. The following information was retrieved: presenting symptoms, diagnosis on admission to the hospital and intensive care unit, evolution, laboratory, paraclinical, biopsy and serological findings, complications in mother and child, management and method of terminating pregnancy. Twelve cases of AFL of Pregnancy were detected. The disease was not suspected on hospital admission in the majority of the cases; all sought attention because of an obstetric complication requiring termination of pregnancy such as acute fetal distress or rupture of membranes. The average age of the patients was 25 years with an average gestational age of the fetuses of 36 weeks. Symptoms were presented one to seven days and consisted of jaundice in 100% of the cases, systemic hypertension in 75%, abdominal pain in 67%, nausea and vomiting in 50%, preeclampsia in 41% and consciousness disturbances in 17%. Outstanding laboratory findings included TGO 57 +/- 108 U/L, TGP 53 +/- 114 U/L, hypocholesterolemia 79 +/- 30 mg/dL, total bilirubin 15.6 +/- 7 mg/dL, coagulation times prolonged almost two fold, leukocytosis, thrombocytopenia of 41,883 +/- 24,352 mm3, hypoglycemia of 51 +/- 16 mg/dL, and serum creatinine of 2.8 +/- 1.7 mg/dL. Ultrasound was performed in all patients but showed no specific alterations. CT scans on four patients demonstrated positive evidence in. Liver biopsies were performed on seven patients. The principal complications were DIC, hypoglycemia, acidosis, acute kidney failure, encephalopathy, three still births and one maternal

  2. [Acute fatty liver of pregnancy. About 22 cases].

    PubMed

    Bahloul, M; Dammak, H; Khlaf-Bouaziz, N; Trabelsi, K; Khabir, A; Ben Hamida, C; Kallel, H; Ksibi, H; Chelly, H; Chaari, A; Rekik, N; Bouaziz, M

    2006-01-01

    To report the clinical experience, biochemical findings, complications and maternal outcome in patients with acute fatty liver of pregnancy (AFLP). Retrospective study over a period of 11 years (1993-2003). The diagnosis of AFLP was confirmed by liver biopsy in 15 women. However, in 7 women a medical committee that took into account clinical symptoms, and laboratory findings assessed the diagnosis. Were included in this study, 22 women with a mean age of 30+/-5.4 years. Only 22.7% of cases were primigravid. The mean gestational age was 36+/-2.76 weeks (range 31-41 weeks). The fetus was a male infant in 75% of cases. Ten women were admitted in the hospital without jaundice. However 15 women had developed an icterus since their hospital admission or during ICU stay. The mean SAPS II on the ICU admission was of 24.86+/-11.2 points. Biological disturbances observed were mainly: liver cytolysis in 91% of cases, a trend to hypoglycaemia in 86%, a hypoprotidemia in 66.7% and CIVD in 32%. During their ICU stay, 19 women (86.4%) developed one or several organ failures associated to the hepatic failure and 18 women required blood transfusion. After an average stay of 7.5 days, evolution was marked by the death of seven patients (31.8%). Factors correlated with a poor prognosis were: the delay of medical consultation, the development of jaundice, the development of encephalopathy, respiratory or a circulatory failure. AFLP is a rare but life-threatening complication. Furthermore AFLP shares features with other more common and less perilous illnesses. An early diagnosis and appropriate therapy of this pathology should improve the poor prognosis in our country.

  3. The association of vitamin D deficiency with non-alcoholic fatty liver disease

    PubMed Central

    Küçükazman, Metin; Ata, Naim; Dal, Kürşat; Yeniova, Abdullah Özgür; Kefeli, Ayşe; Basyigit, Sebahat; Aktas, Bora; Akin, Kadir Okhan; Ağladioğlu, Kadir; Üre, Öznur Sari; Topal, Firdes; Nazligül, Yaşar; Beyan, Esin; Ertugrul, Derun Taner

    2014-01-01

    OBJECTIVE: Vitamin D deficiency has been related to diabetes, hypertension, hyperlipidemia and peripheral vascular disease. In this study, we aimed to investigate the role of vitamin D status in non-alcoholic fatty liver disease. METHODS: We included 211 consecutive subjects to examine the presence of non-alcoholic fatty liver disease. Of these subjects, 57 did not have non-alcoholic fatty liver disease and 154 had non-alcoholic fatty liver disease. RESULTS: The non-alcoholic fatty liver disease group had significantly higher fasting blood glucose (p = 0.005), uric acid (p = 0.001), aspartate aminotransferase (p<0.001), alanine aminotransferase (p<0.001), γ-glutamyltransferase (p<0.0001), alkaline phosphatase (p = 0.028), HbA1c (p<0.001), ferritin (p<0.001), insulin (p = 0.016), C-peptide (p = 0.001), HOMA-IR (p = 0.003), total cholesterol (p = 0.001), triglyceride (p = 0.001) and white blood cell (p = 0.04) levels. In contrast, the non-alcoholic fatty liver disease group had significantly lower 25(OH)D levels (12.3±8.9 ng/dl, p<0.001) compared with those of the control group (20±13.6 ng/dl). CONCLUSIONS: In this study, we found lower serum 25(OH)D levels in patients with non-alcoholic fatty liver disease than in subjects without non-alcoholic fatty liver disease. To establish causality between vitamin D and non-alcoholic fatty liver disease, further interventional studies with a long-term follow-up are needed. PMID:25141113

  4. PCB126-Induced Disruption in Gluconeogenesis and Fatty Acid Oxidation Precedes Fatty Liver in Male Rats

    PubMed Central

    Gadupudi, Gopi S.; Klaren, William D.; Olivier, Alicia K.; Klingelhutz, Aloysius J.; Robertson, Larry W.

    2016-01-01

    3,3′,4,4′,5-Pentachlorobiphenyl (PCB126), a dioxin-like polychlorinated biphenyl (PCB) and a potent aryl hydrocarbon receptor (AhR) agonist, is implicated in the disruption of both carbohydrate and lipid metabolism which ultimately leads to wasting disorders, metabolic disease, and nonalcoholic fatty liver disease. However, the mechanisms are unclear. Because liver is the target organ for PCB toxicity and responsible for metabolic homeostasis, we hypothesized that early disruption of glucose and lipid homeostasis contributes to later manifestations such as hepatic steatosis. To test this hypothesis, groups of male Sprague Dawley rats, fed on AIN-93G diet, were injected (intraperitoneal.) with a single bolus of PCB126 (5 µmol/kg) at various time intervals between 9 h and 12 days prior to euthanasia. An early decrease in serum glucose and a gradual decrease in serum triglycerides were observed over time. Liver lipid accumulation was most severe at 6 and 12 days of exposure. Transcript levels of cytosolic phosphoenol-pyruvate carboxykinase (Pepck-c/Pck1) and glucose transporter (Glut2/Slc2a2) involved in gluconeogenesis and hepatic glucose transport were time-dependently downregulated between 9 h and 12 days of PCB126 exposure. Additionally, transcript levels of Pparα, and its targets acyl-CoA oxidase (Acox1) and hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), were also downregulated, indicating changes in peroxisomal fatty acid oxidation and ketogenesis. In a separate animal study, we found that the measured changes in the transcript levels of Pepck-c, Glut2, Pparα, Acox1, and Hmgcs2 were also dose dependent. Furthermore, PCB126-induced effects on Pepck-c were demonstrated to be AhR dependent in rat H4IIE hepatocytes. These results indicate that PCB126-induced wasting and steatosis are preceded initially by (1) decreased serum glucose caused by decreased hepatic glucose production, followed by (2) decreased peroxisomal fatty acid oxidation. PMID

  5. The effects of TIS and MI on the texture features in ultrasonic fatty liver images

    NASA Astrophysics Data System (ADS)

    Zhao, Yuan; Cheng, Xinyao; Ding, Mingyue

    2017-03-01

    Nonalcoholic fatty liver disease (NAFLD) is prevalent and has a worldwide distribution now. Although ultrasound imaging technology has been deemed as the common method to diagnose fatty liver, it is not able to detect NAFLD in its early stage and limited by the diagnostic instruments and some other factors. B-scan image feature extraction of fatty liver can assist doctor to analyze the patient's situation and enhance the efficiency and accuracy of clinical diagnoses. However, some uncertain factors in ultrasonic diagnoses are often been ignored during feature extraction. In this study, the nonalcoholic fatty liver rabbit model was made and its liver ultrasound images were collected by setting different Thermal index of soft tissue (TIS) and mechanical index (MI). Then, texture features were calculated based on gray level co-occurrence matrix (GLCM) and the impacts of TIS and MI on these features were analyzed and discussed. Furthermore, the receiver operating characteristic (ROC) curve was used to evaluate whether each feature was effective or not when TIS and MI were given. The results showed that TIS and MI do affect the features extracted from the healthy liver, while the texture features of fatty liver are relatively stable. In addition, TIS set to 0.3 and MI equal to 0.9 might be a better choice when using a computer aided diagnosis (CAD) method for fatty liver recognition.

  6. Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Pirola, Carlos J.; Scian, Romina; Gianotti, Tomas Fernández; Dopazo, Hernán; Rohr, Cristian; Martino, Julio San; Castaño, Gustavo O.; Sookoian, Silvia

    2015-01-01

    Abstract The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n = 90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1–3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R = 0.50, P = 0.000382) and PPARGC1A-mRNA levels (R = −0.57, P = 0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4 ± 0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8 ± 0.8), means ± standard deviation, P = 0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10–1.97; P = 0.005). The p.Ile1762Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and

  7. Induction of fatty acid synthesis by pravastatin sodium in rat liver and primary hepatocytes.

    PubMed

    Fujioka, T; Tsujita, Y; Shimotsu, H

    1997-06-11

    We examined the effect of pravastatin sodium (pravastatin), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on fatty acid synthesis in rat liver. The repeated administration of pravastatin to rats at 250 mg/kg for 7 days led to a 2.8-fold increase in fatty acid synthesis in the liver. The diurnal change of fatty acid synthesis was not affected by the treatment. Hepatic fatty acid synthase activity was increased 3.2-fold, while acetyl-CoA carboxylase activity was not changed by the repeated administration of pravastatin. In rat hepatocytes, the incubation with 2 microg/ml pravastatin for 24 h increased fatty acid synthase activity 1.5-fold, as well as HMG-CoA reductase activity 2.8-fold. These results suggest that HMG-CoA reductase inhibitors might increase fatty acid synthesis in vivo through the induction of hepatic fatty acid synthase.

  8. Liver Toxicity of Anabolic Androgenic Steroid Use in an Adolescent with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Awai, Hannah I; Yu, Elizabeth L; Ellis, Linda S; Schwimmer, Jeffrey B

    2013-01-01

    The prevalence of obesity and related morbidities such as nonalcoholic fatty liver disease (NAFLD) is high among adolescents. Current treatment recommendations for NAFLD focus on lifestyle optimization via nutrition and exercise. After encouraging exercise, many adolescents choose to participate in organized sports, which may lead to use of illicit substances such as anabolic androgenic steroids (AAS) to boost athletic performance. Approximately 3,000,000 individuals use non-therapeutic AAS at supra-physiologic doses in the United States.1 In 2012, 5.9% of adolescent boys reported steroid use in the previous year.2 We anticipate adolescents with pre-existing liver disease are at increased risk for AAS induced hepatotoxicity. We present such a case with IRB approval and written individual patient consent. PMID:23568051

  9. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts.

    PubMed

    Ma, Jiantao; Fox, Caroline S; Jacques, Paul F; Speliotes, Elizabeth K; Hoffmann, Udo; Smith, Caren E; Saltzman, Edward; McKeown, Nicola M

    2015-08-01

    Non-alcoholic fatty liver disease affects ∼30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend=0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend=0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. Copyright © 2015 European Association for the Study of the Liver. All rights reserved.

  10. Development of coaxial ultrasonic probe for fatty liver diagnostic system using ultrasonic velocity change

    NASA Astrophysics Data System (ADS)

    Hori, Makoto; Yokota, Daiki; Aotani, Yuhei; Kumagai, Yuta; Wada, Kenji; Matsunaka, Toshiyuki; Morikawa, Hiroyasu; Horinaka, Hiromichi

    2017-07-01

    A diagnostic system for fatty liver at an early stage is needed because fatty liver is linked to metabolic syndrome. We have already proposed a fatty liver diagnosis method based on the temperature coefficient of ultrasonic velocity. In this study, we fabricated a coaxial ultrasonic probe by integrating two kinds of transducers for warming and signal detection. The diagnosis system equipped with the coaxial probe was applied to tissue-mimicking phantoms including the fat area. The fat content rates corresponding to the set rates of the phantoms were estimated by the ultrasonic velocity-change method.

  11. Fatty Liver and Fatty Heart—Where do They Stand in the AMIS Syndrome?

    PubMed Central

    Lautt, W. Wayne; Ming, Zhi; Legare, Dallas J.; Chowdhury, Kawshik K.; Hatch, Grant M.; Wang, Hui Helen

    2015-01-01

    Meal-induced insulin sensitization (MIS) refers to the augmented glucose uptake response to insulin following a meal. Absence of MIS (AMIS) causes significant decrease in post-meal glucose disposal leading to postprandial hyperglycemia, hyperinsulinemia, hyperlipidemia, adiposity, increased free radical stress, and a cluster of progressive metabolic, vascular, and cardiac dysfunctions referred to as the AMIS syndrome. We tested the hypothesis that fat accumulation in the liver and heart is part of the AMIS syndrome. Questions examined in the study: (1) Is prediabetic fat accumulation in the heart and liver a component of the AMIS syndrome? (2) Is fatty liver a cause or consequence of peripheral insulin resistance? (3) Is early cardiac dysfunction in the AMIS syndrome attributable to fat accumulation in the heart? and (4) Can the synergistic antioxidant cocktail SAMEC (S-adenosylmethionine, vitamin E, and vitamin C), known to benefit MIS, affect cardiac and hepatic triglyceride levels? Four animal models of AMIS were used in aged male Sprague-Dawley rats (52 weeks ± sucrose ± SAMEC), compared with young controls (nine weeks). Fat accumulation in the heart was not significant and therefore cannot account for the early cardiac dysfunction. Hepatic triglycerides increased only in the most severe AMIS model but the small changes correlated with the much more rapidly developing peripheral adiposity. Systemic adiposity represents an early stage, whereas accumulation of cardiac and hepatic triglycerides represents a late stage of the prediabetic AMIS syndrome. Fat accumulation in the liver is a consequence, not a cause, of AMIS. SAMEC protected against the sucrose effects on whole body adiposity and hepatic lipid accumulation. PMID:27417789

  12. Fads1 and 2 are promoted to meet instant need for long-chain polyunsaturated fatty acids in goose fatty liver.

    PubMed

    Osman, Rashid H; Liu, Long; Xia, Lili; Zhao, Xing; Wang, Qianqian; Sun, Xiaoxian; Zhang, Yihui; Yang, Biao; Zheng, Yun; Gong, Daoqing; Geng, Tuoyu

    2016-07-01

    Global prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes a threat to human health. Goose is a unique model of NAFLD for discovering therapeutic targets as its liver can develop severe steatosis without overt injury. Fatty acid desaturase (Fads) is a potential therapeutic target as Fads expression and mutations are associated with liver fat. Here, we hypothesized that Fads was promoted to provide a protection for goose fatty liver. To test this, goose Fads1 and Fads2 were sequenced. Fads1/2/6 expression was determined in goose liver and primary hepatocytes by quantitative PCR. Liver fatty acid composition was also analyzed by gas chromatography. Data indicated that hepatic Fads1/2/6 expression was gradually increased with the time of overfeeding. In contrast, trans-C18:1n9 fatty acid (Fads inhibitor) was reduced. However, enhanced Fads capacity for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis was not sufficient to compensate for the depleted LC-PUFAs in goose fatty liver. Moreover, cell studies showed that Fads1/2/6 expression was regulated by fatty liver-associated factors. Together, these findings suggest Fads1/2 as protective components are promoted to meet instant need for LC-PUFAs in goose fatty liver, and we propose this is required for severe hepatic steatosis without liver injury.

  13. Modern approach to the clinical management of non-alcoholic fatty liver disease.

    PubMed

    Del Ben, Maria; Polimeni, Licia; Baratta, Francesco; Pastori, Daniele; Loffredo, Lorenzo; Angelico, Francesco

    2014-07-14

    Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D3. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease.

  14. Phenotype, Body Composition, and Prediction Equations (Indian Fatty Liver Index) for Non-Alcoholic Fatty Liver Disease in Non-Diabetic Asian Indians: A Case-Control Study.

    PubMed

    Bhatt, Surya Prakash; Misra, Anoop; Nigam, Priyanka; Guleria, Randeep; Pasha, M A Qadar

    2015-01-01

    In this study, we have attempted comparison of detailed body composition phenotype of Asian Indians with non-alcoholic fatty liver disease (NAFLD) vs. those without, in a case controlled manner. We also aim to analyse prediction equations for NAFLD for non-diabetic Asian Indians, and compare performance of these with published prediction equations researched from other populations. In this case-control study, 162 cases and 173 age-and sex-matched controls were recruited. Clinical, anthropometric, metabolic, and body composition profiles, and liver ultrasound were done. Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), and serum high sensitive C-reactive protein (hs-CRP) levels were evaluated. Multivariate logistic and linear regression analyses were used to arrive at prediction equations for fatty liver [Indian fatty liver index (IFLI)]. As compared to those without fatty liver, those with fatty liver exhibited the following; Excess dorsocervical fat ('Buffalo hump'), skin tags, xanthelasma, 'double chin', arcus; excess total, abdominal and subcutaneous adiposity, and high blood pressure, blood glucose, measures of insulin resistance (fasting insulin and HOMA-IR values), lipids and hs-CRP levels. Two prediction equations were developed; Clinical [Indian Fatty Liver Index-Clinical; IFLI-C]: 1(double chin) +15.5 (systolic blood pressure) +13.8 (buffalo hump); and IFLI-Clinical and Biochemical (CB): serum triglycerides+12 (insulin)+1(systolic blood pressure) +18 (buffalo hump). On ROC Curve analysis, IFLI performed better than all published prediction equations, except one. Non-diabetic Asian Indians with NAFLD researched by us were overweight/obese, had excess abdominal and subcutaneous fat, multiple other phenotypic markers, had higher insulin resistance, glycemia, dyslipidemia and subclinical inflammation than those without. Prediction score developed by us for NAFLD; IFLI-C and IFLI-CB, should be useful for clinicians

  15. Non-alcoholic fatty liver disease and liver transplantation: Outcomes and advances

    PubMed Central

    Said, Adnan

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide. In the last decade it has become the third most common indication for liver transplantation in the United States. Increasing prevalence of NAFLD in the general population also poses a risk to organ donation, as allograft steatosis can be associated with non-function of the graft. Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease, although long term outcomes beyond 10 year are lacking. NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted. De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease. Predictors for NAFLD post-transplant recurrence include obesity, hyperlipidemia and diabetes as well as steroid dose after liver transplantation. A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk. Although immunosuppression side effects potentiate obesity and the metabolic syndrome, studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population. Based on pre-transplant data, sustained weight loss through diet and exercise is the most effective therapy for NAFLD. Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents. Studies of these therapies are lacking in the post-transplant population. A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD. PMID:24409043

  16. Systemic symptoms in non-alcoholic fatty liver disease.

    PubMed

    Newton, Julia L

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in the Western world and the incidence of the disease is constantly increasing. Most patients with NAFLD do not present with symptoms directly attributable to their underlying liver disease. It is increasingly recognized, however, that those with NAFLD describe a range of non-specific symptoms, which include fatigue and daytime sleepiness, may be the presenting problem and can impact dramatically upon quality of life in this patient group. The recognition of systemic symptoms in NAFLD has important implications for patients as many are potentially modifiable with targeted interventions. Fatigue appears to be a significant problem in NAFLD and the severity of fatigue is not associated with severity of NAFLD or any parameters of liver damage. Instead, fatigue in these patients shows a strong relationship with the symptom of daytime sleepiness and autonomic dysfunction. Daytime sleepiness can frequently be associated with obstructive sleep apnoea in those with NAFLD and is therefore treatable with evidence-based interventions. Recent studies have confirmed the presence of autonomic nervous system dysfunction in those with early stages of NAFLD. The presence of autonomic nervous system dysfunction leads to symptoms such as postural dizziness and syncope and is also associated with a number of clinical consequences in hepatic and non-hepatic diseases such as cognitive dysfunction, falls and fall-related injuries. On direct questioning, problems with memory and concentration are frequently described by those with NAFLD, with our studies confirming that 50% of NAFLD patients experience mild cognitive symptoms and up to 46% moderate or severe cognitive impairment. There were no positive correlations between cognitive symptoms and biochemical or histological markers of liver damage severity, confirming that cognitive impairment in early-stage NAFLD is not related to hepatic encephalopathy. Falls are

  17. The effects of bariatric surgeries on nonalcoholic fatty liver disease.

    PubMed

    Aldoheyan, Tamadar; Hassanain, Mazen; Al-Mulhim, Amnah; Al-Sabhan, Atheer; Al-Amro, Shaden; Bamehriz, Fahad; Al-Khalidi, Hisham

    2017-03-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with obesity. Bariatric surgery has been shown to be the most effective method for weight reduction. However, no conclusive data exists on the effects of weight reduction surgery on NAFLD. This study aimed to characterize liver histology, metabolic status, and liver function changes in patients who underwent bariatric surgery, before and after the weight-reduction procedure. This is a phase 1 report of a prospective cohort study of patients who underwent bariatric surgery. Biopsies were obtained at baseline (intraoperatively) and 3 months postoperatively. Clinical characteristics, biochemical profile, and histopathological data [steatosis, NAFLD activity score (NAS), hepatocyte ballooning, lobular inflammation, and degree of fibrosis] were obtained at each time point. Twenty-seven patients were included (9 men and 18 women), and the median age was 35 ± 8 years old. At baseline, 3 patients had dyslipidemia, 4 had diabetes, and 5 patients had hypertension, which did not change at follow-up. The average body mass index decreased from 44.6 ± 7.8 to 34.2 ± 6.3 kg/m(2) at follow-up (P < 0.001). On histopathology, 12 of the 18 patients with preoperative steatosis (median score 2) had reduced steatosis scores postoperatively (P = 0.025); fibrosis (median score 1) was also reduced in 17 patients (P = 0.012), and NAS was decreased from 4 (3-5) to 2 (1-3) (P = 0.004). The changes in lobular inflammation and hepatocyte ballooning were not statistically significant on follow-up. The phase 1 results of this study described the histopathological changes following weight reduction surgery and suggested that hepatic steatosis, fibrosis, and NAFLD activity score were reduced 3 months after surgery. This clinical trial is financially supported by the National Plan for Science, Technology and Innovation Program grant number (11-MED1910-02).

