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Sample records for hemochromatosis

  1. Hemochromatosis

    MedlinePlus

    Hemochromatosis National Digestive Diseases Information Clearinghouse What is hemochromatosis? Hemochromatosis is the most common form of iron overload disease. Too much iron in the body causes hemochromatosis. Iron is important because it is part of hemoglobin, a molecule ...

  2. Hemochromatosis

    MedlinePlus

    ... unknown. The juvenile form leads to severe iron overload and liver and heart disease in adolescents and ... if patients with these diseases also have iron overload. How is hemochromatosis treated? Treatment for hemochromatosis is ...

  3. Hemochromatosis

    MedlinePlus

    Hemochromatosis is a disease in which too much iron builds up in your body. Your body needs iron but too much of it is toxic. If you have hemochromatosis, you absorb more iron than you need. Your body has no natural ...

  4. Hemochromatosis

    MedlinePlus

    ... Hemochromatosis is the most common form of iron overload disease. Too much iron in the body causes ... much iron in the body leads to iron overload—a buildup of extra iron that, without treatment, ...

  5. Hemochromatosis

    MedlinePlus

    ... in the body. It is also called iron overload. Causes Hemochromatosis may be a genetic disorder passed ... blood transfusions over time may lead to iron overload. Long-term alcohol use and other health conditions. ...

  6. Hemochromatosis

    MedlinePlus

    ... much iron builds up in your body (iron overload). Iron is a mineral found in many foods. ... of another disease or condition that causes iron overload. Most people who have primary hemochromatosis inherit it ...

  7. Hereditary Hemochromatosis

    MedlinePlus

    ... overload, hereditary hemochromatosis, HFE gene, HFE mutations, iron overload, primary hemochromatosis, secondary hemochromatosis Family Health, Men, Seniors, Women April 2003 Copyright © American Academy of Family PhysiciansThis information provides a general overview and may not apply ...

  8. Living with Hemochromatosis

    MedlinePlus

    ... page from the NHLBI on Twitter. Living With Hemochromatosis The outlook for people who have hemochromatosis largely ... do to help you. Screening Family Members for Hemochromatosis Parents, grandparents, brothers and sisters, and children (blood ...

  9. How Is Hemochromatosis Treated?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Hemochromatosis Treated? Treatments for hemochromatosis include therapeutic phlebotomy (fleh-BOT-o-me), iron ... and treatment for complications. The goals of treating hemochromatosis include: Reducing the amount of iron in your ...

  10. Hereditary hemochromatosis.

    PubMed

    Holman, J R

    1997-03-01

    Hereditary hemochromatosis (HHC) is an inherited disease transmitted in an autosomal recessive pattern. With homozygosity occurring in up to 0.5% of the population, HHC is the most prevalent genetic disease among the white population worldwide and has the same prevalence as the sickle cell trait in the African-American population. An asymptomatic 50-year-old white man presented at the family practice clinic and stated that HHC had been diagnosed in his mother. Laboratory findings showed markedly elevated transferrin saturation and ferritin levels. The diagnosis of HHC was made on the basis of the laboratory results and family history, and therapy was begun. Clinical manifestations of HHC occur late and include diabetes mellitus, cirrhosis, and cardiomyopathy. As end-organ damage is preventable, optimal management involves early diagnosis and lifelong phlebotomy. Diagnosis is made by an elevated transferrin saturation level and an increased serum ferritin value. Hereditary hemochromatosis is a genetic disorder of iron metabolism that has an excellent prognosis if diagnosed early.

  11. Neonatal hemochromatosis.

    PubMed

    Feldman, Amy G; Whitington, Peter F

    2013-12-01

    Neonatal hemochromatosis is a clinical condition in which severe liver disease in the newborn is accompanied by extrahepatic siderosis. Gestational alloimmune liver disease (GALD) has been established as the cause of fetal liver injury resulting in nearly all cases of NH. In GALD, a women is exposed to a fetal antigen that she does not recognize as "self" and subsequently begins to produce IgG antibodies that are directed against fetal hepatocytes. These antibodies bind to fetal liver antigen and activate the terminal complement cascade resulting in hepatocyte injury and death. GALD can cause congenital cirrhosis or acute liver failure with and without iron overload and siderosis. Practitioners should consider GALD in cases of fetal demise, stillbirth, and neonatal acute liver failure. Identification of infants with GALD is important as treatment is available and effective for subsequent pregnancies.

  12. Diabetes in HFE Hemochromatosis

    PubMed Central

    Acton, Ronald T.

    2017-01-01

    Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis. PMID:28331855

  13. What Causes Hemochromatosis?

    MedlinePlus

    ... each parent), you're at risk for iron overload and signs and symptoms of hemochromatosis. If you ... of another disease or condition that causes iron overload. Examples of such diseases and conditions include: Certain ...

  14. Learning about Hereditary Hemochromatosis

    MedlinePlus

    ... org] Multimedia educational site including screening and treatment information. Hosted by the Dolan DNA Learning Center at Cold Spring Harbor Laboratory. Iron Overload and Hemochromatosis FAQs [cdc.gov] Questions and answers ...

  15. Hereditary Hemochromatosis (For Parents)

    MedlinePlus

    ... buildup can be prevented. Doctors usually diagnose iron overload with these blood tests: serum ferritin : measures the ... disease. previous continue Treatment Doctors treat the iron overload from hereditary hemochromatosis by regularly drawing blood to ...

  16. Genetics Home Reference: hereditary hemochromatosis

    MedlinePlus

    ... increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hereditary hemochromatosis is also called an iron overload disorder. Early symptoms of hereditary hemochromatosis are nonspecific ...

  17. Management of hemochromatosis. Hemochromatosis Management Working Group.

    PubMed

    Barton, J C; McDonnell, S M; Adams, P C; Brissot, P; Powell, L W; Edwards, C Q; Cook, J D; Kowdley, K V

    1998-12-01

    The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of 1) removal of 1 unit (450 to 500 mL) of blood weekly until the serum ferritin level is 10 to 20 microg/L and 2) maintenance of the serum ferritin level at 50 microg/L or less thereafter by periodic removal of blood. Hyperferritinemia attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrinopathic abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation; reduce retention of nonferrous metals; and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.

  18. What Are the Signs and Symptoms of Hemochromatosis?

    MedlinePlus

    ... Twitter. What Are the Signs and Symptoms of Hemochromatosis? Hemochromatosis can affect many parts of the body ... the disease don't have signs or symptoms. Hemochromatosis Complications If hemochromatosis isn't found and treated ...

  19. Diagnosis and management of hereditary hemochromatosis.

    PubMed

    Salgia, Reena J; Brown, Kimberly

    2015-02-01

    Hereditary hemochromatosis is a rare genetic disorder that can have significant clinical consequences. Hemochromatosis is associated with iron overload, and can initially be recognized through laboratory testing for serum ferritin and transferrin saturation. Genetic testing for the HFE mutation can be performed in patients with elevated iron indices and a suspicion for hemochromatosis or liver disease. The main pathway resulting in iron overload is through altered hepcidin levels. Treatment of patients with the clinical phenotype of hereditary hemochromatosis is commonly through phlebotomy for removal of excess iron stores. This article highlights the current information and data regarding the diagnosis and management of hemochromatosis.

  20. Night sweats: it may be hemochromatosis.

    PubMed

    Murday, H K M; Rusli, F D; Blandy, C; Vollenhoven, B

    2016-08-01

    The aim of this case report is to show that hemochromatosis can present, unusually, with night sweats. At presentation, hemochromatosis often tends to have non-specific symptoms, making it easy to misdiagnose, especially if it presents with rare symptoms. Misdiagnosis of hemochromatosis can lead to lethal outcomes, given it can cause multiple organ dysfunctions if left untreated and hence the need to identify it early on. The case we present is a 41-year-old woman with previously undiagnosed hemochromatosis complaining of night sweats. She thought she was menopausal. The diagnosis of hemochromatosis was made solely on investigations given that she did not have any other symptoms other than night sweats. Her serum iron concentrations were within the normal range due to menstruation. It is uncommon for women to present with symptoms of hemochromatosis during their reproductive life since their iron concentration is kept within normal range through monthly menstrual bleeding.

  1. Pathogenesis, Diagnosis and Treatment of Hemochromatosis.

    PubMed

    Zoller, Heinz; Henninger, Benjamin

    Hemochromatosis is a common cause of chronic liver disease and HFE genotyping allows decisive and non-invasive diagnosis. Molecular and clinical genetic studies have led to the identification of genes other than HFE in patients with inherited diseases associated with increased hepatic iron storage that can cause hemochromatosis, which adds complexity to a diagnostic approach to patients with suspected hemochromatosis. Despite major advances in genetics, hepatic iron quantification by non-invasive methods therefore remains the key to the diagnosis of hemochromatosis. Although associated with homozygosity for the C282Y polymorphism in the HFE gene in >80% of patients, hemochromatosis is a complex genetic disease with strong environmental disease modifiers. Testing for mutations in the non-HFE hemochromatosis genes transferrin receptor 2, hemojuvelin, HAMP and SLC40A1 is complex, costly and time-consuming. Demonstration of hepatic iron overload by liver biopsy or MRI is therefore required before such complex tests are carried out. The pathogenesis of chronic liver disease in hemochromatosis is mainly attributed to the redox potential of tissue iron, and only the more recent studies have focused on the toxic properties of circulating iron. Considering the fact that an increased saturation of transferrin and high iron in plasma are the hallmark of all hemochromatosis forms, an alternative view would be that toxic iron in the circulation is involved in the pathogenesis of hemochromatosis. Recent studies have shown an increased concentration of redox-active iron in plasma in patients with increased transferrin saturation. This finding supports the hypothesis that tissue iron may be the 'smoking gun' of iron-induced organ damage. Taken together, caring for patients with suspected or established hemochromatosis still remains a challenge, where understanding the genetics, biochemistry and cell biology of hemochromatosis will aid better diagnosis and treatment of affected

  2. Hemochromatosis simulating rheumatoid arthritis: a case report.

    PubMed

    Barbosa, Fabíola Brasil; Callegari, Amanda; Sarinho, José Célso; Lucena, Juliana; Casagrande, Renielly; de Souza, Branca Dias Batista

    2014-01-01

    This is a report of a patient who had a previous diagnosis of rheumatoid arthritis, nonerosive, rheumatoid factor negative, that despite the therapeutic approach presented progressive worsening of the articular and general condition. After extensive research, she had a diagnosis of hemochromatosis. Joint symptoms are common manifestations in hemochromatosis. The arthropathy of hemochromatosis may resemble inflammatory arthropathy mimicking RA, particularly in the most common sites as 2nd and 3rd metacarpophalangeal. Radiologically are observed decreased joint space, subchondral sclerosis, cyst formation and chondrocalcinosis. Treatment with disease modifying drugs for rheumatoid arthritis tend to worsen the clinical picture, since the liver is the major site of deposition of iron in hemochromatosis and these medications are known to be hepatotoxic. Phlebotomy treatment for hemochromatosis is apparently ineffective in reversing the articular manifestations, which requires the association with iron chelating drugs. Due to the apparent difficulty in differentiating between the two diseases, a screening profile of iron in patients with rheumatoid arthritis with atypical progression is necessary.

  3. Accuracy of Family History of Hemochromatosis or Iron Overload: The Hemochromatosis and Iron Overload Screening Study

    PubMed Central

    Acton, Ronald T.; Barton, James C.; Passmore, Leah V.; Adams, Paul C.; Mclaren, Gordon D.; Leiendecker–Foster, Catherine; Speechley, Mark R.; Harris, Emily L.; Castro, Oswaldo; Reiss, Jacob A.; Snively, Beverly M.; Harrison, Barbara W.; Mclaren, Christine E.

    2013-01-01

    Background & Aims The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload. Methods A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload. Results The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41–28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53–38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload. Conclusions Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis. PMID:18585964

  4. Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE).

    PubMed

    Bardou-Jacquet, Edouard; Brissot, Pierre

    2014-08-01

    The management and understanding of hereditary hemochromatosis have evolved with recent advances in iron biology and the associated discovery of numerous genes involved in iron metabolism. HFE-related (type 1) hemochromatosis remains the most frequent form, characterized by C282Y mutation homozygosity. Rare forms of hereditary hemochromatosis include type 2 (A and B, juvenile hemochromatosis caused by HJV and HAMP mutation), type 3 (related to TFR2 mutation), and type 4 (A and B, ferroportin disease). The diagnostic evaluation relies on comprehension of the involved pathophysiologic defect, and careful characterization of the phenotype, which gives clues to guide appropriate genetic testing.

  5. Hemochromatosis: discovery of the HFE gene.

    PubMed

    Bacon, Bruce R

    2012-01-01

    Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about 1 in 250 individuals. HH results in an increased absorption of iron at the baso-lateral surface of the enterocyte with aberrant regulation of ferroportin-mediated transfer of iron in turn brought on by a decrease in circulating hepcidin. The medical literature describes a colorful history of HH with important contributions from faculty at Saint Louis University.

  6. Genetics of iron storage and hemochromatosis.

    PubMed

    Beutler, E; Felitti, V; Gelbart, T; Ho, N

    2001-04-01

    The regulation of total body iron is important to all organisms. In mammals, the iron content of the body is controlled almost entirely through regulation of absorption. The precise mechanism by which iron is absorbed and the manner in which the absorption is regulated is unknown, but a number of different proteins that are involved either in the transport process itself or its regulation have been identified. These include HFE, a class 1 HLA molecule involved in hereditary hemochromatosis, the divalent metal transporter (DMT-1), hephaestin, the transferrin receptor, and mobilferrin. Iron overload occurs in a number of hereditary disorders including atransferrinemia, aceruloplasminemia, X-linked hereditary sideroblastic anemia, thalassemia major, congenital dyserythropoietic anemia, and various red cell enzyme deficiencies. In Europeans, most cases of hereditary hemochromatosis are due to mutations of the HFE gene. There are two major mutations of this gene c.845G-->A (C282Y) and c.187C-->G (H63D). These mutations have extraordinarily high prevalence in northern Europe and approximately five in a thousand Europeans are homozygous for the 845A mutation. The penetrance of even the homozygous state for the 845A mutation is very low and that for the compound heterozygote 845A/187G, which is also associated with hemochromatosis, is even lower. The reason for the markedly variable penetrance that exists in this disorder remains unknown.

  7. Transferrin receptor function in hereditary hemochromatosis

    SciTech Connect

    Ward, J.H.; Kushner, J.P.; Ray, F.A.; Kaplan, J.

    1984-02-01

    The binding of /sup 125/I-diferric transferrin to cultured skin fibroblasts and phytohemagglutinin-stimulated lymphocytes was studied in cells derived from individuals homozygous for hereditary hemochromatosis and from normal individuals. Receptors with a high affinity for diferric transferrin were present on all cells. Transferrin receptor number decreased by more than 50% when fibroblasts from both normal and hemochromatotic subjects were maintained in iron-supplemented medium. The number of transferrin receptors expressed by normal and hemochromatotic lymphocytes after mitogen stimulation in iron-supplemented media was less than 50% that of lymphocytes which were mitogen stimulated in standard medium. No change in the affinity of the receptors of diferric transferrin was seen in cells maintained in iron-supplemented medium. Competition experiments in the presence of deferoxamine suggested that the transferrin receptors of fibroblasts and mitogen-stimulated lymphocytes have a 70- to 100-fold higher affinity for diferric transferrin than for apotransferrin. No differences in the properties of transferrin receptors were found between patients with hereditary hemochromatosis and normal individuals. Although transferrin binding decreases when cells are exposed to high levels of iron in the medium, the failure to totally abolish transferrin binding to the receptor suggests that the concentration of diferric transferrin to which cells are exposed may be a major determinant of cellular iron loading in hereditary hemochromatosis.

  8. Monocyte transferrin-iron uptake in hereditary hemochromatosis

    SciTech Connect

    Sizemore, D.J.; Bassett, M.L.

    1984-05-01

    Transferrin-iron uptake by peripheral blood monocytes was studied in vitro to test the hypothesis that the relative paucity of mononuclear phagocyte iron loading in hereditary hemochromatosis results from a defect in uptake of iron from transferrin. Monocytes from nine control subjects and 17 patients with hemochromatosis were cultured in the presence of 59Fe-labelled human transferrin. There was no difference in 59Fe uptake between monocytes from control subjects and monocytes from patients with hemochromatosis who had been treated by phlebotomy and who had normal body iron stores. However, 59Fe uptake by monocytes from iron-loaded patients with hemochromatosis was significantly reduced compared with either control subjects or treated hemochromatosis patients. It is likely that this was a secondary effect of iron loading since iron uptake by monocytes from treated hemochromatosis patients was normal. Assuming that monocytes in culture reflect mononuclear phagocyte iron metabolism in vivo, this study suggests that the relative paucity of mononuclear phagocyte iron loading in hemochromatosis is not related to an abnormality in transferrin-iron uptake by these cells.

  9. Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis

    PubMed Central

    Makker, Jasbir; Hanif, Ahmad; Bajantri, Bharat; Chilimuri, Sridhar

    2015-01-01

    Disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state. Organ damage may result from iron overload and manifest clinically as cirrhosis, diabetes mellitus, arthritis, endocrine abnormalities and cardiomyopathy. Hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder. Expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation (calculated as serum iron/total iron binding capacity × 100). Further testing for the hemochromatosis gene is recommended if transferrin saturation is >45% with or without hyperferritinemia. However, management of individuals with low or normal transferrin saturation is not clear. In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other – primary as well as secondary – causes of iron overload besides hemochromatosis. We present here a possible approach to patients with hyperferritinemia but normal transferrin saturation. PMID:25759633

  10. Dysmetabolic hyperferritinemia: all iron overload is not hemochromatosis.

    PubMed

    Makker, Jasbir; Hanif, Ahmad; Bajantri, Bharat; Chilimuri, Sridhar

    2015-01-01

    Disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state. Organ damage may result from iron overload and manifest clinically as cirrhosis, diabetes mellitus, arthritis, endocrine abnormalities and cardiomyopathy. Hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder. Expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation (calculated as serum iron/total iron binding capacity × 100). Further testing for the hemochromatosis gene is recommended if transferrin saturation is >45% with or without hyperferritinemia. However, management of individuals with low or normal transferrin saturation is not clear. In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other - primary as well as secondary - causes of iron overload besides hemochromatosis. We present here a possible approach to patients with hyperferritinemia but normal transferrin saturation.

  11. [Iron chelate treatment of hereditary sideroblastic anemia complicated by hemochromatosis].

    PubMed

    Kremp, L; Girot, R; Alliot, S; Najean, Y; Douchain, F; Hongre, J F

    1983-01-01

    In a child with sideroblastic anemia complicated with hemochromatosis, iron overload was successfully treated with slow subcutaneous perfusion of deferoxamine. A 28 month-treatment resulted in the inversion of iron balance, which became negative, and the normalization of serum ferritin and abdominal CT scan. These results indicate that deferoxamine perfusion 12/24 hrs is able to restrict or even to remove the iron overload, previously responsible for hemochromatosis, a factor of mortality in this disease.

  12. Hemochromatosis heterozygotes may constitute a radiation-sensitive subpopulation.

    SciTech Connect

    Stevens, R G.; Morris, James E. ); Anderson, Larry E. )

    1999-12-01

    A primary mechanism of radiation-induced DNA damage is by generation of free radicals. Chronically increased oxidative stress from elevated body iron may increase radiation sensitivity by decreasing cellular oxygen radical scavenging capability. Hemochromatosis heterozygotes have elevated body iron. Low-level radiation sensitization by iron may be particularly pertinent for risk of breast cancer. Since ten percent of the population appears to be heterozygous for the hemochromatosis gene, a radiosensitizing effect would have pervasive implications.

  13. Is exchange transfusion a possible treatment for neonatal hemochromatosis?

    PubMed

    Timpani, Giuseppina; Foti, Francesca; Nicolò, Antonino; Nicotina, Pier Antonio; Nicastro, Emanuele; Iorio, Raffaele

    2007-11-01

    Neonatal hemochromatosis is a rare congenital disorder of the liver associated to a poor prognosis. Liver transplantation is often required, since no effective medical treatment has been found. Despite mounting evidence of an alloimmune etiology of this condition, exchange transfusion has never been proposed as a specific treatment for neonatal hemochromatosis. Here we describe two siblings affected by neonatal hemochromatosis. The first, a female, died at 18 days of severe coagulopathy and acute renal failure, diagnosed as affected by neonatal hemochromatosis only when the second sibling was suspected as being affected by the same disease. The second child showed a rapidly worsening coagulopathy which was treated with two exchange transfusions, followed by rapid clinical and laboratory improvement, before reaching a definite diagnosis of neonatal hemochromatosis. He is healthy at present after a follow-up of 12 months. Although exchange transfusion has never been considered as treatment for neonatal hemochromatosis, this case suggests that it could be a feasible treatment option for children affected by this disease, as for other alloimmune conditions.

  14. Biliary excretion of iron and ferritin in idiopathic hemochromatosis

    SciTech Connect

    Hultcrantz, R.; Angelin, B.; Bjoern-Rasmussen, E.E.; Ewerth, S.; Einarsson, K.

    1989-06-01

    The role of biliary excretion of iron and ferritin in iron overload was studied and evaluated. Ten patients with idiopathic hemochromatosis and two groups of controls (14 gallstone patients and 16 healthy subjects) were included. Liver tissue (obtained by percutaneous or operative biopsy) was investigated with light microscopy and transmission electron microscopy in combination with x-ray microanalysis. Fasting bile samples were obtained through duodenal aspiration or at cholecystectomy. Iron was determined in liver tissue and bile using atomic absorption spectroscopy, and ferritin was determined in serum and bile with a radioimmunoassay technique. All patients with hemochromatosis had iron-positive staining as seen in light microscopy. Electron microscopy showed iron-containing proteins in the lysosomes and cytosol of liver parenchymal cells, and this observation was supported by x-ray microanalysis. Hepatic iron concentration was increased about eightfold in the patients with hemochromatosis (p less than 0.001). Biliary iron concentration, expressed per millimole of bile acid, was increased about twofold (p less than 0.05) and biliary ferritin concentration about fivefold (p less than 0.001) in hemochromatosis. Four of the patients with hemochromatosis were reexamined after completed treatment with venesection; this resulted in normalized biliary concentrations of iron and ferritin. We conclude that biliary secretion of ferritin occurs in humans and that both iron and ferritin excretion are enhanced in hepatic iron overload. The apparently limited capacity of biliary iron excretion may be of importance for the hepatic iron accumulation in hemochromatosis.

  15. [The new paradigm of neonatal hemochromatosis: fetal alloimmune hepatitis].

    PubMed

    Costaguta, Alejandro; Alvarez, Fernando

    2012-01-01

    The classical model of neonatal hemochromatosis was based on the analogy with hereditary hemochromatosis. Medical treatment consisted on the antioxidant-chelator cocktail. The new hypothesis of an alloimmune origin of the process by which the pregnant woman mounts an IgG-based destructive response against fetal hepatocytes offers a pathogenic explanation, allowing treatment to be focused on the immunological aspects, with excellent results, and opens the possibility of preventive treatment in future pregnancies. This new paradigm produces a deep impact in diagnosis, prognosis and treatment of the disease, that should be called "fetal alloimmune hepatitis".

  16. Hemochromatosis: a model of metal-related human toxicosis.

    PubMed

    Brissot, Pierre; Cavey, Thibault; Ropert, Martine; Gaboriau, François; Loréal, Olivier

    2016-09-15

    Many environmental agents, such as excessive alcohol intake, xenobiotics, and virus, are able to damage the human body, targeting especially the liver. Metal excess may also assault the liver. Thus, chronic iron overload may cause, especially when associated with cofactors, diffuse organ damage that is a source of significant morbidity and mortality. Iron excess can be either of acquired (mostly transfusional) or of genetic origin. Hemochromatosis is the archetype of genetic iron overload diseases and represents a serious health problem. A better understanding of iron metabolism has deeply modified the hemochromatosis field which today benefits from much more efficient diagnostic and therapeutic approaches.

  17. Juvenile Hemochromatosis in Iran: A Case Report with 5-Year Follow-up after Treatment

    PubMed Central

    Nobakht, Hossein; Zolfaghari, Sheida; Pourazizi, Mohsen; Malek, Mojtaba

    2016-01-01

    Juvenile hemochromatosis is a rare autosomal recessive disorder that typically occurs in the first to third decades of life. Its symptoms are more acute and severe than classic hemochromatosis. We describe a 27-year-old man who was referred to the gastrointestinal clinic with a probable diagnosis of fatty liver and was finally diagnosed as having juvenile hemochromatosis. A review of the scientific literature reveals that recently only three siblings suffering from the disease have been reported in Iran. PMID:27252822

  18. Iron overload complicating sideroblastic anemia--is the gene for hemochromatosis responsible?

    PubMed

    Barron, R; Grace, N D; Sherwood, G; Powell, L W

    1989-04-01

    Idiopathic hemochromatosis is a hereditary disease that is associated with human leucocytic antigens A3, B7, and B14. A genetic association between human leucocytic antigen-linked hemochromatosis and idiopathic refractory sideroblastic anemia has been suggested that may predispose some patients with idiopathic refractory sideroblastic anemia to develop gross iron overload. Study of the family of a patient with idiopathic refractory sideroblastic anemia and hemochromatosis revealed that 2 of 5 first-degree relatives had significant elevations of serum ferritin, and a shared human leucocytic antigen haplotype, supporting the concept that patients with idiopathic refractory sideroblastic anemia and significant iron overload have at least one allele for hemochromatosis.

  19. Hereditary hemochromatosis restores the virulence of plague vaccine strains.

    PubMed

    Quenee, Lauriane E; Hermanas, Timothy M; Ciletti, Nancy; Louvel, Helene; Miller, Nathan C; Elli, Derek; Blaylock, Bill; Mitchell, Anthony; Schroeder, Jay; Krausz, Thomas; Kanabrocki, Joseph; Schneewind, Olaf

    2012-10-01

    Nonpigmented Yersinia pestis (pgm) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout (Hjv(-/-)) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis. Unlike wild-type mice, Hjv(-/-) mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv(-/-) mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines.

  20. Hereditary Hemochromatosis Restores the Virulence of Plague Vaccine Strains

    PubMed Central

    Quenee, Lauriane E.; Hermanas, Timothy M.; Ciletti, Nancy; Louvel, Helene; Miller, Nathan C.; Elli, Derek; Blaylock, Bill; Mitchell, Anthony; Schroeder, Jay; Krausz, Thomas; Kanabrocki, Joseph; Schneewind, Olaf

    2012-01-01

    Nonpigmented Yersinia pestis (pgm) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout (Hjv−/−) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis. Unlike wild-type mice, Hjv−/− mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv−/− mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines. PMID:22896664

  1. Bloodletting therapy in hemochromatosis: Does it affect trace element homeostasis?

    PubMed

    Bolann, Bjørn J; Distante, Sonia; Mørkrid, Lars; Ulvik, Rune J

    2015-01-01

    Hemochromatosis is the most common hereditary disorder in the Nordic population, if left untreated it can result in severe parenchymal iron accumulation. Bloodletting is mainstay treatment. Iron and trace elements partially share cellular uptake and transport mechanisms, and the aim of the present study was to see if bloodletting for hemochromatosis affects trace elements homeostasis. We recruited patients referred for diagnosis and treatment of hemochromatosis, four women and 22 men 23-68 years of age. Thirteen were C282Y homozygote, one was C282Y heterozygote, three were H63D homozygote, seven were compound heterozygote and two had none of the mutations above. Iron and liver function tests were performed; serum levels of trace elements were measured using inductively coupled plasma mass spectrometry. Results before the start of treatment and after normalization of iron parameters were compared. On completion of the bloodlettings the following average serum concentrations increased: Co from 5.6 to 11.5 nmol/L, serum Cu 16.2-17.6 μmol/L, Ni increased from 50.0 to 52.6 nmol/L and Sb from 13.2 to 16.3 nmol/L. Average serum Mn concentration declined from 30.2 to 28.3 nmol/L. All changes were statistically significant (by paired t-test). B, Ba, Cs, Mo, Se, Sr and Zn were not significantly changed. We conclude that bloodlettings in hemochromatosis lead to changes in trace element metabolism, including increased absorption of potentially toxic elements.

  2. HLA-H and associated proteins in patients with hemochromatosis.

    PubMed Central

    Beutler, E.; West, C.; Gelbart, T.