  18. Management of nonalcoholic fatty liver disease: a 60-year-old man with probable nonalcoholic fatty liver disease: weight reduction, liver biopsy, or both?

    PubMed

    Afdhal, Nezam H

    2012-08-08

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common hepatic disorders in the United States, but uncertainty remains as to the optimal way to manage it. Using the case of Mr T, a 60-year-old man with obesity, diabetes mellitus, and increased serum transaminase levels, an evidence-based approach to diagnosis and treatment is discussed. Diagnosis of NAFLD is based on patient clinical profile and risk factors for metabolic syndrome, the exclusion of other liver diseases, radiologic imaging and sometimes biopsy. At this point in Mr T's disease, the most important step is differentiation between simple steatosis and nonalcoholic steatohepatitis (NASH). Simple steatosis has a benign natural history, but NASH is progressive and may lead to cirrhosis, liver failure, and liver cancer. An evidence-based approach to treatment is limited by lack of large randomized trials, particularly of combinations of therapies, but weight loss, exercise, and medical therapies targeted at the mechanism of liver injury in NASH are recommended. Improved noninvasive diagnostic tests, a clearer understanding of the natural history of NAFLD, and large, well-designed clinical trials are needed.

  19. Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids

    PubMed Central

    Song, Byoung-Joon; Moon, Kwan-Hoon; Olsson, Nils U.; Salem, Norman

    2008-01-01

    Background/Aims We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6, omega-6) and docosahexaenoic (DHA,22:6n3, omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver. Methods Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated. Results Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet. Conclusions Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress. PMID:18571270

  20. OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Nam, Minwoo; Lei, Shi; Cooper, Marcus P.

    2015-01-01

    OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance—ROS and PKCε activity—were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD. PMID:25933096

  1. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts

    PubMed Central

    Ma, Jiantao; Fox, Caroline S.; Jacques, Paul F.; Speliotes, Elizabeth K.; Hoffmann, Udo; Smith, Caren E.; Saltzman, Edward; McKeown, Nicola M.

    2016-01-01

    Background & Aims Non-alcoholic fatty liver disease affects ~30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Methods Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/-day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. Results After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend = 0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. Conclusion In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. PMID:26055949

  2. Metabolic Syndrome, Insulin Resistance and Fatty Liver in Obese Iranian Children

    PubMed Central

    Saki, Forough; Karamizadeh, Zohreh

    2014-01-01

    Background: Obesity is a global epidemic and its morbidities such as metabolic syndrome, insulin resistance, and fatty liver leads to a spectrum of psycho-social and medical consequences. Objectives: The objective of this study was to investigate the prevalence of fatty liver in obese Iranian children and its' association with metabolic syndrome and insulin resistance. Patients and Methods: 102 obese Iranian children, referred to pediatric clinics from March 2011 to March 2012, were enrolled in this cross-sectional study. All the patients were visited by a pediatric endocrinologist, a pediatric gastroenterologist and an expert radiologist in the evaluation of fatty liver grading. Results: The grade of fatty liver was higher in older children (P = 0.001). It was also more in taller and heavier children (P = 0.000). The more the BMI was, the more the fatty liver grade was (P = 0.002). Severity of fatty liver according to liver sonography in patient had a positive relationship with waist circumference, hip circumference, serum TG, serum FBS, serum fasting insulin, serum ALT, systolic blood pressure and HOMA index and had a negative correlation with the level of alkaline phosphatase. Severity of fatty liver also had a close relationship with the presence of acanthosis nigricans and HOMA index. Conclusions: Prevalence of fatty liver is high in our obese children. It was associated with criteria of metabolic syndrome and insulin resistance, so visceral fat may participate in the pathogenesis of the metabolic syndrome or merely serve as a marker of increased risk for the metabolic complications of obesity. PMID:25031864

  3. Fatty Liver is Associated With Dyslipidemia and Dysglycemia Independent of Visceral Fat: The Framingham Heart Study

    PubMed Central

    Speliotes, Elizabeth K.; Massaro, Joseph M.; Hoffmann, Udo; Vasan, Ramachandran S.; Meigs, James B.; Sahani, Dushyant N.; Hirschhorn, Joel N.; O’Donnell, Christopher J.; Fox, Caroline S.

    2010-01-01

    Obesity is not uniformly associated with the development of metabolic sequelae. Specific patterns of body fat distribution, in particular fatty liver, may preferentially predispose at-risk individuals to disease. Here we characterize the metabolic correlates of fat in the liver in a large community-based sample with and without respect to visceral fat. Fatty liver was measured by multi-detector computed tomography of the abdomen in 2589 individuals from the community-based Framingham Heart Study (FHS). Logistic and linear regression were used to determine the associations of fatty liver with cardio-metabolic risk factors adjusted for covariates with and without adjustment for other fat depots (body mass index [BMI], waist circumference [WC], and visceral adipose tissue [VAT]). The prevalence of fatty liver was 17%. Compared to participants without fatty liver, individuals with fatty liver had a higher adjusted odds ratio (OR) of diabetes (DM; OR 2.98; 95% confidence interval [CI], 2.12–4.21), metabolic syndrome (MetS; OR, 5.22; 95% CI, 4.15–6.57), hypertension (HTN; OR 2.73; 95% CI, 2.16–3.44), impaired fasting glucose (IFG; OR 2.95; 95% CI, 2.32–3.75), insulin resistance (IR; OR, 6.16; 95% CI, 4.90 – 7.76), higher triglycerides (TG) and systolic and diastolic blood pressure (SBP, DBP) and lower high density lipoprotein (HDL) and adiponectin levels (p<0.001 for all). After adjustment for other fat depots, fatty liver remained associated with DM, HTN, IFG, MetS, HDL, TG and adiponectin levels (all p<.001), whereas associations with SBP and DBP were attenuated (p >0.05). Conclusion Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of VAT and other obesity measures. This work begins to dissect the specific links between fat depots and metabolic disease. PMID:20336705

  4. Expression of mitochondria-related genes is elevated in overfeeding-induced goose fatty liver.

    PubMed

    Osman, Rashid H; Shao, Dan; Liu, Long; Xia, Lili; Sun, Xiaoxian; Zheng, Yun; Wang, Laidi; Zhang, Rui; Zhang, Yihui; Zhang, Jun; Gong, Daoqing; Geng, Tuoyu

    2016-02-01

    Mitochondrion, the power house of the cell, is an important organelle involving in energy homeostasis. Change in mitochondrial mass and function may lead to metabolic disorders. Previous studies indicate that mitochondrial mass loss and dysfunction are associated with non-alcoholic fatty liver disease (NAFLD) in human and mouse. However, it is unclear whether mitochondrial genes are involved in the development of goose fatty liver. To address this, we determined the response of goose mitochondrial genes to overfeeding and other fatty liver-related factors (e.g., hyperinsulinemia, hyperglycemia, and hyperlipidemia). We first employed RNA-seq technology to determine the differentially expressed genes in the livers from normally-fed vs. overfed geese, followed by bioinformatics analysis and quantitative PCR validation. Data indicated that a majority of mitochondrial genes in the liver were induced by overfeeding. To understand how these genes are regulated in the context of fatty liver, we treated goose primary hepatocytes with high levels of glucose, fatty acids and insulin. The results indicated that these factors had an influence on the expression of some mitochondria related genes. Together, these findings suggest that the induction of mitochondrial gene expression by overfeeding is required for the development of goose fatty liver, and this induction is partially attributable to hyperglycemia, hyperlipidemia and hyperinsulinemia. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Risk Factors for Fatty Liver in the Multicenter AIDS Cohort Study

    PubMed Central

    Price, Jennifer C.; Seaberg, Eric C.; Latanich, Rachel; Budoff, Matthew J.; Kingsley, Lawrence A.; Palella, Frank J.; Witt, Mallory D.; Post, Wendy S.; Thio, Chloe L.

    2014-01-01

    OBJECTIVES Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase the risk of fatty liver disease. We determined the prevalence of and risk factors for fatty liver by comparing HIV-infected men with HIV-uninfected men who have sex with men in the Multicenter AIDS Cohort Study (MACS). METHODS In 719 MACS participants who consumed less than three alcoholic drinks daily, fatty liver was defined as a liver-to-spleen attenuation ratio < 1 on noncontrast computed tomography (CT). We genotyped single nucleotide polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and in other genes previously associated with nonalcoholic fatty liver disease. Risk factors for fatty liver were determined using multivariable logistic regression. RESULTS Among 254 HIV-uninfected men and 465 HIV-infected men, 56 % were White with median age 53 years and median body mass index 25.8 kg/m 2. The vast majority of HIV-infected men (92 %) were on ART, and 87 % of the HIV-infected men were treated with a nucleoside reverse transcriptase inhibitor for a median duration of 8.5 years. Overall, 15 % of the cohort had fatty liver, which was more common in the HIV-uninfected compared with the HIV-infected men (19 vs. 13 %, P= 0.02). In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR) = 0.44, P= 0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR = 2.06, P= 0.005), more abdominal visceral adipose tissue (OR = 1.08 per 10 cm2, P< 0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥ 4.9 (OR = 2.50, P= 0.001). Among HIV-infected men, PNPLA3 (rs738409) non-CC genotype was associated with a higher prevalence of fatty liver (OR = 3.30, P= 0.001) and cumulative dideoxynucleoside exposure (OR = 1.44 per 5 years, P= 0.02). CONCLUSIONS CT-defined fatty liver is common among men at risk for HIV infection

  6. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance.

    PubMed

    Yki-Järvinen, Hannele

    2015-11-05

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%-23% fat and 57%-65% carbohydrate lower liver fat compared to diets with 43%-55% fat and 27%-38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

  7. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Yki-Järvinen, Hannele

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance. PMID:26556368

  8. Quantitative characterization of fatty liver disease using x-ray scattering

    NASA Astrophysics Data System (ADS)

    Elsharkawy, Wafaa B.; Elshemey, Wael M.

    2013-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a dynamic condition in which fat abnormally accumulates within the hepatocytes. It is believed to be a marker of risk of later chronic liver diseases, such as liver cirrhosis and carcinoma. The fat content in liver biopsies determines its validity for liver transplantation. Transplantation of livers with severe NAFLD is associated with a high risk of primary non-function. Moreover, NAFLD is recognized as a clinically important feature that influences patient morbidity and mortality after hepatic resection. Unfortunately, there is a lack in a precise, reliable and reproducible method for quantification of NAFLD. This work suggests a method for the quantification of NAFLD. The method is based on the fact that fatty liver tissue would have a characteristic x-ray scattering profile with a relatively intense fat peak at a momentum transfer value of 1.1 nm-1 compared to a soft tissue peak at 1.6 nm-1. The fat content in normal and fatty liver is plotted against three profile characterization parameters (ratio of peak intensities, ratio of area under peaks and ratio of area under fat peak to total profile area) for measured and Monte Carlo simulated x-ray scattering profiles. Results show a high linear dependence (R2>0.9) of the characterization parameters on the liver fat content with a reported high correlation coefficient (>0.9) between measured and simulated data. These results indicate that the current method probably offers reliable quantification of fatty liver disease.

  9. Current treatment options for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

    PubMed

    Beaton, Melanie D

    2012-06-01

    Nonalcoholic fatty liver disease is the leading cause of liver disease in western society. It is a cause of end-stage liver disease, with increased mortality secondary to cirrhosis and its complications. It is also recognized that cardiovascular disease is a significant cause of death in these patients. Significant work evaluating various treatments has been performed in recent years; however, to date, no ideal therapy exists. Lifestyle modification remains the cornerstone of management. The present article reviews the current status of various treatment modalities evaluated in nonalcoholic fatty liver disease.

  10. Effect of cholesterol feeding and estrogen treatment on synthesis of fatty acids in liver.

    PubMed

    Srinivasan, K; Pynadath, T I

    1977-08-01

    The effect of cholesterol feeding and estrogen administration on synthesis of fatty acids in liver mitochondria, microsomes and cytoplasm of male rabbits has been investigated. The synthesis was measured by the incorporation of [1(-14)C] acetyl CoA or [2(-14)C]malonyl CoA into long chain fatty acids under optimal conditions. It was found that atherogenesis markedly decreased the fatty acid synthesis in cytoplasm. The mitochondrial fatty acid synthesis was not affected by the disease. There was a small but measurable decrease in the synthesis of fatty acids in microsomes. Estrogen had no effect on the synthesis of fatty acids in mitochondria or microsomes. But if effectively counteracted, after a short lag period, the decreased synthesis of cytoplasmic fatty acids observed in atherosclerosis. It is possible that liver fatty acid synthetase is one of the enzyme systems through which estrogens exert their atherosclerosis-retarding effect. The decreased cytoplasmic fatty acid synthesis observed in atherosclerosis might account for the low levels of saturated fatty acids reported in liver and plasma lipids of atherosclerotic animals.

  11. Sonographic assessment of fatty liver: intraobserver and interobserver variability.

    PubMed

    Cengiz, Mustafa; Sentürk, Senem; Cetin, Bulent; Bayrak, Aylin Hasanefendioğlu; Bilek, Senem Uysal

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide and ultrasonography is widely used in the diagnosis and the follow-up we purposed to assess intraobserver and interobserver variability in the sonographic evaluation of the existence and steatosis grades of NAFLD. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and AST to ALT (AST/ALT) ratio were compared between the grades of hepatosteatosis. Hepatic ultrasonography (US) examinations consisted of 5-10 static images of 113 successive adult patients, whose records were in the picture archiving and communication system (PACS) of our hospital were retrospectively evaluated by two experienced radiologists. Hepatic images were graded into 4 groups; as normal, mild, moderate or severe hepatic steatosis. Evaluation of hepatic steatosis of the same set of images was repeated after one month under the same conditions. Interobserver and intraobserver agreement was assessed by using kappa (κ) statistics. In each group, the percentage of individuals with high ALT and/or AST, or AST/ALT ratio over 1 was calculated. The intraobserver agreement was 51%, fair kappa (κ=0.356) for observer 1; and 68%, moderate (κ=0.591) for observer 2. The interobserver agreements in the initial and second readings were 39% and 40%, fair (κ=0.208) and (κ=0.225), respectively. Elevations of ALT and/or AST levels were similar between groups depending on the degree of hepatosteatosis among the patients. Visual assessment of NAFLD by ultrasonography has substantial interobserver variability, and reproducibility of results is limited. More objective imaging modalities are needed to evaluate the degree of hepatosteatosis.

  12. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD)

    PubMed Central

    Sawangjit, Ratree; Chongmelaxme, Bunchai; Phisalprapa, Pochamana; Saokaew, Surasak; Thakkinstian, Ammarin; Kowdley, Kris V.; Chaiyakunapruk, Nathorn

    2016-01-01

    Abstract Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best. Methods: A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015. Outcomes include liver histological outcomes (i.e., fibrosis), all-cause mortality, cirrhosis, and safety. A network meta-analysis was applied to estimate pooled risk ratios (RR). Quality of evidence was assessed using GRADE criteria. Results: A total of 44 studies (n = 3802) were eligible. When compared with placebo, obeticholic acid (OCA) was the only intervention that significantly improved fibrosis with RR (95% CI) of 1.91 (1.15, 3.16), while pentoxyfylline (PTX) demonstrated improved fibrosis without statistical significance with RR (95% CI) of 2.27 (0.81, 6.36). Only thiazolidinedione (TZD) and vitamin E use resulted in significant increase in resolution of NASH, while OCA, TZD, and vitamin E significantly improved other outcomes including NAS, steatosis, ballooning, and inflammation outcomes. Quality of evidence varied from very low (i.e., metformin, PTX on mean change of ballooning grade) to high (OCA, TZD, vitamin E on improving histological outcomes). Limitations of this study were lack of relevant long-term outcomes (e.g., cirrhosis, death, safety), possible small study effect, and few head-to-head studies. Conclusions: Our study suggests potential efficacy of OCA, TZD, and vitamin E in improving histologic endpoints in NAFLD. These findings are however based on a small number of studies. Additional studies are awaited to strengthen this network meta-analysis. PMID:27512874

  13. Resveratrol Ameliorates Alcoholic Fatty Liver by Inducing Autophagy.

    PubMed

    Tang, Liying; Yang, Fengli; Fang, Zhirui; Hu, Chengmu

    2016-01-01

    Alcoholic fatty liver (AFL) is early stage of alcoholic liver disease, which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. The pathogenesis of AFL is associated with excessive lipid accumulation in hepatocytes. Resveratrol (RES), a dietary polyphenol found in red wines and grapes, has been shown to have a hepatoprotective effect. Autophagy is a crucial physiological process in cellular catabolism that involves the regulation of lipid droplets. Autophagy maintains a balance between protein synthesis, degradation and self-recycling. In the present study, we evaluated the protective effects of RES (10[Formula: see text]mg/kg, 30[Formula: see text]mg/kg, 100[Formula: see text]mg/kg) on AFL mice fed with an ethanol Lieber-DeCarli liquid diet, and HepG2 cells in the presence of oleic acid and alcohol to investigate whether resveratrol could induce autophagy to attenuate lipid accumulation. The results showed that RES (30[Formula: see text]mg/kg and 100[Formula: see text]mg/kg) treatment significantly attenuated hepatic steatosis and lowered the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low density lipoprotein cholesterol (LDL-C). H&E staining showed that RES reduced hepatic lipid accumulation. Transmission electron microscopy (TEM) images showed that RES treatment increased the number of autophagosomes and promoted the formation of autophagy. Western blot analysis showed that RES treatment increased the levels of microtubule-associated protein light chain3- II (LC3-II) and Beclin1, decreased expression of p62 protein. In addition, in vitro studies also demonstrated that RES led to the formation of acidic vesicular organelles (AVOs), however, 3-Methyladenine (3-MA), a specific inhibitor of autophagy, obviously inhibited the above effects of RES. In conclusion, RES has protective effects on alcoholic hepatic steatosis, and the potential mechanism might be involved

  14. Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease.

    PubMed

    Ditzel, Eric J; Li, Hui; Foy, Caroline E; Perrera, Alec B; Parker, Patricia; Renquist, Benjamin J; Cherrington, Nathan J; Camenisch, Todd D

    2016-07-01

    Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease.

  15. Aspects of the regulation of long-chain fatty acid oxidation in bovine liver

    SciTech Connect

    Jesse, B.W.; Emery, R.S.; Thomas, J.W.