    1997-01-01

    BACKGROUND: The 845A(C282Y) mutation in the HLA-H gene accounts for most cases of hereditary hemochromatosis in patients who are of European origin. Some lack this mutation, however, and it is not present in Asian patients. Thus, other mutations either in HLA-H or associated proteins may be present in such patients. HLA-H associates with beta-2-microglobulin. Calreticulin associates with class 1 HLA proteins and appears to be identical with mobilferrin, a putative iron transport protein. These two proteins are therefore candidates for mutations in patients with hemochromatosis. MATERIALS AND METHODS: We have sequenced the coding region and parts of introns of the HLA-H gene, the beta-2-microglobulin gene, and the calreticulin (mobilferrin) gene of 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the 845A(C282Y) mutation. The number of chromosomes at risk studied were 18 for HLA-H, 14 for beta-2-microglobulin and 10 for calreticulin. RESULTS: We detected 3 new intronic polymorphisms in the HLA-H gene, each a point mutation. Some differences from published sequences of beta-2-microglobulin and calreticulin were documented, but these were uniformly present in all samples. CONCLUSIONS: The lack of additional mutations in the HLA-H gene is remarkable, and we speculate that the C282Y mutation may be a gain-of-function change. PMID:9234244

  3. [Hemochromatosis: one form of iron-overload diseases].

    PubMed

    Szalay, Ferenc

    2013-07-21

    Iron-overload diseases are typically insidious, causing progressive and irreversible organ injury before clinical symptoms develop. Some iron-overload diseases as HFE-associated hemochromatosis and beta-thalassemia are quite common, whereas others are very rare. Early diagnosis is important since iron toxicity can be attenuated or prevented. Significant progress of our knowledge on iron metabolism developed in the past years. We learned a lot about HFE gene mutations, function of ferroportin and hepcidin, the hypoferremia hormone produced by the liver. However, many questions are still open. Special forms of localized iron overload are the Hallervorden-Spatz syndrome and pantothenate kinase gene mutation associated neurodegeneration causing progressive extrapyramidal movement disorders. Neonatal hemochromatosis is a severe systemic iron-overload disorder due to gestational alloimmune liver disease caused by transplacental maternal IgG directed against the fetal liver. This review article gives an overview on iron metabolism and iron-overload disease. Pathomechanism, diagnosis and treatment of hereditary hemochromatosis are discussed.

  4. Perinatal hemochromatosis. Clinical, morphologic, and quantitative iron studies.

    PubMed Central

    Silver, M. M.; Beverley, D. W.; Valberg, L. S.; Cutz, E.; Phillips, M. J.; Shaheed, W. A.

    1987-01-01

    Three sibling and two isolated-case perinates (4 newborn, 1 stillborn) died with siderotic cirrhosis and widespread parenchymal siderosis, the latter similar to that seen in both hereditary and secondary hemochromatosis. Reticuloendothelial siderosis was absent, as occurs in primary hemochromatosis. Studies of iron metabolism were performed antemortem in two of the siblings and ante-, post- and internatally in their mother, who showed hyperferremia antenatally. The only finding in the affected family suggestive of hereditary hemochromatosis was the commonly associated HLA haplotype (A3, B7) in the mother and an infant. Liver morphology, including immunocytochemistry and ultrastructure, was similar in the 5 infants and suggested that liver disease commenced as massive necrosis in midfetal life. Histologic grading and chemical assays for iron and copper on liver and spleen of the 5 index cases were compared with 26 controls; placentas were compared with 12 control placentas. Hepatic iron concentration, but not hepatic copper concentration, was significantly increased in index cases, compared with controls. Hepatic iron to copper ratio was significantly increased in index cases, compared with controls, but this ratio was unaltered in spleen and placenta. Total hepatic iron, but not total hepatic copper, was significantly increased in index cases, compared with a subgroup of 11 controls of low gestational age, similar to the fetal stage when liver disease commenced in utero. The results suggest that, irrespective of the fetal liver disease being genetic or acquired, hepatic iron overload was directly involved in pathogenesis. Images Figure 5 Figure 1 Figure 2 Figure 3 Figure 4 PMID:3307444

  5. A 4.5-megabase YAC contig and physical map over the hemochromatosis gene region

    SciTech Connect

    Burt, M.J.; Smit, D.J.; Pyper, W.R.; Powell, L.W.; Jazwinska, E.C.

    1996-04-15

    We have constructed a yeast artificial chromosome (YAC) contig over the candidate hemochromatosis gene region. This contig comprises hemochromatosis gene region. This contig comprises 16 YACs from the CEPH, Washington University, and ICI YAC libraries and covers 4.5 Mb at 6p21.3-6p22. The complete contig has been restriction mapped, enabling the precise relationship between the YACs to be determined and the mapping of a total of 12 STSs. Nine of these are highly polymorphic STSs that are closely linked to hemochromatosis; this series includes D6S265 and D6S1260, which comprise the most proximal and distal markers linked to HC. This is the first YAC contig that spans the hemochromatosis candidate region, and it provides valuable resource material for the cloning of this and other genes in the region distal to the MHC class I complex. 33 refs., 1 fig., 1 tab.

  6. Synchrotron X-ray microscopy and spectroscopy analysis of iron in hemochromatosis liver and intestines

    SciTech Connect

    Ko, J .Y. Peter; Sham, Tsun-Kong; Chakrabarti, Subrata; Adams, Paul C.

    2009-12-01

    Hemochromatosis is a genetic disorder that causes body to store excess iron in organs such as heart or liver. Distribution of iron, as well as copper, zinc and calcium, and chemical identity of iron in hemochromatosis liver and intestine were investigated by X-ray microprobe experiments, which consist of X-ray microscopy and micro-X-ray absorption fine structure. Our results show that iron concentration in hemochromatosis liver tissue is high, while much less Fe is found in intestinal tissue. Moreover, chemical identity of Fe in hemochromatosis liver can be identified. X-ray microprobe experiments allows for examining elemental distribution at an excellent spatial resolution. Moreover, chemical identity of element of interest can be obtained.

  7. Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis.

    PubMed

    Farrell, Colin P; Parker, Charles J; Phillips, John D

    2015-08-01

    Diagnostic genetic testing for hereditary hemochromatosis is readily available for clinically relevant HFE variants (i.e., those that generate the C282Y, H63D and S65C HFE polymorphisms); however, genetic testing for other known causes of iron overload, including mutations affecting genes encoding hemojuvelin, transferrin receptor 2, HAMP, and ferroportin is not. As an alternative to conventional genetic testing we propose diagnostic use of whole exome sequencing for characterization of non-HFE hemochromatosis. To illustrate the effectiveness of whole exome sequencing as a diagnostic tool, we present the case of an 18-year-old female with a probable case of juvenile hemochromatosis, who was referred for specialty care after testing negative for commonly occurring HFE variants. Whole exome sequencing offered complete coverage of target genes and is a fast, cost effective diagnostic tool for characterization of non-HFE hemochromatosis.

  8. Synchrotron X-ray microscopy and spectroscopy analysis of iron in hemochromatosis liver and intestines

    NASA Astrophysics Data System (ADS)

    Ko, J. Y. Peter; Sham, Tsun-Kong; Chakrabarti, Subrata; Adams, Paul C.

    2009-11-01

    Hemochromatosis is a genetic disorder that causes body to store excess iron in organs such as heart or liver. Distribution of iron, as well as copper, zinc and calcium, and chemical identity of iron in hemochromatosis liver and intestine were investigated by X-ray microprobe experiments, which consist of X-ray microscopy and micro-X-ray absorption fine structure. Our results show that iron concentration in hemochromatosis liver tissue is high, while much less Fe is found in intestinal tissue. Moreover, chemical identity of Fe in hemochromatosis liver can be identified. X-ray microprobe experiments allows for examining elemental distribution at an excellent spatial resolution. Moreover, chemical identity of element of interest can be obtained.

  9. Hemochromatosis due to mutations in transferrin receptor 2.

    PubMed

    Roetto, Antonella; Daraio, Filomena; Alberti, Federica; Porporato, Paolo; Calì, Angelita; De Gobbi, Marco; Camaschella, Clara

    2002-01-01

    A rare recessive disorder which leads to iron overload and severe clinical complications similar to those reported in HFE-related hemochromatosis has been delineated and sometimes called hemochromatosis type 3. The gene responsible is Transferrin Receptor 2 (TFR2), which maps to chromosome 7q22. The TFR2 gene presents a significative homology to transferrin receptor (TFRC) gene, encodes for a transmembrane protein with a large extracellular domain, is able to bind transferrin, even if with lower affinity than TFRC. The TFR2 function is still unclear. The transcript does not contain IRE elements and is not modified by the cellular iron status. At variance with TFRC, interactions between TFR2 and HFE do not occur, at least in their soluble forms. TFR2 is spliced in two alternative forms, alfa and beta. The alfa form is strongly expressed in the liver. The beta form, codified from a start site in exon 4 of the alpha, has a low and ubiquitous expression. Using anti-TFR2 monoclonal antibodies we have confirmed expression of the protein in the liver but also in duodenal epithelial cells, and studied the protein functional behaviour in cell lines, in response to iron addition, iron deprivation and olo-transferrin exposure. Our results suggest a regulatory role of TFR2 in iron metabolism. Five TFR2 homozygous mutations have been documented in HFE3 patients: a nonsense mutation (Y250X); a C insertion that causes a frameshift and a premature stop codon (E60X); a missense mutation (M172K); a 12 basepair deletion in exon 16, that causes 4 aminoacid loss (AVAQ 594-597del) in the extracellular domain of TFR2; a missense mutation in exon 17 (Q690P). The mutation analysis supports the hypothesis that all are private mutations. The pathogenetic role of TFR2 in hemochromatosis has been recently further demonstrated through the targeted expression of the Y250X human mutation in mice, which develop sings of iron overload identical to the human disease. Although the rarity of TFR2

  10. Management of human factors engineering-associated hemochromatosis: A 2015 update.

    PubMed

    Sivakumar, Menaka; Powell, Lawrie W

    2016-03-18

    This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering (HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.

  11. Management of human factors engineering-associated hemochromatosis: A 2015 update

    PubMed Central

    Sivakumar, Menaka; Powell, Lawrie W

    2016-01-01

    This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering (HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research. PMID:27004087

  12. Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

    PubMed

    Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

    2014-10-01

    Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

  13. Epidemiology and diagnostic testing for hemochromatosis and iron overload.

    PubMed

    Adams, P C

    2015-05-01

    Hemochromatosis is the most common genetic disease in northern European populations. Body iron stores progressively increase in most patients, which can lead to cirrhosis of the liver, hepatocellular carcinoma, heart failure, arthritis, and pigmentation. Simple blood tests such as the serum ferritin and transferrin saturation are useful to suggest the diagnosis which can be confirmed in most cases with a simple genetic test for the C282Y mutation of the HFE gene. However, these blood tests are often misinterpreted and there are rare patients with iron overload without HFE mutations. A diagnostic approach is presented based on a large referral practice and a population-based study (HEIRS) which screened for iron overload in 101,168 participants.

  14. Examining the clinical use of hemochromatosis genetic testing

    PubMed Central

    Lanktree, Matthew B; Lanktree, Bruce B; Paré, Guillaume; Waye, John S; Sadikovic, Bekim; Crowther, Mark A

    2015-01-01

    BACKGROUND: Hereditary hemochromatosis leads to an increased lifetime risk for end-organ damage due to excess iron deposition. Guidelines recommend that genetic testing be performed in patients with clinical suspicion of iron overload accompanied by elevated serum ferritin and transferrin saturation levels. OBJECTIVE: To evaluate guideline adherence and the clinical and economic impact of HFE genetic testing. METHODS: The electronic charts of patients submitted for HFE testing in 2012 were reviewed for genetic testing results, biochemical markers of iron overload and clinical history of phlebotomy. RESULTS: A total of 664 samples were sent for testing, with clinical, biochemical and phlebotomy data available for 160 patients. A positive C282Y homozygote or C282Y/H63D compound heterozygote test result was observed in 18% of patients. Patients with an at-risk HFE genotype had significantly higher iron saturation, serum iron and hemoglobin (P<0.001), without higher ferritin or liver enzyme levels. Fifty percent of patients referred for testing did not have biochemical evidence of iron overload (transferrin saturation >45% and ferritin level >300 μg/L). Patients were four times more likely to undergo phlebotomy if they were gene test positive (RR 4.29 [95% CI 2.35 to 7.83]; P<0.00001). DISCUSSION: One-half of patients referred for testing did not exhibit biochemical evidence of iron overload. Many patients with biochemical evidence of iron overload, but with negative genetic test results, did not undergo phlebotomy. A requisition to determine clinical indication for testing may reduce the use of the HFE genetic test. Finally, improvement of current genetic test characteristics would improve rationale for the test. CONCLUSION: A significant proportion of hemochromatosis genetic testing does not adhere to current guidelines and would not alter patient management. PMID:25706573

  15. Characterization of Ferroptosis in Murine Models of Hemochromatosis.

    PubMed

    Wang, Hao; An, Peng; Xie, Enjun; Wu, Qian; Fang, Xuexian; Gao, Hong; Zhang, Zhuzhen; Li, Yuzhu; Wang, Xudong; Zhang, Jiaying; Li, Guoli; Yang, Lei; Liu, Wei; Min, Junxia; Wang, Fudi

    2017-02-13

    Ferroptosis is a recently identified iron-dependent form of non-apoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow-derived macrophages (BMDMs). Next, we screened for ferroptosis in mice fed a high-iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high-iron diet and in two knockout mouse lines that develop severe iron overload (Hjv(-/-) and Smad4(Alb/Alb) mice), but not in a third line that develops only mild iron overload (Hfe(-/-) mice). Moreover, we found that iron overload-induced liver damage was rescued by the ferroptosis inhibitor ferrostatin-1. To identify the genes involved in iron-induced ferroptosis, we performed microarray analyses of iron-treated BMDMs. Interestingly, Slc7a11, a known ferroptosis-related gene, was significantly upregulated in iron-treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron-treated hepatocytes and BMDMs isolated from Slc7a11(-/-) mice fed a high-iron diet. We found that iron treatment induced ferroptosis in Slc7a11(-/-) cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high-iron conditions. These results provide compelling evidence that iron plays a key role in triggering Slc7a11-mediated ferroptosis. These results also suggest that ferroptosis may be a promising target for treating hemochromatosis-related tissue damage. This article is protected by copyright. All rights reserved.

  16. Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis.

    PubMed

    Aguilar-Martinez, P; Esculié-Coste, C; Bismuth, M; Giansily-Blaizot, M; Larrey, D; Schved, J F

    2001-01-01

    More than 80% of the patients affected by hereditary hemochromatosis, a common inherited iron disorder, are homozygotes for the 845G --> A (C282Y) mutation of the HFE gene. However, depending on the population, 10-20% of hereditary hemochromatosis can be linked either to other HFE genotypes, particularly the compound heterozygous state for C282Y and the 187 C --> G (H63D) mutation, or to mutations of new other genes. Recently, Camaschella et al. (Nat. Genet. 25, 14-15, 2000) identified a stop mutation (exon 6 nt 750 C --> T, Y250X) on the transferrin receptor-2 (TFR2) gene in two unrelated Sicilian families with hereditary hemochromatosis. The TFR2 gene is a transferrin receptor gene homologue that seems to be involved in iron metabolism. Moreover, one of the patients described by Camaschella et al. was a H63D homozygote. H63D homozygosity can be associated with various phenotypes from asymptomatic subjects to patients with a typical form of hereditary hemochromatosis. Thus, the Y250X mutation could be the molecular defect responsible for hereditary hemochromatosis in subjects with atypical HFE genotypes. We have searched for the Y250X mutation in 63 unrelated French subjects. Forty-three had a diagnosis of hereditary hemochromatosis based on classical criteria. This group included 12 H63D homozygotes, 3 C282Y heterozygotes, and 3 patients with none of the two most prevalent HFE mutants. These 18 patients had no other HFE sequence change and were subsequently subjected to DNA sequencing of the 15 last exons and flanking sequences of the TFR2 gene. The 25 remaining hereditary hemochromatosis patients who were tested for the Y250X mutant were compound heterozygotes for the C282Y and H63D mutations. Finally, we also tested for this TFR2 mutation 20 H63D homozygotes with milder manifestations of iron overload and no acquired cause of iron overload. None of the 63 tested subjects had the Y250X mutation. Concurrently, none of the 18 hereditary hemochromatosis patients

  17. Recent advances in hemochromatosis: a 2015 update : a summary of proceedings of the 2014 conference held under the auspices of Hemochromatosis Australia.

    PubMed

    Ekanayake, Dilum; Roddick, Clinton; Powell, Lawrie W

    2015-04-01

    This review focuses on iron metabolism, the genetics of hemochromatosis, current treatment protocols and various screening methods. Even though the most common form of hereditary hemochromatosis, C282Y gene mutations in the HFE gene, has been extensively studied, novel mutations in both HFE and non-HFE genes have been implicated in this disease. These have important implications for the Asia-Pacific region. In overload, deposition of iron in various body tissues leads to toxic damage. Patients commonly present with non-specific symptoms of malaise and lethargy. Biochemical, imaging and genetic testing can be carried out to confirm diagnosis. Venesection forms the mainstay of treatment and at present cascade screening of affected families is recommended over population-level screening.

  18. HFE gene knockout produces mouse model of hereditary hemochromatosis

    PubMed Central

    Zhou, Xiao Yan; Tomatsu, Shunji; Fleming, Robert E.; Parkkila, Seppo; Waheed, Abdul; Jiang, Jinxing; Fei, Ying; Brunt, Elizabeth M.; Ruddy, David A.; Prass, Cynthia E.; Schatzman, Randall C.; O’Neill, Rosemary; Britton, Robert S.; Bacon, Bruce R.; Sly, William S.

    1998-01-01

    Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ± 5% vs. 77 ± 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ± 450 vs. 255 ± 23 μg/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload. PMID:9482913

  19. Multihormonal hypopituitarism, hypothyroidism and hypoparathyroidism in a 17-years-old girl with Diamond-Blackfan anemia and secondary hemochromatosis.

    PubMed

    Głąb, Ewa; Barg, Ewa; Wikiera, Beata; Bieniasz, Jolanta

    2013-01-01

    Congenital hypoplastic anemia (Diamond-Blakcfan syndrom) is a genetically determined disorder which is manifested in early childhood with selective deficiency of erythrocyte line in bone marrow. Severe anemia usually appears in the first six months of life. Survival depends on blood transfusions, which in consequence lead to hemochromatosis. The most common complications of transfusional hemochromatosis are hepatic cirrhosis, hypopituitarism, hypogonadism, diabetes mellitus, other endocrinopathies, and cardiomyopathy. We present the case of 17 years old girl with congenital hypoplastic anemia and multihormonal insufficiency due to secondary hemochromatosis.

  20. Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin.

    PubMed

    Pietrangelo, Antonello

    2015-10-01

    The discovery of hepcidin in 2000 and the subsequent unprecedented explosion of research and discoveries in the iron field have dramatically changed our understanding of human disorders of iron metabolism. Today, hereditary hemochromatosis, the paradigmatic iron-loading disorder, is recognized as an endocrine disease due to the genetic loss of hepcidin, the iron hormone produced by the liver. This syndrome is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It is caused by mutations that affect any of the proteins that help hepcidin to monitor serum iron, including HFE and, in rarer instances, transferrin-receptor 2 and hemojuvelin, or make its receptor ferroportin, resistant to the hormone. In Caucasians, C282Y HFE homozygotes are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, due to alcohol abuse or concurrent genetic modifiers that are now being identified. HFE gene testing can be used to diagnose hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-HFE forms of the disease. Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. The mainstay of hemochromatosis management is still removal of iron by phlebotomy, first introduced in 1950s, but identification of hepcidin has not only shed new light on the pathogenesis of the disease and the approach to diagnosis, but etiologic therapeutic applications from these advances are now foreseen.

  1. Restriction mapping of a YAC contig in the hemochromatosis gene region

    SciTech Connect

    Burt, M.J.; Smit, D.J.; Pyper, W.R.

    1994-09-01

    Hemochromatosis is a common inherited disorder of iron metabolism that can lead to cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes and anthropathy. We have mapped the hemochromatosis gene to within 1 cM of HLA-A and the microsatellite D6S105, and our allele association studies have shown that D6S105 is the marker most closely associated with the hemochromatosis gene. We are currently constructing a YAC contig and restriction map of this region as part of a positional cloning strategy to identify the hemochromatosis gene. YACs containing HLA-A or D6S105 were selected, and fluorescent-in-situ-hybridization (FISH) was performed to confirm chromosomal location and exclude chimerism. YAC DNA was digested with a panel of rare cutters, separated by pulsed field gel electrophoresis, Southern blotted and probed with the vector arms to create restriction maps. YAC insert terminal ends were isolated using vectorette methodology. A contig extending 600 kb centromeric and 350 kb telomeric of HLA-A has been established. HLA-A, HLA-F and the microsatellite D6S265 have been positioned on this map. The contig does not yet overlap any D6S105 positive YACs but the telomeric end of the contig has been sequenced and is being used to identify additional YACs to bridge this interval. Restriction mapping of three D6S105 YACs has shown the presence of several CpG islands in this region. As these CpG islands are in close proximity to D6S105, they are being used to isolate coding sequences to determine whether any of these mark the position of the hemochromatosis gene.

  2. Hand and wrist arthropathies of hemochromatosis and calcium pyrophosphate deposition disease: distinct radiographic features

    SciTech Connect

    Adamson, T.C. III; Resnik, C.S.; Guerra, J. Jr.; Vint, V.C.; Weisman, M.H.; Resnick, D.

    1983-05-01

    Radiographic features of hand and wrist involvement in 26 patients with hemochromatosis and in 26 patients with idiopathic calcium pyrophosphate dihydrate (CPPD) crystal deposition disease were compared. Two radiologists independently examined the radiographs without knowledge of the specific group to which the patient belonged. The results of this study clearly establish that structural joint diseases in the two disorders are not identical. Characteristic findings allow the radiologist to favor one diagnosis over the other. These radiograhic differences indicate that the arthropathy of hemochromatosis is related to factors additional to the presence of CPPD crystals, specifically, the more prevalent narrowing of the metacarpophalangeal joint spaces, including those in the fourth and fifth digits, peculiar hook-like osteophytes on the radial aspect of the metacarpal heads, and less prevalent separation of the scaphoid and the lunate.

  3. [Idiopathic hemochromatosis. Review of the literature and study of 17 patients].

    PubMed

    Suárez, J; Aliaga, L; Sirvent, L; Nunes, R; Beloqui, O; Prieto, J

    1987-01-01

    Idiopathic hemochromatosis is an inherited and primary disease. Its definition requires: a) a family history of abnormalities of iron storage; b) an association with HLA; c) inadequate iron absorption in relation to iron stores in liver and other territories; d) the absence of any other known causes of iron overload. The recent evidence of its high family related frequency and the existence of an effective treatment, demand the understanding of this entity and the strongest medical effort towards the diagnosis in the pre-cirrhotic stages. We present here the results from the study of 17 patients diagnosed of idiopathic hemochromatosis over a seven year period in the University Clinic of Navarra. Our aim is to review this subject and to compare our findings with those described in the current literature.

  4. Model of reticuloendothelial iron metabolism in humans: Abnormal behavior in idiopathic hemochromatosis and in inflammation

    SciTech Connect

    Fillet, G.; Beguin, Y.; Baldelli, L. )

    1989-08-01

    Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.

  5. Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients.

    PubMed

    Callebaut, Isabelle; Joubrel, Rozenn; Pissard, Serge; Kannengiesser, Caroline; Gérolami, Victoria; Ged, Cécile; Cadet, Estelle; Cartault, François; Ka, Chandran; Gourlaouen, Isabelle; Gourhant, Lénaick; Oudin, Claire; Goossens, Michel; Grandchamp, Bernard; De Verneuil, Hubert; Rochette, Jacques; Férec, Claude; Le Gac, Gérald

    2014-09-01

    Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss- versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type 4A versus type 4B). However, the vast majority of SLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance of combining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management.

  6. Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D

    2015-07-01

    Iron is an essential component of erythropoiesis and its metabolism is tightly regulated by a variety of internal and external cues including iron storage, tissue hypoxia, inflammation and degree of erythropoiesis. There has been remarkable improvement in our understanding of the molecular mechanisms of iron metabolism past decades. The classical model of iron metabolism with iron response element/iron response protein (IRE/IRP) is now extended to include hepcidin model. Endogenous and exogenous signals funnel down to hepcidin via wide range of signaling pathways including Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3), Bone Morphogenetic Protein/Hemojuvelin/Mothers Against Decapentaplegic Homolog (BMP/HJV/SMAD), and Von Hippel Lindau/Hypoxia-inducible factor/Erythropoietin (VHL/HIF/EPO), then relay to ferroportin, which directly regulates intra- and extracellular iron levels. The successful molecular delineation of iron metabolism further enhanced our understanding of common genetic and acquired disorder, hemochromatosis. The majority of the hereditary hemochromatosis (HH) patients are now shown to have mutations in the genes coding either upstream or downstream proteins of hepcidin, resulting in iron overload. The update on hepcidin centered mechanisms of iron metabolism and their clinical perspective in hemochromatosis will be discussed in this review.

  7. French retrospective multicentric study of neonatal hemochromatosis: importance of autopsy and autoimmune maternal manifestations.

    PubMed

    Collardeau-Frachon, Sophie; Heissat, Sophie; Bouvier, Raymonde; Fabre, Monique; Baruteau, Julien; Broue, Pierre; Cordier, Marie-Pierre; Debray, Dominique; Debiec, Hanna; Ronco, Pierre; Guigonis, Vincent

    2012-01-01

    Neonatal hemochromatosis is a rare disease that causes fetal loss and neonatal death in the 1st weeks of life and is one of the most common causes of liver failure in the neonate. The diagnosis is mostly made retrospectively, based on histopathologic features of severe liver fibrosis associated with hepatic and extrahepatic siderosis. Several etiologies may underlie this phenotype, including a recently hypothesized gestational alloimmune disease. Fifty-one cases of liver failure with intrahepatic siderosis in fetuses and neonates were analyzed retrospectively. Maternal and infant data were collected from hospitalization and autopsy reports. All available slides were reviewed independently by 3 pathologists. Immunologic studies were performed on maternal sera collected immediately after delivery. The diagnosis of neonatal haemochromatosis was retained in 33 cases, including 1 case with Down syndrome and 1 case with myofibromas. Liver siderosis was inversely proportional to fibrosis progression. In fetuses, iron storage was more frequent in the thyroid than in the pancreas. Perls staining in labial salivary glands was positive in 1 of 5 cases. Abnormal low signal intensity by magnetic resonance imaging was detected in the pancreas in 2 of 7 cases. Renal tubular dysgenesis was observed in 7 of 23 autopsy cases. Chronic villitis was seen in 7 of 15 placentas. Half of the mothers presented with an autoimmune background and/or autoantibodies in their sera. Our work highlights the importance of autopsy in cases of neonatal hemochromatosis and marshals additional data in support of the hypothesis that neonatal hemochromatosis could reflect maternal immune system dysregulation.

  8. Recurrent pregnancy-induced diabetes insipidus in a woman with hemochromatosis.

    PubMed

    Krysiak, Robert; Kobielusz-Gembala, Iwona; Okopien, Boguslaw

    2010-01-01

    Diabetes insipidus is a rare disorder in pregnant women, predating pregnancy or appearing for the first time during gestation. In pregnancy it usually affects women with HELLP syndrome or acute fatty liver of pregnancy and results from the reduced hepatic degradation of placental vasopressinase leading to its increased activity. Although infiltrative diseases have been found to cause diabetes insipidus in non-pregnant population, very few studies showed that these disorders may manifest for the first time during gestation. We describe here the case of transient diabetes insipidus in two subsequent pregnancies of a female with hemochromatosis. The first symptoms of this disease appeared for the first time at the beginning of the third trimester of her second pregnancy, and diagnosis was established on the basis of typical clinical presentation, confirmed by a water deprivation test. Diabetes insipidus resulted from the increased activity of vasopressinase, caused by hemochromatosis-induced liver dysfunction, the presence of which was confirmed between the pregnancies by liver biopsy and identification of the HFE gene mutation. Subsequent desferrioxamine treatment resulted in a less severe clinical course of diabetes insipidus in the last patient's pregnancy. In both pregnancies, the patient was successfully treated with oral desmopressin, which is resistant to degradation by placental vasopressinase. Although unrecognized pituitary disorders may pose a serious health problem to the mother and fetus, hemochromatosis-induced diabetes insipidus, as the case of our patient demonstrates, if effectively diagnosed and treated, cannot be regarded as a contraindication for pregnancy.

  9. Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening

    PubMed Central

    McLaren, Gordon D; McLaren, Christine E; Adams, Paul C; Barton, James C; Reboussin, David M; Gordeuk, Victor R; Acton, Ronald T; Harris, Emily L; Speechley, Mark R; Sholinsky, Phyliss; Dawkins, Fitzroy W; Snively, Beverly M; Vogt, Thomas M; Eckfeldt, John H

    2008-01-01

    BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study. PMID:19018338

  10. AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis.

    PubMed

    Hattori, Ai; Wakusawa, Shinnya; Hayashi, Hisao; Harashima, Ai; Sanae, Fujiko; Kawanaka, Miwa; Yamada, Gohtaro; Yano, Motoyashi; Yoshioka, Kenntaro

    2003-06-01

    The majority of Caucasian patients with hemochromatosis are homozygous for C282Y mutation of the HFE gene. In contrast to its high prevalence in Caucasians, hemochromatosis is a rare disorder in Japan. This may be due to the low prevalence of the C282Y mutation of the HFE gene in Japanese. Recent reports suggest that the mutations of transferrin receptor 2 (TfR2) gene may be involved in non-HFE hemochromatosis. Therefore, we investigated the TfR2 gene of 6 sporadic and 5 familiar cases of Japanese hemochromatosis. Three siblings in one family were found to be homozygous for an AVAQ 594-597 deletion. All three had severe iron deposits in the hepatocytes and bile ducts, but none was affected by diabetes mellitus. This mutation was not detected in 100 control individuals. Further study was undertaken to investigate whether the large deletion of the TfR2 gene is the mutation responsible for some of the Japanese hemochromatosis cases.

  11. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis

    PubMed Central

    Girelli, Domenico; Trombini, Paola; Busti, Fabiana; Campostrini, Natascia; Sandri, Marco; Pelucchi, Sara; Westerman, Mark; Ganz, Tomas; Nemeth, Elizabeta; Piperno, Alberto; Camaschella, Clara

    2011-01-01

    Background Inadequate hepcidin production leads to iron overload in nearly all types of hemochromatosis. We explored the acute response of hepcidin to iron challenge in 25 patients with HFE-hemochromatosis, in two with TFR2-hemochromatosis and in 13 controls. Sixteen patients (10 C282Y/C282Y homozygotes, 6 C282Y/H63D compound heterozygotes) had increased iron stores, while nine (6 C282Y/C282Y homozygotes, 3 C282Y/H63D compound heterozygotes) were studied after phlebotomy-induced normalization of iron stores. Design and Methods We analyzed serum iron, transferrin saturation, and serum hepcidin by both enzyme-linked immunosorbent assay and mass-spectrometry at baseline, and 4, 8, 12 and 24 hours after a single 65-mg dose of oral iron. Results Serum iron and transferrin saturation significantly increased at 4 hours and returned to baseline values at 8–12 hours in all groups, except in the iron-normalized patients who showed the highest and longest increase of both parameters. The level of hepcidin increased significantly at 4 hours and returned to baseline at 24 hours in controls and in the C282Y/H63D compound heterozygotes at diagnosis. The hepcidin response was smaller in C282Y-homozygotes than in controls, barely detectable in the patients with iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. Conclusions Our results are consistent with a scenario in which TFR2 plays a prominent and HFE a contributory role in the hepcidin response to a dose of oral iron. In iron-normalized patients with HFE hemochromatosis, both the low baseline hepcidin level and the weak response to iron contribute to hyperabsorption of iron. PMID:21173098

  12. A Novel Rat Model of Hereditary Hemochromatosis Due to a Mutation in Transferrin Receptor 2

    PubMed Central

    Bartnikas, Thomas B; Wildt, Sheryl J; Wineinger, Amy E; Schmitz-Abe, Klaus; Markianos, Kyriacos; Cooper, Dale M; Fleming, Mark D

    2013-01-01

    Sporadic iron overload in rats has been reported, but whether it is due to genetic or environmental causes is unknown. In the current study, phenotypic analysis of Hsd:HHCL Wistar rats revealed a low incidence of histologically detected liver iron overload. Here we characterized the pathophysiology of the iron overload and showed that the phenotype is heritable and due to a mutation in a single gene. We identified a single male rat among the 132 screened animals that exhibited predominantly periportal, hepatocellular iron accumulation. This rat expressed low RNA levels of the iron regulatory hormone hepcidin and low protein levels of transferrin receptor 2 (Tfr2), a membrane protein essential for hepcidin expression in humans and mice and mutated in forms of hereditary hemochromatosis. Sequencing of Tfr2 in the iron-overloaded rat revealed a novel Ala679Gly polymorphism in a highly conserved residue. Quantitative trait locus mapping indicated that this polymorphism correlated strongly with serum iron and transferrin saturations in male rats. Expression of the Gly679 variant in tissue culture cell lines revealed decreased steady-state levels of Tfr2. Characterization of iron metabolism in the progeny of polymorphic rats suggested that homozygosity for the Ala679Gly allele leads to a hemochromatosis phenotype. However, we currently cannot exclude the possibility that a polymorphism or mutation in the noncoding region of Tfr2 contributes to the iron-overload phenotype. Hsd:HHCL rats are the first genetic rat model of hereditary hemochromatosis and may prove useful for understanding the molecular mechanisms underlying the regulation of iron metabolism. PMID:23582421

  13. Plesiomonas shigelloides Septic Shock Leading to Death of Postsplenectomy Patient with Pyruvate Kinase Deficiency and Hemochromatosis

    PubMed Central

    2016-01-01

    Although Plesiomonas shigelloides, a water-borne bacterium of the Enterobacteriaceae family, usually causes self-limiting gastroenteritis with diarrhea, several cases of sepsis have been reported. We report the case of a 43-year-old male patient with hemochromatosis, pyruvate kinase deficiency, and asplenia via splenectomy who developed septic shock caused by P. shigelloides complicated by respiratory failure, renal failure, liver failure, and disseminated intravascular coagulation. Early aggressive antimicrobial therapy and resuscitation measures were unsuccessful and the patient passed away. We kindly suggest clinicians to implement early diagnosis of septic shock, empirical coverage with antibiotics, and prompt volume resuscitation based on the high mortality rate of P. shigelloides bacteremia. PMID:27610253

  14. Genetic hemochromatosis is a rare disease entity among French Basques: a center-based study from the general hospital of Basque County.

    PubMed

    Bauduer, F; Scribans, C; Renoux, M; Borot, N

    2001-08-01

    A center-based study from the general hospital of Basque country has been performed to evaluate the importance of genetic hemochromatosis among French Basques. A sample of 37 patients from 34 families fulfilling the diagnosis criteria of hemochromatosis was obtained. Only four of them were of Basque origin: two homozygotes for C282Y, one homozygote for H63D, and one heterozygote for C282Y. These results suggest a significant lower prevalence of genetic hemochromatosis in Basques than in people from other French regions (P=0.001). They underline further the biological specificity of this population.

  15. Experimental hemochromatosis due to MHC class I HFE deficiency: Immune status and iron metabolism

    PubMed Central

    Bahram, Seiamak; Gilfillan, Susan; Kühn, Lukas C.; Moret, Rémy; Schulze, Johannes B.; Lebeau, Annette; Schümann, Klaus

    1999-01-01

    The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE α1 and α2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE. PMID:10557317

  16. Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Hereditary Hemochromatosis

    PubMed Central

    Chandrasekharan, Subhashini; Pitlick, Emily; Heaney, Christopher; Cook-Deegan, Robert

    2010-01-01

    Hereditary hemochromatosis (HH) is an iron metabolism disorder that leads to excess iron buildup, especially in the heart, liver, and pancreas. Mutations in the HFE gene are the single most common cause of HH, which can be treated effectively if diagnosed early. Patents cover the HFE gene, related proteins, screening methods, and testing kits. Most initial testing for HH is biochemical, but HFE DNA testing or genotyping is used to confirm a diagnosis of inherited hemochromatosis. Concerns over patents covering HFE testing emerged in 2002, when scholars argued that exclusive licensing and the patent-enabled sole provider model then in place led to high prices and limited access. Critics of the sole provider model noted that the test was available at multiple laboratories prior to the enforcement of patents. By 2007, however, Bio-Rad, Limited, acquired the key intellectual property and sub-licensed it widely. In part because of broad, non-exclusive licensing, there are now multiple providers and testing technologies, and research continues. This case study illustrates how both changes in intellectual property ownership and evolving clinical utility of HFE genetic testing in the last decade have effected the licensing of patents and availability of genetic testing. PMID:20393306

  17. Imaging iron in skin and liver: Non-invasive tools for hemochromatosis therapy

    NASA Astrophysics Data System (ADS)

    Pinheiro, T.; Fleming, R.; Gonçalves, A.; Neres, M.; Alves, L. C.; Silva, J. N.; Filipe, P.; Silva, R.

    2009-06-01

    Hemochromatosis is a hereditary disease that causes an inappropriate intestinal absorption of Fe resulting in its accumulation in multiple organs, such as liver, heart and skin. Fe metabolism indicators in the circulation do not provide reliable indication of organ overload as they can be influenced by other clinical conditions. Assessing metabolism organs such as liver requires invasive procedures which is not adequate to patient's serial observations. Our aim was establishing cross sectional and longitudinal information on the amount of Fe that deposited in skin and liver during a life period, how iron is cleared out by therapy intervention and study the relationship of these changes between the two organs using non-invasive methods. Results on skin Fe deposition were evaluated by nuclear microscopy techniques and liver Fe concentrations determined by quantitative magnetic resonance imaging. Skin and liver Fe concentrations were correlated. Though Fe deposits in the two organs were differently associated with blood Fe metabolism conventional markers. Fe serial variations in skin and liver highlighted the value of assessing Fe organ deposits for estimating hemochromatosis evolution and therapy efficacy.

  18. Primary hemochromatosis: anatomic and physiologic characteristics of the cardiac ventricles and their response to phlebotomy

    SciTech Connect

    Dabestani, A.; Child, J.S.; Henze, E.; Perloff, J.K.; Schon, H.; Figueroa, W.G.; Schelbert, H.R.; Thessomboon, S.

    1984-07-01

    M-mode and 2-dimensional echocardiography and gated equilibrium blood pool imaging (rest and exercise) were used in 10 patients with primary hemochromatosis to characterize the spectrum of pathophysiologic abnormalities of the cardiac ventricles and to determine the response to chronic therapeutic phlebotomy. Dilated and restrictive cardiomyopathic patterns were identified in 1 patient each, but our data do not permit conclusions on when in the natural history a given pattern becomes overt. On entry into study, 3 patients had normal ventricles and 7 had ventricular abnormalities on echocardiography and blood pool angiography. In 2 of the latter patients, biventricular dysfunction and increased left ventricular (LV) mass normalized after phlebotomy; 1 patient achieved a normal LV response to exercise. Of the 4 patients with isolated abnormal LV ejection fraction responses to exercise, the EF normalized in 2 after phlebotomy. In 1 patient, isolated right ventricular enlargement and dysfunction (echocardiographic and radionuclide imaging) normalized after phlebotomy. Thus, primary hemochromatosis can effect LV and RV size and function; clinically occult cardiac involvement can be identified by echocardiography and equilibrium blood pool imaging; therapeutic phlebotomy can ameliorate or reverse the deleterious effects of excess cardiac iron deposition which appears to exert its harm, at least in part, by a mechanism other than irreversible connective tissue replacement.

  19. C282Y/H63D hemochromatosis mutations and microevolution: Speculations concerning the Basque population.

    PubMed

    Bauduer, F

    2017-01-01

    The Basques live at the Western extremity of the Pyrenees. According to linguistic and genetic data they could be considered as one of the most ancient European populations. Numerous studies have evidenced particular patterns in the frequency of several genetic polymorphisms in this relatively unmixed human group. We discuss herein the puzzling distribution of the two major hemochromatosis HFE mutations associated with hereditary hemochromatosis. Thus, one can observe a low frequency of C282Y and, in contrast, one of the highest European frequencies of H63D. Genetic drift (enhanced by the long history and the small size of this population), long persistence of Paleolithic iron-rich diet, lower exposure to major infectious threats and limited mixing with both Celts and Vikings (who demonstrate the highest prevalence of C282Y) could be the underlying factors explaining these particular genetic features. Historical and environmental data represent key elements for understanding the role of the different evolutionary forces which shape the genetic profile of human populations.

  20. An unfortunate case of acquired hemochromatosis: a case report review of the clinical presentation, diagnosis, management, and prognosis

    PubMed Central

    Tariq, Anam; Westra, Kevin; Santo, Arben

    2016-01-01

    Background While blood transfusions are commonly used for prophylaxis and treatment for acute chest syndromes and strokes in sickle cell patients, accumulation of excess iron resulting in secondary hemochromatosis remains a rare disease. Chelation is the mainstay for preventing and treating iron overload to deter potential end-organ damages; it is rare when therapy fails. Case report A 52-year-old African American woman with chronic anemia secondary to sickle cell anemia and history of multiple blood transfusions presented with elevated serum ferritin (8000 ng/mL) and bilirubin (16.8 mg/dL). She had no previous personal or family history of liver disease. A magnetic resonance cholangiopancreatography (MRCP) and a liver biopsy confirmed the secondary hemochromatosis with marked fibrosis and 4+ iron deposits, but since she was therapeutically on deferasirox, her treatment regimen involved only closer monitoring. Her hemochromatosis led to readmission within a year for rapid progression of cardiac and hepatic failure. Conclusion Since chronically transfused sickle cell patients are at a significantly higher risk of mortality due to the secondary hemochromatosis and end-stage organ damage, knowledge of prophylactic iron chelation is important. Minimizing unnecessary transfusions should be strongly emphasized to reduce the sequelae as iron burden remains a threat. The effectiveness of iron-chelating therapy is best monitored via periodic magnetic resonance imaging, liver transaminases, bilirubin, creatinine, ferritin, and cardiac function tests. Despite the prophylactic treatment and quarterly blood work, in this case the initial presentation did not correlate with the severity of end-stage liver failure. The damage was not discovered until proven by liver biopsy and MRCP, too late to deter the sequelae and the mortality exactly 1 year after diagnosis of the secondary hemochromatosis. PMID:27994488

  1. Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis.

    PubMed

    Nairz, Manfred; Weiss, Günter

    2006-08-01

    The discovery in recent years of a plethora of new genes whose products are implicated in iron homeostasis has led to rapid expansion of our knowledge in the field of iron metabolism and its underlying complex regulation in both health and disease. Abnormalities of iron metabolism are among the most common disorders encountered in practical medicine and may have significant negative impact on physical condition and life expectancy. Basic insights into the principles of iron homeostasis and the pathophysiological and clinical consequences of iron overload, iron deficiency and misdistribution are thus of crucial importance in modern medicine. This review summarizes our current understanding of human iron metabolism and focuses on the clinically relevant features of hereditary and secondary hemochromatosis, iron deficiency anemia, anemia of chronic disease and anemia of critical illness. The interconnections between iron metabolism and immunity are also addressed, in as much as they may affect the risk and course of infections and malignancies.

  2. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    PubMed Central

    Benyamin, Beben; Esko, Tonu; Ried, Janina S; Radhakrishnan, Aparna; Vermeulen, Sita H; Traglia, Michela; Gögele, Martin; Anderson, Denise; Broer, Linda; Podmore, Clara; Luan, Jian’an; Kutalik, Zoltan; Sanna, Serena; van der Meer, Peter; Tanaka, Toshiko; Wang, Fudi; Westra, Harm-Jan; Franke, Lude; Mihailov, Evelin; Milani, Lili; Häldin, Jonas; Winkelmann, Juliane; Meitinger, Thomas; Thiery, Joachim; Peters, Annette; Waldenberger, Melanie; Rendon, Augusto; Jolley, Jennifer; Sambrook, Jennifer; Kiemeney, Lambertus A; Sweep, Fred C; Sala, Cinzia F; Schwienbacher, Christine; Pichler, Irene; Hui, Jennie; Demirkan, Ayse; Isaacs, Aaron; Amin, Najaf; Steri, Maristella; Waeber, Gérard; Verweij, Niek; Powell, Joseph E; Nyholt, Dale R; Heath, Andrew C; Madden, Pamela AF; Visscher, Peter M; Wright, Margaret J; Montgomery, Grant W; Martin, Nicholas G; Hernandez, Dena; Bandinelli, Stefania; van der Harst, Pim; Uda, Manuela; Vollenweider, Peter; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; van Duijn, Cornelia; Beilby, John; Pramstaller, Peter P; Hicks, Andrew A; Ouwehand, Willem H; Oexle, Konrad; Gieger, Christian; Metspalu, Andres; Camaschella, Clara; Toniolo, Daniela; Swinkels, Dorine W; Whitfield, John B

    2014-01-01

    Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here we analyse genetic association data on biochemical markers of iron status from eleven European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find eleven genome-wide-significant (p < 5 × 10−8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease. PMID:25352340

  3. Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS study initial screening.

    PubMed

    Barton, James C; Acton, Ronald T; Leiendecker-Foster, Catherine; Lovato, Laura; Adams, Paul C; Eckfeldt, John H; McLaren, Christine E; Reiss, Jacob A; McLaren, Gordon D; Reboussin, David M; Gordeuk, Victor R; Speechley, Mark R; Press, Richard D; Dawkins, Fitzroy W

    2008-02-01

    There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25-29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25-29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.

  4. Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

    PubMed

    Shizukuda, Yukitaka; Tripodi, Dorothy J; Zalos, Gloria; Bolan, Charles D; Yau, Yu-Ying; Leitman, Susan F; Waclawiw, Myron A; Rosing, Douglas R

    2012-03-15

    It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p < 0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation.

  5. Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis.

    PubMed

    Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Cuadrado-Grande, Nuria; Alvarez-Sala-Walther, Luis-Antonio; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

    2012-10-15

    Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype.

  6. Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS Study initial screening

    PubMed Central

    Barton, James C.; Acton, Ronald T.; Leiendecker-Foster, Catherine; Lovato, Laura; Adams, Paul C.; Eckfeldt, John H.; McLaren, Christine E.; Reiss, Jacob A.; McLaren, Gordon D.; Reboussin, David M.; Gordeuk, Victor R.; Speechley, Mark R.; Press, Richard D.; Dawkins, Fitzroy W.

    2013-01-01

    There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25–29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire. PMID:17726683

  7. Therapeutic Depletion of Iron Stores Is Not Associated with a Reduced Hemoglobin Mass in a Hemochromatosis Patient

    PubMed Central

    Wrobel, Nina; Pottgiesser, Torben; Birkner, Philipp; Deibert, Peter; Ahlgrim, Christoph

    2016-01-01

    Introduction Hereditary hemochromatosis features a dysregulated iron absorption leading to iron overload and organ damage. The regulation of total hemoglobin mass during depletion of iron deposits by therapeutic phlebotomy has not been studied. Case Presentation The initial ferritin level of the 52-year-old male subject was 1,276 μg/l. Despite successful depletion of iron stores (ferritinmin: 53 μg/l) through phlebotomies, total hemoglobin mass stabilized at the pretherapy level. However, regeneration of total hemoglobin mass was accelerated (up to 10.8 g/day). Conclusion In this hemochromatosis patient, the total hemoglobin mass was not altered in the long term, but regeneration was accelerated, possibly due to elevated body iron content. PMID:27721733

  8. A Case Study of Hemochromatosis and Conflicting Point Shear Wave Measurements in the Assessment of Liver Fibrosis.

    PubMed

    Cohen, Tal; Barr, Richard G

    2017-01-09

    There are multiple factors that affect the shear wave speed in the assessment of liver stiffness. In this case report, we present a case of hemochromatosis that has elevated liver stiffness suggestive of significant fibrosis or cirrhosis; however on liver biopsy, no fibrosis was identified. This article will discuss the possibility that liver iron deposition may affect SWE measurements of the liver, leading to inaccurate assessment of liver fibrosis. In these cases, a liver biopsy may be required for accurate liver assessment.

  9. Distribution of the C282Y and H63D polymorphisms in hereditary hemochromatosis patients from the French Basque Country.

    PubMed

    Bauduer, F; Scribans, C; Degioanni, A; Renoux, M; Dutour, O

    2005-02-01

    The distribution of HFE mutations was studied in patients from the French Basque Country with hereditary hemochromatosis (HH). The C282Y mutation was underrepresented but H63D seemed to demonstrate the highest prevalence when compared with other European countries. In addition, symptomatic HH was rarer in autochthonous Basques. This profile is interesting to consider in view of population genetics and should be associated with the search for non-HFE mutations.

  10. Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency.

    PubMed

    Byrnes, V; Barrett, S; Ryan, E; Kelleher, T; O'Keane, C; Coughlan, B; Crowe, J

    2002-01-01

    HFE-associated hereditary hemochromatosis is characterized by imbalances of iron homeostasis and alterations in intestinal iron absorption. The identification of the HFE gene and the apical iron transporter divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary hemochromatosis. Small bowel biopsies and serum iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary hemochromatosis (C282Y homozygous), 10 patients with iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1 protein expression was additionally assessed by immunohistochemistry. Levels of HFE mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1 mRNA levels were at least twofold greater in patients with hereditary hemochromatosis and iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1 protein expression correlated with mRNA levels in all patients. Loss of HFE function in hereditary hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal iron deficiency in hereditary hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body iron stores observed in those presenting with clinical features of hereditary hemochromatosis.

  11. Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

    SciTech Connect

    Yaouanq, J.; Perichon, M.; Treut, A.L.; Kahloun, A.E.; Mauvieux, V.; Blayau, M.; Jouanolle, A.M.; Chauvel, B.; Le Gall, J.Y.; David, V. )

    1994-02-01

    The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I gene; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. The authors therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes for the Brittany population. In this report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. 69 refs., 1 fig., 5 tabs.

  12. Effect of C282Y Genotype on Self-Reported Musculoskeletal Complications in Hereditary Hemochromatosis

    PubMed Central

    Simão, Márcio; Cancela, Leonor; Ottaviani, Sébastien; Cohen-Solal, Martine; Richette, Pascal

    2015-01-01

    Objective Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. Methods A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. Results In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) µg/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2–5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1–12.1]). Conclusion Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH. PMID:25822977

  13. Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis.

    PubMed

    Wang, Yongwei; Du, Yali; Liu, Gang; Guo, Shanshan; Hou, Bo; Jiang, Xianyong; Han, Bing; Chang, Yanzhong; Nie, Guangjun

    2017-04-01

    Hereditary hemochromatosis (HH) is a group of inherited iron-overload disorders associated with pathogenic defects in the genes encoding hemochromatosis (HFE), hemojuvelin (HJV/HFE2), hepcidin (HAMP), transferrin receptor 2 (TfR2), and ferroportin (FPN1/SLC40A1) proteins, and the clinical features are well described. However, there have been only a few detailed reports of HH in Chinese populations. Thus, there is insufficient patient information for population-based analyses in Chinese populations or comparative studies among different ethical groups. In the current work, we describe eight Chinese cases of hereditary hemochromatosis. Gene sequencing results revealed eight mutations (five novel mutations) in HFE, HFE2, TfR2, and SLC40A1 genes in these Chinese HH patients. In addition, we used Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), and a sequence alignment program to predict the molecular consequences of missense mutations.

  14. Changes in Exercise Capacity of Cardiac Asymptomatic Hereditary Hemochromatosis Subjects over 5-Year Follow up

    PubMed Central

    Shizukuda, Yukitaka; Smith, Kevin P.; Tripodi, Dorothy J.; Arena, Ross; Yau, Yu-Ying; Bolan, Charles D.; Waclawiw, Myron A.; Leitman, Susan F.; Rosing, Douglas R.

    2012-01-01

    Objective A long-term effect of hereditary hemochromatosis (HH) on aerobic exercise capacity (AEC) has not been well described. Design Forty-three HH and 21 volunteer control (VC) subjects who were asymptomatic underwent cardiopulmonary exercise testing using the Bruce protocol. AEC was assessed with minute ventilation (VE), oxygen uptake (VO2), and carbon dioxide production (VCO2) at baseline (BL) at a 5-year follow up (5Y) assessment. A paired t-test was used for analyses of normality data; otherwise, a Wilcoxon singed rank sum test was used. Results Thirty-three HH subjects and 18 VC subjects returned for a repeat CPX at 5Y (80% overall return rate). At 5Y, AEC was not different between the two groups. As compared with BL measurements, exercise time, peak VO2, and the VE/VCO2 slope did not differ statistically at 5Y between both groups. Iron depletion by phlebotomy for 5 years did not significantly affect AEC in newly diagnosed HH subjects at baseline (n=14) and cardiac arrhythmias during exercise tended to decrease after 5 years of therapy in this group. Conclusions The AEC of asymptomatic HH subjects treated with conventional therapy is not statistically affected by the disease over a 5-year period. PMID:22311055

  15. Educational outcomes of a workplace screening program for genetic susceptibility to hemochromatosis.

    PubMed

    Nisselle, A E; Collins, V R; Gason, A A; Flouris, A; Delatycki, M B; Allen, K J; Aitken, M A; Metcalfe, S A

    2006-02-01

    Education is an essential component of a genetic screening program. Knowledge outcomes were measured after large-scale workplace education and screening for genetic susceptibility to hereditary hemochromatosis. The aim was to assess knowledge of concepts presented, impact of mode of delivery, and knowledge retention. Education in a group setting was delivered via oral or video presentation and knowledge assessed using self-administered questionnaires at baseline, 1 month, and 12 months. Over 60% of 11 679 participants correctly answered all questions at baseline, scoring higher with clinical concepts (disease etiology and treatment) than genetic concepts (penetrance and genetic heterogeneity). Revising the education program significantly increased correct responses for etiology (p < 0.002), whilst modifying the knowledge assessment tool significantly increased correct responses for etiology (p < 0.001) and gene penetrance (p < 0.001). For three of the four concepts assessed, use of video was as effective as oral presentation for knowledge outcomes. A significantly higher proportion of those at increased risk of disease (n = 44) responded correctly at 12 months than did controls (n = 82; p = 0.011 for etiology, p = 0.002 for treatment and p = 0.003 for penetrance). Hence, genetic screening can be successfully offered in a group workplace setting, with participants remembering clinical concepts better than genetic concepts up to 1 year later.

  16. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

    PubMed

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-04-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

  17. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

    PubMed Central

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-01-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

  18. Structural basis of urea-induced unfolding: Unraveling the folding pathway of hemochromatosis factor E.

    PubMed

    Khan, Parvez; Prakash, Amresh; Haque, Md Anzarul; Islam, Asimul; Hassan, Md Imtaiyaz; Ahmad, Faizan

    2016-10-01

    Hereditary hemochromatosis factor E (HFE) is a type 1 transmembrane protein, and acts as a negative regulator of iron-uptake. The equilibrium unfolding and conformational stability of the HFE protein was examined in the presence of urea. The folding and unfolding transitions were monitored with the help of circular dichroism (CD), intrinsic fluorescence and absorption spectroscopy. Analysis of transition curves revealed that the folding of HFE is not a two-state process. However, it involved stable intermediates. Transition curves (plot of fluorescence (F346) and CD signal at 222nm (θ222) versus [Urea], the molar urea concentration) revealed a biphasic transition with midpoint (Cm) values at 2.88M and 4.95M urea. Whereas, absorption analysis shows one two-state transition centered at 2.96M. To estimate the protein stability, denaturation curves were analyzed for Gibbs free energy change in the absence of urea (ΔGD(0)) associated with the equilibrium of denaturation exist between native state↔denatured state. The intermediate state was further characterized by hydrophobic probe, 1-anilinonaphthalene-8-sulfonic acid (ANS-binding). For seeing the effect of urea on the structure and dynamics of HFE, molecular dynamics simulation for 60ns was also performed. A clear correspondence was established between the in vitro and in silico studies.

  19. A common deletion at D6S265 in the hemochromatosis gene region

    SciTech Connect

    Pyper, W.R.; Burt, M.J.; Powell, L.W.

    1994-09-01

    Positional cloning of the hemochromatosis (HC) gene on chromosome 6p has utilized a number of highly polymorphic microsatellite markers. While the putative HC gene has been localized within 1 cM of HLA-A, definition of the genetic limits of the HC locus has been controversial. Isolation and characterization of additional markers within this region will enable construction of a physical map upon which the HC gene can located. D6S265 is one such microsatellite, physically mapped within 120 kb centromeric of HLA-A. Recombinant and linkage analysis of this dinucleotide repeat in 24 Australian families segregating for HC positioned D6S265 within 1 cM of the HC gene, while allele association analysis showed allele 1 to be significantly increased in HC patients ({chi}{sup 2}=41.4, p<0.001, RR=5.75). In 6 of the 24 HC families, a D6265 locus deletion was found to segregate with HLA-A25 and HLA-A26 alleles. The D6S265 locus deletion was not associated with expression of HC. This study enables us to exclude candidate HC genes from the deleted region involving D6S265, and gives further support for an area of instability in the HLA class I region.

  20. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis.

    PubMed

    Ramos, Emilio; Ruchala, Piotr; Goodnough, Julia B; Kautz, Léon; Preza, Gloria C; Nemeth, Elizabeta; Ganz, Tomas

    2012-11-01

    The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation.