    1986-09-01

    Factors involved in regulation of bovine hepatic fatty acid oxidation were examined using liver slices. Fatty acid oxidation was measured as the conversion of l-(/sup 14/C) palmitate to /sup 14/CO/sub 2/ and total (/sup 14/C) acid-soluble metabolites. Extended (5 to 7 d) fasting of Holstein cows had relatively little effect on palmitate oxidation to acid-soluble metabolites by liver slices, although oxidation to CO/sup 2/ was decreased. Feeding a restricted roughage, high concentrate ration to lactating cows resulted in inhibition of palmitate oxidation. Insulin, glucose, and acetate inhibited palmitate oxidation by bovine liver slices. The authors suggest the regulation of bovine hepatic fatty acid oxidation may be less dependent on hormonally induced alterations in enzyme activity as observed in rat liver and more dependent upon action of rumen fermentation products or their metabolites on enzyme systems involved in fatty acid oxidation.

  16. Isolated fatty liver from prolonged propofol use in a pediatric patient with refractory status epilepticus.

    PubMed

    Rison, Richard A; Ko, David Y

    2009-07-01

    Propofol is a widely used rapidly acting sedating or hypnotic agent in the intensive care setting. It is generally considered safe in both pediatric and adult patients and has been used frequently in cases of refractory status epilepticus. The formulation of propofol is highly lipophilic to facilitate central nervous system penetration and has a high fat content, and prolonged infusions have been known to cause both extrahepatic complications and hepatomegaly secondary to fatty liver. Whereas extrahepatic manifestations of prolonged propofol infusions have been well reported in non-neurologic intensive care patients, cases of pathologically confirmed fatty liver in patients with status epilepticus are relatively few. Furthermore, these cases of hepatomegaly and fatty liver have been also in the context of concomitant extrahepatic side effects. We report on a pediatric patient with refractory status epilepticus treated with a prolonged propofol infusion who developed isolated pathologically confirmed fatty liver without the usually reported extrahepatic manifestations.

  17. An association of hardness of water with incidence of fatty liver syndrome in laying hens.

    PubMed

    Jensen, L S; Casey, J M; Savage, S I; Britton, W M

    1976-03-01

    Twenty-one samples of water were collected from commercial egg production farms in Georgial with or without a history of fatty liver syndrome. These samples plus a sample of water from the University of Georgia Poultry Farm were analyzed for various mineral elements by atomic absorption, direct reading emission spectroscopy and by neutron activation. Water samples from farms with a history of fatty liver syndrome had signficantly more calcium, magnesium, strontium, sodium, iron and barium than water samples from farms reporting no significant problem with fatty liver syndrome. Levels of manganese, boron, copper zinic and aluminum were not significantly different. Although the results do not prove that water quality is the cause of the disease, they do demonstrate an association of hardness of water with fatty liver syndrome that should be further investigated.

  18. [Retinal and carotid changes in non-alcoholic fatty liver disease].

    PubMed

    Baloşeanu, Cristina; Rogoveanu, I; Mocanu, Carmen

    2013-01-01

    This article presents the results of a study on 85 patients with non-alcoholic fatty liver disease (NAFLD). We evaluate the retinal vascular changes using retinal photography and carotid vascular changes, by ultrasounds, occured in this group of patients.

  19. Which is the best route of administration for cell therapy in experimental model of small-for size syndrome in rats?

    PubMed

    Nacif, Lucas Souto; Ferreira, Amanda Olivotti; Maria, Durvanei Augusto; Kubrusly, Márcia Saldanha; Molan, Nilza; Chaib, Eleazar; D'Albuquerque, Luiz Carneiro; Andraus, Wellington

    2015-02-01

    To evaluate which is the best route of administration for cell therapy in experimental rat model of small-for size syndrome. A total of 40 rats underwent partial hepatectomy (70%) that induces the small-for-size syndrome and were divided into four groups of route administration: intravenous, intraperitoneal, enteral and tracheal. The small-for-size syndrome model was designed with extended partial hepatectomy (70%). The animals were divided into four groups of routes administration: intravenous (n=10) - intravenously through the dorsal vein of the penis; intraperitoneal (n=10) - intraperitoneally in the abdominal cavity; enteral (n=10) - oroenteral with the placement of a number 4 urethral probe and maintained at third duodenal portion; tracheal (n=10) - after tracheal intubation. We track the animals and monitor them for 21 days; during this follow-up we evaluated the result of cell therapy application tracking animals using ultrasound, radiography and PET-scan. Statistical analysis was performed using GraphPad Prism Software(r). Differences were considered significant with the p<0.05. Data are presented as the median and variation for continuous variables. Comparisons between groups were made using analysis of the imaging test by the researchers. All four groups underwent partial hepatectomy of 70% liver tissue targeting the same weight of resected liver. Initially the PET-scan tests showed similarity in administered cells by different routes. However, in few days the route of intravenous administration showed to be the most appropriated to lead cells to the liver followed by enteral. The tracheal and peritoneal routes were not as much successful for this goal. The intravenous route is the best one to cell therapy in experimental rat model of small-for size-syndrome.

  20. Nonalcoholic fatty liver is a risk factor for postprandial hyperglycemia, but not for impaired fasting glucose.

    PubMed

    Shiga, Tomoko; Moriyoshi, Yuriko; Nagahara, Hikaru; Shiratori, Keiko

    2009-01-01

    The first aim of this study was to elucidate the relationship between impaired glucose tolerance (IGT) and nonalcoholic fatty liver. The second was to make a rule regarding to whom 75-g oral glucose tolerance tests (OGTTs) should be applied to identify subjects with IGT and diabetes mellitus (DM) in the annual check-up at the human dry dock. A total of 716 subjects who visited the Department of General Medicine of the International Medical Center of Japan from May 2001 through January 2008 for an annual check-up at the human dry dock were analyzed. We evaluated risk factors related to nonalcoholic fatty liver using multivariate logistic regression analysis and compared the difference of body mass index (BMI) and glucose level at 75-g OGTT at two different time points in subjects whose fatty change had improved or worsened. Nonalcoholic fatty liver was strongly related to 2-h- and 1-h-post-challenge glucose level (P<0.0001 and P=0.018, respectively), but not fasting plasma glucose (FPG) (P=0.706). The risk factors for IGT were nonalcoholic fatty liver (P<0.05), low levels of high-density lipoprotein cholesterol (HDL-C) (P=0.026) and age (P=0.013). A clearly positive relationship was observed between the difference of BMI and 2-h-post-challenge glucose level among the subjects whose fatty change had improved or worsened (R=0.6, P=0.018). Nonalcoholic fatty liver was clearly related to the 2-h- or 1-h-post-challenge glucose level, but not to FPG, in 75-g OGTT, and this IGT was corrected by body weight reduction in accordance with diminished nonalcoholic fatty liver. Thus, 75-g OGTT should be applied to subjects with nonalcoholic fatty liver to evaluate IGT.

  1. [Fine particulate matter and nonalcoholic fatty liver disease].

    PubMed

    Li, M; Li, Y M

    2016-09-20

    Fine particulate matter is defined as the particulate matter with an aerodynamic diameter of < 2.5 μm, i.e., PM2.5. Its surface absorbs large amounts of toxic and hazardous substances, which can deposit in pulmonary alveoli through respiration and reach other organs through pulmonary ventilation. Many studies have confirmed that PM2.5 is closely associated with pulmonary and cardiovascular diseases. Nonalcoholic fatty liver disease(NAFLD)has similar risk factors as these diseases, as well as obesity, hyperlipidemia, and type 2 diabetes, and it is considered a part of metabolic syndrome. In this view, many studies focus on the possible association between PM2.5 and NAFLD in recent years, including epidemiological study and experimental study, so as to investigate possible pathogenic mechanisms. With reference to the research advances in PM2.5 and NAFLD, this article reviews the association between PM2.5 and NAFLD from the aspects of lipid deposition, oxidative stress, and insulin resistance.

  2. Telomere Dysfunction in Nonalcoholic Fatty Liver Disease and Cryptogenic Cirrhosis.

    PubMed

    Laish, Ido; Mannasse-Green, Batya; Hadary, Ruth; Biron-Shental, Tal; Konikoff, Fred M; Amiel, Aliza; Kitay-Cohen, Yona

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC) are considered preneoplastic conditions that might progress to hepatocellular carcinoma. We evaluated parameters of telomere dysfunction in these patient groups to study the correlation between telomere length and the progression of NAFLD. We analyzed peripheral lymphocytes from 22 patients with NAFLD, 20 patients with CC, and 20 healthy, age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization, and cellular senescence was evaluated by the percentage of cells with senescence-associated heterochromatin foci. The expression of telomerase reverse transcriptase (hTERT) mRNA was measured using polymerase chain reaction, and telomere capture (TC) was assessed with 2 Cytocell probes, 15qter and 13qter. Shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD, compared to the CC patients and healthy controls. While hTERT mRNA was significantly decreased, TC was increased in CC patients, compared to the NAFLD group and healthy individuals. Thus, there is a correlation between hTERT mRNA expression and telomere length in patients with NAFLD, which might be related to associated metabolic disorders and the risk of malignant transformation. Patients with CC, on the contrary, elongate their telomeres through the TC mechanism.

  3. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease.

    PubMed

    Jiang, Changtao; Xie, Cen; Li, Fei; Zhang, Limin; Nichols, Robert G; Krausz, Kristopher W; Cai, Jingwei; Qi, Yunpeng; Fang, Zhong-Ze; Takahashi, Shogo; Tanaka, Naoki; Desai, Dhimant; Amin, Shantu G; Albert, Istvan; Patterson, Andrew D; Gonzalez, Frank J

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota-associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.

  4. Audio-visual aid in teaching "fatty liver".

    PubMed

    Dash, Sambit; Kamath, Ullas; Rao, Guruprasad; Prakash, Jay; Mishra, Snigdha

    2016-05-06

    Use of audio visual tools to aid in medical education is ever on a rise. Our study intends to find the efficacy of a video prepared on "fatty liver," a topic that is often a challenge for pre-clinical teachers, in enhancing cognitive processing and ultimately learning. We prepared a video presentation of 11:36 min, incorporating various concepts of the topic, while keeping in view Mayer's and Ellaway guidelines for multimedia presentation. A pre-post test study on subject knowledge was conducted for 100 students with the video shown as intervention. A retrospective pre study was conducted as a survey which inquired about students understanding of the key concepts of the topic and a feedback on our video was taken. Students performed significantly better in the post test (mean score 8.52 vs. 5.45 in pre-test), positively responded in the retrospective pre-test and gave a positive feedback for our video presentation. Well-designed multimedia tools can aid in cognitive processing and enhance working memory capacity as shown in our study. In times when "smart" device penetration is high, information and communication tools in medical education, which can act as essential aid and not as replacement for traditional curriculums, can be beneficial to the students. © 2015 by The International Union of Biochemistry and Molecular Biology, 44:241-245, 2016. © 2015 The International Union of Biochemistry and Molecular Biology.

  5. Cardiovascular Autonomic Dysfunction in Patients of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Kumar, Mavidi Sunil; Singh, Akanksha; Jaryal, Ashok Kumar; Ranjan, Piyush; Deepak, K. K.; Sharma, Sanjay; Pandey, R. M.

    2016-01-01

    Aim. The present study was designed to evaluate the heart rate variability (HRV) in nonalcoholic fatty liver disease (NAFLD) and to assess the effect of grade of NAFLD and diabetic status on HRV. Methods. This cross-sectional study included 75 subjects (25 NAFLD without diabetes, 25 NAFLD with diabetes, and 25 controls). Measurements included anthropometry, body composition analysis, estimation of plasma glucose, serum lipids, hsCRP, and serum insulin. HRV analysis was performed in both time and frequency domains. Results. The time and frequency domain indices of overall variability (SDNN, total power) were significantly lower in NAFLD with diabetes as compared to the controls. However, the LF : HF ratio did not differ among the three groups. The variables related to obesity, lipid profile, and glucose metabolism were also higher in NAFLD with diabetes and those with Grade II NAFLD without diabetes, as compared to controls. Multivariate stepwise regression analysis showed a negative correlation between HRV and total cholesterol and fat percentage. Conclusion. The grade of NAFLD as well as diabetic status contributes to the decrease in the cardiovascular autonomic function, with diabetic status rather than grade of NAFLD playing a critical role. Serum lipids and adiposity may also contribute to cardiac autonomic dysfunction. PMID:28053786

  6. Nonalcoholic fatty liver disease and aging: Epidemiology to management

    PubMed Central

    Bertolotti, Marco; Lonardo, Amedeo; Mussi, Chiara; Baldelli, Enrica; Pellegrini, Elisa; Ballestri, Stefano; Romagnoli, Dante; Loria, Paola

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients. PMID:25339806

  7. Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey.

    PubMed

    Ruhl, C E; Everhart, J E

    2015-01-01

    Validated non-invasive measures of fatty liver are needed that can be applied across populations and over time. A fatty liver index (FLI) including body mass index, waist circumference, triglycerides and gamma glutamyltransferase (GGT) activity was developed in an Italian municipality, but has not been validated widely or examined in a multiethnic population. We evaluated this FLI in the multiethnic U.S. National Health and Nutrition Examination Survey (NHANES) and also to explore whether an improved index for the U.S. population (US FLI) could be derived. The US FLI would then used to examine U.S. time trends in fatty liver prevalence. We studied 5869 fasted, viral hepatitis negative adult participants with abdominal ultrasound data on fatty liver in the 1988-1994 NHANES. Time trend analyses included 21 712 NHANES 1988-1994 and 1999-2012 participants. The prevalence of fatty liver was 20%. For the FLI, the area under the receiver operating characteristic curve [AUC; 95% confidence interval (CI)] was 0.78 (0.74-0.81). The US FLI included age, race-ethnicity, waist circumference, GGT activity, fasting insulin and fasting glucose and had an AUC (95% CI) of 0.80 (0.77-0.83). Defining fatty liver as a US FLI ≥ 30, the prevalence increased from 18% in 1988-1991 to 29% in 1999-2000 to 31% in 2011-2012. For predicting fatty liver, the US FLI was a modest improvement over the FLI in the multiethnic U.S. population. Using this measure, the fatty liver prevalence in the U.S. population increased substantially over two decades. © 2014 John Wiley & Sons Ltd.

  8. Physical activity as a protective factor for development of non-alcoholic fatty liver in men

    PubMed Central

    Pinto, Carla Giuliano de Sá; Marega, Marcio; de Carvalho, José Antonio Maluf; Carmona, Felipe Gambetta; Lopes, Carlos Eduardo Felix; Ceschini, Fabio Luis; Bocalini, Danilo Sales; Figueira, Aylton José

    2015-01-01

    Objective To determine the impact of physical activity on the prevalence of fatty liver, metabolic and cardiovascular disease in adult men. Methods This study evaluated 1,399 men (40.7±8.18 years) with body mass index of 26.7kg/m2 (±3.4) who participated in the Protocol of Preventive Health Check-up at Hospital Israelita Albert Einstein from January to October 2011. We conducted tests of serum blood glucose, total cholesterol, LDL, HDL, triglycerides, reactive c-protein, aspartate transaminase, alanine transaminase and gamma-glutamyl transpeptidase. The statistical analysis comprised in the comparison of mean and standard deviation. The analysis of variance was based in two paths of two way ANOVA, Student’s t-test, Mann Whitney U test, Wald test and χ2. We considered a significance level at p<0.05 and correlation of univariate Poison with 95% confidence interval. Results :Fatty liver was diagnosed in 37.0% of the sample. Triglyceride levels of active men with fatty liver were 148.2±77.6mg/dL while inactive men with fatty liver had 173.4±15.6mg/dL. The remaining serum levels were normal. Inactive individuals showed higher values than active. In addition, inactive individuals have 10.68 times higher risk of developing fatty liver compared with active. Conclusion Physical activity improves metabolic parameters such as triglycerides, weight control, HDL, which interfere in the development of fatty liver. Physically active individuals had lower fatty liver prevalence regardless of values of body composition and lipid profile, leading the conclusion that physical activity has a protective role against development of fatty liver. PMID:25993066

  9. [Changes in lipoglycoprotein metabolism in toxic fatty liver].

    PubMed

    Barisione, G; Fontana, L; Cottalasso, D; Domenicotti, C; Pronzato, M A; Nanni, G

    1993-09-01

    A number of agents that produce liver injury also cause the accumulation of an abnormal amount of fat, predominantly triglycerides (TGs) in the parenchymal cells. Fatty liver (FL) is the result of an hepatocyte imbalance between the rate of synthesis and output of TGs into the plasma. TGs are not secreted as such, but combined with a glycoprotein moiety, and particularly with the very low density lipoproteins (VLDLs). This fraction is involved in the transport of hepatic TGs to extrahepatic tissues. FL can be induced by either acute or chronic administration of ethanol (EtOH), and/or several haloalkanes (carbon tetrachloride, CCl4; 1.2-dichloroethane, DCE; 1.1.2.2-tetrachloroethane, TTCE), both in laboratory animals and in man. Since the pathogenesis of this disease is a crucial problem, as yet undefined, the purpose of this article is to summarize the studies which have unraveled some of the mechanisms involved in FL, particularly the role played by impaired lipoglycoproteins (LGP) metabolism in rat liver. An important element in the pathogenesis of EtOH- and haloalkanes-induced FL is the impairment of hepatic secretion of VLDLs, which occurs soon after poisoning. Various steps of the secretory pathway are probably involved in the expression of such damage. The intoxication of rats with these xenobiotics leads to an early impairment of the hepatocyte system responsible for terminal glycosylation and maturation of LGP at the level of three different subfractions (F1, F2 and F3) of purified Golgi apparatus (GA). The earliest functional change is a block of LGP transit through the GA cisternae and vesicles, both in isolated hepatocyte model and in the whole animal. The glycosylation of LGP is a multistep process which starts in the rough endoplasmic reticulum (RER), and comes to its end in the GA. Dolichols (Dol) are a family of long-chain polyisoprenoid alcohols, present either as neutral free-Dol and dolichyl-phosphate (Dol-P). The latter acts as a glycosyl carrier

  10. Association between nocturnal hypoxia and liver injury in the setting of nonalcoholic fatty liver disease.

    PubMed

    Lin, Qi-Chang; Chen, Li-Da; Chen, Gong-Ping; Zhao, Jian-Ming; Chen, Xiao; Huang, Jie-Feng; Wu, Li-Hua

    2015-03-01

    Obstructive sleep apnea (OSA) is suggested as a potential risk factor of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism is still far from clear. The aim of this observational study was to investigate the influence of OSA-related hypoxia on severity of liver injury in patients with NAFLD. Consecutive patients with ultrasound-diagnosed NAFLD who underwent standard polysomnography were enrolled. Fasting blood samples were obtained from all patients for biological profile measurements, and demographic data were collected. Subjects were divided into control, moderate, and severe groups. A total of 85 subjects with 73 males and 12 females were included (mean age, 44.67 ± 1.28 years; mean body mass index, 27.28 ± 0.33 kg/m(2)). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, gamma glutamyltransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose, and high-sensitivity C-reactive protein significantly increased with the aggravation of OSA. In multivariate analysis, oxygen desaturation index was the major contributing factor for elevated ALT (β = 0.435, p = 0.000), average O2 saturation was the major independent predictor of elevated AST (β = -0.269, p = 0.020). OSA-related hypoxia was independently associated with the biochemical evidence of liver injury in the presence of NAFLD.

  11. Sex impact on the quality of fatty liver and its genetic determinism in mule ducks.

    PubMed

    Marie-Etancelin, C; Retailleau, B; Alinier, A; Vitezica, Z G

    2015-09-01

    Recent changes to French regulations now allow farmers to produce "foie gras" from both male and female mule ducks. The aim of this study was to assess the quality of female fatty liver and to compare, from a phenotypic and genetic point of view, liver quality in males and females. A total of 914 mule ducks (591 males and 323 females), hatched in a single pedigree batch, were reared until 86 d of age and then force-fed for 12 d, before being slaughtered. Carcasses and livers were weighed and liver quality was assessed by grading the extent of liver veining and measuring the liver melting rate, either after sterilization of 60 g of liver or pasteurization of 180 g of liver. Sexual dimorphism was observed in favor of males, with a difference of approximately 10% in carcass and liver weights and up to 54% for the liver melting rate. Moreover, one-third of female livers showed moderate to high veining, whereas this was not the case for male livers. The fatty livers of female mule ducks are, therefore, of poorer quality and could not be transformed into a product with the appellation "100% fatty liver." According to sex and parental line, heritability values ranged from 0.12 ± 0.05 to 0.18 ± 0.07 for fatty liver weight and from 0.09 ± 0.05 to 0.18 ± 0.05 for the 2 melting rate traits. The genetic correlations between the fatty liver weight and both melting rates were high (greater than +0.80) in the Muscovy population, whereas in the Pekin population, the liver weight and melting rates were less strongly correlated (estimates ranging from +0.36 ± 0.30 to +0.45 ± 0.28). Selection for lower liver melting rates without reducing the liver weight would, therefore, be easier to achieve in the Pekin population. Finally, as the 2 melting rate measurements are highly correlated (0.91 and over 0.95 for phenotypic and genetic correlations, respectively), we suggest using the easiest method, that is, sterilization of 60 g of liver.