  1. Does rapidly progressive iron overload in a young girl with sideroblastic anemia also signify the presence of hereditary hemochromatosis?

    PubMed

    Scimeca, P G; Weinblatt, M E; Kahn, E; Kochen, J A

    1994-01-01

    A severely anemic 3-year-old girl with refractory sideroblastic anemia and fulminant, fatal hemochromatosis is described. The patient had transfusion-dependent anemia with clinical cardiac, liver, and endocrine dysfunction that resulted from iron loading. The patient was minimally transfused, and deferoxamine chelation was started at age 34 months. Despite treatment, the patient died at age 46 months as a result of severe iron overload. Sideroblastic anemia and iron overload in childhood are reviewed, and a pathophysiologic mechanism for the patient's clinical course is postulated.

  2. Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3.

    PubMed

    Joshi, Ricky; Shvartsman, Maya; Morán, Erica; Lois, Sergi; Aranda, Jessica; Barqué, Anna; de la Cruz, Xavier; Bruguera, Miquel; Vagace, José Manuel; Gervasini, Guillermo; Sanz, Cristina; Sánchez, Mayka

    2015-05-01

    Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.

  3. Duodenal expression of iron transport molecules in patients with hereditary hemochromatosis or iron deficiency

    PubMed Central

    Dostalikova-Cimburova, Marketa; Kratka, Karolina; Balusikova, Kamila; Chmelikova, Jitka; Hejda, Vaclav; Hnanicek, Jan; Neubauerova, Jitka; Vranova, Jana; Kovar, Jan; Horak, Jiri

    2012-01-01

    Abstract Disturbances of iron metabolism are observed in chronic liver diseases. In the present study, we examined gene expression of duodenal iron transport molecules and hepcidin in patients with hereditary hemochromatosis (HHC) (treated and untreated), involving various genotypes (genotypes which represent risk for HHC were examined), and in patients with iron deficiency anaemia (IDA). Gene expressions of DMT1, ferroportin, Dcytb, hephaestin, HFE and TFR1 were measured in duodenal biopsies using real-time PCR and Western blot. Serum hepcidin levels were measured using ELISA. DMT1, ferroportin and TFR1 mRNA levels were significantly increased in post-phlebotomized hemochromatics relative to controls. mRNAs of all tested molecules were significantly increased in patients with IDA compared to controls. The protein expression of ferroportin was increased in both groups of patients but not significantly. Spearman rank correlations showed that DMT1 versus ferroportin, Dcytb versus hephaestin and DMT1 versus TFR1 mRNAs were positively correlated regardless of the underlying cause, similarly to protein levels of ferroportin versus Dcytb and ferroportin versus hephaestin. Serum ferritin was negatively correlated with DMT1 mRNA in investigated groups of patients, except for HHC group. A decrease of serum hepcidin was observed in IDA patients, but this was not statistically significant. Our data showed that although untreated HHC patients do not have increased mRNA levels of iron transport molecules when compared to normal subjects, the expression is relatively increased in relation to body iron stores. On the other hand, post-phlebotomized HHC patients had increased DMT1 and ferroportin mRNA levels possibly due to stimulated erythropoiesis after phlebotomy. PMID:21973163

  4. Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3

    PubMed Central

    Joshi, Ricky; Shvartsman, Maya; Morán, Erica; Lois, Sergi; Aranda, Jessica; Barqué, Anna; de la Cruz, Xavier; Bruguera, Miquel; Vagace, José Manuel; Gervasini, Guillermo; Sanz, Cristina; Sánchez, Mayka

    2015-01-01

    Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload. PMID:26029709

  5. SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis.

    PubMed

    Jenkitkasemwong, Supak; Wang, Chia-Yu; Coffey, Richard; Zhang, Wei; Chan, Alan; Biel, Thomas; Kim, Jae-Sung; Hojyo, Shintaro; Fukada, Toshiyuki; Knutson, Mitchell D

    2015-07-07

    Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.

  6. Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study.

    PubMed

    Cançado, Rodolfo; Melo, Murilo R; de Moraes Bastos, Roberto; Santos, Paulo C J L; Guerra-Shinohara, Elivira M; Chiattone, Carlos; Ballas, Samir K

    2015-12-01

    This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.

  7. Diabetes in first-degree family members: a predictor of type 2 diabetes in 159 nonscreening Alabama hemochromatosis probands with HFE C282Y homozygosity.

    PubMed

    Barton, James C; Barton, J Clayborn; Acton, Ronald T

    2014-01-01

    OBJECTIVE We sought to identify predictors of diabetes diagnosed before hemochromatosis. RESEARCH DESIGN AND METHODS We studied these 16 variables in 159 nonscreening hemochromatosis probands with HFE C282Y homozygosity: age; sex; BMI; diabetes reports in first-degree family members (dichotomous); heavy ethanol consumption; cigarette smoking; elevated serum alanine aminotransferase/aspartate aminotransferase levels; nonalcoholic fatty liver; chronic viral hepatitis; cirrhosis; hand arthropathy; iron removed by phlebotomy; and positivity for HLA-A*01, B*08; A*03, B*07; and A*03, B*14 haplotypes. We performed univariable and multivariable analyses. RESULTS Twenty-three probands (14.5%) had diabetes; 19 were men. Each of the 23 probands had type 2 diabetes. Mean BMI was greater in probands with diabetes (31.7 ± 8.5 [SD] kg/m(2) vs. 27.6 ± 5.1 kg/m(2); P = 0.032). Reports of any first-degree family member with diabetes were more prevalent in probands with than in probands without diabetes (69.6 vs. 17.6%; P < 0.0001). In probands with diabetes, the odds ratio (OR) of maternal diabetes was 6.7 (95% CI 2.3-19.7; P = 0.0005) and of sibling diabetes was 11.7 (3.0-45.5; P = 0.0004). In a logistic regression model, predictors of diabetes at hemochromatosis diagnosis in 159 probands were diabetes reports in family members (OR 8.5 [95% CI 2.9-24.8]; P < 0.0001) and BMI (1.1 [1.0-1.2]; P = 0.049). This model explained 26.0% of total deviance contributing to diabetes. CONCLUSIONS In nonscreening hemochromatosis probands with HFE C282Y homozygosity, a heritable factor(s) increases the risk of diabetes diagnosed before hemochromatosis.

  8. Localization of the hemochromatosis gene close to D6S105

    SciTech Connect

    Jazwinska, E.C.; Lee, S.C.; Webb, S.I.; Halliday, J.W.; Powell, L.W. )

    1993-08-01

    The hemochromatosis (HC) gene is known to be linked to HLA-A (6p21.3); however, its precise location has been difficult to determine because of a lack of additional highly polymorphic markers for this region. The recent identification of short tandem repeat sequences (microsatellites) has now provided this area with a number of markers with similar polymorphic index to the HLA serological polymorphisms. Using four microsatellites - D6S105, D6S109, D6S89, and F13A - together with the HLA class I loci HLA-A and HLA-B in 13 large pedigrees clearly segregating for HC, the authors have been able to refine the location of the HC gene. They identified no recombination between HC and HLA-A or D6S105, and two-point analyses placed the HC gene within one centimorgan (cM) of HLA-A and D6S105. The markers HLA-B, D6S109, D6S89, and F13A were separated from the HC locus by recombination, defining the centromeric and telomeric limits for the HC gene as HLA-B and D5S109, respectively. A multipoint map constructed using HLA-B, HLA-A, and D6S109 indicates that the HC gene is located in a region less than 1 cM proximal to HLA-A and less than 1 cM telomeric of HLA-A. These pedigree data indicate an association between HC and specific alleles at HLA-A and D6S105 (i.e., HLA-A3 and D6S105 allele 8). To determine the significance of these allelic associations, the authors have analyzed the allele's frequency in 82 unrelated HC patients and 82 unrelated healthy controls. D6S105 allele 8 was present in 93% of patients and only 21% of controls ([chi][sup 2] = 86.46; P < .0001). The approximate relative risk for this allele was 48.4 HLA-A3 was present in 62% of patients and 26% of controls ([chi][sup 2] = 22.28; P<.001). Approximate relative risk for A3 was 4.8. They conclude that the microsatellite marker D6S105 is the closest marker to the HC gene reported to date. 26 refs., 1 fig., 3 tabs.

  9. Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation

    PubMed Central

    Gordeuk, Victor R; Lovato, Laura; Barton, James C; Vitolins, Mara; McLaren, Gordon; Acton, Ronald T; McLaren, Christine; Harris, Emily L; Speechley, Mark; Eckfeldt, John H; Diaz, Sharmin; Sholinsky, Phyliss; Adams, Paul

    2012-01-01

    BACKGROUND: HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals. OBJECTIVE: To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration. DESIGN: Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada. RESULTS: No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found. CONCLUSION: These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America. PMID:22720276

  10. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.

    PubMed Central

    Mendez, M; Sorkin, L; Rossetti, M V; Astrin, K H; del C Batlle, A M; Parera, V E; Aizencang, G; Desnick, R J

    1998-01-01

    Familial porphyria cutanea tarda (f-PCT) results from the half-normal activity of uroporphyrinogen decarboxylase (URO-D). Heterozygotes for this autosomal dominant trait are predisposed to photosensitive cutaneous lesions by various ecogenic factors, including iron overload and alcohol abuse. The 3.6-kb URO-D gene was completely sequenced, and a long-range PCR method was developed to amplify the entire gene for mutation analysis. Four missense mutations (M165R, L195F, N304K, and R332H), a microinsertion (g10insA), a deletion (g645Delta1053), and a novel exonic splicing defect (E314E) were identified. Expression of the L195F, N304K, and R332H polypeptides revealed significant residual activity, whereas reverse transcription-PCR and sequencing demonstrated that the E314E lesion caused abnormal splicing and exon 9 skipping. Haplotyping indicated that three of the four families with the g10insA mutation were unrelated, indicating that these microinsertions resulted from independent mutational events. Screening of nine f-PCT probands revealed that 44% were heterozygous or homozygous for the common hemochromatosis mutations, which suggests that iron overload may predispose to clinical expression. However, there was no clear correlation between f-PCT disease severity and the URO-D and/or hemochromatosis genotypes. These studies doubled the number of known f-PCT mutations, demonstrated that marked genetic heterogeneity underlies f-PCT, and permitted presymptomatic molecular diagnosis and counseling in these families to enable family members to avoid disease-precipitating factors. PMID:9792863

  11. Hereditary hemochromatosis: Generation of a transcription map within a refined and extended map of the HLA class I region

    SciTech Connect

    Totaro, A.; Grifa, A.; Gasparini, P.

    1996-02-01

    Hereditary hemochromatosis, a common severe inherited disease, maps to the short arm of chromosome 6 close to the HLA-A locus. Recently, linkage data on Italian and French populations confirmed this location, while a similar analysis on Australian and British populations located the gene closer to D6S105, a marker residing telomeric of HLA-A. To increase our knowledge on the region of highest linkage disequilibrium in our population and possibly to identify the disease gene, a 1.2-Mb detailed physical and transcription map was generated, spanning the HLA class I region. Thirty-eight unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of fetal brain, adult brain, liver, placenta, and the CaCo{sub 2} cell line, were characterized. All cDNA fragments were positioned in a refined and extended map of the human major histocompatibility complex spanning from HLA-E to approximately 500 kb telomeric of HLA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription units in addition to the HLA genes have been detected and integrated in the map. Thirteen cDNA fragments show no similarity with known sequences and could be candidates for the disease. Their characterization and assessment for involvement in hemochromatosis are still under investigation. Seven new polymorphisms, some tightly linked to the disease, were also identified and localized. 29 refs., 2 figs., 3 tabs.

  12. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE.

    PubMed

    West, A P; Bennett, M J; Sellers, V M; Andrews, N C; Enns, C A; Bjorkman, P J

    2000-12-08

    The transferrin receptor (TfR) interacts with two proteins important for iron metabolism, transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625). TfR2 has a pattern of expression and regulation that is distinct from TfR, and mutations in TfR2 have been recognized as the cause of a non-HFE linked form of hemochromatosis (Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P. (2000) Nat. Genet. 25, 14-15). To investigate the relationship between TfR, TfR2, Tf, and HFE, we performed a series of binding experiments using soluble forms of these proteins. We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay. The affinity of TfR2 for iron-loaded Tf was determined to be 27 nm, 25-fold lower than the affinity of TfR for Tf. These results imply that HFE regulates Tf-mediated iron uptake only from the classical TfR and that TfR2 does not compete for HFE binding in cells expressing both forms of TfR.

  13. Population-based analysis of the frequency of HFE gene polymorphisms: Correlation with the susceptibility to develop hereditary hemochromatosis.

    PubMed

    Katsarou, Martha-Spyridoula; Latsi, Rosana; Papasavva, Maria; Demertzis, Nikolaos; Kalogridis, Thodoris; Tsatsakis, Aristides M; Spandidos, Demetrios A; Drakoulis, Nikolaos

    2016-07-01

    Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease, characterized by increased dietary iron absorption. Due to the absence of an effective excretory mechanism, the excess iron in the body may accumulate resulting in toxic effects. The HFE gene also affects the activity of hepcidin, a hormone which acts as a negative regulator of iron metabolism. In this study, we performed a population-based analysis of the distribution of three hemochromatosis-related polymorphisms in the HFE gene (rs1800562, rs1799945 and rs1800730). DNA from 1,446 non‑related individuals of Greek ethnicity was collected and analyzed, either from whole blood or buccal swabs. The frequency distribution of these HFE gene polymorphisms was then determined. The results revealed that in our Greek population cohort (gr) the frequencies of each polymorphism were as follows: rs1800562: GG (wild‑type)=97.0%, GA=1.5%, AA=1.5%; rs1799945: CC (wild‑type)=74.4%, CG=23.4%, GG=2.2%; rs1800730: AA (wild‑type)=98.1%, AT=1.5% and TT=0.4%. No association between the HFE polymorphisms rs1800562, rs1799945 and rs1800730 and gender could be established. As regards the rs1800562 polymorphism, the A allele (mutant) was ~1.8‑fold more frequent in the European population (eur) than in the Greek population [(gr)=2,3%<(eur)=4%]. As for the rs1799945 polymorphism, the G allele (mutant) was 1.2‑fold more frequent in the European population than in the Greek population [(gr)=13,9%<(eur)=17%]. As regards the rs1800730 polymorphism, the T allele (mutant) was ~1.7‑fold more frequent in the European population than in the Greek population [(gr)=1.2%<(eur)=2%]. However, these pathogenic mutations were found more frequently in the Greek population compared to the global population (gl) [rs1800562: (gl)=1%<(gr)=2,3%; rs1799945: (gl)=7%<(gr)=13,9%; rs1800730: (gl)=<1%<(gr)=1.2%]. This suggests that the Greek population may differ genetically from the northern European population

  14. Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population.

    PubMed

    Faria, Ricardo; Silva, Bruno; Silva, Catarina; Loureiro, Pedro; Queiroz, Ana; Fraga, Sofia; Esteves, Jorge; Mendes, Diana; Fleming, Rita; Vieira, Luís; Gonçalves, João; Faustino, Paula

    2016-10-01

    Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients. A total of 1241 genetic alterations were detected corresponding to 53 different variants, 13 of which were not described in the available public databases. Among them, five were predicted to be potentially pathogenic: three novel mutations in TFR2 [two missense (p.Leu750Pro and p.Ala777Val) and one intronic splicing mutation (c.967-1G>C)], one missense mutation in HFE (p.Tyr230Cys), and one mutation in the 5'-UTR of HAMP gene (c.-25G>A). The results reported here illustrate the usefulness of NGS for targeted iron metabolism-related gene panels, as a likely cost-effective approach for molecular genetics diagnosis of non-classic HH patients. Simultaneously, it has contributed to the knowledge of the pathophysiology of those rare iron metabolism-related disorders.

  15. Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene

    SciTech Connect

    Crawford, D.H.G.; Powell, L.W.; Leggett, B.A.

    1995-08-01

    Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency. 18 refs., 3 tabs.

  16. Interaction of the Hereditary Hemochromatosis Protein, HFE, with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

    PubMed Central

    Gao, Junwei; Chen, Juxing; Kramer, Maxwell; Tsukamoto, Hidekazu; Zhang, An-Sheng; Enns, Caroline A.

    2009-01-01

    SUMMARY The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein, HFE. They have lower levels of hepcidin, than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the α3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE α3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf. PMID:19254567

  17. Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis.

    PubMed

    Chua, Anita C G; Olynyk, John K; Leedman, Peter J; Trinder, Debbie

    2004-09-01

    Hereditary hemochromatosis (HH) is an iron-overload disorder caused by a C282Y mutation in the HFE gene. In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate. The aim of this study was to examine the importance of NTBI in the pathogenesis of hepatic iron loading in Hfe knockout mice. Plasma NTBI levels were increased 2.5-fold in Hfe knockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 +/- 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 +/- 2.7 pmol Fe/mg protein/min; P <.001; mean +/- SEM; n = 7). Ferrous ion chelators, bathophenanthroline disulfonate, and 2',2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types. Divalent metal ions inhibited ferric citrate uptake by hepatocytes, as did diferric transferrin. Divalent metal transporter 1 (DMT1) mRNA and protein expression was increased approximately 2-fold by hepatocytes from Hfe knockout mice. We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading. Ferric ion was reduced to ferrous ion and taken up by hepatocytes by a pathway shared with diferric transferrin. Inhibition of uptake by divalent metals and up-regulation of DMT1 expression suggested that NTBI uptake was mediated by DMT1.

  18. Isolation of novel non-HLA gene fragments from the hemochromatosis region (6p21. 3) by cDNA hybridization selection

    SciTech Connect

    Goei, V.L.; Capossela, A.; Gruen, J.R.; Parimoo, S.; Chu, T.W. )

    1994-02-01

    It has previously been shown that cDNA hybridization selection can identify and recover novel genes from large cloned genomic DNA such as cosmids or YACs. In an effort to identify candidate genes for hemochromatosis, this technique was applied to a 320-kb YAC containing the HLA-A gene. A short fragment cDNA library derived from human duodenum was selected with the YAC DNA. Ten novel gene fragments were isolated, characterized, and localized on the physical map of the YAC. 39 refs., 4 figs., 3 tabs.

  19. Thyroid-Stimulating Hormone and Free Thyroxine Levels in Persons with HFE C282Y Homozygosity, a Common Hemochromatosis Genotype: The HEIRS Study

    PubMed Central

    Leiendecker-Foster, Catherine; Reboussin, David M.; Adams, Paul C.; Acton, Ronald T.; Eckfeldt, John H.

    2008-01-01

    Background Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care–based Hemochromatosis and Iron Overload Screening (HEIRS) Study. Methods We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU/L and free T4 <0.70 ng/dL, and hyperthyroidism as having TSH <0.400 mIU/L and free T4 >1.85 ng/dL. Multivariate analyses were performed using age, sex, Field Center, log10 serum ferritin (SF), HFE genotype, log10 TSH, and log10 free T4. Results Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log10 SF with log10 free T4 were positive (p = 0.2368, C282Y homozygotes; p = 0.0492, controls). Independent predictors of log10 free T4 were log10 TSH (negative association) and age (positive association); positive predictors of log10 SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly. Conclusions Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs. PMID:18651828

  20. The Effect of the Hemochromatosis (HFE) Genotype on Lead Load and Iron Metabolism among Lead Smelter Workers

    PubMed Central

    Fan, Guangqin; Du, Guihua; Li, Huijun; Lin, Fen; Sun, Ziyong; Yang, Wei; Feng, Chang; Zhu, Gaochun; Li, Yanshu; Chen, Ying; Jiao, Huan; Zhou, Fankun

    2014-01-01

    Background Both an excess of toxic lead (Pb) and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE) gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking. Objectives To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant) on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure. Methods Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted. Results Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin. Conclusions No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally. PMID:24988074

  1. Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis

    SciTech Connect

    Craven, C.M.; Alexander, J.; Eldridge, M.; Kushner, J.P.; Bernstein, S.; Kaplan, J.

    1987-05-01

    Genetically hypotransferrinemic mice accumulate iron in the liver and pancreas. A similar pattern of tissue iron accumulation occurs in humans with hereditary hemochromatosis. In both disorders, there is a decrease plasma concentration of apotransferrin. To test the hypothesis that nontransferrin-bound iron exists and is clear by the parenchymal tissues, the tissue distribution of /sup 59/Fe was studied in animals lacking apotransferrin. Two groups of animals were used: normal rats and mice whose transferrin had been saturated by an intravenous injection of nonradiolabeled iron, and mice with congential hypotransferrinemia. In control animals, injected /sup 59/Fe was found primarily in the bone marrow and spleen. In the transferrin iron-saturated animals, injected /sup 59/Fe accumulated in the liver and pancreas. Gastrointestinally absorbed iron in hypotransferrinemic or transferrin iron-saturated mice was deposited in the liver. This indicates that newly absorbed iron is released from mucosal cells not bound to transferrin. Clearance studies demonstrated that transferrin-bound /sup 59/Fe was removed from the circulation of rats with a half-time of 50 min. In transferrin iron-saturated animals, injected /sup 59/Fe was removed with a half-time of <30 s. Analysis of the distribution of /sup 59/Fe in serum samples by polyacrylamide gel electrophoresis demonstrated the presence of /sup 59/Fe not bound to transferrin. These results demonstrate the existence of and uptake system for non-transferrin-bound iron. These observations support the hypothesis that parenchymal iron overload is consequence of reduced concentrations of apotransferrin.

  2. Heme carrier protein 1 (HCP1) genetic variants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study participants

    PubMed Central

    Wang, XinJing; Leiendecker-Foster, Catherine; Acton, Ronald T.; Barton, James C.; McLaren, Christine E.; McLaren, Gordon D.; Gordeuk, Victor R.; Eckfeldt, John H.

    2009-01-01

    Heme carrier protein 1 (HCP1) has been identified as a possible heme carrier by in vitro analysis. To determine the association of mutations within the HCP1 gene with iron phenotypes, we examined the entire coding region of the HCP1 gene in 788 US and Canadian participants selected from the Hemochromatosis and Iron Overload Screening (HEIRS) Study using denaturing high-performance liquid chromatography. We sequenced the exon and flanking intronic regions if variants were detected. We tested 298 non-C282Y homozygotes from four racial/ethnic backgrounds (White, Black, Asian, and Hispanic) selected because they had high serum ferritin (SF) and transferrin saturations (TS). As controls, we chose 300 other random participants of the same racial/ethnic backgrounds from the same geographic locations. From the 333 HEIRS Study C282Y homozygotes, we selected 75 based on high SF and TS, 75 based on low SF and TS; 75 were selected randomly as controls. Thirty-five of the randomly selected C282Y homozygotes were also included in the high and the low SF and TS groups due to numerical limitations. We identified eight different HCP1 genetic variants; each occurred in a heterozygous state. Except one, each was found in a single HEIRS Study participant. Thus, HCP1 variants are infrequent in the populations that we tested. Five HEIRS Study participants had non-synonymous, coding region HCP1 variants. Each of these five had TS above the 84th gender- and ethnic/racial group-specific percentile (TS percentiles: 84.7, 91.3, 97.9, 99.5, and 99.9). PMID:19176287

  3. Course of iron parameters in HFE-hemochromatosis patients during initial treatment with erythrocytapheresis compared to phlebotomy.

    PubMed

    Rombout-Sestrienkova, Eva; Koek, Ger H; Neslo, Rabin; van Kraaij, Marian; Menheere, Paul P; Masclee, Ad; Swinkels, Dorine W

    2016-12-01

    Current treatment for newly diagnosed patients with hereditary hemochromatosis (HH) and iron overload consist of weekly phlebotomy or less frequent and more personalized erythrocytapheresis. Previous observations during phlebotomy suggest an increase in intestinal iron uptake caused by lowering of hepcidin as a result of intensive bloodletting. It is not known whether such an effect is present or even more pronounced using erythrocytapheresis since a larger amount of iron is extracted per procedure. In this study we aimed to assess the effect of erythrocytapheresis on the course of iron parameters, with special focus on serum hepcidin. We performed a retrospective proof-of-principle observational study, comparing serum iron parameters in 12 males during the depletion phase using either phlebotomy (n = 6) or erythrocytapheresis (n = 6). Decreases in serum ferritin over time were similar for both treatments but more pronounced using erythrocytapheresis when expressed per treatment procedure. Hemoglobin did not change during erythrocytapheresis, whereas during phlebotomy decreased with 10%. Increase of erythropoietin and soluble transferrin receptor and decrease in transferrin saturation were similar for both treatments. Reduction in serum hepcidin was higher (50% versus 25% of initial value) and occurred more early using phlebotomy (10 versus 20 weeks after start). In aggregate, compared to phlebotomy, the less frequent and more personalized erythrocytapheresis leads to a more pronounced decrease in serum ferritin per treatment procedure, without a larger decrease in serum hepcidin. This may be clinically relevant and may prevent an increase in intestinal iron uptake and an ensuing vicious circle of more frequent treatment procedures. J. Clin. Apheresis 31:564-570, 2016. © 2015 Wiley Periodicals, Inc.

  4. Effects of hemochromatosis and transferrin gene mutations on peripheral iron dyshomeostasis in mild cognitive impairment and Alzheimer's and Parkinson's diseases

    PubMed Central

    Mariani, S.; Ventriglia, M.; Simonelli, I.; Spalletta, G.; Bucossi, S.; Siotto, M.; Assogna, F.; Melgari, J. M.; Vernieri, F.; Squitti, R.

    2013-01-01

    Deregulation of iron metabolism has been observed in patients with neurodegenerative diseases. We have carried out a molecular analysis investigating the interaction between iron specific gene variants [transferrin (TF, P589S), hemochromatosis (HFE) C282Y and (H63D)], iron biochemical variables [iron, Tf, ceruloplasmin (Cp), Cp:Tf ratio and % of Tf saturation (% Tf-sat)] and apolipoprotein E (APOE) gene variants in 139 Alzheimer's disease (AD), 27 Mild Cognitive Impairment (MCI), 78 Parkinson's disease (PD) patients and 139 healthy controls to investigate mechanisms of iron regulation or toxicity. No difference in genetic variant distributions between patients and controls was found in our Italian sample, but the stratification for the APOEε4 allele revealed that among the APOEε4 carriers was higher the frequency of those carriers of at least a mutated TF P589S allele. Decreased Tf in both AD and MCI and increased Cp:Tf ratio in AD vs. controls were detected. A multinomial logistic regression model revealed that increased iron and Cp:Tf ratio and being man instead of woman increased the risk of having PD, that increased values of Cp:Tf ratio corresponded to a 4-fold increase of the relative risk of having MCI, while higher Cp levels were protective for PD and MCI. Our study has some limitations: the small size of the samples, one ethnic group considered, the rarity of some alleles which prevent the statistical power of some genetic analysis. Even though they need confirmation in larger cohorts, our data suggest the hypothesis that deregulation of iron metabolism, in addition to other factors, has some effect on the PD disease risk. PMID:23935582

  5. Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

    PubMed

    Agudo, Antonio; Bonet, Catalina; Sala, Núria; Muñoz, Xavier; Aranda, Núria; Fonseca-Nunes, Ana; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie Christine; Vineis, Paolo; Panico, Salvatore; Palli, Domenico; Tumino, Rosario; Grioni, Sara; Quirós, J Ramón; Molina, Esther; Navarro, Carmen; Barricarte, Aurelio; Chamosa, Saioa; Allen, Naomi E; Khaw, Kay-Tee; Bueno-de-Mesquita, H Bas; Siersema, Peter D; Numans, Mattijs E; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Kaaks, Rudof; Canzian, Federico; Boeing, Heiner; Meidtner, Karina; Johansson, Mattias; Sund, Malin; Manjer, Jonas; Overvad, Kim; Tjonneland, Anne; Lund, Eiliv; Weiderpass, Elisabete; Jenab, Mazda; Fedirko, Veronika; Offerhaus, G Johan A; Riboli, Elio; González, Carlos A; Jakszyn, Paula

    2013-06-01

    Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03-1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16-2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27-2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.

  6. Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in Native Americans and whites in the Hemochromatosis and Iron Overload Screening Study.

    PubMed

    Barton, J C; Acton, R T; Lovato, L; Speechley, M R; McLaren, C E; Harris, E L; Reboussin, D M; Adams, P C; Dawkins, F W; Gordeuk, V R; Walker, A P

    2006-01-01

    We compared initial screening transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes of 645 Native American and 43,453 white Hemochromatosis and Iron Overload Screening Study participants who did not report a previous diagnosis of hemochromatosis or iron overload. Elevated measurements were defined as TfSat >50% in men and >45% in women and SF >300 ng/ml in men and >200 ng/ml in women. Mean TfSat was 31% in Native American men and 32% in white men (p = 0.0337) and 25% in Native American women and 27% in white women (p < 0.0001). Mean SF was 153 microg/l in Native American and 151 microg/l in white men (p = 0.8256); mean SF was 55 microg/l in Native American women and 63 microg/l in white women (p = 0.0015). The C282Y allele frequency was 0.0340 in Native Americans and 0.0683 in whites (p < 0.0001). The H63D allele frequency was 0.1150 in Native Americans and 0.1532 in whites (p = 0.0001). We conclude that the screening TfSat and SF phenotypes of Native Americans are similar to those of whites. The allele frequencies of HFE C282Y and H63D are significantly lower in Native Americans than in whites.