  12. A novel cause for abnormal liver function tests in pregnancy and the puerperium: non-alcoholic fatty liver disease.

    PubMed

    Page, L M; Girling, J C

    2011-11-01

    Non-alcoholic fatty liver disease (NAFLD) is the commonest liver disease in the western world, but has never been reported in pregnancy before. We suggest that NAFLD should also be considered as a cause for abnormal liver function tests during pregnancy. As NAFLD is driven by insulin resistance, it is biologically plausible that pregnancy may reveal previously subclinical disease. Obstetricians have a vital role in optimising maternal health during and after pregnancy and therefore we need to include NAFLD in the differential diagnosis for abnormal liver function tests and recommend lifestyle modifications that may prevent progression to cirrhosis and hepatocellular carcinoma.

  13. Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease.

    PubMed

    Nobili, Valerio; Giorgio, Valentina; Liccardo, Daniela; Bedogni, Giorgio; Morino, Giuseppe; Alisi, Anna; Cianfarani, Stefano

    2014-04-01

    To investigate the association between plasma vitamin D (VD) levels and histological liver damage in children with nonalcoholic fatty liver disease (NAFLD). In this cross-sectional study, carried out in a tertiary care center for obesity, 73 consecutive overweight and obese children with persistently elevated serum aminotransferase levels and diffusely hyperechogenic liver on ultrasonography were selected for liver biopsy. Nonalcoholic steatohepatitis (NASH) and fibrosis were histologically diagnosed using NAFLD Clinical Research Network (CRN) criteria. The plasma levels of 25-OH-VD were measured by HPLC. Bone mineral density (BMD) of lumbar spine was evaluated by dual-energy X-ray absorptiometry. Multiple linear regression analysis was used to evaluate the association between 25-OH-VD levels and the predictors of interest after correction for age, gender, waist circumference, BMI, and other potential confounders. The children (64% males) were aged 8-18 years, and their median BMI was 2.45 SDS. Both parathyroid hormone levels and BMD were within the normal range. All cases of fibrosis were detected in children with NASH. On multivariable linear regression with correction for age, gender, and BMI, 25-OH-VD levels were found to be 9 (95% CI 12-6) ng/ml lower in children with NASH than in those without NASH (P<0.001) and 9 (12-6) ng/ml lower in children with stage 1 fibrosis than in those with stage 0 fibrosis and 9 (13-6) ng/ml lower in children with stage 2 than in those with stage 0 fibrosis (P<0.001 for both). VD levels are inversely associated with NASH and fibrosis in children with NAFLD.

  14. Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects.

    PubMed

    Sato, Motoya; Kamada, Yoshihiro; Takeda, Yuri; Kida, Sachiho; Ohara, Yuka; Fujii, Hironobu; Akita, Maaya; Mizutani, Kayo; Yoshida, Yuichi; Yamada, Makoto; Hougaku, Hidetaka; Takehara, Tetsuo; Miyoshi, Eiji

    2015-03-01

    Fetuin-A (α2HS-glycoprotein), a liver secretory glycoprotein, is known as a transforming growth factor (TGF)-β1 signalling inhibitor. Serum fetuin-A concentration is associated with nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease. However, the usefulness of serum fetuin-A as a predictive fibrosis biomarker in NAFLD patients remains unclear. In this study, we investigated the relationship between circulating fetuin-A levels and fibrosis-related markers [platelet count, NAFLD fibrosis score and carotid intima media thickness (IMT)] in subjects with NAFLD. A total of 295 subjects (male, 164; female, 131) who received medical health check-ups were enrolled in this study. NAFLD was diagnosed using abdominal ultrasonography. Serum fetuin-A was measured by ELISA. IMT was assessed using a high-resolution ultrasound scanner. Using recombinant human fetuin-A, we investigated the effects of fetuin-A on hepatic stellate cells, which play a pivotal role in the process of hepatic fibrosis. Serum fetuin-A concentration was significantly correlated with platelet count (R = 0.19, P < 0.01), NAFLD fibrosis score (R = -0.25, P < 0.01) and mean IMT (R = -0.22, P < 0.01). Multivariate analyses revealed that the fetuin-A concentration is a significant and independent determinant of platelet count, NAFLD fibrosis score and mean IMT. Recombinant fetuin-A suppressed TGF-β1 signalling and fibrosis-related gene expression and increased the expression of TGF-β1 pseudoreceptor bone morphogenic protein and activin membrane-bound inhibitor (BAMBI). Serum fetuin-A level is associated with liver/vessel fibrosis-related markers in NAFLD patients. Circulating fetuin-A could be a useful serum biomarker for predicting liver and vascular fibrosis progression in NAFLD patients. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Fatty Liver Disease is Associated with Underlying Cardiovascular Disease in HIV-Infected Persons

    PubMed Central

    Crum-Cianflone, Nancy; Krause, David; Wessman, Dylan; Medina, Sheila; Stepenosky, James; Brandt, Carolyn; Boswell, Gilbert

    2010-01-01

    Background Cardiovascular disease is an increasing concern among HIV-infected persons and their providers. We determined if fatty liver disease is a marker for underlying coronary atherosclerosis among HIV-infected persons. Methods We performed a cross-sectional study among HIV-infected adults to evaluate the prevalence of and factors, including fatty liver disease, associated with subclinical coronary atherosclerosis. All participants underwent computed tomography for determination of coronary artery calcium (CAC; positive defined as a score >0) and fatty liver disease (defined as a liver-to-spleen ratio <1.0). Factors associated with CAC were determined using multivariate logistic regression models. Results We studied 223 HIV-infected adults with a median age of 43 years (IQR 36–50), 96% were male, and 49% were Caucasian. Median CD4 count was 586 cells/mm3, and 83% were receiving antiretroviral medications. Seventy-five (34%) had a positive CAC score, and 29 (13%) subjects had fatty liver disease. Among those with CAC scores of 0, 1–100, >100, the percentage with concurrent fatty liver disease was 8%, 18%, and 41%, respectively (p=0.001). In the multivariate model, CAC was associated with increasing age (OR 4.3 per 10 years, p<0.01), hypertension (OR 2.6, p<0.01), and fatty liver disease (OR 3.8, p<0.01). Conclusions Coronary atherosclerosis as detected by CAC is prevalent among young HIV-infected persons. The detection of fatty liver disease among HIV-infected adults should prompt consideration for assessment for underlying cardiovascular disease and risk factor reduction. PMID:21251186

  16. EX VIVO STUDY OF QUANTITATIVE ULTRASOUND PARAMETERS IN FATTY RABBIT LIVERS

    PubMed Central

    Ghoshal, Goutam; Lavarello, Roberto J.; Kemmerer, Jeremy P.; Miller, Rita J.; Oelze, Michael L.

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) affects more than 30% of Americans, and with increasing problems of obesity in the United States, NAFLD is poised to become an even more serious medical concern. At present, accurate classification of steatosis (fatty liver) represents a significant challenge. In this study, the use of high-frequency (8 to 25 MHz) quantitative ultrasound (QUS) imaging to quantify fatty liver was explored. QUS is an imaging technique that can be used to quantify properties of tissue giving rise to scattered ultrasound. The changes in the ultrasound properties of livers in rabbits undergoing atherogenic diets of varying durations were investigated using QUS. Rabbits were placed on a special fatty diet for 0, 3, or 6 weeks. The fattiness of the livers was quantified by estimating the total lipid content of the livers. Ultrasonic properties, such as speed of sound, attenuation, and backscatter coefficients, were estimated in ex vivo rabbit liver samples from animals that had been on the diet for varying periods. Two QUS parameters were estimated based on the backscatter coefficient: effective scatterer diameter (ESD) and effective acoustic concentration (EAC), using a spherical Gaussian scattering model. Two parameters were estimated based on the backscattered envelope statistics (the k parameter and the μ parameter) according to the homodyned K distribution. The speed of sound decreased from 1574 to 1565 m/s and the attenuation coefficient increased from 0.71 to 1.27 dB/cm/MHz, respectively, with increasing fat content in the liver. The ESD decreased from 31 to 17 μm and the EAC increased from 38 to 63 dB/cm3 with increasing fat content in the liver. A significant increase in the μ parameter from 0.18 to 0.93 scatterers/mm3 was observed with increasing fat content in the liver samples. The results of this study indicate that QUS parameters are sensitive to fat content in the liver. PMID:23062376

  17. Fatty acids and cholesterol in the liver cell nuclei of hibernating Yakutian ground squirrels.

    PubMed

    Kolomiytseva, I K; Lakhina, A A; Markevich, L N; Fesenko, E E

    2016-09-01

    The content of neutral lipids in tissue homogenates and liver cell nuclei of hibernating Yakutian ground squirrels was studied. In homogenates, hibernation increases the content of fatty acids and reduces the content of glycerides and cholesterol. When studying the liver cell nuclei of torpid winter ground squirrels, we detected a twofold increase in the content of fatty acids, cholesterol, and monoglycerides as compared to the "summer" ground squirrels. In the active "winter" ground squirrels, as compared to the torpid winter ones, the content of cholesterol did not change, whereas the content of fatty acids, monoglycerides, and diglycerides decreased but remained higher than in the "summer" ground squirrels.

  18. The Effects of Metabolic Surgery on Fatty Liver Disease and Nonalcoholic Steatohepatitis.

    PubMed

    Clanton, Jesse; Subichin, Michael

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is an under-recognized but increasingly important manifestation of the metabolic syndrome. Bariatric surgery, both through direct weight loss and more indirect effects on insulin resistance and improvements in inflammatory proteins, can have a profound effect on NAFLD, resulting in improvement or resolution of even high-grade liver disease.

  19. Factors affecting liver fat accumulation and liver hemorrhages associated with fatty liver-hemorrhagic syndrome in laying chickens.

    PubMed

    Lee, K; Flegal, C J; Wolford, J H

    1975-03-01

    A series of four experiments was conducted with a commercial strain of laying chickens in an attempt to experimentally produce Fatty Liver-Hemorrhagic syndrome (FLHS). Different dietary energy sources, environmental temperatures and feeding schedules were the experimental variables. Increasing the environmental temperature from 12.2 degrees C. (experiment 1) to 27.8 degrees C. (experiment 2) did not drastically alter total liver fat, 2.7 g. (experiment 1) vs. 2.9 g. (experiment 2) or the incidence of FLHS, 0.0% (experiment 1) vs. 1.0% (experiment 2). Likewise, in experiment 4, changing the environmental temperature from 22.2 degrees C. to 30.6 degrees C. or from 30.6 degrees C. to 22.2 degrees C. did not significantly (P greater than .05) alter total liver fat or liver wet weight. The greatest incidence (50%) of FLHS occurred in birds which were restricted in feed intake and exposed to an environmental temperature of 30.6 degrees C. from 32-36 weeks of age followed by ad libitum feeding at a temperature of 22.2 degrees C. from 36-40 weeks of age. These birds ate 26.8% more feed than the control birds during the ad libitum feeding period. Restricted feed schedules (experiment 3) resulted in significantly (P less than .05) lower 40 week liver wet weights and total fat when applied during the growing (14-20 weeks of age) and early lay (20-28 weeks of age) periods.

  20. Metabolic syndrome in childhood from impaired carbohydrate metabolism to nonalcoholic fatty liver disease.

    PubMed

    Manco, Melania

    2011-10-01

    Compelling evidence supports the concept that nonalcoholic fatty liver disease (NAFLD) represents the hepatic component of metabolic syndrome (MetS). Intrahepatic fat seems to predict more strongly than does visceral adiposity an individual's cardiovascular risk and the likelihood that metabolic abnormalities are present in youth. Young individuals with fatty liver are more insulin resistant and present with a higher prevalence of metabolic abnormalities than do individuals without intrahepatic fat accumulation. They also present with a certain endothelial dysfunction and greater carotid intima-media thickness. Conversely, youth with MetS seem to have an increased risk of developing liver inflammation, a condition termed nonalcoholic steatohepatitis (NASH), and fibrosis. In the context of MetS, the liver is central in that it can drive both hepatic and systemic insulin resistance, trigger low-grade inflammation, and promote atherogenic processes. In the context of MetS, NAFLD and altered carbohydrate metabolism track from childhood to adulthood. Thus, prevention, recognition, and effective treatment of these two abnormalities may limit the burden of morbidity and mortality associated with obesity and may delay onset of cardiovascular disease in early adulthood. The present review aims at systematically presenting evidence of the critical interplay of fatty liver and altered glucose metabolism in youth. It attempts to provide pathogenetic explanations for such an association and the rationale for its treatment, with particular regard to nutritional interventions. Key teaching points: Overweight and obese youth should be screened for fatty liver disease once after puberty by liver function tests and ultrasonography. Screening for fatty liver should be accurately performed in young patients with features of metabolic syndrome. Obese patients with fatty liver are at increased risk for altered glucose metabolism, thus they should undergo an oral glucose tolerance test

  1. Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver-mesenteric adipose tissue fatty acid mobilization

    USDA-ARS?s Scientific Manuscript database

    The incidence of nonalcoholic fatty liver disease (NAFLD) is escalating paralleled with obesity rates in both adults and children. Mammalian sirtuin 1 (SIRT1), a highly conserved NAD+-dependent protein deacetylase, has been identified as a metabolic regulator of lipid homeostasis and a potential tar...

  2. Non-alcoholic fatty liver disease: a new epidemic in children.

    PubMed

    Ciocca, Mirta; Ramonet, Margarita; Álvarez, Fernando

    2016-12-01

    Non-alcoholic fatty liver disease is considered one of the most common causes of liver disease in adults and children, consistent with the increased prevalence of obesity in both populations worldwide. It is a multifactorial condition involving a broad spectrum of liver diseases than range from simple steatosis to steatohepatitis, and characterized by histological findings of inflammation and fibrosis. Its pathogenesis and progression are not fully understood yet, and a more complete understanding of liver disease may aid in developing new therapies and noninvasive diagnostic tools. Liver biopsy remains the gold standard for disease staging. Although lifestyle and diet modifications are the keys in non-alcoholic fatty liver disease treatment, the development of new drugs may be promising for patients failing first-line therapy. Sociedad Argentina de Pediatría.

  3. Expression of liver fatty acid binding protein in hepatocellular carcinoma☆

    PubMed Central

    Cho, Soo-Jin; Ferrell, Linda D.; Gill, Ryan M.

    2017-01-01

    Summary Loss of expression of liver fatty acid binding protein (LFABP) by immunohistochemistry has been shown to be characteristic of a subset of hepatocellular adenomas (HCAs) in which HNF1A is inactivated. Transformation to hepatocellular carcinoma is thought to be a very rare phenomenon in the HNF1A-inactivated variant of HCA. However, we recently observed 2 cases at our institution, 1 definite hepatocellular carcinoma and 1 possible hepatocellular carcinoma, with loss of LFABP staining, raising the possibility that LFABP down-regulation may be associated with hepatocellular carcinogenesis. Our aim was to evaluate hepatocellular carcinomas arising in various backgrounds and with varying degrees of differentiation for loss of LFABP staining. Twenty total cases of hepatocellular carcinoma were examined. Thirteen cases arose in a background of cirrhosis due to hepatitis C (n = 8) or steatohepatitis (n = 5); 7 cases arose in a noncirrhotic background, with 2 cases arising within HNF1A-inactivated variant HCA and 2 cases arising within inflammatory variant HCA. Complete loss of expression of LFABP was seen in 6 of 20 cases, including 2 cases of hepatocellular carcinoma arising within HNF1A-inactivated variant HCA. Thus, loss of staining for LFABP appears to be common in hepatocellular carcinoma and may be seen in well-differentiated hepatocellular carcinoma. Therefore, LFABP loss should not be interpreted as evidence for hepatocellular adenoma over carcinoma, when other features support a diagnosis of hepatocellular carcinoma. The findings raise consideration for a role of HNF1A inactivation in hepatocellular carcinogenesis, particularly in less differentiated tumors. PMID:26997447

  4. Prevalence of Hypothyroidism in Nonalcoholic Fatty Liver disease

    PubMed Central

    Pagadala, Mangesh R.; Zein, Claudia O.; Dasarathy, Srinivasan; Yerian, Lisa; Lopez, Rocio; McCullough, Arthur J.

    2014-01-01

    Background A possible association between nonalcoholic fatty liver disease (NAFLD) and hypothyroidism has been suggested. Possible explanations for this association are the recognized links between hypothyroidism and various elements of the metabolic syndrome which is often present in NAFLD. To further explore this association, we determined the prevalence of hypothyroidism in a cohort of patients with NAFLD and analyzed the potential factors associated with hypothyroidism in this patient population. Methods Two hundred and forty six patients with biopsy proven NAFLD attending hepatology clinics at the Cleveland Clinic between October 2006 to June 2009 and 430 age, gender, race and BMI matched control subjects seen in the general internal medicine clinic were included. Patients with a clinical diagnosis of hypothyroidism who were on thyroid replacement therapy were considered to be hypothyroid. Results Hypothyroidism was more frequent among patients with NAFLD (21%vs 9.5%.; P<0.01) compared to controls and was higher in NASH patients than NAFLD patients without NASH (25% vs 12.8%, P=0.03). Subjects with hypothyroidism were 2.1 (95% CI: 1.1, 3.9,P=0.02)) and 3.8 (95% CI:2,6.9, P<0.001) times more likely to have NAFLD and NASH respectively. By Multivariate analysis, female gender (P<0.001) and increased BMI (P=.03) were associated with hypothyroidism. NAFLD subjects who reported mild alcohol consumption were less likely to have hypothyroidism compared to those who reported complete abstinence (OR 0.37, P=0.008). Conclusions A higher prevalence of hypothyroidism was demonstrated in patients with NAFLD compared to controls. Patients with hypothyroidism were more likely to have NASH. Among subjects with NALFD, female gender, increased BMI and history of abstinence from alcohol were associated with hypothyroidism. Further studies are needed in order to confirm and better characterized these findings as well as the described associations and their pathogenesis. PMID

  5. Prevalence of Nonalcoholic Fatty Liver Disease and Economy.

    PubMed

    Zhu, Jin-Zhou; Dai, Yi-Ning; Wang, Yu-Ming; Zhou, Qin-Yi; Yu, Chao-Hui; Li, You-Ming

    2015-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a growing health issue around the world. This study is to investigate whether adult prevalence of NAFLD correlates with national economic status. Literature search on PubMed database was conducted to identify eligible records fully published before September 2014. Gross national income (GNI) per capita was chosen to evaluate national economic status. Pearson coefficient, linear regression, and unpaired t test were performed in the statistical analyses. Twenty-one population-based surveys (seven in East Asia, five in South Asia, three in Middle East, and six in Europe) were included. The pooled prevalence of NAFLD was 24.24%, and the global prevalence was positively correlated with GNI per capita (r = 0.4782, P = 0.0283). Europe witnessed a higher prevalence (28.04%) than Middle East (12.95%, P = 0.0092) and East Asia (19.24%, P = 0.0083). Male presented a higher prevalence than female (P = 0.019), especially in Europe (P = 0.0132) and in Caucasians (P = 0.0383). Furthermore, male prevalence and rural prevalence individually were correlated with economic status (r = 0.5725, P = 0.0257 and r = 0.7389, P = 0.0060). Lastly, the urban (23.93%) witnessed a higher prevalence than the rural or the urban + rural (12.65%, P = 0.0141) in the countries of GNI per capita <$10,000. This study suggested that countries with higher economic status tend to present a higher prevalence of NAFLD. It is believed to provide a distinctive epidemiologic perspective to global situation of NAFLD.

  6. Clinical significance of fatty liver associated with metabolic syndrome.

    PubMed

    Kogiso, Tomomi; Moriyoshi, Yuriko; Nagahara, Hikaru

    2007-09-01

    Metabolic syndrome (MS) has been recognized as a high-risk disorder that leads to life-threatening diseases, such as coronary vascular disease. The aim of the present study was to investigate the association of fatty liver (FL) with MS in order to establish an effective treatment for FL. One thousand two hundred and fifty-four individuals (694 males, 560 females) who visited the Department of General Medicine, International Medical Center of Japan for a human dry dock annual check-up from 2000 to 2004 were analyzed. FL was diagnosed in 41.5% of the males and 10.7% of the females, with the prevalence rate increasing in postmenopausal females over 55 years old. High body mass index and waist circumference were observed in those with FL, whereas body mass index reduction was strongly correlated with a decrease in alanine aminotransferase level (R = 0.6,P < 0.01). MS complications were more common in subjects with FL and the most common initial events of MS were shown to be obesity, hyperlipidemia and FL, followed by glucose intolerance and hypertension. Subjects with FL showed a higher level of high-sensitivity C-reactive protein (hs-CRP) (normal: FL = 0.38: 0.73 mg/L, P < 0.05), which was strongly correlated with serum markers that indicated lipid and glucose metabolism in females with FL (R = 0.61-0.77, P < 0.05). FL could be a part of or, at least, a predictor of MS. Further, bodyweight reduction is an effective treatment for FL.