  7. Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy.

    PubMed

    Grootveld, M; Bell, J D; Halliwell, B; Aruoma, O I; Bomford, A; Sadler, P J

    1989-03-15

    The nature of non-transferrin-bound iron in the plasma or serum of iron-overloaded hemochromatosis patients was studied by high performance liquid chromatography (HPLC) and high resolution nuclear magnetic resonance (NMR). 500-MHz proton Hahn spin-echo NMR spectra of plasma or serum, combined with the use of the iron chelator desferrioxamine, suggests complexation of iron ions with citrate and a possible involvement of acetate. Addition of FeCl3 to hemochromatosis samples broadened the NMR signals from citrate. HPLC analysis rigorously confirmed the presence of an iron-citrate complex in ultrafiltrates of plasma or serum studies with added FeCl3 or desferrioxamine supported this conclusion. It is proposed that non-transferrin-bound iron in the plasma of iron-overloaded patients exists largely as complexes with citrate and possibly also as ternary iron-citrate-acetate complexes. The presence of such complexes would account for the ability of non-transferrin-bound iron to be measurable by the bleomycin assay and for its rapid clearance from the circulation by the liver.

  8. Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis

    PubMed Central

    Fleming, Robert E.; Migas, Mary C.; Holden, Christopher C.; Waheed, Abdul; Britton, Robert S.; Tomatsu, Shunji; Bacon, Bruce R.; Sly, William S.

    2000-01-01

    Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite down-regulation of the classical transferrin receptor (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-length murine EST encoding the mouse orthologue of the human TfR2. Although homologous to murine TfR in the coding region, the TfR2 transcript does not contain the iron-responsive elements found in the 3′ untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models of dietary iron overload (2% carbonyl iron), dietary iron deficiency (gastric parietal cell ablation), and HH (HFE −/−). Northern blot analyses demonstrated distinct tissue-specific patterns of expression for TfR and TfR2, with TfR2 expressed highly only in liver where TfR expression is low. In situ hybridization demonstrated abundant TfR2 expression in hepatocytes. In contrast to TfR, TfR2 expression in liver was not increased in iron deficiency. Furthermore, hepatic expression of TfR2 was not down-regulated with dietary iron loading or in the HFE −/− model of HH. From these observations, we propose that TfR2 allows continued uptake of Tf-bound iron by hepatocytes even after TfR has been down-regulated by iron overload, and this uptake contributes to the susceptibility of liver to iron loading in HH. PMID:10681454

  9. Potential Nonresponse Bias in a Clinical Examination After Initial Screening Using Iron Phenotyping and HFE Genotyping in the Hemochromatosis and Iron Overload Screening Study

    PubMed Central

    Barton, James C.; Passmore, Leah; Harrison, Helen; Reboussin, David M.; Harris, Emily L.; Rivers, Charles A.; Fadojutimi-Akinsiku, Margaret; Wenzel, Lari; Diaz, Sharmin

    2009-01-01

    Background: Little is known about the factors affecting participation in clinical assessments after HEmochromatosis and IRon Overload Screening. Methods: Initial screening of 101,168 primary care patients in the HEmochromatosis and IRon Overload Screening study was performed using serum iron measures and hemochromatosis gene (HFE) genotyping. Using iron phenotypes and HFE genotypes, we identified 2256 cases and 1232 controls eligible to participate in a clinical examination. To assess the potential for nonresponse bias, we compared the sociodemographic, health status, and attitudinal characteristics of participants and nonparticipants using adjusted odds ratios (ORs) and 95% confidence interval (CI). Results: Overall participation was 74% in cases and 52% in controls; in both groups, participation was highest at a health maintenance organization and lowest among those under 45 years of age (cases: OR = 0.68; 95% CI 0.53, 0.87; controls: OR = 0.59; 95% CI 0.44, 0.78). In controls only, participation was also lower among those over 65 years of age than the reference group aged 46–64 (OR = 0.64; 95% CI 0.47, 0.88). Among cases, participation was higher in HFE C282Y homozygotes (OR = 3.98; 95% CI 2.60, 6.09), H63D homozygotes (OR = 2.79; 95% CI 1.23, 6.32), and C282Y/H63D compound heterozygotes (OR = 1.82; 95% CI 1.03, 3.22) than in other genotypes, and lower among non-Caucasians and those who preferred a non-English language than in Caucasians and those who preferred English (p < 0.0001). Conclusions: Subjects with greatest risk to have iron overload (C282Y homozygotes; cases ≥45 years; Caucasians) were more likely to participate in a postscreening clinical examination than other subjects. We detected no evidence of strong selection bias. PMID:19860558

  10. Effect of Hereditary Hemochromatosis Gene H63D and C282Y Mutations on Iron Overload in Sickle Cell Disease Patients

    PubMed Central

    Terzi, Yunus Kasım; Bulakbaşı Balcı, Tuğçe; Boğa, Can; Koç, Zafer; Yılmaz Çelik, Zerrin; Özdoğu, Hakan; Karakuş, Sema; Şahin, Feride İffet

    2016-01-01

    Objective: Hemochromatosis is an autosomal recessive disease that is one of the most important reasons for iron overload. Sickle cell disease is a hemoglobinopathy that occurs as a result of a homozygous mutation in the hemoglobin gene. Erythrocyte transfusion is frequently used in the treatment of this disease. Iron overload as a result of transfusion is important in the mortality and morbidity of sickle cell anemia patients as well as in other hemoglobinopathies. In this study, the effect of hemochromatosis gene (HFE) p.H63D and p.C282Y mutations on transfusion-related cardiac and liver iron overload in sickle cell disease patients who carry homozygous hemoglobin S mutation has been investigated. Materials and Methods: This is a prospective single-center cross-sectional study in patients with homozygous hemoglobin S mutation between the years 2008 and 2013. The patients were divided into two groups. The first group (group A, n=31) was receiving chelation therapy and the second group (group B, n=13) was not. Direct and indirect iron loads were analyzed by magnetic resonance imaging and biochemically, respectively. HFE gene mutations were analyzed by polymerase chain reaction-restriction fragment length polymorphism method. Statistical analyses were performed by independent samples t-test. Results: p.H63D mutation was detected in 10 (32.3%) patients in group A and in only 1 patient (7.7%) in group B. When the 2 groups were compared for iron overload, iron deposition in the liver was significantly higher in group B (p=0.046). In addition, in group A, iron deposition was significantly higher in HFE mutation carriers compared to patients without the mutation (p=0.05). Conclusion: Results of this study showed that HFE gene mutations are important in iron deposition in the liver in patients with sickle cell disease. PMID:27095682

  11. Iron, copper, zinc and bromine mapping in cirrhotic liver slices from patients with hemochromatosis studied by microscopic synchrotron radiation X-ray fluorescence analysis in continuous scanning mode

    NASA Astrophysics Data System (ADS)

    Osterode, W.; Falkenberg, G.; Höftberger, R.; Wrba, F.

    2007-07-01

    Iron (Fe) and copper (Cu) are essential metals in physiological cell metabolism. While Fe is easy to determine biochemically in histological slices, Cu and zinc (Zn) distribution is frequently critical in confirming the presence of an overload in disturbed Fe/Cu metabolism. To analyze Fe, Cu and Zn in a near histological resolution, energy dispersive microscopic synchrotron radiation X-ray fluorescence was applied. In normal liver tissue, after fixation and imbedding in paraffin, mean Fe, Cu and Zn concentrations were 152 ± 54, 20.1 ± 4.3 and 88.919.5 μg/g sample weight, respectively. No substantial, characteristic differences in their distribution were found in the two-dimensional scans. In slices from patients with hemochromatosis mean Fe, Cu and Zn concentrations were 1102 ± 539, 35.9 ± 14.6 and 27.2 ± 6.7 μg/g sample weight, respectively. Additionally, a significant decrease in phosphorus and sulphur concentrations existed. An increased Cu around cirrhotic regenerations nodules is mostly associated with a lymphocytic infiltration in this region. Analyzing concentrations of Fe in different regions of the samples show a clear negative dependency between Fe and Cu, Cu and Zn, but a positive one between Fe and Zn. Conclusion: With a focal beam size of 15 μm in diameter a resolution of the elemental distribution was achieved which is widely comparable with stained histological slices (20× light microscope). The analysis of simultaneous determined elements reveals metabolic differences between Fe, Cu and Zn in liver tissue from patients with hemochromatosis.

  12. How Is Hemochromatosis Diagnosed?

    MedlinePlus

    ... they started and their severity. Whether you take iron (pills or injections) with or without vitamin C supplements (vitamin C helps your body absorb iron from food). If so, your doctor may ask ...

  13. Hereditary Hemochromatosis (For Parents)

    MedlinePlus

    ... defect or a health problem that affects iron absorption, such as alcohol abuse or hepatitis , an inflammation ... oolong teas have tannins, which help reduce iron absorption. (Herbal teas won't help because they don' ...

  14. The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: a mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis.

    PubMed

    Evers, Dorothea; Kerkhoffs, Jean-Louis; Van Egmond, Liane; Schipperus, Martin R; Wijermans, Pierre W

    2014-06-01

    Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE.

  15. Hereditary hemochromatosis type 1 phenotype modifiers in Italian patients. The controversial role of variants in HAMP, BMP2, FTL and SLC40A1 genes.

    PubMed

    Radio, Francesca Clementina; Majore, Silvia; Aurizi, Caterina; Sorge, Fiammetta; Biolcati, Gianfranco; Bernabini, Sara; Giotti, Irene; Torricelli, Francesca; Giannarelli, Diana; De Bernardo, Carmelilia; Grammatico, Paola

    2015-06-01

    Hereditary hemochromatosis (HH) is a heterogeneous disorder of iron metabolism. The most common form of the disease is Classic or type 1 HH, mainly caused by a biallelic missense p.Cys282Tyr (c.845G>A) mutation in the HFE gene. However, the penetrance of p.Cys282Tyr/p.Cys282Tyr genotype is incomplete in terms of both biochemical and clinical expressivity. Lack of penetrance is thought to be caused by several genetic and environmental factors. Recently, a lot of evidences on HH genetic modifiers were produced, often without conclusive results. We investigated 6 polymorphisms (rs10421768 in HAMP gene, rs235756 in BMP2 gene, rs2230267 in FTL gene, rs1439816 in SLC40A1 gene, rs41295942 in TFR2 gene and rs2111833 in TMPRSS6 gene) with uncertain function in order to further evaluate their role in an independent cohort of 109 HH type 1 patients. Our results make it likely the role of rs10421768, rs235756, rs2230267 and rs1439816 polymorphisms, respectively in HAMP, BMP2, FTL and SLC40A1 genes in HH expressivity. In addition, previous and our findings support a hypothetical multifactorial model of HH, characterized by a principal gene (HFE in HH type 1) and minor genetic and environmental factors that still have to be fully elucidated.

  16. Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain).

    PubMed

    Ropero, Paloma; Briceño, Olga; Mateo, Marta; Polo, Marta; Mora, Asunción; González, Fernando Ataulfo; Villegas, Ana

    2006-05-01

    For centuries in Europe, population movements have contributed to ethnic groups, cultures, and consequently, inheritance mixing. There are certain genetic diseases such as hereditary hemochromatosis whose distribution is directly related to the population movements. The objective of the present investigation was to determine the C282Y and H63D mutation frequency of the HFE gene in a cohort study of 1,000 neonates in the Community of Madrid (Spain), thus contributing to the HFE gene mutations distribution research in Europe and establishing the origin of the mutations in Spain. The allelic frequency of C282Y mutation was 1.7% (CI 95% 1.1-2.3) and the H63D allele was present in 16.4% of chromosomes (CI 95% 14.8-18). In Spain, the presence of C282Y mutation and its distribution could be due more to Celtic than to Viking legacy, whereas it is assumed that the one in relation to the H63D variant occurred in the Basque Country during the Paleolithic Period.

  17. Percutaneous excretion of iron and ferritin (through Al-hijamah) as a novel treatment for iron overload in beta-thalassemia major, hemochromatosis and sideroblastic anemia.

    PubMed

    El Sayed, Salah Mohamed; Abou-Taleb, Ashraf; Mahmoud, Hany Salah; Baghdadi, Hussam; Maria, Reham A; Ahmed, Nagwa Sayed; Nabo, Manal Mohamed Helmy

    2014-08-01

    Iron overload is a big challenge when treating thalassemia (TM), hemochromatosis and sideroblastic anemia. It persists even after cure of TM with bone marrow transplantation. Iron overload results from increased iron absorption and repeated blood transfusions causing increased iron in plasma and interstitial fluids. Iron deposition in tissues e.g. heart, liver, endocrine glands and others leads to tissue damage and organ dysfunction. Iron chelation therapy and phlebotomy for iron overload have treatment difficulties, side effects and contraindications. As mean iron level in skin of TM patients increases by more than 200%, percutaneous iron excretion may be beneficial. Wet cupping therapy (WCT) is a simple, safe and economic treatment. WCT is a familiar treatment modality in some European countries and in Chinese hospitals in treating different diseases. WCT was reported to clear both blood plasma and interstitial spaces from causative pathological substances (CPS). Standard WCT method is Al-hijamah (cupping, puncturing and cupping, CPC) method of WCT that was reported to clear blood and interstitial fluids better than the traditional WCT (puncturing and cupping method, PC method of WCT). In other word, traditional WCT may be described as scarification and suction method (double S technique), while Al-hijamah may be described as suction, scarification and suction method (triple S technique). Al-hijamah is a more comprehensive treatment modality that includes all steps and therapeutic benefits of traditional dry cupping therapy and WCT altogether according to the evidence-based Taibah mechanism (Taibah theory). During the first cupping step of Al-hijamah, a fluid mixture is collected inside skin uplifting due to the effect of negative pressure inside sucking cups. This fluid mixture contains collected interstitial fluids with CPS (iron, ferritin and hemolyzed RBCs in thalassemia), filtered fluids (from blood capillaries) with iron and hemolyzed blood cells (hemolyzed

  18. Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood.

    PubMed

    Kayaalti, Zeliha; Kaya-Akyüzlü, Dilek; Söylemez, Esma; Söylemezoğlu, Tülin

    2015-07-01

    Human hemochromatosis protein (HFE), a major histocompatibility complex class I-like integral membrane protein, participates in the down regulation of intestinal iron absorption by binding to transferrin receptor (TR). HFE competes with transferrin-bound iron for the TR and thus reduces uptake of iron into cells. On the other hand, a lack of HFE increases the intestinal absorption of iron similarly to iron deficiency associated with increasing in absorption and deposition of lead. During pregnancy, placenta cannot prevent transfer lead to the fetus; even low-level lead poisoning causes neurodevelopmental toxicity in children. The aim of this study was to determine the association between the maternal HFE H63D single-nucleotide polymorphism and lead levels in placental tissue, maternal blood and umbilical cord bloods. The study population comprised 93 mother-placenta pairs. Venous blood from mother was collected to investigate lead levels and HFE polymorphism that was detected by standard PCR-RFLP technique. Cord bloods and placentas were collected for lead levels which were analyzed by dual atomic absorption spectrometer system. The HFE H63D genotype frequencies of mothers were found as 75.3% homozygote typical (HH), 23.6% heterozygote (HD) and 1.1% homozygote atypical (DD). Our study results showed that the placental tissue, umbilical cord and maternal blood lead levels of mothers with HD+DD genotypes were significantly higher than those with HH genotype (p<0.05). The present study indicated for the first time that mothers with H63D gene variants have higher lead levels of their newborn's placentas and umbilical cord bloods.

  19. Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

    SciTech Connect

    Kayaalti, Zeliha; Kaya-Akyüzlü, Dilek; Söylemez, Esma; Söylemezoğlu, Tülin

    2015-07-15

    Human hemochromatosis protein (HFE), a major histocompatibility complex class I-like integral membrane protein, participates in the down regulation of intestinal iron absorption by binding to transferrin receptor (TR). HFE competes with transferrin-bound iron for the TR and thus reduces uptake of iron into cells. On the other hand, a lack of HFE increases the intestinal absorption of iron similarly to iron deficiency associated with increasing in absorption and deposition of lead. During pregnancy, placenta cannot prevent transfer lead to the fetus; even low-level lead poisoning causes neurodevelopmental toxicity in children. The aim of this study was to determine the association between the maternal HFE H63D single-nucleotide polymorphism and lead levels in placental tissue, maternal blood and umbilical cord bloods. The study population comprised 93 mother–placenta pairs. Venous blood from mother was collected to investigate lead levels and HFE polymorphism that was detected by standard PCR–RFLP technique. Cord bloods and placentas were collected for lead levels which were analyzed by dual atomic absorption spectrometer system. The HFE H63D genotype frequencies of mothers were found as 75.3% homozygote typical (HH), 23.6% heterozygote (HD) and 1.1% homozygote atypical (DD). Our study results showed that the placental tissue, umbilical cord and maternal blood lead levels of mothers with HD+DD genotypes were significantly higher than those with HH genotype (p<0.05). The present study indicated for the first time that mothers with H63D gene variants have higher lead levels of their newborn's placentas and umbilical cord bloods. - Highlights: • Mothers with H63D gene variants have higher lead levels of their newborn's umbilical cord blood. • Unborn child of women with HD+DD genotypes may be at increased risk of internal exposure to lead. • Maternal HFE status may have an effect on increased placenta, maternal and cord blood lead levels. • Maternal HFE

  20. Bivariate mixture modeling of transferrin saturation and serum ferritin concentration in Asians, African Americans, Hispanics, and whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

    PubMed Central

    Mclaren, Christine E.; Gordeuk, Victor R.; Chen, Wen-Pin; Barton, James C.; Acton, Ronald T.; Speechley, Mark; Castro, Oswaldo; Adams, Paul C.; Snively, Beverly M.; Harris, Emily L.; Reboussin, David M.; Mclachlan, Geoffrey J.; Bean, Richard

    2013-01-01

    Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43–82 μg/L for women, 165–242 μg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 μg/L for women (<47 μg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9–47.5 for women, 60.6–3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4–1.8 for women, 1.2–1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement. PMID:18201677

  1. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.

    PubMed

    Cotter, P D; May, A; Li, L; Al-Sabah, A I; Fitzsimons, E J; Cazzola, M; Bishop, D F

    1999-03-01

    X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband's maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance of HFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

  2. Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.

    PubMed

    Gallego, Carlos J; Burt, Amber; Sundaresan, Agnes S; Ye, Zi; Shaw, Christopher; Crosslin, David R; Crane, Paul K; Fullerton, S Malia; Hansen, Kris; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; de Andrade, Mariza; McCarty, Catherine A; Kitchner, Terrie E; Ragon, Brittany K; Stallings, Sarah C; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E; Aufox, Sharon A; Pacheco, Jennifer A; Patel, Vaibhav; Friesema, Elisha M; Erwin, Angelika Ludtke; Gottesman, Omri; Gerhard, Glenn S; Ritchie, Marylyn; Motulsky, Arno G; Kullo, Iftikhar J; Larson, Eric B; Tromp, Gerard; Brilliant, Murray H; Bottinger, Erwin; Denny, Joshua C; Roden, Dan M; Williams, Marc S; Jarvik, Gail P

    2015-10-01

    Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

  3. Secondary Hemochromatosis due to Chronic Oral Iron Supplementation

    PubMed Central

    Isang, Emmanuel

    2017-01-01

    Iron may accumulate in excess due to a mutation in the HFE gene that upregulates absorption or when it is ingested or infused at levels that exceed the body's ability to clear it. Excess iron deposition in parenchymal tissue causes injury and ultimately organ dysfunction. Diabetes mellitus and hepatic cirrhosis due to pancreas and liver damage are just two examples of diseases that result from iron overload. Despite the rapid growth of information regarding iron metabolism and iron overload states, the most effective treatment is still serial phlebotomies. We present a patient who developed iron overload due to chronic ingestion of oral ferrous sulfate. This case illustrates the importance of querying geriatric patients regarding their use of nonprescription iron products without a medical indication. PMID:28133557

  4. Sensitivity to Radiation-Induced Cancer in Hemochromatosis

    SciTech Connect

    Bull. Richard J.; Anderson, Larry E.

    2000-06-01

    The objectives of this pilot project using HFE-knockout homozygotes and heterozygotes are to (1) determine whether the knock-out mice have greater sensitivity to radiation-induced cancer of the colon, liver and breast, (2) establish the dependence of this sensitivity on the accumulation of iron, (3) determine the extent to which cell replication and apoptosis occur in these target tissues with varying iron load, and (4) correlate the increases in sensitivity with changes in insulin-related signaling in tumors and normal tissue from each target organ. Three experimental designs will be used in the pilot project. The sequence of experiments is designed to first explore the influence of iron load on the response and demonstrate that HFE knockout mice are more sensitive than the wild type to radiation-induced cancer in one or more of three target tissues (liver, colon and breast). The dose response relationships with a broader set of radiation doses will be explored in the second experiment. The final experiment is designed to explore the extent to which heterozygotes display the increased susceptibility to cancer induction and to independently assess the importance of iron load to the initiation versus promotion of tumors.

  5. Towards the isolation of the idiopathic hemochromatosis disease gene

    SciTech Connect

    Chorney, M.J.; Venditti, C.P.; Harris, J.M.

    1994-09-01

    Despite the existence of many useful reagents which exist to aid in the positional cloning of the idiopathic hermochromatosis disease gene (HFE), the nature and precise location of this common genetic disease has remained elusive. Our group has pursued an MHC-based positional cloning approach which has centered on the precise physical definition of HLA-A variant chromosomes. Using deletion breakpoint locations in combination with genetic data derived from the Brittany founder population, we have used cDNA selection techniques to isolate new members of distinct multigene families which reside in the HFE critical region (distal to the HLA-A9 breakpoint/proximal to HLA-F). We have also initiated an independent set of cytogenetic and physical mapping studies to position the marker D6S105 with respect to the telomeric end of the class I subregion. Toward this end, we have performed double labelling FISH experiments which have allowed the localization of D6S105-containing YACs with respect to the HLA-A subregion and to the major G-bands which contain these loci. We have also derived single-copy probes, cosmids and cDNA clones from the region which have been used to create a physical map around D6S105. The combination of the cytogenetic and physical mapping data indicate that D6S105 is at least 2 Mb from HLA-A and that the distal limit of the MHC class I region may extend much further into the the euchromatic region of 6p21.3 than previously expected. A mega-YAC walk is now in progress to link the two loci. Finally, we have identified and characterized a family which is segregating a balanced inversion in phase with HFE. The breakpoint locations of this mutant chromosome may be important in the precise positioning of the HFE gene and attempts to define coding sequences in the proximity of this rearrangement are underway.

  6. Heritability of Serum Iron Measures in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study

    PubMed Central

    McLaren, Christine E.; Barton, James C.; Eckfeldt, John H.; McLaren, Gordon D.; Acton, Ronald T.; Adams, Paul C.; Henkin, Leora F.; Gordeuk, Victor R.; Vulpe, Chris D.; Harris, Emily L.; Harrison, Barbara W.; Reiss, Jacob A.; Snively, Beverly M.

    2013-01-01

    Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation. PMID:20095037

  7. Hypercoagulation

    MedlinePlus

    ... overload, hereditary hemochromatosis, HFE gene, HFE mutations, iron overload, primary hemochromatosis, secondary hemochromatosis Family Health, Kids and Teens, Women September 2000 Copyright © American Academy of Family PhysiciansThis information provides a general overview and may not apply ...

  8. Iron content and acid phosphatase activity in hepatic parenchymal lysosomes of patients with hemochromatosis before and after phlebotomy treatment

    SciTech Connect

    Cleton, M.I.; de Bruijn, W.C.; van Blokland, W.T.; Marx, J.J.; Roelofs, J.M.; Rademakers, L.H.

    1988-03-01

    Lysosomal structures in liver parenchymal cells of 3 patients with iron overload and of 3 subjects without iron-storage disorders were investigated. A combination of enzyme cytochemistry--with cerium as a captive ion to demonstrate lysosomal acid phosphatase activity--and electron probe X-ray microanalysis (EPMA) was used. We were able (1) to define and quantify lysosomal structures as lysosomes, siderosomes, or residual bodies, (2) to quantify the amount of iron and cerium simultaneously in these structures, and (3) to evaluate a possible relation between iron storage and enzyme activity. With histopathologically increased iron storage, the number of siderosomes had increased at the cost of lysosomes, with a corresponding increase in acid phosphatase activity in both organelles. In histopahtologically severe iron overload, however, acid phosphatase activity was low or not detectable and most of the iron was stored in residual bodies. After phlebotomy treatment, the number of siderosomes had decreased in favor of the lysosomes, approaching values obtained in control subjects, and acid phosphatase activity was present in all iron-containing structures. In this way a relationship between iron storage and enzyme activity was established. The iron content of the individual lysosomal structures per unit area had increased with histopathologically increased iron storage and had decreased after phlebotomy treatment. From this observation, it is concluded that the iron status of the patient is not only reflected by the amount of iron-containing hepatocytes but, as well, by the iron content lysosomal unit area.

  9. Frequency of Hereditary Hemochromatosis (HFE) Gene Mutations in Egyptian Beta Thalassemia Patients and its Relation to Iron Overload

    PubMed Central

    Enein, Azza Aboul; El Dessouky, Nermine A.; Mohamed, Khalda S.; Botros, Shahira K.A.; Abd El Gawad, Mona F.; Hamdy, Mona; Dyaa, Nehal

    2016-01-01

    AIM: This study aimed to detect the most common HFE gene mutations (C282Y, H63D, and S56C) in Egyptian beta thalassemia major patients and its relation to their iron status. SUBJECTS AND METHODS: The study included 50 beta thalassemia major patients and 30 age and sex matched healthy persons as a control group. Serum ferritin, serum iron and TIBC level were measured. Detection of the three HFE gene mutations (C282Y, H63D and S65C) was done by PCR-RFLP analysis. Confirmation of positive cases for the mutations was done by sequencing. RESULTS: Neither homozygote nor carrier status for the C282Y or S65C alleles was found. The H63D heterozygous state was detected in 5/50 (10%) thalassemic patients and in 1/30 (3.3%) controls with no statistically significant difference between patients and control groups (p = 0.22). Significantly higher levels of the serum ferritin and serum iron in patients with this mutation (p = 001). CONCLUSION: Our results suggest that there is an association between H63D mutation and the severity of iron overload in thalassemic patients. PMID:27335591

  10. Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbbth3/+ (heterozygous b1/b2 globin gene deletion) mice

    PubMed Central

    Gelderman, Monique P.; Baek, Jin Hyen; Yalamanoglu, Ayla; Puglia, Michele; Vallelian, Florence; Burla, Bo; Vostal, Jaroslav; Schaer, Dominik J.; Buehler, Paul W.

    2015-01-01

    Intermediate beta-thalassemia has a broad spectrum of sequelae and affected subjects may require occasional blood transfusions over their lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron in plasma. The iron scavenger and transport protein transferrin is a potential treatment being studied for correction of anemia. However, transferrin may also function to prevent or reduce iron loading of tissues when exposure to non-transferrin bound iron increases. Here we evaluate the effects of apotransferrin administration on tissue iron loading and early tissue pathology in non-transfused and transfused Hbbth3/+ mice. Mice with the Hbbth3/+ phenotype have mild to moderate anemia and consistent tissue iron accumulation in the spleen, liver, kidneys and myocardium. Chronic apotransferrin administration resulted in normalization of the anemia. Furthermore, it normalized tissue iron content in the liver, kidney and heart and attenuated early tissue changes in non-transfused Hbbth3/+ mice. Apotransferrin treatment was also found to attenuate transfusion-mediated increases in plasma non-transferrin bound iron and associated excess tissue iron loading. These therapeutic effects were associated with normalization of transferrin saturation and suppressed plasma non-transferrin bound iron. Apotransferrin treatment modulated a fundamental iron regulatory pathway, as evidenced by decreased erythroid Fam132b gene (erythroferrone) expression, increased liver hepcidin gene expression and plasma hepcidin-25 levels and consequently reduced intestinal ferroportin-1 in apotransferrin-treated thalassemic mice. PMID:25616571

  11. Structure-function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues.

    PubMed

    Le Gac, Gérald; Ka, Chandran; Joubrel, Rozenn; Gourlaouen, Isabelle; Lehn, Pierre; Mornon, Jean-Paul; Férec, Claude; Callebaut, Isabelle

    2013-10-01

    Ferroportin (SLC40A1) is the only known iron exporter in mammals and is considered a key coordinator of the iron balance between intracellular and systemic iron homeostasis. However, the structural organization of ferroportin in the lipid bilayer remains controversial and very little is known about the mechanism underlying iron egress. In the present study, we have developed an approach based on comparative modeling, which has led to the construction of a model of the three-dimensional (3D) structure of ferroportin by homology to the crystal structure of a Major Facilitator Superfamily member (EmrD). This model predicts atomic details for the organization of ferroportin transmembrane helices and is in agreement with our current understanding of the ferroportin function and its interaction with hepcidin. Using in vitro experiments, we demonstrate that this model can be used to identify novel critical amino acids. In particular, we show that the tryptophan residue 42 (p.Trp42), which is localized within the extracellular end of the ferroportin pore, is likely involved in both the iron export function and in the mechanism of inhibition by hepcidin. Thus, our 3D model provides a new perspective for understanding the molecular basis of ferroportin functions and dysfunctions.