  7. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.

    PubMed

    Tilg, Herbert; Moschen, Alexander R

    2010-11-01

    Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

  8. The blind men ‘see’ the elephant-the many faces of fatty liver disease

    PubMed Central

    Sanal, Madhusudana Girija

    2008-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual’s immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis ‘NAFLD’ can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse. PMID:18240340

  9. The blind men 'see' the elephant-the many faces of fatty liver disease.

    PubMed

    Sanal, Madhusudana Girija

    2008-02-14

    Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual's immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis 'NAFLD' can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.

  10. Adenosine signaling contributes to ethanol-induced fatty liver in mice

    PubMed Central

    Peng, Zhongsheng; Borea, Pier Andrea; Wilder, Tuere; Yee, Herman; Chiriboga, Luis; Blackburn, Michael R.; Azzena, Gianfranco; Resta, Giuseppe; Cronstein, Bruce N.

    2009-01-01

    Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5′-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the Lieber-DeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5′-nucleotidase or adenosine A1 or A2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A1 or A2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A2B receptors. In vitro studies supported roles for adenosine A1 receptors in promoting fatty acid synthesis and for A2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A1 and A2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver. PMID:19221436

  11. Effect of dietary omega-3 and omega-6 fatty acids on clotting activities of Factor V, VII and X in fatty liver haemorrhagic syndrome-susceptible laying hens.

    PubMed

    Yeh, E; Wood, R D; Leeson, S; Squires, E J

    2009-05-01

    1. The relationship between concentrations of omega-3 and omega-6 fatty acids in plasma and Factor V, VII and X clotting activities was determined using a crossover feeding trial with diets supplemented with either soy oil or flax oil. 2. Laying hens on the soy diet, which is high in omega-6 fatty acids, had substantially higher clotting activity for all three factors compared to laying hens on the flax diet that was high in omega-3 fatty acids. 3. Positive associations were seen between liver haemorrhage score and the percentage of liver weight and between the percentage of liver weight and the severity of haemorrhagic and fatty changes seen on histology. 4. These results support the hypothesis that concentrations of omega-6 and omega-3 fatty acids in plasma affect clotting activity; however, there was no relationship between the extent of liver haemorrhages and the composition of plasma fatty acids.

  12. Maternal high-fat-diet programs rat offspring liver fatty acid metabolism.

    PubMed

    Seet, Emily L; Yee, Jennifer K; Jellyman, Juanita K; Han, Guang; Ross, Michael G; Desai, Mina

    2015-06-01

    In offspring exposed in utero to a maternal diet high in fat (HF), we have previously demonstrated that despite similar birth weights, HF adult offspring at 6 months of age had significantly higher body weights, greater adiposity, and increased triacylglycerol (TAG) levels as compared to controls. We hypothesized that a maternal HF diet predisposes to offspring adiposity via a programmed increase in the synthesis of monounsaturated fatty acids in the liver and hence increased substrate availability for liver TAG synthesis. We further hypothesized that programmed changes in offspring liver fatty acid metabolism are associated with increased liver expression of the lipogenic enzyme stearoyl-CoA desaturase-1 (SCD-1). Female rats were maintained on a HF diet rich in monounsaturated fatty acids (MUFA) prior to and throughout pregnancy and lactation. After birth, newborns were nursed by the same dam, and all offspring were weaned to control diet. Plasma and liver fatty acid compositions were determined using gas chromatography/mass spectrometry. Fatty acid C16 desaturation indices of palmitoleic/palmitic and (vaccenic + palmitoleic)/palmitic and the C18 desaturation index of oleic/stearic were calculated. Liver protein abundance of SCD-1 was analyzed in newborns and adult offspring. Plasma and liver C16 desaturation indices were decreased in HF newborns, but increased in the adult offspring. Liver SCD-1 expression was increased in the HF adult offspring. These data show that the maternal HF diet during pregnancy and lactation increases offspring liver SCD-1 protein abundance and alters the liver C16 desaturase pathway.

  13. Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Kahali, Bratati; Halligan, Brian; Speliotes, Elizabeth K.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future. PMID:26676813

  14. Nonalcoholic fatty liver disease: a frequent condition in type 2 diabetic patients.

    PubMed

    Sima, Alexandra; Timar, Romulus; Vlad, Adrian; Timar, Bogdan; Rosu, Mihaela; Dan, Isabel; Sirli, Roxana; Popescu, Alina; Sporea, Ioan

    2014-06-01

    Nonalcoholic fatty liver disease represents an excessive fat accumulation in the liver of patients with no other liver disease and no history of alcohol abuse. It is associated with insulin resistance, being more prevalent in obesity and type 2 diabetes. Our aim was to assess the prevalence of fatty liver and nonalcoholic steatohepatitis in patients with type 2 diabetes and to evaluate the influence of obesity on its prevalence. We included 348 type 2 diabetes patients (age: 18-65 years), without a history of liver disease or alcohol abuse. We assessed demographical data, medical history, physical examination, blood tests, and abdominal ultrasonography. The prevalence of liver steatosis in our group was 87.1 %, with no significant differences between men and women. Patients with steatosis had higher abdominal circumference, body mass index (BMI; p = 0.001), and serum triglyceride (p < 0.0001), HbA1c (p < 0.001), and alaninaminotranspherase levels (ALT, p = 0.001). The value of BMI, abdominal circumference, and serum triglyceride levels independently influenced the prevalence of liver steatosis; the influence of HbA1c level was not significant. In 23.9 % of the patients with steatosis, we found elevated liver enzymes. We observed an elevated prevalence of nonalcoholic fatty liver disease (87.1 %) in type 2 diabetic patients. The factors influencing this prevalence are BMI, abdominal circumference,and serum triglyceride levels.

  15. Identification of Plants That Inhibit Lipid Droplet Formation in Liver Cells: Rubus suavissimus Leaf Extract Protects Mice from High-Fat Diet-Induced Fatty Liver by Directly Affecting Liver Cells

    PubMed Central

    Takahashi, Tomohiro; Sugawara, Wataru; Takiguchi, Yuya; Takizawa, Kento; Nakabayashi, Ami; Nakamura, Mitsuo; Nagano-Ito, Michiyo; Ichikawa, Shinichi

    2016-01-01

    Fatty liver disease is a condition in which abnormally large numbers of lipid droplets accumulate in liver cells. Fatty liver disease induces inflammation under conditions of oxidative stress and may result in cancer. To identify plants that protect against fatty liver disease, we examined the inhibitory effects of plant extracts on lipid droplet formation in mouse hepatoma cells. A screen of 98 water extracts of plants revealed 4 extracts with inhibitory effects. One of these extracts, Rubus suavissimus S. Lee (Tien-cha or Chinese sweet tea) leaf extract, which showed strong inhibitory effects, was tested in a mouse fatty liver model. In these mouse experiments, intake of the plant extract significantly protected mice against fatty liver disease without affecting body weight gain. Our results suggest that RSE directly affects liver cells and protects them from fatty liver disease. PMID:27429636

  16. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents.

    PubMed

    Schwimmer, Jeffrey B; McGreal, Nancy; Deutsch, Reena; Finegold, Milton J; Lavine, Joel E

    2005-05-01

    Fatty liver is a common cause of liver disease in children. However, the epidemiology of pediatric fatty liver is limited to single-center case series of nonalcoholic fatty liver disease (NAFLD). Obesity and insulin resistance are major established risk factors for NAFLD. The role of gender, race, and ethnicity on the prevalence of fatty liver in obese children is unknown. We recruited obese 12th-grade participants from the Child and Adolescent Trial for Cardiovascular Health in California, Louisiana, Minnesota, and Texas. Serum samples were collected at school when the participants were well. Alanine aminotransferase (ALT) was measured by kinetic enzymatic assay, and ALT >40 U/L was defined as abnormal. Causes of abnormal ALT other than NAFLD were excluded by serum testing. A total of 127 obese students (73 female, 54 male) had a mean BMI of 35.2 kg/m2. Unexplained ALT elevation was present in 23% of participants overall. The mean ALT for participants with normal values was 28 U/L and for participants with an abnormal ALT was 56 U/L. Abnormal ALT was significantly more prevalent in boys (44%) than in girls (7%). The prevalence of abnormal ALT differed significantly by race and ethnicity (Hispanic: 36%; white: 22%; black: 14%). Serum ALT value was significantly predicted by the combination of gender, race/ethnicity, and BMI. After controlling for gender and BMI, Hispanic ethnicity significantly predicted greater ALT than black race. In a national, school-based sample of obese adolescents, boys were 6 times more likely than girls to have an unexplained elevated ALT. Given that participants were well and causes of chronic liver disease were excluded, we speculate that obese adolescent boys have an increased prevalence of fatty liver compared with obese adolescent girls. This population-based study also supports the hypothesis that NAFLD is more common in Hispanic adolescents. These findings have implications for both disease screening and studies of fatty liver

  17. Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.

    PubMed

    Zelber-Sagi, Shira; Salomone, Federico; Webb, Muriel; Lotan, Roni; Yeshua, Hanny; Halpern, Zamir; Santo, Erwin; Oren, Ran; Shibolet, Oren

    2015-03-01

    Retrospective studies suggest that coffee consumption may exert beneficial effects in patients with nonalcoholic fatty liver; however, prospective data supporting a protective role on liver steatosis development are lacking. In this study, we aimed to evaluate the association between coffee consumption and fatty liver onset in the general population. The analysis was performed both in a cross-sectional cohort (n = 347) and, prospectively, in a subcohort of patients without fatty liver at baseline and followed-up for 7 years (n = 147). Fatty liver was diagnosed with abdominal ultrasound and liver steatosis was quantified noninvasively by hepatorenal index (HRI) and SteatoTest, whereas FibroTest was used to assess fibrosis degree. A structured questionnaire on coffee consumption was administrated during a face-to-face interview. Neither the incidence nor the prevalence of fatty liver according to ultrasonography, SteatoTest, and the HRI was associated with coffee consumption. In the cross-sectional study, high coffee consumption was associated with a lower proportion of clinically significant fibrosis ≥ F2 (8.8% vs 16.3%; P = 0.038); consistently, in multivariate logistic regression analysis, high coffee consumption was associated with lower odds for significant fibrosis (odds ratio = 0.49, 95% confidence interval, 0.25-0.97; P = 0.041) and was the strongest predictor for significant fibrosis. No association was demonstrated between coffee consumption and the new onset of nonalcoholic fatty liver, but coffee intake may exert beneficial effects on fibrosis progression. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Oxidative stress and altered lipid homeostasis in the programming of offspring fatty liver by maternal obesity.

    PubMed

    Alfaradhi, Maria Z; Fernandez-Twinn, Denise S; Martin-Gronert, Malgorzata S; Musial, Barbara; Fowden, Abigail; Ozanne, Susan E

    2014-07-01

    Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARγ and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring.

  19. Transcriptome analysis of garlic-induced hepatoprotection against alcoholic fatty liver.

    PubMed

    Raghu, Rajasekaran; Liu, Chun-Ting; Tsai, Mong-Hsun; Tang, Xiaojia; Kalari, Krishna R; Subramanian, Subbaya; Sheen, Lee-Yan

    2012-11-07

    Fatty liver induced by alcohol abuse is a major worldwide health hazard leading to morbidity and mortality. Previous studies indicate antifatty liver properties of garlic. This study investigated the molecular mechanisms of garlic oil (GO) or diallyl disulfide (DADS) imparted hepatoprotection against alcohol induced fatty liver in C57BL/6 mice using microarray-based global gene expression analysis. Alcohol liquid diet resulted in severe fatty liver with increased levels of serum aspartate aminotransferease and alanine aminotransferease as well as triglycerides and decreased levels of liver glutathione and antioxidant enzymes. The major canonical pathways implicated by alcohol treatment are the metabolisms of xenobiotics by cytochrome P450, glutathione, and arachidonic acid. Treatment with DADS or GO normalized the serum aminotransferease levels and liver antioxidant enzymes and reduced the contents of triglycerides and cholesterol. The canonical pathways involved in the amelioration of liver include arachidonic acid metabolism, altered T cell and B cell signaling, tryptophan metabolism, antigen presentation pathway for DADS, metabolism of xenobiotics, mitotic roles of Polo-like kinase, fatty acid metabolism, LPS/IL-1 mediated inhibition of RXR function, and C21-steroid hormone metabolism for GO.

  20. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey.

    PubMed

    Tokushige, Katsutoshi; Hyogo, Hideyuki; Nakajima, Tomoaki; Ono, Masafumi; Kawaguchi, Takumi; Honda, Koichi; Eguchi, Yuichiro; Nozaki, Yuichi; Kawanaka, Miwa; Tanaka, Saiyu; Imajo, Kento; Sumida, Yoshio; Kamada, Yoshihiro; Fujii, Hideki; Suzuki, Yasuaki; Kogiso, Tomomi; Karino, Yoshiyasu; Munekage, Kensuke; Kuromatsu, Ryoko; Oeda, Satoshi; Yanase, Mikio; Mori, Kohjiro; Ogawa, Yuji; Seko, Yuya; Takehara, Tetsuo; Itoh, Yoshito; Nakajima, Atsushi; Kanemasa, Kazuyuki; Nishino, Ken; Masaki, Naohiko; Takahashi, Hirokazu; Seike, Masataka; Torimura, Takuji; Saibara, Toshiji; Toyota, Joji; Chayama, Kazuaki; Hashimoto, Etsuko

    2016-06-01

    In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC. Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013. The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC. Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

  1. Sarcopenia is associated with severe liver fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Petta, S; Ciminnisi, S; Di Marco, V; Cabibi, D; Cammà, C; Licata, A; Marchesini, G; Craxì, A

    2017-02-01

    Sarcopenia recognises insulin resistance and obesity as risk factors, and is frequently associated with cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD). To test the prevalence of sarcopenia and its relation with the severity of fibrosis (main outcome) and the entire spectrum of liver histology in patients with NAFLD. We considered 225 consecutive patients with histological diagnosis of NAFLD (Kleiner score). The skeletal muscle index (%) (total appendicular skeletal muscle mass (kg)/weight (kg) × 100), a validated measure of sarcopenia, was assessed by bioelectrical impedance analysis. Sarcopenia was defined as a skeletal muscle mass index ≤37 in males and ≤28 in females. The prevalence of sarcopenia showed a linear increase with the severity of fibrosis, and severe fibrosis (F3-F4) was more than doubled in sarcopenia (48.3% vs. 20.4% in fibrosis ≤F2, P < 0.001). After adjusting for confounders, the association of sarcopenia with severe fibrosis was maintained (OR 2.36, CI 1.16-4.77, P = 0.01), together with age > 50 (OR 6.53, CI 2.95-14.4, P < 0.001), IFG/Diabetes (OR 2.14, CI 1.05-4.35, P = 0.03) and NASH (OR 13.3, CI 1.64-108.1, P = 0.01). Similarly, a significant association was found between sarcopenia and NASH (P = 0.01), steatosis severity (P = 0.006), and ballooning (P = 0.01), but only the association with severe steatosis was maintained (OR 2.02, CI 1.06-3.83, P = 0.03) after adjusting for confounders. In Western patients with NAFLD, with high prevalence of metabolic disorders and advanced liver disease, sarcopenia was associated with the severity of fibrosis and steatosis, independently of hepatic and metabolic risk factors. Studies are needed to assess the impact of interventions to reduce sarcopenia on NAFLD progression. © 2016 John Wiley & Sons Ltd.

  2. Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.

    PubMed

    Reilly, Norelle R; Lebwohl, Benjamin; Hultcrantz, Rolf; Green, Peter H R; Ludvigsson, Jonas F

    2015-06-01

    Non-alcoholic fatty liver disease is a common cause of chronic liver disease. Celiac disease alters intestinal permeability and treatment with a gluten-free diet often causes weight gain, but so far there are few reports of non-alcoholic fatty liver disease in patients with celiac disease. Population-based cohort study. We compared the risk of non-alcoholic fatty liver disease diagnosed from 1997 to 2009 in individuals with celiac disease (n = 26,816) to matched reference individuals (n = 130,051). Patients with any liver disease prior to celiac disease were excluded, as were individuals with a lifetime diagnosis of alcohol-related disorder to minimize misclassification of non-alcoholic fatty liver disease. Cox regression estimated hazard ratios for non-alcoholic fatty liver disease were determined. During 246,559 person-years of follow-up, 53 individuals with celiac disease had a diagnosis of non-alcoholic fatty liver disease (21/100,000 person-years). In comparison, we identified 85 reference individuals diagnosed with non-alcoholic fatty liver disease during 1,488,413 person-years (6/100,000 person-years). This corresponded to a hazard ratio of 2.8 (95% CI 2.0-3.8), with the highest risk estimates seen in children (HR = 4.6; 95% CI 2.3-9.1). The risk increase in the first year after celiac disease diagnosis was 13.3 (95% CI 3.5-50.3) but remained significantly elevated even beyond 15 years after the diagnosis of celiac disease (HR = 2.5; 95% CI 1.0-5.9). Individuals with celiac disease are at increased risk of non-alcoholic fatty liver disease compared to the general population. Excess risks were highest in the first year after celiac disease diagnosis, but persisted through 15 years after diagnosis with celiac disease. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  3. ¹H and ³¹P NMR lipidome of ethanol-induced fatty liver.

    PubMed

    Fernando, Harshica; Kondraganti, Shakuntala; Bhopale, Kamlesh K; Volk, David E; Neerathilingam, Muniasamy; Kaphalia, Bhupendra S; Luxon, Bruce A; Boor, Paul J; Shakeel Ansari, G A

    2010-11-01

     Hepatic steatosis (fatty liver), an early and reversible stage of alcoholic liver disease, is characterized by triglyceride deposition in hepatocytes, which can advance to steatohepatitis, fibrosis, cirrhosis, and ultimately to hepatocellular carcinoma. In the present work, we studied altered plasma and hepatic lipid metabolome (lipidome) to understand the mechanisms and lipid pattern of early-stage alcohol-induced-fatty liver.  Male Fischer 344 rats were fed 5% alcohol in a Lieber-DeCarli diet. Control rats were pair-fed an equivalent amount of maltose-dextrin. After 1 month, animals were killed and plasma collected. Livers were excised for morphological, immunohistochemical, and biochemical studies. The lipids from plasma and livers were extracted with methyl-tert-butyl ether and analyzed by 750/800 MHz proton nuclear magnetic resonance (¹H NMR) and phosphorus (³¹P) NMR spectroscopy on a 600 MHz spectrometer. The NMR data were then subjected to multivariate statistical analysis.  Hematoxylin and Eosin and Oil Red O stained liver sections showed significant fatty infiltration. Immunohistochemical analysis of liver sections from ethanol-fed rats showed no inflammation (absence of CD3 positive cells) or oxidative stress (absence of malondialdehyde reactivity or 4-hydroxynonenal positive staining). Cluster analysis and principal component analysis of ¹H NMR data of lipid extracts of both plasma and livers showed a significant difference in the lipid metabolome of ethanol-fed versus control rats. ³¹P NMR data of liver lipid extracts showed significant changes in phospholipids similar to ¹H NMR data. ¹H NMR data of plasma and liver reflected several changes, while comparison of ¹H NMR and ³¹P NMR data offered a correlation among the phospholipids.  Our results show that alcohol consumption alters metabolism of cholesterol, triglycerides, and phospholipids that could contribute to the development of fatty liver. These studies also indicate that fatty

  4. Modern approach to the clinical management of non-alcoholic fatty liver disease

    PubMed Central

    Del Ben, Maria; Polimeni, Licia; Baratta, Francesco; Pastori, Daniele; Loffredo, Lorenzo; Angelico, Francesco

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D3. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease. PMID:25024593

  5. Effects of Fatty Liver Induced by Excess Orotic Acid on B-Group Vitamin Concentrations of Liver, Blood, and Urine in Rats.