  12. Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African-Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

    PubMed Central

    Rivers, Charles A.; Barton, James C.; Gordeuk, Victor R.; Acton, Ronald T.; Speechley, Mark R.; Snively, Beverly M.; Leiendecker-Foster, Catherine; Press, Richard D.; Adams, Paul C.; McLaren, Gordon D.; Dawkins, Fitzroy W.; McLaren, Christine E.; Reboussin, David M.

    2007-01-01

    The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥300 μg/L in men and ≥200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P = 0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P = 0.047); corresponding differences were not observed among women. This appeared to be unrelated to self-reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P = 0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF. PMID:17276706

  13. Effect of Hereditary Hemochromatosis Gene H63D and C282Y Mutations on Iron Overload in Sickle Cell Disease Patients.

    PubMed

    Terzi, Yunus Kasım; Bulakbaşı Balcı, Tuğçe; Boğa, Can; Koç, Zafer; Yılmaz Çelik, Zerrin; Özdoğu, Hakan; Karakuş, Sema; Şahin, Feride İffet

    2016-12-01

    Amaç: Hemokromatozis, demir birikiminin önemli nedenlerinden biri olan otozomal resesif bir hastalıktır. Orak hücreli anemi, hemoglobin genindeki homozigot mutasyon sonucu ortaya çıkan bir hemoglobinopatidir. Eritrosit transfüzyonu, bu hastalığın tedavisinde sıklıkla kullanılmaktadır. Transfüzyonun yarattığı demir yükü diğer hemoglobinopatilerde olduğu gibi orak hücreli anemi hastalarının mortalite ve morbiditesinde önem kazanmaktadır. Bu çalışmada hemokromatozis geni (HFE) p.H63D ve p.C282Y mutasyonlarının, homozigot hemoglobin S mutasyonu taşıyan orak hücreli anemi hastalarında, kalp ve karaciğerde transfüzyonla ilişkili demir yüklenmesine olan etkisi araştırılmıştır. Gereç ve Yöntemler: Bu çalışma, homozigot hemoglobin S mutasyonu olan hastalarda 2008-2013 yıllarını kapsayan prospektif, tek merkezli kesitsel bir çalışmadır. Hastalar şelasyon tedavisi alan (n=31) ve almayan (n=13) olarak iki gruba ayrıldı. Hastalarda direk ve endirekt demir yükü sırasıyla manyetik rezonans görüntüleme ve biyokimyasal olarak analiz edildi. HFE geni mutasyon analizi polimeraz zincir reaksiyonu-restriksiyon fragment uzunluk polimorfizmi yöntemleri ile gerçekleştirildi. İstatistik analizi Independent samples t-testi uygulanarak gerçekleştirildi. Bulgular: p.H63D mutasyonu grup A’da 10 hastada (%32,3), grup B’de ise sadece 1 (%7,7) hastada saptandı. Demir birikimi açısından gruplar karşılaştırıldığında karaciğerde demir birikiminin grup B’de istatistiksel olarak anlamlı derecede yüksek olduğu görülmüştür (p<0,05). Grup A’da, mutasyonu olan bireylerde olmayanlara göre karaciğerdeki demir birikiminin istatistiksel olarak anlamlı derecede yüksek olduğu görülmüştür (p=0,05). Sonuç: Bu çalışmanın sonucu HFE genindeki mutasyonların, orak hücreli anemi hastalarında karaciğerde demir birikimi üzerinde etkili olduğunu göstermektedir.

  14. Non HFE related hereditary haemochromatosis.

    PubMed

    Sharma, S K; Mangudkar, Sangram; Rathod, Mehul; Verma, Amrita; Phanikumar, R L V; Garg, Subodh; Dhakne, Ajinkya; Barure, Ramdas

    2014-03-01

    Hereditary hemochromatosis (HH) is manifested as iron overload in different organs due to homozygosity of a single autosomal mutation. Two different mutations C282Y and H63D in the HFE gene have been associated with hereditary hemochromatosis cases. This disease is seen in northern european populations, but in India it is a rare disease. We report a young male with severe abnormalty of liver functions due to Non HFE related Hereditary Hemochromatosis.

  15. Early Detection of Breast Cancer via Multiplane Correlation Breast Imaging

    DTIC Science & Technology

    2007-04-01

    survival rates of patients through early diagnosis. Additionally, disorders such as hemochromatosis (liver iron overload associated with...34 Curr Opin Hematol, vol. 4, pp. 436-41, 1997. [15] L. W. Powell and K. J. Isselbacher, " Hemochromatosis ," in Harrison’s Principles of Internal...Medicine: McGraw-Hill. [16] L. W. Powell, "Diagnosis of hemochromatosis ," Semin Gastrointest Dis, vol. 13, pp. 80-8, 2002. [17] L. W. Powell, D. K

  16. Examination of HFE C282Y/H63D Heterozygotes as a Potential Human Modeling System for Low Level Liver Damage

    DTIC Science & Technology

    2001-03-01

    NOTES Poster Presentation at the Society of Toxicology, San Diego CA, March 2006 14. ABSTRACT Individuals heterozygous for hemochromatosis gene (HFE...Wright Patterson AFB, OH USA 288 MDOS/SGOPC, Wright-Patterson AFB, OH, U.S.A. Abstract Individuals heterozygous for hemochromatosis gene (HFE) mutations...heterzygtote samples in sub-clinical human liver dysfunction modeling. Introduction Hereditary hemochromatosis (HHC) is an autosomal recessive disorder that

  17. Hormone Replacement Therapy, Iron, and Breast Cancer

    DTIC Science & Technology

    2004-11-01

    accumulates due to the mutation of the HFE gene ( hemochromatosis EeJ, iron elevated in the mouse body mimics the post-menopausal condition. In the present...model. Since iron slowly accumulates due to the mutation of the HFE gene ( hemochromatosis Fe), iron elevated in the mouse body mimics the post...94:606-16(2002). Bahram S, Gilfillan S, Kuhn LC, Moret R, Schulze JB, Lebeau A, Schumann K. Experimental hemochromatosis due to MHC class I HFE

  18. Identification, Biochemical Effects and Molecular Determinants of Iron Toxicity in a Military Setting

    DTIC Science & Technology

    2003-08-02

    Hemochromatosis is a disorder that has both a long and short history. While many individuals have been affected over time, it has only been recently...that clinical diagnosis has been possible. Hemochromatosis is an autosomal recessive disorder. There are numerous autosomal recessive disorders. Some...can make the diagnosis of hemochromatosis especially troublesome. In all but the very late stages of the disorder, the only way for diagnosis to

  19. 21 CFR 862.1410 - Iron (non-heme) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... characterized by pigmentation of the skin), and chronic renal disease. (b) Classification. Class I. ... diagnosis and treatment of diseases such as iron deficiency anemia, hemochromatosis (a disease...

  20. Primary Biliary Cholangitis (Primary Biliary Cirrhosis)

    MedlinePlus

    ... Liver Disease & NASH Definition & Facts Symptoms & Causes Diagnosis Treatment Eating, Diet, & Nutrition Clinical Trials Biliary Atresia Cirrhosis Hemochromatosis Hepatitis A through E (Viral Hepatitis) Hepatitis ...

  1. Biochemical Markers of Brain Injury: An Integrated Proteomics-Based Approach

    DTIC Science & Technology

    2005-02-01

    norvegicus] 36 13-- 17 NM_000410 hemochromatosis protein 1 [Homo sapiens] 10 35 -- 50 NM_017025 lactate dehydrogenase A [Rattus norvegicus] 36 27 -- 33...4A2 [Mus NM_013506 musculus]. 46 35--50 transferrin; hypotransferrinemia with NM_133977 hemochromatosis [Mus musculus] 77 50 -- 75 NM_003026 SH3

  2. Iron storage disease in tapirs.

    PubMed

    Bonar, Christopher J; Trupkiewicz, John G; Toddes, Barbara; Lewandowski, Albert H

    2006-03-01

    Recent studies of serum iron and iron binding capacity have indicated that tapirs could be at risk of developing hemochromatosis. However, in recent surveys of pathologic findings in tapirs, hemochromatosis was not reported as a cause of death. This study reviews necropsy reports from three species of tapir (Baird's tapir [Tapirus bairdii], Malayan tapir [Tapirus indicus], and Brazilian tapir [Tapirus terrestris]) at the Philadelphia Zoological Garden between 1902 and 1994. Twelve cases of hemosiderosis, including fatal hemochromatosis in two Baird's tapirs, were found among 19 cases examined histologically. Hemochromatosis has previously been reported in the horse, rhinoceros, and in one Brazilian tapir. Dietary factors were investigated but could not be confirmed to have contributed to the incidence of hemosiderosis and hemochromatosis in the three species of tapir in the Philadelphia Zoological Garden collection.

  3. [Genetics of hereditary iron overload].

    PubMed

    Le Gall, Jean-Yves; Jouanolle, Anne-Marie; Fergelot, Patricia; Mosser, Jean; David, Véronique

    2004-01-01

    The classification of hereditary abnormalities of iron metabolism was recently expanded and diversified. Genetic hemochromatosis now corresponds to six diseases, namely classical hemochromatosis HFE 1; juvenile hemochromatosis HFE 2 due to mutations in an unidentified gene on chromosome 1; hemochromatosis HFE 3 due to mutations in the transferrin receptor 2 (TfR2); hemochromatosis HFE 4 caused by a mutation in the H subunit of ferritin; and hemochromatosis HFE 6 whose gene is hepcidine (HAMP). Systemic iron overload is also associated with aceruloplasminemia, atransferrinemia and the "Gracile" syndrome caused by mutations in BCS1L. The genes responsible for neonatal and African forms of iron overload are unknown. Other genetic diseases are due to localized iron overload: Friedreich's ataxia results from the expansion of triple nucleotide repeats within the frataxin (FRDA) gene; two forms of X-linked sideroblastic anemia are due to mutations within the delta aminolevulinate synthetase (ALAS 2) or ABC-7 genes; Hallervorden-Spatz syndrome is caused by a pantothenate kinase 2 gene (PANK-2) defect; neuroferritinopathies; and hyperferritinemia--cataract syndrome due to a mutation within the L-ferritin gene. In addition to this wide range of genetic abnormalities, two other features characterize these iron disorders: 1) most are transmitted by an autosomal recessive mechanism, but some, including hemochromatosis type 4, have dominant transmission; and 2) most correspond to cytosolic iron accumulation while some, like Friedreich's ataxia, are disorders of mitochondrial metabolism.

  4. Hemosiderosis secondary to chronic parenteral iron therapy in maintenance hemodialysis patients.

    PubMed

    Pitts, T O; Barbour, G L

    1978-01-01

    Autopsy data on 24 chronic maintenance hemodialysis patients who had received varying doses of parenteral iron as the iron-dextran complex were reviewed for evidence of iron overload (hemosiderosis) and tissue fibrosis or organ dysfunction (hemochromatosis). Hemosiderosis was frequent in patients who received high total doses of iron but absent in those who received little or no iron. The degree of tissue iron did not increase with increased iron administration above a total of 2.5 g. Hemochromatosis or organ dysfunction secondary to tissue iron deposition was not noted in any patient. Chronic parenteral iron administration may improve anemia and result in tissue iron deposition but does not lead to hemochromatosis.

  5. Skin - abnormally dark or light

    MedlinePlus

    ... Endocrine diseases such as Addison disease Hemochromatosis (iron overload) Sun exposure Pregnancy Causes of hypopigmentation include: Skin ... to achieve this important distinction for online health information and services. Learn more about A.D.A. ...

  6. Genetics Home Reference: X-linked sideroblastic anemia

    MedlinePlus

    ... in hemochromatosis, which is another type of iron overload disorder. Learn more about the genes associated with X-linked sideroblastic anemia ALAS2 HFE Related Information What is a gene? What is a gene ...

  7. TIBC, UIBC and Transferrin

    MedlinePlus

    ... suspected of having either iron deficiency or iron overload. These two tests are used to calculate the ... thus transferrin saturation becomes very low. In iron overload states, such as hemochromatosis , the iron level will ...

  8. LH response to GnRH blood test

    MedlinePlus

    ... in the body ( hemochromatosis ) Eating disorders, such as anorexia Recent significant weight loss, such as after bariatric ... PA: Elsevier Saunders; 2015:chap 116. Read More Anorexia Autoimmune disorders Catecholamine blood test Endocrine glands Estradiol ...

  9. Testicular failure

    MedlinePlus

    ... medicines Diseases that affect the testicle, including hemochromatosis , mumps , orchitis , and testicular cancer Injury or trauma to ... PA: Elsevier Saunders; 2013:chap 44. Read More Mumps Scrotum Substance use Testes Testicular cancer Testicular torsion ...

  10. Iron overload: what is the role of public health?

    PubMed

    Hulihan, Mary M; Sayers, Cindy A; Grosse, Scott D; Garrison, Cheryl; Grant, Althea M

    2011-12-01

    Hereditary hemochromatosis type 1, also known as hereditary hemochromatosis classical (HHC), is an iron overload disorder associated, in most cases, with mutations of the hemochromatosis (HFE) gene. Although suggested algorithms for diagnosing iron overload are available, there are still questions about options for genetic and biochemical screening for hemochromatosis and duration of treatment. This article provides a summary of an expert workgroup meeting convened on September 24-25, 2009, entitled "Iron Overload: What is the Role of Public Health?" The purpose of the meeting was to enable subject matter experts to share their most recent clinical and scientific iron overload information and to facilitate the discussion of future endeavors, with special emphasis on the role of public health in this field. The two main topics were the research priorities of the field, including clinical, genetic, and public health issues, and the concerns about the validity of current screening recommendations for the condition.

  11. HEPATIC IRON STORAGE AND ERYTHROKINETICS AFTER PORTACAVAL SHUNT,

    DTIC Science & Technology

    used in the production of hemoglobin is stored in the liver as hemosiderin. The significance of these findings relative to the reported human cases of hemochromatosis after portal-systemic shunting is discussed. (Author)

  12. Blood Transfusion

    MedlinePlus

    ... notice a decrease in red blood cell levels. Iron overload If you receive multiple blood transfusions, you may end up with too much iron in your blood. Iron overload (hemochromatosis) can damage ...

  13. Anemia

    MedlinePlus

    ... body gets more iron than it needs? Iron overload happens when too much iron builds up in ... heart, and pancreas. Many problems can cause iron overload. Most people with hemochromatosis inherit it from their ...

  14. 21 CFR 866.5340 - Ferritin immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...-storing protein) in serum and other body fluids. Measurements of ferritin aid in the diagnosis of diseases affecting iron metabolism, such as hemochromatosis (iron overload) and iron deficiency amemia....

  15. Idiopathic hemochromotosis and alpha-1-antitrypsin deficiency: coexistence in a family with progressive liver disease in the proband.

    PubMed

    Anand, S; Schade, R R; Bendetti, C; Kelly, R; Rabin, B S; Krause, J; Starzl, T E; Iwatsuki, S; Van Thiel, D H

    1983-01-01

    A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed.

  16. Idiopathic Hemochromotosis and Alpha-1-Antitrypsin Deficiency: Coexistence in a Family with Progressive Liver Disease in the Proband

    PubMed Central

    Anand, Suri; Schade, Robert R.; Bendetti, Carlos; Kelly, Robert; Rabin, Bruce S.; Krause, John; Starzl, Thomas E.; Iwatsuki, Shunzaburo; Van Thiel, David H.

    2010-01-01

    A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed. PMID:6604688

  17. Cardiac iron overload in thalassemic patients: an endomyocardial biopsy study.

    PubMed

    Lombardo, T; Tamburino, C; Bartoloni, G; Morrone, M L; Frontini, V; Italia, F; Cordaro, S; Privitera, A; Calvi, V

    1995-09-01

    Secondary heart failure induced by organ siderosis is the main cause of death in patients affected by thalassemia major. At present it cannot be predicted whether heart siderosis is correlated with iron overload and little is known about the real cardiac histological pattern of post transfusional hemochromatosis in patients with thalassemia major and intermedia. The study aim was to evaluate cardiac iron overload by non invasive and invasive techniques. Fifteen thalassemic patients were investigated and endomyocardial biopsy performed in ten revealed different grades of endomyocardial iron overload with histochemical positivity. Non invasive techniques are not able to furnish an exact picture of the cardiac hemochromatosis. There was a significant correlation between serum ferritin and myocardial iron grade. Patients with elevated ferritin levels and poor compliance to chelating therapy are at high risk of severe heart hemochromatosis. It was seen that endomyocardial biopsy is a useful tool in studying myocardial iron.

  18. HAMP — EDRN Public Portal

    Cancer.gov

    HEPC, also known as HAMP, is involved in the maintenance of iron homeostasis, and it is necessary for the regulation of iron storage in macrophages, and for intestinal iron absorption. The preproprotein is post-translationally cleaved into mature peptides of 20, 22 and 25 amino acids, and these active peptides are rich in cysteines, which form intramolecular bonds that stabilize their beta-sheet structures. These peptides exhibit antimicrobial activity. Mutations in this gene cause hemochromatosis type 2B, also known as juvenile hemochromatosis, a disease caused by severe iron overload that results in cardiomyopathy, cirrhosis, and endocrine failure.

  19. [Unilateral hip arthrosis: expression of joint haemochromatosis].

    PubMed

    Prieto Zancudo, C; Villán Villán, Y F; Tascón Guerra, M F

    2012-10-01

    Hereditary haemochromatosis is the most common genetic disorder in the Caucasian population, with an estimated prevalence of 1/200-1/400 (homozygous) and 1/8-1/10 in carriers (heterozygous). The transmission is recessive and linked to HLA. The clinical expression of disease appears only in homozygous and will depend on the time of diagnosis and the degree of organ involvement. The clinical case presented below describes the process of differential diagnosis made in a young patient with unilateral coxarthrosis and clinical suspicion of hemochromatosis. Early diagnosis of hereditary hemochromatosis in primary care can reduce morbidity and mortality of this disease by detecting homozygous at younger ages.

  20. The Power of Natural Selection: A Guided Investigation of Three Case Studies

    ERIC Educational Resources Information Center

    Beachly, William

    2010-01-01

    I describe a quantitative approach to three case studies in evolution that can be used to challenge college freshmen to explore the power of natural selection and ask questions that foster a deeper understanding of its operation and relevance. Hemochromatosis, the peppered moth, and hominid cranial capacity are investigated with a common algebraic…

  1. 21 CFR 862.1410 - Iron (non-heme) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... intended to measure iron (non-heme) in serum and plasma. Iron (non-heme) measurements are used in the diagnosis and treatment of diseases such as iron deficiency anemia, hemochromatosis (a disease associated... characterized by pigmentation of the skin), and chronic renal disease. (b) Classification. Class I....

  2. A human homologue to the yeast omnipotent suppressor 45 maps 100 kb centromeric to HLA-A

    SciTech Connect

    Chauvel, B.; Dorval, I.; Fergelot, P.

    1995-04-01

    Idipathic hemochromatosis is a common autosomal recessive inherited disorder of iron metabolism. The molecular defect is unknown. However, the gene responsible for the disease (HFE) has been localized on the short arm of chromosome 6. It is closely linked to the HLA class I genes and possibly within a 350 kilobase (kb) region around the HLA-A locus. In order to identify candidate genes for hemochromatosis, we applied a cDNA selection technique to isolate transcribed sequences encoded on yeast artificial chromosomes (YAC). At first, we screened a cDNA library derived from normal human duodenal mucosa with the YAC B30 H3. This YAC contains a 320 kb DNA insert including the HLA-A gene and spanning 150 kb of the 350 kb zone where the hemochromatosis gene is in linkage disequilibrium with restriction fragment length polymorphism (RFLP) markers. Preparation of the cDNA library of duodenal mucosa in Lambda Zap II phage and library screening with YAC B30 were carried out as previously described. In this way, we isolated seven non-HLA-A cDNAs corresponding to seven new genomic sequences. These potential genes were named hemochromatosis candidate gene (HCG) and numbered I to VII. The survey of all these cDNAs and their corresponding genomic sequences is in progress. In this work, we are especially interested in one of the seven non-HLA class I cDNA clones, named clone 58. 12 refs., 2 figs.

  3. Demonstration of iron and thorium in autopsy tissues by x-ray microanalysis

    SciTech Connect

    Landas, S.; Turner, J.W.; Moore, K.C.; Mitros, F.A.

    1984-03-01

    We performed x-ray microanalysis of autopsy specimens using a scanning-transmission electron microscopy mode. Tissues were obtained at necropsy from a patient with history of angiography using thorium dioxide and from a patient with hemochromatosis. X-ray microanalysis confirmed the presence of thorium and iron in their respective tissues. Effects of staining reagents were examined.

  4. Feasibility Study of NMR Based Serum Metabolomic Profiling to Animal Health Monitoring: A Case Study on Iron Storage Disease in Captive Sumatran Rhinoceros (Dicerorhinus sumatrensis)

    PubMed Central

    Watanabe, Miki; Roth, Terri L.; Bauer, Stuart J.; Lane, Adam; Romick-Rosendale, Lindsey E.

    2016-01-01

    A variety of wildlife species maintained in captivity are susceptible to iron storage disease (ISD), or hemochromatosis, a disease resulting from the deposition of excess iron into insoluble iron clusters in soft tissue. Sumatran rhinoceros (Dicerorhinus sumatrensis) is one of the rhinoceros species that has evolutionarily adapted to a low-iron diet and is susceptible to iron overload. Hemosiderosis is reported at necropsy in many African black and Sumatran rhinoceroses but only a small number of animals reportedly die from hemochromatosis. The underlying cause and reasons for differences in susceptibility to hemochromatosis within the taxon remains unclear. Although serum ferritin concentrations have been useful in monitoring the progression of ISD in many species, there is some question regarding their value in diagnosing hemochromatosis in the Sumatran rhino. To investigate the metabolic changes during the development of hemochromatosis and possibly increase our understanding of its progression and individual susceptibility differences, the serum metabolome from a Sumatran rhinoceros was investigated by nuclear magnetic resonance (NMR)-based metabolomics. The study involved samples from female rhinoceros at the Cincinnati Zoo (n = 3), including two animals that died from liver failure caused by ISD, and the Sungai Dusun Rhinoceros Conservation Centre in Peninsular Malaysia (n = 4). Principal component analysis was performed to visually and statistically compare the metabolic profiles of the healthy animals. The results indicated that significant differences were present between the animals at the zoo and the animals in the conservation center. A comparison of the 43 serum metabolomes of three zoo rhinoceros showed two distinct groupings, healthy (n = 30) and unhealthy (n = 13). A total of eighteen altered metabolites were identified in healthy versus unhealthy samples. Results strongly suggest that NMR-based metabolomics is a valuable tool for animal health

  5. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus.

    PubMed

    Arezes, João; Jung, Grace; Gabayan, Victoria; Valore, Erika; Ruchala, Piotr; Gulig, Paul A; Ganz, Tomas; Nemeth, Elizabeta; Bulut, Yonca

    2015-01-14

    Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.

  6. Using skin to assess iron accumulation in human metabolic disorders

    NASA Astrophysics Data System (ADS)

    Guinote, I.; Fleming, R.; Silva, R.; Filipe, P.; Silva, J. N.; Veríssimo, A.; Napoleão, P.; Alves, L. C.; Pinheiro, T.

    2006-08-01

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  7. Label-free detection of DNA hybridization using carbon nanotube network field-effect transistors

    NASA Astrophysics Data System (ADS)

    Star, Alexander; Tu, Eugene; Niemann, Joseph; Gabriel, Jean-Christophe P.; Joiner, C. Steve; Valcke, Christian

    2006-01-01

    We report carbon nanotube network field-effect transistors (NTNFETs) that function as selective detectors of DNA immobilization and hybridization. NTNFETs with immobilized synthetic oligonucleotides have been shown to specifically recognize target DNA sequences, including H63D single-nucleotide polymorphism (SNP) discrimination in the HFE gene, responsible for hereditary hemochromatosis. The electronic responses of NTNFETs upon single-stranded DNA immobilization and subsequent DNA hybridization events were confirmed by using fluorescence-labeled oligonucleotides and then were further explored for label-free DNA detection at picomolar to micromolar concentrations. We have also observed a strong effect of DNA counterions on the electronic response, thus suggesting a charge-based mechanism of DNA detection using NTNFET devices. Implementation of label-free electronic detection assays using NTNFETs constitutes an important step toward low-cost, low-complexity, highly sensitive and accurate molecular diagnostics. hemochromatosis | SNP | biosensor

  8. Radiation absorbed doses from iron-52, iron-55, and iron-59 used to study ferrokinetics

    SciTech Connect

    Robertson, J.S.; Price, R.R.; Budinger, T.F.; Fairbanks, V.F.; Pollycove, M.

    1983-04-01

    Biological data obtained principally with Fe-59 citrate are used with physical data to calculate radiation absorbed doses for ionic or weak chelate forms of Fe-52, Fe-55, and Fe-59, administered by intravenous injection. Doses are calculated for normal subjects, primary hemochromatosis (also called idiopathic or hereditary hemochromatosis), pernicious anemia in relapse, iron-deficiency anemia, and polycythemia vera. The Fe-52 doses include the dose from the Mn-52m daughter generated after injection of Fe-52. Special attention has been given to the dose to the spleen, which has a relatively high concentration of RBCs and therefore of radioiron, and which varies significantly in size in both health and disease.

  9. HFE2 — EDRN Public Portal

    Cancer.gov

    HFE2, also known as RGM-C, is a member of the repulsive guidance molecule (RGM) family and is involved in iron metabolism. HFE2 may act as a bone morphogenetic protein (BMP) coreceptor. It is also thought to be a component of the signaling pathway which activates hepcidin or it may act as a modulator of hepcidin expression. It could also represent the cellular receptor for hepcidin. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Mutations in the HFE2 gene cause hemochromatosis type 2A, also called juvenile hemochromatosis (JH), an early-onset autosomal recessive disorder due to severe iron overload resulting in hypogonadotrophic hypogonadism, hepatic fibrosis or cirrhosis and cardiomyopathy, occurring typically before age of 30.

  10. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders.

    PubMed

    Ganz, Tomas; Nemeth, Elizabeta

    2011-01-01

    The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed.