    PubMed

    Shibata, Katsumi; Morita, Nobuya; Kawamura, Tomoyo; Tsuji, Ai; Fukuwatari, Tsutomu

    2015-01-01

    Fatty liver is caused when rats are given orotic acid of the pyrimidine base in large quantities. The lack of B-group vitamins suppresses the biosynthesis of fatty acids. We investigated how orotic acid-induced fatty liver affects the concentrations of liver, blood, and urine B-group vitamins in rats. The vitamin B6 and B12 concentrations of liver, blood, and urine were not affected by orotic acid-induced fatty liver. Vitamin B2 was measured only in the urine, but was unchanged. The liver, blood, and urine concentrations of niacin and its metabolites fell dramatically. Niacin and its metabolites in the liver, blood, and urine were affected as expected. Although the concentrations of vitamin B1, pantothenic acid, folate, and biotin in liver and blood were decreased by orotic acid-induced fatty liver, these urinary excretion amounts showed a specific pattern toward increase. Generally, as for the typical urinary excretion of B-group vitamins, these are excreted when the body is saturated. However, the ability to sustain vitamin B1, pantothenic acid, folate, and biotin decreased in fatty liver, which is hypothesized as a specific phenomenon. This metabolic response might occur to prevent an abnormally increased biosynthesis of fatty acids by orotic acid.

  6. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

    USDA-ARS?s Scientific Manuscript database

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

  7. An ultrastructural study of the liver, kidney and myocardium in the fatty liver and kidney syndrome in the fowl.

    PubMed

    Siller, W G; Wight, P A

    1976-07-01

    In birds with the fatty liver and kidney syndrome large lipid droplets measuring up to 4 mum in diameter were observed in increased numbers in liver, kidney and heart muscle, particularly in the livers and the proximal convoluted tubules (PCT) of the kidneys. In the hepatocytes and the PCT a much smaller type of lipid particle (LP) was also observed, both intracellularly within the cisternae of the Golgi-ER system and outside the plasma membranes in the space between neighbouring parenchymal cells, within the space of Disse and among the basal processes of the PCT. The origin of these LP is discussed.

  8. [Relationship between ideal cardiovascular behaviors/factors and the prevalence of nonalcoholic fatty liver disease].

    PubMed

    Xing, Aijun; Ji, Chunpeng; Shi, Jihong; Du, Xin; Huang, Zhe; Lin, Liming; Xiong, Hailiang; Wu, Shouling

    2015-01-01

    To investigate the relationship between ideal cardiovascular behaviors/factors and nonalcoholic fatty liver disease. In our study, 54 303 workers who had participated in the 2006-2007 Kailuan health examination with complete data and without history of drinking, myocardial infarction, stroke or cancer, were recruited. All workers were under observation and their prevalence of nonalcoholic fatty liver disease recorded. According to the American Heart Association definition of ideal cardiovascular health behaviors and factors, multiple logistic regression method was used to calculate the OR and 95% CI for baseline behaviors and factors. The prevalence of nonalcoholic fatty liver disease according to 0-1, 2, 3, 4, 5-7 ideal cardiovascular health behaviors/factors were 62.6% , 48.9% , 33.3% , 16.1% and 7.5% , respectively. Results from the logistic model showed that after adjustment for age, gender, income, education level and other confounders, the ideal cardiovascular health behaviors/factors were associated with nonalcoholic fatty liver disease and the ORs (95% CI) were reduced gradually with the increase of ideal cardiovascular health behaviors/factors, which were 1,0.61(0.56-0.66), 0.37(0.34-0.40), 0.17(0.15-0.18) and 0.08 (0.07-0.09), respectively, in the 2, 3, 4, 5-7 ideal behaviors/factors groups. Ideal cardiovascular health behaviors and factors were associated with nonalcoholic fatty liver disease.

  9. Therapeutic effect of Pleurotus eryngii cellulose on experimental fatty liver in rats.

    PubMed

    Huang, J F; Zhan, T; Yu, X L; He, Q A; Huang, W J; Lin, L Z; Du, Y T; Pan, Y T

    2016-02-26

    The aim of this study was to explore the therapeutic effect of Pleurotus eryngii cellulose on experimental fatty liver in rats. Rats were fed high-fat fodder to establish a rat fatty liver model, and were then fed different concentrations of Pleurotus eryngii cellulose for six weeks. Lipitor was used as a positive control. Measured levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and total triglyceride (TG); the activity of malondialdehyde (MDA), superoxide dismutase (SOD), hepatic lipase (HL), and lipoprotein lipase; and liver histopathological changes. Successfully established rat fatty liver model after feeding high-fat fodder for one week. A diet of P. eryngii cellulose for six weeks significantly reduced ALT, AST, TC, and TG levels in rat serum (P < 0.01); TC and AST levels in P. eryngii cellulose high-dose group and Lipitor group were not significantly different from those of the control (P > 0.05). SOD activity increased significantly, while MDA and HL activity decreased (P < 0.05); fatty degeneration and fat accumulation both decreased in hepatic tissue. Hepatic protection of P. eryngii cellulose showed dose-related effect. P. eryngii cellulose can affect lipid metabolism, having therapeutic effects on fatty liver in rats.

  10. The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease.

    PubMed

    Schuck, Robert N; Zha, Weibin; Edin, Matthew L; Gruzdev, Artiom; Vendrov, Kimberly C; Miller, Tricia M; Xu, Zhenghong; Lih, Fred B; DeGraff, Laura M; Tomer, Kenneth B; Jones, H Michael; Makowski, Liza; Huang, Leaf; Poloyac, Samuel M; Zeldin, Darryl C; Lee, Craig R

    2014-01-01

    Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.

  11. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease.

    PubMed

    Dumas, Marc-Emmanuel; Kinross, James; Nicholson, Jeremy K

    2014-01-01

    Metabolic syndrome, a cluster of risk factors for type 2 diabetes mellitus and cardiovascular disease, is becoming an increasing global health concern. Insulin resistance is often associated with metabolic syndrome and also typical hepatic manifestations such as nonalcoholic fatty liver disease. Profiling of metabolic products (metabolic phenotyping or metabotyping) has provided new insights into metabolic syndrome and nonalcoholic fatty liver disease. Data from nuclear magnetic resonance spectroscopy and mass spectrometry combined with statistical modeling and top-down systems biology have allowed us to analyze and interpret metabolic signatures in terms of metabolic pathways and protein interaction networks and to identify the genomic and metagenomic determinants of metabolism. For example, metabolic phenotyping has shown that relationships between host cells and the microbiome affect development of the metabolic syndrome and fatty liver disease. We review recent developments in metabolic phenotyping and systems biology technologies and how these methodologies have provided insights into the mechanisms of metabolic syndrome and nonalcoholic fatty liver disease. We discuss emerging areas of research in this field and outline our vision for how metabolic phenotyping could be used to study metabolic syndrome and fatty liver disease. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  12. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease

    PubMed Central

    Wood, Kayleigh L; Miller, Michael H; Dillon, John F

    2015-01-01

    Non-alcoholic fatty liver disease has an increasing prevalence in Western countries, affecting up to 20% of the population. Objective The aim of this project was to systematically review and summarise the genetic association studies that investigate possible genetic influences that confer susceptibility to non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Design The MEDLINE and SCOPUS databases were searched to identify candidate gene studies on histologically diagnosed non-alcoholic fatty liver disease. Results A total of 85 articles have been summarised and categorised on the basis of the general pathway each candidate gene is involved in, including lipid metabolism, lipoprotein processing, cholesterol synthesis, glucose homoeostasis, inflammatory response, protection against oxidative stress and whole body metabolism. Conclusions The main findings demonstrate a small but consistent association of PNPLA3 with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Genetic association studies have investigated general disease susceptibility, histological characteristics, severity and progression. However, further study is required to better elucidate the genetic factors influencing fatty liver disease. PMID:26462272

  13. In ovo injection of betaine alleviates corticosterone-induced fatty liver in chickens through epigenetic modifications

    PubMed Central

    Hu, Yun; Sun, Qinwei; Liu, Jie; Jia, Yimin; Cai, Demin; Idriss, Abdulrahman A.; Omer, Nagmeldin A.; Zhao, Ruqian

    2017-01-01

    Betaine alleviates high-fat diet-induced fatty liver and prenatal betaine programs offspring hepatic lipid metabolism. Excessive corticosterone (CORT) exposure causes fatty liver in chickens, yet it remains unknown whether and how prenatal betaine modulates the susceptibility of CORT-induced fatty liver later in life. In this study, fertilized eggs were injected with saline or betaine before incubation, and the hatchlings were raised at 8 weeks of age followed by 7 days of subcutaneous CORT injection. CORT-induced fatty liver was less severe in betaine-treated chickens, with significantly reduced oil-red staining and hepatic triglyceride content (P < 0.05). The protective effect of prenatal betaine was associated with significantly up-regulated expression of PPARα and CPT1α, as well as mitochondrial DNA (mtDNA)-encoded genes (P < 0.05). Moreover, betaine rescued CORT-induced alterations in methionine cycle genes, which coincided with modifications of CpG methylation on CPT1α gene promoter and mtDNA D-loop regions. Furthermore, the elevation of hepatic GR protein content after CORT treatment was significantly reduced (P < 0.05), while the reduction of GR binding to the control region of affected genes was significantly increased (P < 0.05), in betaine-treated chickens. These results indicate that in ovo betaine injection protects the juvenile chickens from CORT-induced fatty liver. PMID:28059170

  14. In ovo injection of betaine alleviates corticosterone-induced fatty liver in chickens through epigenetic modifications.

    PubMed

    Hu, Yun; Sun, Qinwei; Liu, Jie; Jia, Yimin; Cai, Demin; Idriss, Abdulrahman A; Omer, Nagmeldin A; Zhao, Ruqian

    2017-01-06

    Betaine alleviates high-fat diet-induced fatty liver and prenatal betaine programs offspring hepatic lipid metabolism. Excessive corticosterone (CORT) exposure causes fatty liver in chickens, yet it remains unknown whether and how prenatal betaine modulates the susceptibility of CORT-induced fatty liver later in life. In this study, fertilized eggs were injected with saline or betaine before incubation, and the hatchlings were raised at 8 weeks of age followed by 7 days of subcutaneous CORT injection. CORT-induced fatty liver was less severe in betaine-treated chickens, with significantly reduced oil-red staining and hepatic triglyceride content (P < 0.05). The protective effect of prenatal betaine was associated with significantly up-regulated expression of PPARα and CPT1α, as well as mitochondrial DNA (mtDNA)-encoded genes (P < 0.05). Moreover, betaine rescued CORT-induced alterations in methionine cycle genes, which coincided with modifications of CpG methylation on CPT1α gene promoter and mtDNA D-loop regions. Furthermore, the elevation of hepatic GR protein content after CORT treatment was significantly reduced (P < 0.05), while the reduction of GR binding to the control region of affected genes was significantly increased (P < 0.05), in betaine-treated chickens. These results indicate that in ovo betaine injection protects the juvenile chickens from CORT-induced fatty liver.

  15. Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPARδ Regulation in Hyperlipidemic and Hypertensive Conditions

    PubMed Central

    Jang, Yoo-Na; Han, Yoon-Mi; Kim, Hyun-Min; Jeong, Jong-Min

    2017-01-01

    To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs) given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ), phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase (p-ACC), malonyl-CoA decarboxylase (MCD), medium chain acyl-CoA dehydrogenase (MCAD), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1), fatty acid synthase (FAS), and tumor necrosis factor-alpha (TNF-α). Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660). Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway. PMID:28386270

  16. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV.

    PubMed

    Rockstroh, Jürgen Kurt

    2017-04-01

    Abnormal liver enzymes (LE) are common in patients infected with the human immunodeficiency virus (HIV) even in the absence of viral hepatitis or alcohol abuse. With availability of antiretroviral combination therapy, life expectancy has improved dramatically and as a consequence the spectrum of liver disease is changing. Increased reports on the development of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in HIV coinfected patients raise questions around prevalence, clinical manifestations, and clinical outcome of these liver diseases in HIV coinfection. Moreover, the potential impact of combination antiretroviral therapy as well as direct HIV effects on the emergence of non-alcoholic fatty liver disease needs to be explored. This review summarizes the recent literature on NAFLD and NASH in HIV.

  17. A novel therapeutic drug (copper nicotinic acid complex) for non-alcoholic fatty liver.

    PubMed

    Salama, Ragaa H M; Nassar, Ahmed Y A; Nafady, Allam A M; Mohamed, Hesham H T

    2007-05-01

    Fatty liver is the accumulation of fat in liver cells, which leads to disruption of the normal liver structure and function. A non-alcoholic fatty liver rat model received copper (Cu) (I)-nicotinate complex [CuCl(HNA)2] for 4 weeks. Clinical signs and histopathological examinations showed obvious improvements in rats that received Cu complex who were continuously on an (HCFF) diet than those returned to standard diet with Cu complex. The improvement was matched in total lipids in sera and hepatic tissue, with disappearance of fat droplets from liver sections. Furthermore, the gain in body weight and the corresponding decrease in liver weight, decreased liver transaminases and alkaline phosphatase were prominent. The oxidative stress markers such as nitric oxide, lipid peroxides, glutathione and superoxide dismutase were obviously changed to healthy normal levels. The Cu complex may serve as a novel chemical restoring agent in fatty degenerated liver cells and for renewal of their structure and functions. However, clinical trials are required for more evaluation of the Cu complex in humans.

  18. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease].

    PubMed

    Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt

    2009-11-29

    The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

  19. Television viewing and fatty liver in early midlife. The Cardiovascular Risk in Young Finns Study.

    PubMed

    Helajärvi, Harri; Pahkala, Katja; Heinonen, Olli J; Juonala, Markus; Oikonen, Mervi; Tammelin, Tuija; Hutri-Kähönen, Nina; Kähönen, Mika; Lehtimäki, Terho; Mikkilä, Vera; Viikari, Jorma; Raitakari, Olli T

    2015-01-01

    Both sedentary behaviour and fatty liver are associated with increased risk of obesity and non-communicable diseases, but their relationship remains unknown. We investigated the relationship of television (TV) viewing time with serum gamma-glutamyltransferase (GGT) and Fatty Liver Index (FLI), and ultrasonographically assessed liver fat. A total of 1,367 adults of the population-based Cardiovascular Risk in Young Finns study (748 women, 619 men, aged 34-49 years) had fasting serum GGT, triglycerides, weight, height, and waist circumference, and self-reported TV time data from 2001, 2007, and 2011. Changes in GGT and FLI, and liver ultrasound images in 2011 were studied in groups with constantly low (≤ 1 h/d), moderate (1-3 h/d), or high (≥ 3 h/d) daily TV time, and in groups with ≥ 1 hour increase/decrease in daily TV time between 2001 and 2011. Constantly high TV time was associated with higher GGT and FLI (P < 0.02 in both), and 2.3-fold (95% CI 1.2-4.5) increased risk of fatty liver regardless of age, sex, leisure-time and occupational physical activity, energy intake, diet composition, alcohol use, sleep duration, socioeconomic status, and smoking. Adjustment for BMI partly attenuated the associations. High TV viewing increases fatty liver risk. It may be one mechanism linking sedentary behaviour with increased cardiometabolic disease risks.

  20. A CAD system for B-mode fatty liver ultrasound images using texture features.

    PubMed

    Subramanya, M B; Kumar, Vinod; Mukherjee, Shaktidev; Saini, Manju

    2015-02-01

    The present study proposes a computer-aided diagnosis (CAD) system for the diagnosis of grades of fatty liver disease, namely mild, moderate and severe fatty liver along with normal liver tissue. Fifty-three B-mode ultrasound images consisting of 12 normal, 14 mild, 14 moderate and 13 severe fatty liver images are used. Based on the visual interpretations by the radiologists, region of interests (ROIs) from within the liver and one ROI from the diaphragm region are considered from each image. The texture features of these ROIs are combined in three ways to form ratio features, inverse ratio features and additive features. The sub-sets of optimal features are obtained by a differential evolution feature selection (DEFS) algorithm and a support vector machine (SVM) has been used for the classification task. The Laws ratio features have shown better performance with an average accuracy and standard deviation of 84.9±3.2. Hence, the CAD system could be useful to the radiologists in diagnosing grades of fatty liver disease.

  1. FT-IR imaging for quantitative determination of liver fat content in non-alcoholic fatty liver.

    PubMed

    Kochan, K; Maslak, E; Chlopicki, S; Baranska, M

    2015-08-07

    In this work we apply FT-IR imaging of large areas of liver tissue cross-section samples (∼5 cm × 5 cm) for quantitative assessment of steatosis in murine model of Non-Alcoholic Fatty Liver (NAFLD). We quantified the area of liver tissue occupied by lipid droplets (LDs) by FT-IR imaging and Oil Red O (ORO) staining for comparison. Two alternative FT-IR based approaches are presented. The first, straightforward method, was based on average spectra from tissues and provided values of the fat content by using a PLS regression model and the reference method. The second one – the chemometric-based method – enabled us to determine the values of the fat content, independently of the reference method by means of k-means cluster (KMC) analysis. In summary, FT-IR images of large size liver sections may prove to be useful for quantifying liver steatosis without the need of tissue staining.

  2. Serum inflammatory markers in overweight children and adolescents with non-alcoholic fatty liver disease.

    PubMed

    Neuman, Gal; Sagi, Rami; Shalitin, Shlomit; Reif, Shimon

    2010-07-01

    Obesity, a worldwide pandemia, is associated with a large variety of comorbidities, among which is non-alcoholic fatty liver disease. NAFLD is a complex disease that may eventually lead to cirrhosis, posing a high risk for the patient and thus necessitating early diagnosis and treatment. To evaluate the association between ultrasonographically diagnosed non-alcoholic fatty liver disease and the levels of serum inflammatory markers in obese children and adolescents. This prospective cohort study was conducted in children and adolescents attending the endocrine obesity clinic in a tertiary care children's hospital in 2001-2003. Blood tests and ultrasound were performed to detect the presence of fatty liver. The severity of fatty liver was determined by measuring the liver/kidney echogenicity ratio (hepatorenal index). Blood tests included complete blood count, liver enzymes, lipid profile, erythrocyte sedimentation rate, high sensitivity C-reactive protein, serum amyloid A, and the degree of erythrocyte adhesiveness/aggregation as measured in peripheral blood slides. The 30 boys and 34 girls, age 9-21 years, who participated in the study were divided into those who evidenced NAFLD on ultrasound (Group 1, n=37) and those whose liver appeared normal on ultrasound (Group 2, n=24). ESR, hs-CRP, SAA and the degree of erythrocyte adhesiveness/aggregation were compared between the groups. There was no significant association between elevated ESR, the levels of CRP, SAA and/or the degree of erythrocyte adhesiveness/aggregation and the hepatorenal index and NAFLD. The degree of erythrocyte adhesiveness/ aggregation correlated with body mass index-standard deviation score in both genders (P < 0.05). Fatty liver itself may not be a cofactor in stimulating inflammatory markers in obese patients. Obese children diagnosed with NAFLD may have simple steatosis and their increased inflammatory markers are therefore compatible with those expected in obesity.

  3. Activities of the enzymes of hepatic gluconeogenesis in periparturient dairy cows with induced fatty liver.

    PubMed

    Murondoti, Absolom; Jorritsma, Ruurd; Beynen, Anton C; Wensing, Theo; Geelen, Math J H

    2004-05-01

    The objective was to measure the activities of all the enzymes essential for hepatic gluconeogenesis in dairy cows with induced fatty liver. We aimed to induce severe fatty liver in ten experimental cows by overfeeding them during the dry period while seven control cows were maintained on a restricted diet. To induce a marked negative energy balance, the experimental cows were deprived of feed for 8 h immediately after parturition. In addition, the experimental cows were given a restricted amount of diet during the first 5 d of lactation. Liver samples were collected 1 week before and 1, 2 and 4 weeks after parturition. Before parturition, liver triacylglycerol concentrations did not differ between the two groups. After parturition, the experimental cows developed marked fatty liver as indicated by a higher level of triacylglycerols in the liver compared with the control cows. Before parturition, all gluconeogenic enzymes in the liver were lower in experimental cows than in control cows. Phosphoenolpyruvate carboxykinase, pyruvate carboxylase and propionyl-CoA carboxylase were significantly lower and fructose 1,6-bisphosphatase and glucose 6-phosphatase tended to be lower in the experimental cows. The activities of two crucial enzymes for gluconeogenesis in ruminants, i.e., phosphoenolpyruvate carboxykinase and propionyl-CoA carboxylase, remained low throughout the sampling period post partum. Activities of pyruvate carboxylase and glucose 6-phosphatase in the experimental cows post partum were upgraded to values similar to those of the control cows. The results showed that the capacity for hepatic gluconeogenesis before parturition was lower in cows with induced fatty liver than in control cows. After parturition, the low activities of crucial gluconeogenic enzymes indicated insufficient production of glucose. It is suggested that the low gluconeogenic capacity leads successively to low blood glucose concentrations, low insulin levels and high rates of

  4. Lactate administration and fatty liver and kidney syndrome development in biotin-deficient chicks.

    PubMed

    Balnave, D; Pearce, J

    1979-01-01

    Two experiments were carried out to determine whether administration of lactate to biotin-deficient chicks induced fatty liver and kidney syndrome (FLKS). 2. The results suggest that increased serum lactate concentrations are a consequence of the syndrome rather than a contributory factor in its incidence. 3. The increase in liver lipids of birds affected by FLKS was not associated with an increase in the specific activity of the hepatic lipogenic enzyme acetyl CoA carboxylase accept when birds developed FLKS spontaneously in experiment 2. 4. Some biotin-deficient chicks did not show physical symptoms of deficiency although mean liver biotin concentrations were low (0.31 microgram/g liver).

  5. The oestrogenised chick as an experimental model for fatty liver-haemorrhagic syndrome in the fowl.

    PubMed

    Pearson, A W; Butler, E J

    1978-01-01

    A syndrome resembling fatty liver-haemorrhagic syndrome in laying hens was reproduced in six- to seven-week-old chickens by injecting oestradiol-17beta-dipropionate intramuscularly (total dose 20-50 mg/kg). The degree of hepatic steatosis and the severity and extent of haemorrhage from the liver varied with the dose and the results suggested a pathogenic relationship between the two conditions. There was no evidence of reticulolysis in the liver. When food was withdrawn for 24 h after the last injection there was a dramatic fall in the haemorrhage score and a reduction in the lipid content of the liver.

  6. Cytokeratin-18 and hyaluronic acid levels predict liver fibrosis in children with non-alcoholic fatty liver disease.

    PubMed

    Lebensztejn, Dariusz M; Wierzbicka, Aldona; Socha, Piotr; Pronicki, Maciej; Skiba, Elżbieta; Werpachowska, Irena; Kaczmarski, Maciej

    2011-01-01

    There is a need to replace liver biopsy with non-invasive markers that predict the degree of liver fibrosis in fatty liver disease related to obesity. Therefore, we studied four potential serum markers of liver fibrosis and compared them with histopathological findings in liver biopsy in children with non-alcoholic fatty liver disease (NAFLD). We determined fasting serum level of hyaluronic acid (HA), laminin, YKL-40 and cytokeratin-18 M30 in 52 children (age range 4-19, mean 12 years, 80 % of them were overweight or obese) with biopsy-verified NAFLD. Viral hepatitis, autoimmune and metabolic liver diseases (Wilson's disease, alpha-1-antitrypsin deficiency, cystic fibrosis) were excluded. Fibrosis stage was assessed in a blinded fashion by one pathologist according to Kleiner. Receiver operating characteristics (ROC) analysis was used to calculate the power of the assays to detect liver fibrosis (AccuROC, Canada). Liver fibrosis was diagnosed in 19 children (37 %). The levels of HA and CK18M30 were significantly higher in children with fibrosis compared to children without fibrosis (p=0.04 and 0.05 respectively). The ability of serum HA (cut-off 19.1 ng/ml, Se=84 %, Sp=55 %, PPV=52 %, NPV=86 %) and CK18M30 (cut-off 210 u/l, Se=79 %, Sp=60 %, PPV=56 %, NPV=82 %) to differentiate children with fibrosis from those without fibrosis was significant (AUC=0.672 and 0.666, respectively). The combination of both markers was superior (AUC=0.73, p=0.002). Laminin and YKL-40 levels did not allow a useful prediction. Cytokeratin-18 and hyaluronic acid are suitable serum markers predicting liver fibrosis in children with NAFLD. Studying these markers may identify patients at risk of disease progression.

  7. Nonalcoholic fatty liver disease, association with cardiovascular disease and treatment. (I). Nonalcoholic fatty liver disease and its association with cardiovascular disease.

    PubMed

    Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan

    Non-alcoholic fatty liver disease (NAFLD) comprises a series of histologically lesions similar to those induced by alcohol consumption in people with very little or no liver damage. The importance of NAFLD is its high prevalence in the Western world and, from the point of view of the liver, in its gradual progression from steatosis to steatohepatitis, cirrhosis, and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with acceleration of arteriosclerosis and events related to it, being the main cause of its morbidity and mortality. This review, updated to January 2016, consists of two parts, with the first part analysing the association of NAFLD with cardiovascular disease. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Hydroxypropyl methylcellulose, a viscous soluble fiber, reduces insulin resistance and decreases fatty liver in Zucker Diabetic Fatty rats.

    PubMed

    Brockman, David A; Chen, Xiaoli; Gallaher, Daniel D

    2012-11-12

    Diets producing a high glycemic response result in exaggerated insulin secretion which induces hepatic lipogenesis, contributing to development of insulin resistance and fatty liver. Viscous dietary fibers blunt the postprandial rise in blood glucose, however their effect on type 2 diabetes and obesity are not entirely known. This study examined the effect of chronic consumption of the viscous, non-fermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), on glucose control, insulin resistance and liver lipids in an obese diabetic rat model. Three groups of Zucker Diabetic Fatty (ZDF) rats were fed diets containing either 5% non-viscous cellulose (control), low viscosity HPMC (LV-HPMC) or high viscosity HPMC (HV- HPMC) for six weeks. Zucker lean littermates consuming cellulose served as a negative control. Markers of glucose control, including oral glucose tolerance test, glycated hemoglobin and urinary glucose, were measured as well as adiposity and the accumulation of liver lipids. The HPMC diets increased the viscosity of the small intestinal contents and reduced the postprandial rise in blood glucose. The food efficiency ratio was greater with HPMC feeding compared to the obese control and urinary excretion of glucose and ketone bodies was reduced. The two HPMC groups had lower glycated hemoglobin and kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Epididymal fat pad weight as percent of body weight was reduced in the HV-HPMC group compared to the obese control group. The HV-HPMC group also had lower concentrations of liver lipid and cholesterol and reduced liver weight. However, HV-HPMC feeding did not affect hepatic gene expression of SREBP-1c or FAS. Muscle concentration of acylcarnitines, a lipid intermediate in fatty acid β-oxidation, was not different between the HPMC groups and obese control, suggesting no change in muscle fatty acid oxidation by HPMC. Consumption of the

  9. Mitotherapy for Fatty Liver by Intravenous Administration of Exogenous Mitochondria in Male Mice.

    PubMed

    Fu, Ailing; Shi, Xianxun; Zhang, Huajing; Fu, Bin

    2017-01-01

    Mitochondrial dysfunction is a major and common mechanism in developing non-alcoholic fatty liver disease (NAFLD). Replacement of dysfunctional mitochondria by functional exogenous mitochondria may attenuate intrahepatic excessive lipid and recover hepatocyte function. However, no data shows that mitochondria can be systemically administrated to animals to date. Here we suggest that mitochondria isolated from hepatoma cells are used as a mitotherapy agent to treat mouse fatty liver induced by high-fat diets. When the mitochondria were intravenously injected into the mice, serum aminotransferase activity and cholesterol level decreased in a dose-dependent manner. Also, the mitotherapy reduced lipid accumulation and oxidation injury of the fatty liver mice, improved energy production, and consequently restored hepatocyte function. The mitotherapy strategy offers a new potential therapeutic approach for treating NAFLD.

  10. Accurate Identification of Fatty Liver Disease in Data Warehouse Utilizing Natural Language Processing.

    PubMed

    Redman, Joseph S; Natarajan, Yamini; Hou, Jason K; Wang, Jingqi; Hanif, Muzammil; Feng, Hua; Kramer, Jennifer R; Desiderio, Roxanne; Xu, Hua; El-Serag, Hashem B; Kanwal, Fasiha

    2017-08-31

    Natural language processing is a powerful technique of machine learning capable of maximizing data extraction from complex electronic medical records. We utilized this technique to develop algorithms capable of "reading" full-text radiology reports to accurately identify the presence of fatty liver disease. Abdominal ultrasound, computerized tomography, and magnetic resonance imaging reports were retrieved from the Veterans Affairs Corporate Data Warehouse from a random national sample of 652 patients. Radiographic fatty liver disease was determined by manual review by two physicians and verified with an expert radiologist. A split validation method was utilized for algorithm development. For all three imaging modalities, the algorithms could identify fatty liver disease with >90% recall and precision, with F-measures >90%. These algorithms could be used to rapidly screen patient records to establish a large cohort to facilitate epidemiological and clinical studies and examine the clinic course and outcomes of patients with radiographic hepatic steatosis.

  11. Non-Alcoholic Fatty Liver Disease in Children: Focus on Nutritional Interventions

    PubMed Central

    Yang, Min; Gong, Sitang; Ye, Shui Qing; Lyman, Beth; Geng, Lanlan; Chen, Peiyu; Li, Ding-You

    2014-01-01

    With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD. PMID:25353664

  12. Non-alcoholic fatty liver disease in children: focus on nutritional interventions.

    PubMed

    Yang, Min; Gong, Sitang; Ye, Shui Qing; Lyman, Beth; Geng, Lanlan; Chen, Peiyu; Li, Ding-You

    2014-10-28

    With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD.

  13. The Role of TCA Cycle Anaplerosis in Ketosis and Fatty Liver in Periparturient Dairy Cows

    PubMed Central

    White, Heather M.

    2015-01-01

    The transition to lactation period in dairy cattle is characterized by metabolic challenges, negative energy balance, and adipose tissue mobilization. Metabolism of mobilized adipose tissue is part of the adaptive response to negative energy balance in dairy cattle; however, the capacity of the liver to completely oxidize nonesterified fatty acids may be limited and is reflective of oxaloacetate pool, the carbon carrier of the tricarboxylic acid cycle. Alternative metabolic fates of acetyl-CoA from nonesterified fatty acids include esterification to triacylglycerides and ketogenesis, and when excessive, these pathways lead to fatty liver and ketosis. Examination of the anaplerotic and cataplerotic pull of oxaloacetate by the tricarboxylic acid cycle and gluconeogenesis may provide insight into the balance of oxidation and esterification of acetyl-CoA within the liver of periparturient dairy cows. PMID:26479386

  14. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD).

    PubMed Central

    Song, Jiannan; Costa, Kerry Ann da; Fischer, Leslie M.; Kohlmeier, Martin; Kwock, Lester; Wang, Shuli; Zeisel, Steven H.

    2005-01-01

    Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT gene polymorphisms. DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT which leads to a V175M substitution. V175M is a loss of function mutation, as determined by transiently transfecting McArdle-RH7777 cells with constructs of wildtype PEMT open reading frame or the V175M mutant. Met/Met at residue 175 (loss of function SNP) occurred in 67.9% of the NAFLD subjects and in only 40.7% of control subjects (p< 0.03). For the first time we report that a polymorphism of the human PEMT gene (V175M) is associated with diminished activity and may confer susceptibility to NAFLD. PMID:16051693

  15. [Prevalence of no alcohol fatty liver disease (NAFLD) in a population of obese children in Valencia, Venezuela].

    PubMed

    Pontiles de Sánchez, Milagros; Morón de Salim, Alba; Rodríguez de Perdomo, Henny; Perdomo Oramas, Germán

    2014-06-01

    No Alcoholic Fatty Liver Disease (NAFLD) is characterized by an abnormal accumulation of fat in hepatocytes, without alcohol, where overweight and obesity are determinants. Ecosonografia evaluated the prevalence of fatty liver in obese pediatric patients and its relation to nutritional assessment. The sample consisted of 85 children (51 females, 34 males), age 3-17. The abdominal ecosonography, BMI, waist circumference were performed; Godard Test for physical activity, history of diabetes, dyslipidemia, obesity and cardiovascular disease were questioned. Lipid profile, glucose and insulin resistance were determined. Data analyzed from descriptive and comparative tables. We obtained: mean age 9.8 ± 2.7 females and males 9.6 ± 2.7 years. The ecosonography indicated 50% and 50% fatty liver-pancreas fatty liver in children aged 3-6 years; 7-11 years 39.7% fatty liver-pancreas; 12-17yrs 31.6% fatty liver-pancreas (p > 0.05); BMI > 26 kg/m2 42.9% fatty liver-pancreas; 21 to 25 kg/m2 44.7% fatty liver; 15 to 20 kg/m2 60%fatty liver-pancreas (p> 0.05). 97.6% with high CC; 68.2% with inadequate physical activity; high frequency of history of chronic non-communicable diseases. We concluded that this population had predominantly fatty liver fatty replacement of the pancreas (HG-RGP) in the groups with higher BMI, CC and high male unrelated insulin resistance, altered lipid profile and diagnosis HG. We inferred that the anthropometric assessment of waist circumference and abdominal ecosonography indicate the presence of visceral obesity, a condition that predisposes to hepatic steatosis, pancreas and/or liver-pancreas.

  16. Effects of Bariatric Surgery on Liver Function Tests in Patients with Nonalcoholic Fatty Liver Disease.

    PubMed

    Ooi, Geraldine J; Burton, Paul R; Doyle, Lisa; Wentworth, John M; Bhathal, Prithi S; Sikaris, Ken; Cowley, Michael A; Roberts, Stuart K; Kemp, William; Earnest, Arul; O'Brien, Paul E; Brown, Wendy A

    2017-06-01

    Nonalcoholic fatty liver disease (NAFLD) affects over 80% of obese patients and is fueled by the metabolic syndrome. Weight loss is strongly advocated as a central treatment for NAFLD and has been shown to induce histological improvement. We aimed to define the patterns of improvement in NAFLD with weight loss and determine target weight goals for NAFLD resolution. A prospective study of 84 morbidly obese patients with NAFLD undergoing bariatric surgery was conducted. Intraoperative liver biopsies were taken. Monthly follow-up, including blood tests and measurements, was performed. We monitored improvements in NAFLD by monthly alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels over 1 year. There was rapid improvement in ALT, particularly in the first 6 months following surgery, with statistically significant reduction in ALT at 2 months (35 vs 27 IU/L, p < 0.001). In multivariate analysis, there were significantly increased odds of ALT normalization after a %TBWL of 10-15% (odds ratio 2.49, p = 0.005). The odds of resolution increased with increasing weight loss. Triglyceride levels (odds ratio 0.59, p = 0.021) and baseline NAFLD activity score (odds ratio 0.28, p < 0.001) were also significantly related to ALT normalization. Improvements in ALT occurred prior to metabolic improvement and well before traditional ideal weight goals were reached. Improvements in NAFLD occurred rapidly after bariatric surgery and were closely related to weight loss and metabolic factors. A 10-15% reduction in body weight is an appropriate target to achieve substantial improvement in ALT levels. Australian Clinical Trials Registry (ACTRN12610000049077).

  17. Schisandra chinensis Prevents Alcohol-Induced Fatty Liver Disease in Rats

    PubMed Central

    Park, Hyoung Joon; Lee, Soo-Jung; Song, Yuno; Jang, Sun-Hee; Ko, Yeoung-Gyu; Kang, Suk Nam; Chung, Byung Yeoup; Kim, Hong-Duck; Kim, Gon-Sup

    2014-01-01

    Abstract Schisandra chinensis (SC), a traditional herbal medicine, has been prescribed for patients suffering from various liver diseases, including hepatic cancer, hypercholesterolemia, and CCl4-induced liver injury. We investigated whether SC extract has a protective effect on alcohol-induced fatty liver and studied its underlying mechanisms. Rats were fed with ethanol by intragastric administration every day for 5 weeks to induce alcoholic fatty liver. Ethanol treatment resulted in a significant increase in alanine aminotransferase, aspartate aminotransferase, and hepatic triglyceride (TG) levels and caused fatty degeneration of liver. Ethanol administration also elevated serum TG and total cholesterol (TC) and decreased high-density lipoprotein (HDL) cholesterol levels. However, after administration of ethanol plus SC extracts, the ethanol-induced elevation in liver TC and TG levels was reversed. Elevation in serum TG was not observed after treatment with SC. Moreover, compared with the ethanol-fed group, the rats administered ethanol along with SC extracts for 5 weeks showed attenuated fatty degeneration and an altered lipid profile with decreased serum TC and TG, and increased HDL cholesterol levels. Chronic ethanol consumption did not affect peroxisome proliferator-activated receptor γ (PPARγ) levels, but it decreased PPARα and phospho-AMP-activated protein kinase (AMPK) levels in the liver. However, SC prevented the ethanol-induced decrease in PPARα expression and induced a significant decrease in sterol regulatory element-binding protein-1 expression and increase in phospho-AMPK expression in rats with alcoholic fatty liver. SC administration resulted in a significant decrease in intracellular lipid accumulation in hepatocytes along with a decrease in serum TG levels, and it reversed fatty liver to normal conditions, as measured by biochemical and histological analyses. Our results indicate that the protective effect of SC is accompanied by a

  18. Steatohepatitis and liver fibrosis are predicted by the characteristics of very low density lipoprotein in nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Zhenghui G.; Tapper, Elliot B.; Connelly, Margery A.; Pimentel, Carolina F. M. G.; Feldbrügge, Linda; Kim, Misung; Krawczyk, Sarah; Afdhal, Nezam; Robson, Simon C.; Herman, Mark A.; Otvos, James D.; Mukamal, Kenneth J.; Lai, Michelle

    2016-01-01

    Background & Aims A major challenge in the management of nonalcoholic fatty liver disease (NAFLD) is to identify patients with nonalcoholic steatohepatitis (NASH) and early liver fibrosis. The progression of NAFLD is accompanied by distinctive changes in very low density lipoprotein (VLDL), a lipoprotein particle produced exclusively in the liver. Herein, we sought to determine the characteristics of VLDL profiles associated with NASH and liver fibrosis. Methods We evaluated VLDL profiles of 128 patients from a single centre NAFLD registry, and examined VLDL size, total and subclass VLDL concentrations in relation to NAFLD activity score (NAS), steatohepatitis and liver fibrosis as determined by liver biopsy. Results A near linear relationship was observed between mean VLDL particle size and NAFLD activity score (NAS). In multivariate models, VLDL particle size was significantly associated with both NAS and NASH, after adjustment for BMI and diabetes. A decrease in small VLDL particle concentration was associated with more advanced liver fibrosis. In receiver operative characteristic analyses, mean VLDL size performed similarly to cytokeratin 18 in predicting NASH, whereas small VLDL particle concentration had similar performance to NAFLD fibrosis score in predicting stage 2 or above liver fibrosis. Conclusions The increase in mean VLDL size in NASH and decrease in small VLDL particle concentration in liver fibrosis likely reflect changes in the number and state of hepatocytes associated with NASH and fibrosis. In addition to its value in risk stratification of cardiovascular diseases, circulating VLDL profile may provide information for the staging of NAFLD disease severity. PMID:26815314

  19. Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Kumagai, Erina; Sugiyama, Masaya; Korenaga, Masaaki; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aikata, Hiroshi; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Nozaki, Yuichi; Kawaguchi, Takumi; Torimura, Takuji; Abe, Masanori; Hiasa, Yoichi; Fukai, Moto; Kamiyama, Toshiya; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

    2016-07-01

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)-1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients.

  20. Dietary β-conglycinin prevents acute ethanol-induced fatty liver in mice.

    PubMed

    Ikaga, Reina; Li, Dongyang; Yamazaki, Tomomi

    2017-09-01

    Alcoholic fatty liver is the earliest stage of alcohol-induced liver disease leading to liver cirrhosis. β-Conglycinin, one of the soy proteins, is known to prevent non-alcoholic fatty liver, hyperlipidemia and obesity. Therefore, we examined whether β-conglycinin feeding has an effect on the prevention of acute ethanol-induced fatty liver in mice. Male C57BL/6J mice were fed with 20 energy% β-conglycinin or casein for 4 weeks prior to ethanol administration and were then given ethanol or glucose, as a control, by gavage. Ethanol significantly increased liver triglyceride (TG) in mice fed casein due to the activation of peroxisome proliferator-activated receptor (PPAR) γ2, a nuclear transcription factor known for regulating lipid metabolism and de novo lipogenesis. The liver TG of ethanol-administered β-conglycinin-fed mice was significantly lower than that in those fed casein, although ethanol increased the amount of liver TG in mice fed β-conglycinin. The increased levels of PPARγ2 protein and its target gene CD36 in response to an ethanol were not observed in mice fed β-conglycinin. Moreover, β-conglycinin decreased the basal expression of de novo lipogenesis-related genes such as stearoyl-CoA desaturase-1, and therefore, the expressions of these genes were lower in the ethanol-administered β-conglycinin-fed mice than in the casein-fed mice. In conclusion, β-conglycinin supplementation appears to prevent the development of fatty liver in mice caused by ethanol consumption via the suppression of alcohol-induced activation of PPARγ2 and the downregulation of the basal expression of de novo lipogenesis. Copyright © 2017. Published by Elsevier Inc.

  1. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease

    PubMed Central

    Arora, Anil; Sharma, Praveen

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation. PMID:25755423

  2. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease.

    PubMed

    Arora, Anil; Sharma, Praveen

    2012-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation.

  3. Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis.