  11. Iron Indices in Bottlenose Dolphins (Tursiops truncatus)

    PubMed Central

    Mazzaro, Lisa M; Johnson, Shawn P; Fair, Patricia A; Bossart, Greg; Carlin, Kevin P; Jensen, Eric D; Smith, Cynthia R; Andrews, Gordon A; Chavey, Patricia S; Venn-Watson, Stephanie

    2012-01-01

    Bottlenose dolphins can have iron overload (that is, hemochromatosis), and managed populations of dolphins may be more susceptible to this disease than are wild dolphins. Serum iron, total iron-binding capacity (TIBC), transferrin saturation, and ferritin were measured in 181 samples from 141 dolphins in 2 managed collections and 2 free-ranging populations. Although no iron indices increased with age among free-ranging dolphins, ferritin increased with age in managed collections. Dolphins from managed collections had higher iron, ferritin, and transferrin saturation values than did free-ranging dolphins. Dolphins with high serum iron (exceeding 300 μg/dL) were more likely to have elevated ferritin but not ceruloplasmin or haptoglobin, demonstrating that high serum levels of iron are due to a true increase in total body iron. A time-series study of 4 dolphins with hemochromatosis that were treated with phlebotomy demonstrated significant decreases in serum ferritin, iron, and TIBC between pre- and posttreatment samples; transferrin saturation initially fell but returned to prephlebotomy levels by 6 mo after treatment. Compared with those in managed collections, wild dolphins were 15 times more likely to have low serum iron (100 μg/dL or less), and this measure was associated with lower haptoglobin. In conclusion, bottlenose dolphins in managed collections are more likely to have greater iron stores than are free-ranging dolphins. Determining why this situation occurs among some dolphin populations and not others may improve the treatment of hemochromatosis in dolphins and provide clues to causes of nonhereditary hemochromatosis in humans. PMID:23561885

  12. Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2013-12-01

    responses to therapy due to HFE genotype and differential responses to therapy due to gender. Genetic variations in the HFE gene have been...associated with the iron-overload disorder hereditary hemochromatosis. In the human population, genetic variations in the 9 HFE gene, particularly H63D...plasma membrane to control intracellular iron uptake (26). The H63D genetic polymorphism of the HFE gene mutation alters the HFE repressor function

  13. Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

    DTIC Science & Technology

    2013-09-01

    be of clinical relevance: differential responses to therapy due to HFE genotype and differential responses to therapy due to gender. Genetic ...variations in the HFE gene have been associated with the iron-overload disorder hereditary hemochromatosis. In the human population, genetic variations in...interacts with the transferrin receptor on the plasma membrane to control intracellular iron uptake (26). The H63D genetic polymorphism of the HFE gene

  14. The extrahepatic role of TFR2 in iron homeostasis

    PubMed Central

    Silvestri, Laura; Nai, Antonella; Pagani, Alessia; Camaschella, Clara

    2014-01-01

    Transferrin receptor 2 (TFR2), a protein homologous to the cell iron importer TFR1, is expressed in the liver and erythroid cells and is reported to bind diferric transferrin, although at lower affinity than TFR1. TFR2 gene is mutated in type 3 hemochromatosis, a disorder characterized by iron overload and inability to upregulate hepcidin in response to iron. Liver TFR2 is considered a sensor of diferric transferrin, possibly in a complex with hemochromatosis protein. In erythroid cells TFR2 is a partner of erythropoietin receptor (EPOR) and stabilizes the receptor on the cell surface. However, Tfr2 null mice as well as TFR2 hemochromatosis patients do not show defective erythropoiesis and tolerate repeated phlebotomy. The iron deficient Tfr2-Tmprss6 double knock out mice have higher red cells count and more severe microcytosis than the liver-specific Tfr2 and Tmprss6 double knock out mice. TFR2 in the bone marrow might be a sensor of iron deficiency that protects against excessive microcytosis in a way that involves EPOR, although the mechanisms remain to be worked out. PMID:24847265

  15. Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice.

    PubMed

    Alsulimani, Helal Hussain; Ye, Qi; Kim, Jonghan

    2015-12-01

    Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and

  16. Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosiss

    PubMed Central

    Doyard, Mathilde; Chappard, Daniel; Leroyer, Patricia; Roth, Marie-Paule; Loréal, Olivier; Guggenbuhl, Pascal

    2016-01-01

    Osteoporosis may complicate iron overload diseases such as genetic hemochromatosis. However, molecular mechanisms involved in the iron-related osteoporosis remains poorly understood. Recent in vitro studies support a role of osteoblast impairment in iron-related osteoporosis. Our aim was to analyse the impact of excess iron in Hfe-/- mice on osteoblast activity and on bone microarchitecture. We studied the bone formation rate, a dynamic parameter reflecting osteoblast activity, and the bone phenotype of Hfe−/− male mice, a mouse model of human hemochromatosis, by using histomorphometry. Hfe−/− animals were sacrificed at 6 months and compared to controls. We found that bone contains excess iron associated with increased hepatic iron concentration in Hfe−/− mice. We have shown that animals with iron overload have decreased bone formation rate, suggesting a direct impact of iron excess on active osteoblasts number. For bone mass parameters, we showed that iron deposition was associated with bone loss by producing microarchitectural impairment with a decreased tendency in bone trabecular volume and trabecular number. A disorganization of trabecular network was found with marrow spaces increased, which was confirmed by enhanced trabecular separation and star volume of marrow spaces. These microarchitectural changes led to a loss of connectivity and complexity in the trabecular network, which was confirmed by decreased interconnectivity index and increased Minkowski’s fractal dimension. Our results suggest for the first time in a genetic hemochromatosis mouse model, that iron overload decreases bone formation and leads to alterations in bone mass and microarchitecture. These observations support a negative effect of iron on osteoblast recruitment and/or function, which may contribute to iron-related osteoporosis. PMID:26829642

  17. The impact of H63D HFE gene carriage on hemoglobin and iron status in children.

    PubMed

    Barbara, Kaczorowska-Hac; Marcin, Luszczyk; Jedrzej, Antosiewicz; Wieslaw, Ziolkowski; Elzbieta, Adamkiewicz-Drozynska; Malgorzata, Mysliwiec; Ewa, Milosz; Jacek, Kaczor Jan

    2016-12-01

    The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. Hereditary hemochromatosis is a heterogenic metabolic syndrome which is due to unchecked transfer of iron into the bloodstream and its toxic effects on parenchymatous organs. It is caused by the mutation of genes that encode proteins that help hepcidin to monitor serum iron. These proteins include the human hemochromatosis protein -HFE, transferrin-receptor 2, hemojuvelin in rare instances, and ferroportin. HFE-related hemochromatosis is the most frequent form of the disease. Interestingly, the low penetrance of polymorphic HFE genes results in rare clinical presentation of the disease, predominantly in middle-aged males. Taking into account the wide dispersion of HFE mutation in our population and also its unknown role in heterozygotes, we analyzed the impact of H63D HFE carriage in the developmental age, with respect to gender, on the iron status and hemoglobin concentration of carriers in comparison to those of wild-type HFE gene (12.7 ± 3.07 years, 42 boys and 41 girls). H63D carriers presented higher blood iron, transferrin saturation, and ferritin concentration than wild-type probands (p < 0.05.) Interestingly, male H63D carriers showed higher hemoglobin concentration than the unburdened children. Moreover, in the H63D carrier group, a positive correlation between iron and hemoglobin was noted. In conclusion, this study demonstrates that changes in iron metabolism occur at a young age in HFE heterozygotes.

  18. Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice

    PubMed Central

    Alsulimani, Helal Hussain; Ye, Qi

    2015-01-01

    Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe-/-) and their control wild-type (Hfe+/+) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe+/+ mice, but not in Hfe-/- mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe+/+ compared with water-drinking Hfe+/+ mice. However, Mn-exposed Hfe-/- mice spent more time to find the target hole than Mn-drinking Hfe+/+ mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload

  19. A RETROSPECTIVE STUDY OF THE LESIONS ASSOCIATED WITH IRON STORAGE DISEASE IN CAPTIVE EGYPTIAN FRUIT BATS (ROUSETTUS AEGYPTIACUS).

    PubMed

    Leone, Angelique M; Crawshaw, Graham J; Garner, Michael M; Frasca, Salvatore; Stasiak, Iga; Rose, Karrie; Neal, Dan; Farina, Lisa L

    2016-03-01

    Egyptian fruit bats (Rousettus aegyptiacus) are one of many species within zoologic collections that frequently develop iron storage disease. The goals of this retrospective multi-institutional study were to determine the tissue distribution of iron storage in captive adult Egyptian fruit bats and the incidence of intercurrent neoplasia and infection, which may be directly or indirectly related to iron overload. Tissue sections from 83 adult Egyptian fruit bats were histologically evaluated by using tissue sections stained with hematoxylin and eosin, trichrome, and Prussian blue techniques. The liver and spleen consistently had the largest amount of iron, but significant amounts of iron were also detected in the pancreas, kidney, skeletal muscle, and lung. Hepatocellular carcinoma (HCC; 11) was the most common neoplasm, followed by cholangiocarcinoma (4). Extrahepatic neoplasms included bronchioloalveolar adenoma (3), pulmonary carcinosarcoma (1), oral sarcoma (1), renal adenocarcinoma (1), transitional cell carcinoma of the urinary bladder (1), mammary gland adenoma (1), and parathyroid adenoma (1). There were also metastatic neoplasms of undetermined primary origin that included three poorly differentiated carcinomas, a poorly differentiated sarcoma, and a neuroendocrine tumor. Bats with hemochromatosis were significantly more likely to have HCC than bats with hemosiderosis (P = 0.032). Cardiomyopathy was identified in 35/77 bats with evaluable heart tissue, but no direct association was found between cardiac damage and the amount of iron observed within the liver or heart. Hepatic abscesses occurred in multiple bats, although a significant association was not observed between hemochromatosis and bacterial infection. To the authors' knowledge, this is the first publication providing evidence of a positive correlation between hemochromatosis and HCC in any species other than humans.

  20. Hepcidin and iron disorders: new biology and clinical approaches.

    PubMed

    Arezes, J; Nemeth, E

    2015-05-01

    Hepatic hormone hepcidin is a principal regulator of iron homeostasis and a pathogenic factor in common iron disorders. Hepcidin deficiency causes iron overload in hereditary hemochromatosis and iron-loading anemias, whereas hepcidin excess causes or contributes to the development of iron-restricted anemia in inflammatory diseases, infections, some cancers, and chronic kidney disease. Because of this, hepcidin may become a useful tool for diagnosis and management of iron disorders. Furthermore, a number of strategies that target hepcidin, its receptor, and its regulators are under development as novel therapeutic approaches for diseases associated with iron dysregulation.

  1. Modulation of hepcidin to treat iron deregulation: potential clinical applications.

    PubMed

    Blanchette, Nicole L; Manz, David H; Torti, Frank M; Torti, Suzy V

    2016-01-01

    The secreted peptide hormone hepcidin regulates systemic and local iron homeostasis through degradation of the iron exporter ferroportin. Dysregulation of hepcidin leads to altered iron homeostasis and development of pathological disorders including hemochromatosis, and iron loading and iron restrictive anemias. Therapeutic modulation of hepcidin is a promising method to ameliorate these conditions. Several approaches have been taken to enhance or reduce the effects of hepcidin in vitro and in vivo. Based on these approaches, hepcidin modulating drugs have been developed and are undergoing clinical evaluation. In this article we review the rationale for development of these drugs, the data concerning their safety and efficacy, their therapeutic uses, and potential future prospects.

  2. Hepatocellular carcinoma and the risk of occupational exposure

    PubMed Central

    Rapisarda, Venerando; Loreto, Carla; Malaguarnera, Michele; Ardiri, Annalisa; Proiti, Maria; Rigano, Giuseppe; Frazzetto, Evelise; Ruggeri, Maria Irene; Malaguarnera, Giulia; Bertino, Nicoletta; Malaguarnera, Mariano; Catania, Vito Emanuele; Di Carlo, Isidoro; Toro, Adriana; Bertino, Emanuele; Mangano, Dario; Bertino, Gaetano

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson’s disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem. PMID:27168870

  3. [Modern radiologic imaging in the diagnosis of abdominal diseases. Magnetic resonance imaging and spectroscopy].

    PubMed

    Fuchs, W A

    1989-04-01

    The diagnostic value of magnet resonance imaging for the diagnosis of pathological abdominal conditions has been limited sofar because of artefacts due to movement susceptibility. The current indications comprise: liver: differential diagnosis of metastases, cysts and hemangiomas, identification of small metastases, demonstration of malignant vascular invasion, evaluation of hemochromatosis; kidneys: evaluation of transplant rejection, analysis of complex cysts, demonstration of malignant tumoral invasion. The application of magnetic resonance will be greatly extended by the introduction of rapid image sequences and the application of specific contrast media.

  4. Neonatal liver failure: aetiologies and management--state of the art.

    PubMed

    Shanmugam, Naresh P; Bansal, Sanjay; Greenough, Anne; Verma, Anita; Dhawan, Anil

    2011-05-01

    Acute liver failure in neonates is rare, but carries a high mortality. Neonatal liver failure can be defined as "failure of the synthetic function of liver within 4 weeks of birth". Encephalopathy is not essential for the diagnosis. Acute liver failure in neonates differs from children with regard to aetiology and outcome. Common causes of neonatal liver failure are neonatal hemochromatosis, haematological malignancies, viral infections and liver-based metabolic defects. Early diagnosis and referral to a paediatric liver centre is recommended as liver transplantation is the only definitive treatment when supportive or a disease-specific treatment fails.

  5. Reversal of liver cirrhosis in autoimmune hepatitis.

    PubMed

    Shah, Anish M; Malhotra, Ashish; Kothari, Shivangi; Baddoura, Walid; Depasquale, Joseph; Spira, Robert

    2011-01-01

    Liver cirrhosis is generally considered irreversible but there are reports in which there is documented reversal of fibrosis/cirrhosis in various clinical conditions like Wilson's disease, hemochromatosis, primary biliary cirrhosis and autoimmune hepatitis. The subgroup of patients with autoimmune hepatitis that will have reversal of cirrhosis is not known. We present two cases with documented liver cirrhosis that had reversal of cirrhosis after treatment with immunosuppressive agents. We postulate that patients presenting with acute hepatitis and no other fibrogenic factors have higher chances of reversal of liver cirrhosis as compared to those presenting as chronic liver injury.

  6. Neonatal acute liver failure: a diagnosis challenge.

    PubMed

    Ciocca, Mirta; Álvarez, Fernando

    2017-04-01

    Neonatal acute liver failure is a rare, very severe disease with a high rate of mortality. It is clinically and etiologically different from acute liver failure seen in older children and adults. Coagulopathy with an international normalized ratio ≥ 3 is the critical parameter that defines it. The most common causes are fetal alloimmune hepatitis, previously called neonatal hemochromatosis, viral infections, metabolic disorders, and hemophagocytic lymphohistiocytosis. There is a group of treatable diseases that require a very early diagnosis for the prescription of an adequate treatment. Patients should be immediately referred to a specialized facility where pediatric liver transplantation is available to implement such therapeutic alternative, if indicated.

  7. [Hemochromatotic cirrhosis complicating pyridoxine-sensitive hereditary sideroblastic anemia. Case report].

    PubMed

    Abadia, R; Rochant, H; Levy, V G

    1983-01-01

    A further case of sporadic congenital sideroblastic anaemia is reported. Despite no contributing factors such as blood transfusion, oral ingestion of iron or alcoholic beverages, were present excessive iron stores occurred with consecutive tissue damage resulting in cirrhosis of the liver, portal hypertension and diabetes mellitus. HLA phenotype was A3 B7 as in primary hemochromatosis. Correction of anemia was obtained by vitamin B6 administration. Improvement of iron overload was achieved through the use of daily subcutaneous infusions of the iron chelating drug desferrioxamine with a portable infusion pump.

  8. Computed tomography of the spleen and liver in sickle cell disease

    SciTech Connect

    Magid, D.; Fishman, E.K.; Siegelman, S.S.

    1984-08-01

    The spleen was assessed in 10 patients with sickle cell disease studied with computed tomography (CT) for abdominal pain and/or unexplained fever. Patients with homozygous sickle cell anemia were found to have small, densely calcified spleens with occasional low-density infarcts. Five of six had hepatomegaly, and there was one case each of hepatic abscess, infarcts, and hemochromatosis. All patients with heterozygous sickle cell disease were found to have splenomegaly, with a variety of findings including acute hemorrhage, acute and chronic infarcts, rupture, and possible sequestration. It was concluded that CT is useful for evaluating the status of the spleen and liver in symptomatic patients with sickle cell disease.

  9. Modulation of hepcidin to treat iron deregulation: potential clinical applications

    PubMed Central

    Blanchette, Nicole L.; Manz, David H.; Torti, Frank M.

    2016-01-01

    The secreted peptide hormone hepcidin regulates systemic and local iron homeostasis through degradation of the iron exporter ferroportin. Dysregulation of hepcidin leads to altered iron homeostasis and development of pathological disorders including hemochromatosis, and iron loading and iron restrictive anemias. Therapeutic modulation of hepcidin is a promising method to ameliorate these conditions. Several approaches have been taken to enhance or reduce the effects of hepcidin in vitro and in vivo. Based on these approaches, hepcidin modulating drugs have been developed and are undergoing clinical evaluation. In this article we review the rationale for development of these drugs, the data concerning their safety and efficacy, their therapeutic uses, and potential future prospects. PMID:26669208

  10. Study of Alzheimer family case reveals hemochromotosis-associated HFE mutation

    PubMed Central

    Artemov, Artem V; Boulygina, Eugenia S; Tsygankova, Svetlana V; Nedoluzhko, Artem V; Chekanov, Nikolay N; Gruzdeva, Natalia M; Selezneva, Natalia D; Roshchina, Irina F; Gavrilova, Svetlana I; Velichkovsky, Boris B; Skryabin, Konstantin G; Prokhortchouk, Egor B

    2014-01-01

    We report a family case of type II early-onset Alzheimer’s disease (AD) inherited over three generations. None of the patients in the family had mutations in the genes believed to be the major risk factors for AD, such as APP, presenilin 1 or 2. Targeted exome sequencing of 249 genes that were previously reported to be associated with AD revealed a rare mutation in hemochromatosis (HFE) gene known to be associated with hemochromotosis. Compared to previous studies, we show that HFE mutation can possess the risk of AD in transferrin-, APOE- and APP-normal patients. PMID:27081498

  11. Study of Alzheimer family case reveals hemochromotosis-associated HFE mutation.

    PubMed

    Artemov, Artem V; Boulygina, Eugenia S; Tsygankova, Svetlana V; Nedoluzhko, Artem V; Chekanov, Nikolay N; Gruzdeva, Natalia M; Selezneva, Natalia D; Roshchina, Irina F; Gavrilova, Svetlana I; Velichkovsky, Boris B; Skryabin, Konstantin G; Prokhortchouk, Egor B

    2014-01-01

    We report a family case of type II early-onset Alzheimer's disease (AD) inherited over three generations. None of the patients in the family had mutations in the genes believed to be the major risk factors for AD, such as APP, presenilin 1 or 2. Targeted exome sequencing of 249 genes that were previously reported to be associated with AD revealed a rare mutation in hemochromatosis (HFE) gene known to be associated with hemochromotosis. Compared to previous studies, we show that HFE mutation can possess the risk of AD in transferrin-, APOE- and APP-normal patients.

  12. The effect of iron on the biodistribution of bone scanning agents in humans

    SciTech Connect

    Choy, D.; Murray, I.P.; Hoschl, R.

    1981-07-01

    Nine patients with chronic iron overload, resulting from either repeated transfusions or hemochromatosis, had bone scans that were characterized by a reduction of bony uptake, marked increase in renal activity, and a significant increase in soft-tissue accumulation of 99mTc-labeled bone-seeking agents. These findings were supported by semiquantitative computer analysis. The probable mechanisms of altered biodistribution and the possible role of serum ferritin are discussed. The importance of realizing the effect of excess iron on skeletal scintigraphy is further emphasized by the results of bone scanning in another patient in whom acute iron overload following infusion of iron-dextran resulted in excessive blood pool labeling.

  13. The Role of Hepcidin in Iron Metabolism

    PubMed Central

    Nemeth, Elizabeta; Ganz, Tomas

    2009-01-01

    Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler played a significant role in advancing our understanding of the function of hepcidin. This review is dedicated to his memory. PMID:19907144

  14. [Ankle joint arthritis--etiology, diagnosis and treatment].

    PubMed

    Uri, Ofir; Haim, Amir

    2008-11-01

    Ankle joint arthritis causes functional limitation and affects the quality of life many patients. It follows traumatic injuries, inflammatory joint arthritis, primary osteoarthritis, hemochromatosis and infections. Understanding the unique anatomy and biomechanics of the ankle is important for diagnosis and treatment of ankle joint pathology. The treatment of ankle joint arthritis has advanced considerably in recent years and it is still a surgical challenge. Total ankle replacement seems to be a promising form of treatment, even though current data does not demonstrate advantages over ankle joint arthrodesis.

  15. Clinical applications of therapeutic phlebotomy

    PubMed Central

    Kim, Kyung Hee; Oh, Ki Young

    2016-01-01

    Phlebotomy is the removal of blood from the body, and therapeutic phlebotomy is the preferred treatment for blood disorders in which the removal of red blood cells or serum iron is the most efficient method for managing the symptoms and complications. Therapeutic phlebotomy is currently indicated for the treatment of hemochromatosis, polycythemia vera, porphyria cutanea tarda, sickle cell disease, and nonalcoholic fatty liver disease with hyperferritinemia. This review discusses therapeutic phlebotomy and the related disorders and also offers guidelines for establishing a therapeutic phlebotomy program. PMID:27486346

  16. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice.

    PubMed

    Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David M; Harding, Cary O; Fleming, Robert E; Koeberl, Dwight D; Enns, Caroline A

    2010-04-22

    Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes.

  17. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

    PubMed Central

    Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David M.; Harding, Cary O.; Fleming, Robert E.; Koeberl, Dwight D.

    2010-01-01

    Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes. PMID:20177050

  18. The Emerging Role of Cardiovascular Magnetic Resonance Imaging in the Evaluation of Metabolic Cardiomyopathies.

    PubMed

    Mavrogeni, S; Markousis-Mavrogenis, G; Markussis, V; Kolovou, G

    2015-08-01

    The aim of this review is to discuss the role of Cardiovascular Magnetic Resonance (CMR) in the diagnosis, risk stratification, and follow-up of metabolic cardiomyopathies. The classification of myocardial diseases, proposed by WHO/ISFC task force, distinguished specific cardiomyopathies, caused by metabolic disorders, into 4 types: 1) endocrine disorders, 2) storage or infiltration disorders (amyloidosis, hemochromatosis and familial storage disorders), 3) nutritional disorders (Kwashiorkor, beri-beri, obesity, and alcohol), and 4) diabetic heart. Thyroid disease, pheochromocytoma, and growth hormone excess or deficiency may contribute to usually reversible dilated cardiomyopathy. Glucogen storage diseases can be presented with myopathy, liver, and heart failure. Lysosomal storage diseases can provoke cardiac hypertrophy, mimicking hypertrophic cardiomyopathy and arrhythmias. Hereditary hemochromatosis, an inherited disorder of iron metabolism, leads to tissue iron overload in different organs, including the heart. Cardiac amyloidosis is the result of amyloid deposition in the heart, formed from breakdown of normal or abnormal proteins that leads to increased heart stiffness, restrictive cardiomyopathy, and heart failure. Finally, nutritional disturbances and metabolic diseases, such as Kwashiorkor, beri-beri, obesity, alcohol consumption, and diabetes mellitus may also lead to severe cardiac dysfunction. CMR, through its capability to reliably assess anatomy, function, inflammation, rest-stress myocardial perfusion, myocardial fibrosis, aortic distensibility, iron and/or fat deposition can serve as an excellent tool for early diagnosis of heart involvement, risk stratification, treatment evaluation, and long term follow-up of patients with metabolic cardiomyopathies.

  19. Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors

    PubMed Central

    Anur, Praveen; Friedman, Danielle N; Sklar, Charles; Oeffinger, Kevin; Castiel, Mercedes; Kearney, Julia; Singh, Bhuvanesh; Prockop, Susan E; Kernan, Nancy A; Scaradavou, Andromachi; Kobos, Rachel; Curran, Kevin; Ruggiero, Julianne; Zakak, Nicole; O’Reilly, Richard J; Boulad, Farid

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least one year post-HSCT. Patients underwent either a total body irradiation (TBI) (N=18) or busulfan (N=4) based cytoreduction followed by T-cell depleted transplants from alternative donors. Twenty patients were alive at time of study with a 5 and 10 year overall survival of 100% and 84% and no evidence of chronic GVHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, four (22%) developed hypothyroidism, seven (39%) had insulin resistance and five (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism, and gonadal dysfunction after Busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes. PMID:26999465

  20. A Single Center Study Comparing the Stainable Iron Depositions in 1000 Explanted Cirrhotic Livers of Different Causes

    PubMed Central

    Geramizadeh, Bita; Ghazanfari, Yalda; Nikeghbalian, Saman; Malekhosseini, Seyed-Ali

    2015-01-01

    Background: There have been very few studies evaluating the close association between excess iron and cirrhosis; however, cirrhosis could be regarded as an iron-loading disorder. Objectives: In this study, the goal was to show the levels of the iron content in the liver tissue in certain types of cirrhosis. Patients and Methods: In this 7 year study (2008 - 2014), in 1000 explanted livers, the amount of iron was scored and compared according to the cause of the cirrhosis. The amount of iron in the liver was determined via the histochemical staining of the liver tissue, using Prussian-blue staining. Additionally, in each patient, the serum iron was determined and compared according to the cause of cirrhosis. Results: The highest content of iron has been found in cirrhosis caused by chronic hepatitis (i.e. hepatitis B, C, and autoimmune hepatitis), as well as in alcoholic cirrhosis. The least amount of stainable iron has been shown in biliary cirrhosis. Conclusions: The presence of high stainable iron in patients with cirrhosis, secondary to chronic viral hepatitis, autoimmune hepatitis, and alcoholic hepatitis, should not be considered indicative of the presence of hereditary hemochromatosis; however, in those patients with biliary cirrhosis, a high iron content is rare, and can be a sign of the presence of the high iron Fe (HFE) gene mutation, or another type of hereditary hemochromatosis. PMID:26977170

  1. Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism Against the Siderophilic Bacterium Vibrio vulnificus

    PubMed Central

    Arezes, João; Jung, Grace; Gabayan, Victoria; Valore, Erika; Ruchala, Piotr; Gulig, Paul A.; Ganz, Tomas; Nemeth, Elizabeta; Bulut, Yonca

    2014-01-01

    SUMMARY Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus, and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth, and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia. PMID:25590758

  2. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

    PubMed Central

    Axton, Jacob H.; McCullough, John M.; Harris, Nathan

    2016-01-01

    ABSTRACT Objectives The C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment. Materials and Methods To address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis. Results Our findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend. Discussion The results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic. Am J Phys Anthropol 160:86–101, 2016. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc. PMID:26799452

  3. Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases

    PubMed Central

    Heidari, Moones; Gerami, Sam H.; Bassett, Brianna; Graham, Ross M.; Chua, Anita C.G.; Aryal, Ritambhara; House, Michael J.; Collingwood, Joanna F.; Bettencourt, Conceição; Houlden, Henry; Ryten, Mina; Olynyk, John K.; Trinder, Debbie; Johnstone, Daniel M.; Milward, Elizabeth A.

    2016-01-01

    ABSTRACT We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe−/−xTfr2mut mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family ‘neurodegeneration with brain iron accumulation’ (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders. PMID:27500074

  4. Structural analysis of the HLA-A/HLA-F subregion: Precise localization of two new multigene families closely associated with the HLA class I sequences

    SciTech Connect

    Pichon, L.; Carn, G.; Bouric, P.

    1996-03-01

    Positional cloning strategies for the hemochromatosis gene have previously concentrated on a target area restricted to a maximum genomic expanse of 400 kb around the HLA-A and HLA-F loci. Recently, the candidate region has been extended to 2-3 Mb on the distal side of the MHC. In this study, 10 coding sequences [hemochromatosis candidate genes (HCG) I to X] were isolated by cDNA selection using YACs covering the HLA-A/HLA-F subregion. Two of these (HCG II and HCG IV) belong to multigene families, as well as other sequences already described in this region, i.e., P5, pMC 6.7, and HLA class I. Fingerprinting of the four YACSs overlapping the region was performed and allowed partial localization of the different multigene family sequences on each YAC without defining their exact positions. Fingerprinting on cosmids isolated from the ICRF chromosome 6-specific cosmid library allowed more precise localization of the redundant sequences in all of the multigene families and revealed their apparent organization in clusters. Further examination of these intertwined sequences demonstrated that this structural organization resulted from a succession of complex phenomena, including duplications and contractions. This study presents a precise description of the structural organization of the HLA-A/HLA-F region and a determination of the sequences involved in the megabase size polymorphism observed among the A3, A24, and A31 haplotypes. 29 refs., 2 figs., 2 tabs.

  5. The relationship between the iron isotopic composition of human whole blood and iron status parameters.

    PubMed

    Van Heghe, Lana; Delanghe, Joris; Van Vlierberghe, Hans; Vanhaecke, Frank

    2013-11-01

    As the iron status of an individual cannot be adequately assessed on the basis of the (total) Fe concentration in whole blood or serum, in medicine a number of parameters, such as the serum concentrations of ferritin, transferrin and soluble transferrin receptor and the transferrin saturation, are routinely determined instead. As previous research has shown that also the isotopic composition of Fe in blood and tissues is dependent on the metabolism, the present study assessed whether Fe isotopic composition in whole blood provides information as to an individual's iron status. Fe isotopic analysis of whole blood samples from a reference population (healthy volunteers) was carried out using multi-collector ICP-mass spectrometry (after chromatographic target element isolation) and the results obtained were investigated by statistical means as to their potential relation with the iron status parameters conventionally used in medicine. A low δ(56)Fe value was demonstrated to coincide with high iron status and a high δ(56)Fe value with low iron status, thus reflecting the response of the body to this iron status in terms of iron uptake, distribution between blood and stores and mobilization of storage iron. In a second phase, the iron isotopic composition in blood from patients treated for hemochromatosis type I and from patients with anemia of chronic disease (ACD) was determined. The results for hemochromatosis patients plotted with the values of low iron status, while those for ACD patients plotted with the values of high iron status. By taking a closer look at the aberrant iron metabolism that comes with these diseases, it can be seen that the patient samples confirm the conclusions drawn for the reference population. Patients with hemochromatosis type I have a strongly upregulated iron uptake, like healthy individuals with low iron status. The metabolism of patients suffering from ACD tries to remove iron from the circulation by downregulating the iron uptake

  6. Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism.