    PubMed

    Adams, Leon A; Feldstein, Ariel E

    2011-02-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the USA and many other parts of the world. Its prevalence continues to rise; currently affecting about one in four adults and 10% of children in the USA. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, no-progressive clinical course, to nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Currently, the diagnosis of NASH requires an invasive liver biopsy with drawbacks of sampling and interpretation error. Clinical risk factors for NASH include diabetes and the metabolic syndrome; however, these are not sufficiently predictive of the condition by themselves. Routine liver enzyme levels are not reliable; however, novel plasma hepatocyte cell death markers either alone or in combination with clinical risk factors are potential non-invasive diagnostic tools for the future. This review provides a concise overview of the role non-invasive diagnostic tools for the differentiation of fatty liver from NASH as well as for the determination of presence and extent of fibrosis.

  4. Altered Fatty Acid Metabolism-Related Gene Expression in Liver from Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Auguet, Teresa; Berlanga, Alba; Guiu-Jurado, Esther; Martinez, Salomé; Porras, José Antonio; Aragonès, Gemma; Sabench, Fátima; Hernandez, Mercé; Aguilar, Carmen; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2014-01-01

    Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis. PMID:25474087

  5. Altered fatty acid metabolism-related gene expression in liver from morbidly obese women with non-alcoholic fatty liver disease.

    PubMed

    Auguet, Teresa; Berlanga, Alba; Guiu-Jurado, Esther; Martinez, Salomé; Porras, José Antonio; Aragonès, Gemma; Sabench, Fátima; Hernandez, Mercé; Aguilar, Carmen; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2014-12-02

    Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis.

  6. Fatty Liver, Insulin Resistance, and Obesity: Relationships With Increase in Coronary Artery Calcium Over Time.

    PubMed

    Sung, Ki-Chul; Ryu, Seungho; Lee, Jong-Young; Lee, Sung Ho; Cheong, Eun Sun; Wild, Sarah H; Byrne, Christopher D

    2016-06-01

    Nonalcoholic fatty liver disease, insulin resistance (IR), and obesity frequently coexist with type 2 diabetes mellitus (DM), but it is uncertain whether these risk factors for vascular disease contribute to a change in atherosclerosis over time, independently of DM status. We hypothesized that the combination of fatty liver, IR, and obesity would be associated with an increase in coronary artery calcium (CAC) score over time, independently of DM status, other cardiovascular risk factors, and medications. Data were analyzed from a South Korean occupational cohort of 2175 people. The outcome was increase in cardiac computed tomography CAC score between baseline and follow-up. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR) ≥75th percentile and fatty liver by ultrasound. In 592 (27.2%) participants, CAC score increased from baseline (mean ± SD; mean age at baseline, 44.8 ± 5.5 years); and in 1583 subjects, CAC did not change or improved during follow-up (mean age, 41.6 ± 5.6 years). Diabetes mellitus, HOMA-IR, fatty liver, and obesity prevalence were all higher (all P < 0.001) in participants whose CAC score increased from baseline. Adjusting for DM and potential confounders, the combination of IR, obesity, and fatty liver was independently associated with increase in CAC score over time (hazard ratio: 2.46, 95% confidence interval: 1.50-4.03). The combination of fatty liver, IR, and obesity is associated with progression of atherosclerosis over time independently of DM, cardiovascular risk factors, and all medications for cardiovascular disease and DM. © 2016 Wiley Periodicals, Inc.

  7. The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

    SciTech Connect

    Reue, K.; Rehnmark, S.; Cohen, R.D.; Leete, T.H.; Doolittle, M.H. |; Giometti, C.S.; Mishler, K.; Slavin, B.G.

    1997-07-01

    Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and these droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.

  8. Silymarin’s Protective Effects and Possible Mechanisms on Alcoholic Fatty Liver for Rats

    PubMed Central

    Zhang, Wei; Hong, Rutao; Tian, Tulei

    2013-01-01

    Silymarin has been introduced fairly recently as a hepatoprotective agent. But its mechanisms of action still have not been well established. The aim of this study was to make alcoholic fatty liver model of rats in a short time and investigate silymarin’s protective effects and possible mechanisms on alcoholic fatty liver for rats. The model of rat’s alcoholic fatty liver was induced by intragastric infusion of ethanol and high-fat diet for six weeks. Histopathological changes were assessed by hematoxylin and eosin staining (HE). The activities of alanine transarninase (ALT) and aspartate aminotransferase (AST), the levels of total bilirubin (TBIL), total cholesterol (TC) and triglyceride (TG) in serum were detected with routine laboratory methods using an autoanalyzer. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and the level of malondialdehyde (MDA) in liver homogenates were measured by spectrophotometry. The TG content in liver tissue was determined by spectrophotometry. The expression of nuclear factor-κB (NF-κB), intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6) in the liver were analyzed by immunohistochemistry. Silymarin effectively protected liver from alcohol-induced injury as evidenced by improving histological damage situation, reducing ALT and AST activities and TBIL level in serum, increasing SOD and GPx activities and decreasing MDA content in liver homogenates and reducing TG content in liver tissue. Additionally, silymarin markedly downregulated the expression of NF-κB p65, ICAM-1 and IL-6 in liver tissue. In conclusion, Silymarin could protect against the liver injury caused by ethanol administration. The effect may be related to alleviating lipid peroxidation and inhibiting the expression of NF-κB. PMID:24244810

  9. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.

    PubMed

    Kawano, Yuki; Cohen, David E

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.

  10. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity.

    PubMed

    Hartmann, Phillipp; Seebauer, Caroline T; Mazagova, Magdalena; Horvath, Angela; Wang, Lirui; Llorente, Cristina; Varki, Nissi M; Brandl, Katharina; Ho, Samuel B; Schnabl, Bernd

    2016-03-01

    Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid β-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome.

  11. Early onset of fatty liver in growth-restricted rat fetuses and newborns.

    PubMed

    Yamada, Makiko; Wolfe, Diana; Han, Guang; French, Samuel W; Ross, Michael G; Desai, Mina

    2011-12-01

    Intrauterine growth-restricted (IUGR) newborns have increased risk of adult metabolic syndrome, including fatty liver. However, it is unclear whether the fatty liver development is "programmed" or secondary to the accompanying obesity. In this study, we examined hepatic lipid accumulation and lipid-regulatory factors (sterol regulatory element-binding protein-1c and fatty acid synthase) in IUGR and Control fetal (embryonic day 20; e20) and newborn (postnatal day 1; p1) rat pups. Notably, despite of in utero undernutrition state, IUGR fetuses demonstrated "fatty liver" with upregulation of these lipogenic indices at as early as e20. Both IUGR and Control newborns exhibited the same extent of massive increase in hepatic lipid content, whereas IUGR newborns continued to exhibit upregulated lipogenic indices. The persistent upregulation of the lipogenic indices in fetal and newborn IUGR suggests that fatty liver is gestationally programmed. Our study suggested that IUGR offspring were born with an altered metabolic life strategy of increased fuel/lipid storage which could be a distinct metabolic pathway of the thrifty phenotype.

  12. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity

    PubMed Central

    Hartmann, Phillipp; Seebauer, Caroline T.; Mazagova, Magdalena; Horvath, Angela; Wang, Lirui; Llorente, Cristina; Varki, Nissi M.; Brandl, Katharina; Ho, Samuel B.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid β-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome. PMID:26702135

  13. Brain and liver fatty acid composition changes upon consumption of Lactobacillus rhamnosus LA68.

    PubMed

    Ivanovic, Nevena; Minic, Rajna; Djuricic, Ivana; Dimitrijevic, Ljiljana; Sobajic, Sladjana; Zivkovic, Irena; Djordjevic, Brizita

    2015-02-01

    Recent reports suggest that the metabolic activity of the enteric microbiota may influence the fatty acid composition of the host tissue. There are many studies dealing with the influence of lactobacilli on various pathological conditions, and some of the effects are strain-specific. This study was designed to test the effects of a particular Lactobacillus strain, Lactobacillus rhamnosus LA68 on fatty acid composition of the liver and the brain of C57BL/6 mice in the absence of an underlying pathological condition. Female mice were supplemented with live L. rhamnosus LA68 bacteria for the duration of 1 month. Serum biochemistry was analyzed and liver and brain fatty acid composition was assessed by gas-liquid chromatography. Significant changes in liver and brain fatty acid composition were detected. In the liver tissue we detected an increase in palmitoleic acid (p = 0.038), while in the brain compartment we found an increase in palmitic (p = 0.042), stearic (p = 0.017), arachidonic acid (p = 0.009) and docosahexaenoic acid (p = 0.004) for control versus experimental group. These results show discrete changes caused by LA68 strain consumption. Even short duration of administration of LA68 influences the fatty acid composition of the host which adds to the existing knowledge about Lactobacillus host interaction, and adds to the growing knowledge of metabolic intervention possibilities.

  14. Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence?

    PubMed

    Cheah, Irwin K; Tang, Richard; Ye, Peng; Yew, Terry S Z; Lim, Keith H S; Halliwell, Barry

    2016-01-01

    L-ergothioneine (ET), a putative antioxidant compound acquired by animals through dietary sources, has been suggested to accumulate in certain cells and tissues in the body that are predisposed to high oxidative stress. In the present study, we identified an elevation of ET in the liver of a guinea pig model of non-alcoholic fatty liver disease (NAFLD), elucidated a possible mechanism for the increased uptake and investigated the possible role for this accumulation. This increase in liver ET levels correlated with cholesterol accumulation and disease severity. We identified an increase in the transcriptional factor, RUNX1, which has been shown to upregulate the expression of the ET-specific transporter OCTN1, and could consequently lead to the observable elevation in ET. An increase was also seen in heat shock protein 70 (HSP70) which seemingly corresponds to ET elevation. No significant increase was observed in oxidative damage markers, F2-isoprostanes, and protein carbonyls, which could possibly be attributed to the increase in liver ET through direct antioxidant action, induction of HSP70, or by chelation of Fe(2+), preventing redox chemistry. The data suggest a novel mechanism by which the guinea pig fatty liver accumulates ET via upregulation of its transporter, as a possible stress response by the damaged liver to further suppress oxidative damage and delay tissue injury. Similar events may happen in other animal models of disease, and researchers should be aware of the possibility.

  15. Scintigraphic appearance of focal fatty infiltration of the liver using single-photon emission computed tomography

    SciTech Connect

    Kudo, M.; Hirasa, M.; Ibuki, Y.; Takakuwa, H.; Fujimi, K.; Veda, S.; Tomita, S.; Komori, H.; Todo, A.; Kitaura, Y.

    1984-01-01

    Fatty infiltration of the liver had been considered to assume a uniform distribution until quite recently. However, the development of X-ray computed tomography (XCT) and the ultrasound (US) has proven that fatty infiltration of the liver may sometimes assume a nonuniform distribution (focal fatty infiltration (FFI)). This investigation was undertaken to evaluate the scintigraphic appearance of FFI using single-photon emission computed tomography (SPECT) with a GE Maxicamera 400T. Radionuclide images including SPECT were evaluated in 12 cases with FFI which were diagnosed by XCT and US. Most of them were histrogically confirmed to be positive fatty infiltration in the liver. The results were as follows. The fatty infiltrated area was visualized as a hot spot in one case, a defect in 2 cases, a low uptake in one case and a normal uptake in 8 cases. Radionuclide imaging of FFI shows a large variety of findings and it suggests that Kupffer cell function varies with the causes or stage of fatty infiltration. And one can understand the pathological state of FFI from a viewpoint of Kupffer cell function only by radionuclide imaging including SPECT, which is very useful to compare the images with XCT images.

  16. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Tilg, Herbert; Moschen, Alexander R; Szabo, Gyongyi

    2016-09-01

    Both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease are characterized by massive lipid accumulation in the liver accompanied by inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma in a substantial subgroup of patients. At several stages in these diseases, mediators of the immune system, such as cytokines or inflammasomes, are crucially involved. In ALD, chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides through Toll-like receptors, e.g., Toll-like receptor 4. This sensitization enhances the production of various proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha, thereby contributing to hepatocyte dysfunction, necrosis, and apoptosis and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis. Indeed, neutralization of IL-1 by IL-1 receptor antagonist has recently been shown to potently prevent liver injury in murine models of ALD. As IL-1 is clearly linked to key clinical symptoms of acute alcoholic hepatitis such as fever, neutrophilia, and wasting, interfering with the IL-1 pathway might be an attractive treatment strategy in the future. An important role for IL-1-type cytokines and certain inflammasomes has also been demonstrated in murine models of nonalcoholic fatty liver disease. IL-1-type cytokines can regulate hepatic steatosis; the NLR family pyrin domain containing 3 inflammasome is critically involved in metabolic dysregulation. IL-1 cytokine family members and various inflammasomes mediate different aspects of both ALD and nonalcoholic fatty liver disease. (Hepatology 2016;64:955-965). © 2016 by the American Association for the Study of Liver Diseases.

  17. [Non-alcoholic fatty liver disease in obese children and adolescents].

    PubMed

    Denzer, C

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adolescents in industrialized countries. Recent studies have demonstrated a prevalence rate of NAFLD in overweight and obese children and adolescents in Germany of up to 30%. The spectrum of NAFLD ranges from pure fatty infiltration (simple steatosis) to inflammation (steatohepatitis, synonymous NASH) to fibrosis and cirrhosis. Age, gender, ethnicity, insulin resistance, and sex steroids are implicated in the pathogenesis of NAFLD in childhood and adolescence. Moreover, NAFLD in the pediatric age group is associated with marked cardiovascular comorbidities. This review focuses on current data regarding epidemiology, pathophysiology, comorbidities, and treatment of NAFLD in children and adolescents.

  18. Supplementing dietary sugar promotes endoplasmic reticulum stress-independent insulin resistance and fatty liver in goose.

    PubMed

    Geng, Tuoyu; Zhao, Xing; Xia, Lili; Liu, Long; Li, Fuyuan; Yang, Biao; Wang, Qianqian; Montgomery, Sean; Cui, Hengmi; Gong, Daoqing

    2016-08-05

    It is known that endoplasmic reticulum stress (ERS) contributes to insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in mammals. However, we recently demonstrated that overfeeding with a traditional diet (mainly consisting of cooked maize) does not induce ERS in goose. As cellular studies show that high glucose and palmitate can trigger ERS in mammalian cells, we hypothesized that supplementing sugar to the traditional diet could induce ERS, thus promoting insulin resistance and fatty liver. To test the hypothesis, we first treated goose primary hepatocytes with high glucose (25 mM and 50 mM) and palmitate (0.5 mM) supplemented with or without 0.25 mM oleate. Data indicated that, as in mammalian cells, high glucose and palmitate indeed induced ERS in goose primary hepatocytes, and palmitate-induced ERS was suppressed by supplemental 0.25 mM oleate. We then tested the hypothesis with an in vivo study, in which Landes geese overfed with traditional or novel diets (i.e., the traditional diet supplemented with sugar) were compared with control geese (normally fed with cooked maize) for ERS, IR and fatty liver. The differences in glucose tolerance, insulin tolerance and postprandial blood glucose between the geese overfed with traditional and novel diets suggested that supplementing dietary sugar promoted IR. This promotion was accompanied with an increasing trend of liver weight and abdominal fat weight relative to body weight. Surprisingly, compared to overfeeding with the traditional diet, overfeeding with the novel diet did not induce ERS, even further suppressed ERS in goose fatty liver. Together, our findings suggest that supplementing dietary sugar promotes ERS-independent IR and fatty liver in goose. It is intriguing to discover the factor(s) protecting goose liver from ERS as well as the non-ERS mechanism underlying IR. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations.

    PubMed

    Milić, Sandra; Lulić, Davorka; Štimac, Davor

    2014-07-28

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m(2). However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m(2)) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.

  20. [Experimental food-induced fatty liver and its adjuvant therapy with natural bioactive substances].

    PubMed

    Hegedüs, Viktor; Gerö, Domokos; Mihály, Zoltán; Szijártó, Attila; Zelles, Tivadar; Sárdi, Eva

    2011-06-26

    Changes of redox-homeostasis generate cytokines, and free radicals influence many intracellular signaling pathways in different liver diseases. Liophylised table beet and carrot powder (GPS Powder Kft. 1361/004/2003BFÁÉÉÁ) containing bioactive components such as betaine, betanins, betaxanthins, flavonoids, polyphenols, glutamine, beta carotene, vitamins and folic acid may induce changes in various cellular pathways. The aim of this study was to determine the protecting effects of bioactive agents of the liophylised table beet and carrot powder on fatty liver in a "short term" experiment. Male Wistar rats were fed with chow with or without high fat (2% cholesterol, 0.5% cholic acid, 20% sunflower oil) and treated with 0.1 or 1 g/bwkg/day natural product for ten days parallel with the feedings. Cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA levels were determined using molecular biologic methods. Free radicals, H-donating activity, reducing power and free SH-group concentrations were determined by luminometry and spectrophotometry. Mobilized methyl groups were assayed by high pressure liquid chromatography method in liver homogenates. It was found that the higher dose of the natural product better decreased the induced free radical reactions, cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA-levels both in normal and fatty liver tissues. Although treatments failed to exert significant changes in all global antioxidant parameters, mobilized methyl group concentrations were higher after treatments in fatty liver. Favorable tendencies were also noted in the redox-homeostasis of the fatty liver after treatment. As expected, lyophylised table beet and carrot proved to be a "functional food" in rats with alimentary fat induced fatty liver. It cannot be ruled out that this beneficial effect may have clinical relevance.

  1. The role of endoplasmic reticulum stress and insulin resistance in the occurrence of goose fatty liver.

    PubMed

    Geng, Tuoyu; Xia, Lili; Li, Fuyuan; Xia, Jing; Zhang, Yihui; Wang, Qianqian; Yang, Biao; Montgomery, Sean; Cui, Hengmi; Gong, Daoqing

    2015-09-11

    In mammals, insulin resistance (IR) is required for the occurrence of non-alcoholic fatty liver disease, and endoplasmic reticulum stress (ERS) contributes to IR. As geese have physiological and metabolic characteristics different from mammals, it is unclear whether these mechanisms also underlie the occurrence of goose fatty liver. To address this, 70-day-old geese were treated with an ERS inducer or overfed, and variables associated with ERS or IR were subsequently determined. The data indicated that the group of geese treated with the ERS inducer for 20d appeared to be more intolerant to blood glucose than the control group, and their livers showed features of hepatic steatosis, suggesting ERS can induce IR and hepatic steatosis in geese. In contrast, overfeeding did not induce ERS, probably due to the upregulated expression of fatty acid desaturases, but induced higher fasting/postprandial blood glucose as well as glucose intolerance in geese, which was accompanied by a dramatic increase of liver weight. Taken together, these findings delineated the role of ERS and IR in the occurrence of goose fatty liver. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Antioxidant dietary approach in treatment of fatty liver: New insights and updates

    PubMed Central

    Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids (i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates (i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver. PMID:28694655

  3. Prevalence and features of fatty liver detected by physical examination in Guangzhou

    PubMed Central

    Liao, Xian-Hua; Cao, Xu; Liu, Jie; Xie, Xiao-Hua; Sun, Yan-Hong; Zhong, Bi-Hui

    2013-01-01

    AIM: To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics. METHODS: A total of 3433 consecutive patients who received physical examinations at the Huangpu Division of the First Affiliated Hospital at Sun Yat-sen University in Guangzhou, China from June 2010 to December 2010 were retrospectively enrolled in the study. Results of biochemical tests, abdominal ultrasound, electrocardiography, and chest X-ray were collected. The diagnosis of fatty liver was made if a patient met any two of the three following ultrasonic criteria: (1) liver and kidney echo discrepancy and presence of an increased liver echogenicity (bright); (2) unclear intrahepatic duct structure; and (3) liver far field echo decay. RESULTS: The study population consisted of 2201 males and 1232 females, with a mean age of 37.4 ± 12.8 years. When all 3433 patients were considered, the overall prevalence of hyperlipidemia was 38.1%, of fatty liver was 26.0%, of increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels was 11.9%, of gallstone was 11.4%, of hyperglycemia was 7.3%, of hypertension was 7.1%, and of hyperuricemia was 6.2%. Of the 2605 patients who completed the abdominal ultrasonography exam, 677 (26.0%) were diagnosed with fatty liver and the prevalence was higher in males (32.5% vs females: 15.3%, P < 0.001). The overall prevalence of fatty liver increased with age, with the peak prevalence (39.5%) found in the 60 to 70-year-old age group. Among patients between the ages of 18 to 50-year-old, the prevalence of fatty liver was significantly higher in males (20.2% vs females: 8.7%, P < 0.001); the difference in prevalence between the two sexes in patients > 50-year-old did not reach statistical significance. Only 430 of the patients diagnosed with fatty liver had complete information; among those, increased ALT and/or AST levels were detected in only 30%, with

  4. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

    PubMed

    Firneisz, Gábor

    2014-07-21

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.