    PubMed

    Brittenham, Gary M.; Weiss, Günter; Brissot, Pierre; Lainé, Fabrice; Guillygomarc'h, Anne; Guyader, Dominique; Moirand, Romain; Deugnier, Yves

    2000-01-01

    This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on

  7. Influence of Lead on Repetitive Behavior and Dopamine Metabolism in a Mouse Model of Iron Overload

    PubMed Central

    Kueon, Chojin; Kim, Jonghan

    2014-01-01

    Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that

  8. Illness representations, knowledge and motivation to perform presymptomatic testing for late-onset genetic diseases.

    PubMed

    Leite, Ângela; Dinis, Maria Alzira P; Sequeiros, Jorge; Paúl, Constança

    2017-02-01

    This study addresses the relation between illness representations, knowledge and motivation to perform the presymptomatic testing (PST) of subjects at-risk for Familial Amyloydotic Polyneuropathy (FAP), Huntington's disease (HD) and Machado-Joseph disease (MJD), compared with subjects at-risk for Hereditary Hemochromatosis (HH). The sample comprised a clinical group of 213 subjects at genetic risk for FAP, HD and MJD, and a comparison group of 31 subjects at genetic risk for HH, that answered three open-ended questions relating illness representations, knowledge about the disease, and motivation to perform PST. People at-risk for FAP, HD and MJD use more metaphors, make more references to the family, are more concerned with the future and feel more out of curiosity and to learn, than for HH. These subjects at-risk correspond to the profile of somatic individual or personhood, wherein the unsubjectivation of the disease can function as a coping mechanism.

  9. Recent advances in iron metabolism and related disorders.

    PubMed

    Camaschella, Clara; Strati, Paolo

    2010-10-01

    Iron is essential for life, because it is indispensable for several biological reactions such as oxygen transport, DNA synthesis and cell proliferation, but is toxic if present in excess since it causes cellular damage through free radical formation. Either cellular or systemic iron regulation can be disrupted in disorders of iron metabolism. In the past few years, our understanding of iron metabolism and its regulation has dramatically changed. New disorders of iron metabolism have emerged and the role of iron has started to be recognized as a cofactor of other disorders. The study of genetic conditions such as hemochromatosis and iron-refractory-iron-deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited for a more effective treatment of both genetic and acquired iron disorders.

  10. Iron homeostasis: new tales from the crypt.

    PubMed

    Roy, C N; Enns, C A

    2000-12-15

    The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)-transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

  11. Iron homeostasis: new players, newer insights.

    PubMed

    Edison, Eunice S; Bajel, Ashish; Chandy, Mammen

    2008-12-01

    Although iron is a relatively abundant element in the universe, it is estimated that more than 2 billion people worldwide suffer from iron deficiency anemia. Iron deficiency results in impaired production of iron-containing proteins, the most prominent of which is hemoglobin. Cellular iron deficiency inhibits cell growth and subsequently leads to cell death. Hemochromatosis, an inherited disorder results in disproportionate absorption of iron and the extra iron builds up in tissues resulting in organ damage. As both iron deficiency and iron overload have adverse effects, cellular and systemic iron homeostasis is critically important. Recent advances in the field of iron metabolism have led to newer understanding of the pathways involved in iron homeostasis and the diseases which arise from alteration in the regulators. Although insight into this complex regulation of the proteins involved in iron homeostasis has been obtained mainly through animal studies, it is most likely that this knowledge can be directly extrapolated to humans.

  12. Variation in an Iron Metabolism Gene Moderates the Association Between Blood Lead Levels and Attention-Deficit/Hyperactivity Disorder in Children

    PubMed Central

    Nigg, Joel T.; Elmore, Alexis L.; Natarajan, Neil; Friderici, Karen H.; Nikolas, Molly A.

    2016-01-01

    Although attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental condition, there is also considerable scientific and public interest in environmental modulators of its etiology. Exposure to neurotoxins is one potential source of perturbation of neural, and hence psychological, development. Exposure to lead in particular has been widely investigated and is correlated with neurodevelopmental outcomes, including ADHD. To investigate whether this effect is likely to be causal, we used a Mendelian randomization design with a functional gene variant. In a case-control study, we examined the association between ADHD symptoms in children and blood lead level as moderated by variants in the hemochromatosis (HFE) gene. The HFE gene regulates iron uptake and secondarily modulates lead metabolism. Statistical moderation was observed: The magnitude of the association of blood lead with symptoms of ADHD was altered by functional HFE genotype, which is consistent with a causal hypothesis. PMID:26710823

  13. Health and nutritional status of a perturbed black-necked swan (Cygnus melanocoryphus) population: diet quality.

    PubMed

    Norambuena, M Cecilia; Bozinovic, Francisco

    2009-12-01

    The Cayumapu River's black-necked swan population in southern Chile lost its main dietary item, Egeria densa, during an environmental crisis which occurred in 2004 in the Carlos Andwanter Nature Sanctuary. The main goal of this study was to test the effect of diet on the physiologic response to this new ecologic challenge. The results revealed that the new diet of this population was composed primarily of roots and sedimentary microalgae, with chemical and energetic content similar to the diet of the control population. Nevertheless, the mean body mass of the Cayumapu River swans was 25% lower than that of control birds. In addition, the biochemical and hematologic profiles of the study population were indicative of malnutrition and a hyperferremic, hyperphosphatemic, and lymphopenic condition. Liver enzyme activities did not support that the malnutrition was a secondary consequence of liver dysfunction, as is expected under hemochromatosis or environmental toxics exposure.

  14. The Role of Iron and Iron Overload in Chronic Liver Disease

    PubMed Central

    Milic, Sandra; Mikolasevic, Ivana; Orlic, Lidija; Devcic, Edita; Starcevic-Cizmarevic, Nada; Stimac, Davor; Kapovic, Miljenko; Ristic, Smiljana

    2016-01-01

    The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models. PMID:27332079

  15. [Unexplained, subclinical chronically elevated transaminases].

    PubMed

    Vital Durand, D; Lega, J-C; Fassier, T; Zenone, T; Durieu, I

    2013-08-01

    Unexplained, subclinical chronically elevated transaminases is mainly a marker of non-alcoholic fatty liver disease, metabolic syndrome, alcoholism and diabetes, which are very common situations but viral hepatitis and iatrogenic origin must also be considered. Before looking for hepatic or genetic rare diseases, it is worth considering hypertransaminasemia as a clue for muscular disease, particularly in paediatric settings, and creatine phosphokinase is a specific marker. Then, patient history, examination and appropriate biologic requests can permit the identification of less frequent disorders where isolated hypertransaminasemia is possibly the unique marker of the disease for a long while: hemochromatosis, celiac disease, autoimmune hepatitis, Wilson's disease, α1-anti-trypsine deficiency, thyroid dysfunctions, Addison's disease. Liver biopsy should be performed only in patients with aspartate aminotransferases upper the normal range or alanine aminotransferases higher than twice the normal range after 6 months delay with dietetic corrections.

  16. Reduced size liver transplantation from a donor supported by a Berlin Heart.

    PubMed

    Misra, M V; Smithers, C J; Krawczuk, L E; Jenkins, R L; Linden, B C; Weldon, C B; Kim, H B

    2009-11-01

    Patients on cardiac assist devices are often considered to be high-risk solid organ donors. We report the first case of a reduced size liver transplant performed using the left lateral segment of a pediatric donor whose cardiac function was supported by a Berlin Heart. The recipient was a 22-day-old boy with neonatal hemochromatosis who developed fulminant liver failure shortly after birth. The transplant was complicated by mild delayed graft function, which required delayed biliary reconstruction and abdominal wall closure, as well as a bile leak. However, the graft function improved quickly over the first week and the patient was discharged home with normal liver function 8 weeks after transplant. The presence of a cardiac assist device should not be considered an absolute contraindication for abdominal organ donation. Normal organ procurement procedures may require alteration due to the unusual technical obstacles that are encountered when the donor has a cardiac assist device.

  17. Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers.

    PubMed

    Roy, C N; Andrews, N C

    2001-10-01

    The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and DCYTB: Ongoing studies of Friedreich's ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.

  18. The clinical significance of pancreatic steatosis.

    PubMed

    Smits, Mark M; van Geenen, Erwin J M

    2011-03-01

    More research is now focused on pancreatic steatosis. Multiple definitions, clinical associations and synonyms for pancreatic steatosis are described in the literature and can be confusing. The integration and comparison of several studies concerning this topic is therefore challenging. In the past, pancreatic steatosis was considered an innocuous condition, a bystander of many underlying diseases (such as congenital syndromes, hemochromatosis and viral infection). However, evidence that pancreatic steatosis (strongly associated with obesity and the metabolic syndrome) has a role in type 2 diabetes mellitus, pancreatic exocrine dysfunction, acute pancreatitis, pancreatic cancer and the formation of pancreatic fistula after pancreatic surgery is emerging. This Review focuses on the different etiological factors and the clinical consequences of pancreatic steatosis.

  19. Modulating the selectivity of matriptase-2 inhibitors with unnatural amino acids.

    PubMed

    St-Georges, Catherine; Désilets, Antoine; Béliveau, François; Ghinet, Mariana; Dion, Sébastien P; Colombo, Éloic; Boudreault, Pierre-Luc; Najmanovich, Rafael J; Leduc, Richard; Marsault, Éric

    2017-03-31

    Matriptase-2, a type II transmembrane serine protease (TTSP), is expressed in the liver and regulates iron homeostasis via the cleavage of hemojuvelin. Matriptase-2 emerges as an attractive target for the treatment of conditions associated with iron overload, such as hemochromatosis or beta-thalassemia. Starting from the crystal structure of its closest homolog matriptase, we constructed a homology model of matriptase-2 in order to further optimize the selectivity of serine trap peptidomimetic inhibitors for matriptase-2 vs matriptase. Careful modifications of the P4, P3 and P2 positions with the help of unnatural amino acids led to a thorough understanding of Structure-Activity Relationship and a >60-fold increase in selectivity for matriptase-2 vs matriptase. Additionally, the introduction of unnatural amino acids led to significant increases in plasma stability. Such compounds represent useful pharmacological tools to test matriptase-2 inhibition in a context of iron overload.

  20. Iron Homeostasis in Health and Disease

    PubMed Central

    Gozzelino, Raffaella; Arosio, Paolo

    2016-01-01

    Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload. PMID:26805813

  1. New perspectives on iron: an introduction.

    PubMed

    Boldt, D H

    1999-10-01

    Iron is an essential nutritional element for all life forms. Iron plays critical roles in electron transport and cellular respiration, cell proliferation and differentiation, and regulation of gene expression. Two emerging new functions for iron are its necessary role in supporting transcription of certain key genes required for cell growth and function [eg, nitric oxide synthase, protein kinase C-beta, p21 (CIP1/WAF1)] and its complex role in hematopoietic cell differentiation. However, iron is also potentially deleterious. Reactive oxygen species generated by Fenton chemistry may contribute to major pathological processes such as cancer, atherosclerosis, and neurodegenerative diseases. Iron-generated reactive oxygen species may also function in normal intracellular signaling. Therefore, roles of iron are both essential and extraordinarily diverse. This symposium explores this diversity by covering topics of iron absorption and transport, the regulation of gene expression by iron responsive proteins, the cellular biology of heme, hereditary hemochromatosis, and clinical use of serum transferrin receptor measurements.

  2. Inborn anemias in mice: (Annual report, 1981-1982)

    SciTech Connect

    Bernstein, S.E.

    1982-07-19

    Hereditary anemias of mice are the chief objects of investigation, specificially four macrocytic anemias, 3 types of hemolytic anemia, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, the autoimmune hemolytic anemia of NZB mice, an ..cap alpha..-thalassemia and a new hypochromic anemia with hemochromatosis. New types of anemia may be analyzed as new mutations appear. Three new mutations have been identified during the past 18 months. These anemias are studied through characterization of peripheral blood values, determinations of radiosensitivity under a variety of conditions, measurements of iron metabolism and heme synthesis, study of normal and abnormal erythrocyte membrane proteins, histological and biochemical characterization of blood-forming tissue, functional tests of the stem-cell component, examination of responses to erythroid stimuli, and transplantation of tissue and parabiosis between individuals of differently affected genotypes. 31 refs.

  3. Effect of iron on the biodistribution of bone scanning agents in humans

    SciTech Connect

    Choy, D.; Murray, I.P.C.; Hoschl, R.

    1981-07-01

    Nine patients with chronic iron overload, resulting from either repeated transfusions or hemochromatosis, had bone scans that were characterized by a reduction of bony uptake, marked increase in renal activity, and a significant increase in soft-tissue accumulation of /sup 99m/Tc-labeled bone-seeking agents. These findings were supported by semiquantitative computer analysis. The probable mechanisms of altered biodistribution and the possible role of serum ferritin are discussed. The importance of realizing the effect of excess iron on skeletal scintigraphy is further emphasized by the results of bone scanning in another patient in whom acute iron overload following infusion of iron-dextran resulted in excessive blood pool labeling.

  4. Nuclear magnetic resonance of iron and copper disease states

    SciTech Connect

    Runge, V.M.; Clanton, J.A.; Smith, F.W.; Hutchison, J.; Mallard, J.; Partain, C.L.; James, A.E. Jr.

    1983-11-01

    The tissue levels of paramagnetic ions are an important factor in the determination of T/sub 1/ values as observed by nuclear magnetic resonance (NMR) imaging. The increased levels of iron present in human disease states such as hemochromatosis lead to decreased T/sub 1/ values. The mean liver T/sub 1/ of three patients with iron storage disease was determined to be 130 msec, significantly different from the value of 154 msec, the mean for 14 normal controls. Whether NMR will be able to detect the increased copper levels in liver and brain in Wilson disease remains for further clinical trials to evaluate. NMR imaging, however, does serve as a noninvasive method for the diagnosis of states of iron overload and as a technique to follow progression of disease or response to medical therapy.

  5. Iron metabolism and toxicity

    SciTech Connect

    Papanikolaou, G.; Pantopoulos, K. . E-mail: kostas.pantopoulos@mcgill.ca

    2005-01-15

    Iron is an essential nutrient with limited bioavailability. When present in excess, iron poses a threat to cells and tissues, and therefore iron homeostasis has to be tightly controlled. Iron's toxicity is largely based on its ability to catalyze the generation of radicals, which attack and damage cellular macromolecules and promote cell death and tissue injury. This is lucidly illustrated in diseases of iron overload, such as hereditary hemochromatosis or transfusional siderosis, where excessive iron accumulation results in tissue damage and organ failure. Pathological iron accumulation in the liver has also been linked to the development of hepatocellular cancer. Here we provide a background on the biology and toxicity of iron and the basic concepts of iron homeostasis at the cellular and systemic level. In addition, we provide an overview of the various disorders of iron overload, which are directly linked to iron's toxicity. Finally, we discuss the potential role of iron in malignant transformation and cancer.

  6. The clearance of /sup 131/I-human plasma ferritin in man

    SciTech Connect

    Worwood, M.; Cragg, S.J.; Williams, A.M.; Wagstaff, M.; Jacobs, A.

    1982-10-01

    Ferritin was purified 33,000-fold from the plasma of patients with idiopathic hemochromatosis. The plasma ferritin was labeled with /sup 131/I and injected into 2 normal men. Clearance was found to be relatively slow, with 50% /sup 131/I-ferritin remaining in the plasma at 27-30 hr. The fraction of plasma ferritin that bound to concanavalin-A was found to be cleared more slowly than the nonbinding fraction. These findings confirm our previous suggestion that glycosylation is a major factor prolonging the survival of ferritin in the plasma, but differ from the results of earlier studies in experimental animals and preterm infants, which indicated very rapid plasma ferritin turnover.

  7. Disorders of heavy metals.

    PubMed

    Woimant, France; Trocello, Jean-Marc

    2014-01-01

    Heavy metals and trace elements play an important role in relation to the physiology and pathology of the nervous system. Neurologic diseases related to disorders of metabolism of copper and iron are reviewed. Copper disorders are divided into two classes: ATP7A- or ATP7B-related inherited copper transport disorders (Menkes disease, occipital horn syndrome, ATP7A-related distal motor neuropathy, and Wilson disease) and acquired diseases associated with copper deficiency or copper excess. Iron brain disorders are divided into genetic neurodegeneration with brain iron accumulation (NBIA, neuroferritinopathy, and aceruloplasminemia), genetic systemic iron accumulation with neurologic features (hemochromatosis), and acquired diseases associated with iron excess (superficial siderosis) or iron deficiency (restless leg syndrome). The main features of cadmium, lead, aluminum, mercury, and manganese toxicity are summarized.

  8. Genetic discrimination in health insurance: current legal protections and industry practices.

    PubMed

    Pollitz, Karen; Peshkin, Beth N; Bangit, Eliza; Lucia, Kevin

    2007-01-01

    Most states have enacted genetic nondiscrimination laws in health insurance, and federal legislation is pending in Congress. Scientists worry fear of discrimination discourages some patients from participating in clinical trials and hampers important medical research. This paper describes a study of medical underwriting practices in the individual health insurance market related to genetic information. Underwriters from 23 companies participated in a survey that asked them to underwrite four pairs of hypothetical applicants for health insurance. One person in each pair had received a positive genetic test result indicating increased risk of a future health condition--breast cancer, hemochromatosis, or heart disease--for a total of 92 underwriting decisions on applications involving genetic information. In seven of these 92 applications, underwriters said they would deny coverage, place a surcharge on premiums,or limit covered benefits based on an applicant's genetic information.

  9. An Update on Laboratory Diagnosis of Liver Inherited Diseases

    PubMed Central

    Elce, Ausilia; Amato, Felice

    2013-01-01

    Liver inherited diseases are a group of genetically determined clinical entities that appear with an early chronic liver involvement. They include Wilson's disease (hepatolenticular degeneration), hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. In addition, cystic fibrosis, although it is not specifically a liver disease, may cause a severe liver involvement in a significant percentage of cases. For all these pathologies, the disease gene is known, and molecular analysis may contribute to the unequivocal diagnosis. This approach could avoid the patient invasive procedures and limit complications associated with a delay in diagnosis. We review liver inherited diseases on the basis of the genetic defect, focusing on the contribution of molecular analysis in the multistep diagnostic workup. PMID:24222913

  10. Quantification of Liver Iron with MRI: State of the Art and Remaining Challenges

    PubMed Central

    Hernando, Diego; Levin, Yakir S; Sirlin, Claude B; Reeder, Scott B

    2015-01-01

    Liver iron overload is the histological hallmark of hereditary hemochromatosis and transfusional hemosiderosis, and can also occur in chronic hepatopathies. Iron overload can result in liver damage, with the eventual development of cirrhosis, liver failure and hepatocellular carcinoma. Assessment of liver iron levels is necessary for detection and quantitative staging of iron overload, and monitoring of iron-reducing treatments. This article discusses the need for non-invasive assessment of liver iron, and reviews qualitative and quantitative methods with a particular emphasis on MRI. Specific MRI methods for liver iron quantification include signal intensity ratio as well as R2 and R2* relaxometry techniques. Methods that are in clinical use, as well as their limitations, are described. Remaining challenges, unsolved problems, and emerging techniques to provide improved characterization of liver iron deposition are discussed. PMID:24585403

  11. Trichohepatoenteric syndrome: founder mutation in asian indians.

    PubMed

    Kotecha, U H; Movva, S; Puri, R D; Verma, I C

    2012-08-01

    Trichohepatoenteric syndrome (THES) is characterized by chronic diarrhea, dysmorphic facies and hair abnormalities. Hepatic involvement varies from no abnormality to cirrhosis and hemochromatosis. Recently, mutations in the tetratricopeptide repeat domain 37 (TTC37) gene were identified to cause THES. The c.2808G>A variation was suggested as a possible founder mutation among the South Asians. We further report 2 unrelated cases of Asian-Indian ethnicity (Gujrati) with THES, wherein targeted mutation analysis revealed the same mutation in homozygous form in both cases. These findings, as well as haplotype analysis, corroborate the founder mutation hypothesis amongst Asian Indo-Pakistani ethnic groups. A restriction enzyme-based method is also described to identify this founder mutation. One of our probands had multiple hepatic hemangiomas, a feature not previously observed in this syndrome.

  12. Identification of disease genes: example-driven web-based tutorial.

    PubMed

    Bhagwat, Medha

    2007-01-01

    The National Center for Biotechnology Information (NCBI) has developed several web-based mini-courses (www.ncbi.nlm.nih.gov/Class/minicourses) illustrating the applications of NCBI resources. This chapter describes the problem-based minicourse called "Identification of Disease Genes." The mini-course guides us through one of the several ways to identify disease related genes, starting from the expressed sequence data such as that may have been obtained from patients. The chapter first provides an introduction to the human genome assembly and the resources such as the Basic Local Alignment Search Tool, Map Viewer, Single Nucleotide Polymorphism database, and Online Mendelian Inheritance in Man. The chapter then demonstrates the practical application of these resources to the identification of genes related to two diseases, hemochromatosis and sickle cell anemia. The chapter also provides links to the mini-course web pages and includes the screen images of the results of the applied steps.

  13. Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes.

    PubMed

    Chen, Simeng; Feng, Teng; Vujić Spasić, Maja; Altamura, Sandro; Breitkopf-Heinlein, Katja; Altenöder, Jutta; Weiss, Thomas S; Dooley, Steven; Muckenthaler, Martina U

    2016-06-17

    The hepatic hormone hepcidin is the master regulator of systemic iron homeostasis. Its expression level is adjusted to alterations in iron levels, inflammatory cues, and iron requirements for erythropoiesis. Bone morphogenetic protein 6 (BMP6) contributes to the iron-dependent control of hepcidin. In addition, TGF-β1 may stimulate hepcidin mRNA expression in murine hepatocytes and human leukocytes. However, receptors and downstream signaling proteins involved in TGF-β1-induced hepcidin expression are still unclear. Here we show that TGF-β1 treatment of mouse and human hepatocytes, as well as ectopic expression of TGF-β1 in mice, increases hepcidin mRNA levels. The hepcidin response to TGF-β1 depends on functional TGF-β1 type I receptor (ALK5) and TGF-β1 type II receptor (TβRII) and is mediated by a noncanonical mechanism that involves Smad1/5/8 phosphorylation. Interestingly, increasing availability of canonical Smad2/3 decreases TGF-β1-induced hepcidin regulation, whereas the BMP6-hepcidin signal was enhanced, indicating a signaling component stoichiometry-dependent cross-talk between the two pathways. Although ALK2/3-dependent hepcidin activation by BMP6 can be modulated by each of the three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and TfR2 (transferrin receptor 2), these proteins do not control the ALK5-mediated hepcidin response to TGF-β1. TGF-β1 mRNA levels are increased in mouse models of iron overload, indicating that TGF-β1 may contribute to hepcidin synthesis under these conditions. In conclusion, these data demonstrate that a complex regulatory network involving TGF-β1 and BMP6 may control the sensing of systemic and/or hepatic iron levels.

  14. Hepcidin: A Promising Therapeutic Target for Iron Disorders: A Systematic Review.

    PubMed

    Liu, Jing; Sun, Bingbing; Yin, Huijun; Liu, Sijin

    2016-04-01

    Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced.Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin.Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated.Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving ineffective

  15. Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

    PubMed Central

    Heidari, M; Johnstone, D M; Bassett, B; Graham, R M; Chua, A C G; House, M J; Collingwood, J F; Bettencourt, C; Houlden, H; Ryten, M; Olynyk, J K; Trinder, D; Milward, E A

    2016-01-01

    The ‘neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe−/− × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n ≥5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe−/− × Tfr2mut brain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe−/− × Tfr2mut brain and post-mortem NBIA basal ganglia. Hfe−/− × Tfr2mut mice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments. PMID:26728570

  16. Enrichment of reticulocytes from whole blood using aqueous multiphase systems of polymers.

    PubMed

    Kumar, Ashok A; Lim, Caeul; Moreno, Yovany; Mace, Charles R; Syed, Abeer; Van Tyne, Daria; Wirth, Dyann F; Duraisingh, Manoj T; Whitesides, George M

    2015-01-01

    This paper demonstrates the enrichment of reticulocytes by centrifuging whole blood through aqueous multiphase systems (AMPSs)-immiscible phases of solutions of polymers that form step-gradients in density. The interfaces of an AMPS concentrate cells; this concentration facilitates the extraction of blood enriched for reticulocytes. AMPS enrich reticulocytes from blood from both healthy and hemochromatosis donors. Varying the osmolality and density of the phases of AMPS provides different levels of enrichment and yield of reticulocytes. A maximum enrichment of reticulocytemia of 64 ± 3% was obtained from donors with hemochromatosis. When used on peripheral blood from normal donors, AMPS can provide a higher yield of enriched reticulocytes and a higher proportion of reticulocytes expressing CD71 than differential centrifugation followed by centrifugation over Percoll. Blood enriched for reticulocytes by AMPS could be useful for research on malaria. Several species of malaria parasites show a preference to invade young erythrocytes and reticulocytes; this preference complicates in vitro cultivation of these species in human blood. Plasmodium knowlesi malaria parasites invade normal human blood enriched for reticulocytes by AMPSs at a rate 2.2 times greater (P < 0.01) than they invade unenriched blood. Parasite invasion in normal blood enriched by AMPS was 1.8 times greater (P < 0.05) than in blood enriched to a similar reticulocytemia by differential centrifugation followed by centrifugation over Percoll. The enrichment of reticulocytes that are invaded by malaria parasites demonstrates that AMPSs can provide a label-free method to enrich cells for biological research.

  17. Hepcidin: A Promising Therapeutic Target for Iron Disorders

    PubMed Central

    Liu, Jing; Sun, Bingbing; Yin, Huijun; Liu, Sijin

    2016-01-01

    Abstract Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced. Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin. Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated. Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving

  18. Biological variability of transferrin saturation and unsaturated iron binding capacity

    PubMed Central

    Adams, PC; Reboussin, DM; Press, RD; Barton, JC; Acton, RT; Moses, GC; Leiendecker-Foster, C; McLaren, GD; Dawkins, FW; Gordeuk, VR; Lovato, L; Eckfeldt, JH

    2007-01-01

    Background Transferrin saturation is widely considered the preferred screening test for hemochromatosis. Unsaturated iron binding capacity has similar performance at lower cost. However, the within-person biological variability of both these tests may limit their ability at commonly used cut points to detect HFE C282Y homozygous patients. Methods The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 primary care participants for iron overload using tansferrin saturation, unsaturated iron binding capacity, ferritin and HFE C282Y and H63D genotyping. Transferrin saturation and unsaturated iron binding capacity were performed at initial screening and again when selected participants and controls returned for a clinical examination several months later. A missed case was defined as a C282Y homozygote who had transferrin saturation below cut point (45 % women, 50 % men) or unsaturated iron binding capacity above cut point (150 μmol/L women, 125 μmol/L men) at either the initial screening or clinical examination, or both, regardless of serum ferritin. Results There were 209 C282Y previously undiagnosed homozygotes with transferrin saturation and unsaturated iron binding capacity testing done at initial screening and clinical examination. Sixty-eight C282Y homozygotes (33%) would have been missed at these transferrin saturation cut points (19 men, 49 women, median SF 170 μg/L, first and third quartiles 50 and 474 μg/L), and 58 homozygotes (28 %) would have been missed at the unsaturated iron binding capacity cut points (20 men, 38 women, median SF 168 μg/L, quartiles 38 and 454 μg/L). There was no advantage to using fasting samples. Conclusions The within-person biological variability of transferrin saturation and unsaturated iron binding capacity limit their usefulness as an initial screening test for expressing C282Y homozygotes. PMID:17976429

  19. Stoichiometries of Transferrin Receptors 1 and 2 in Human Liver

    PubMed Central

    Chloupková, Maja; Zhang, An-Sheng; Enns, Caroline A.

    2009-01-01

    Mutations in either the hereditary hemochromatosis protein, HFE, or transferrin receptor 2, TfR2, result in a similarly severe form of the most common type of iron overload disease called hereditary hemochromatosis. Models of the interactions between HFE, TfR1, and TfR2 imply that these proteins are present in different molar concentrations in the liver, where they control expression of the iron regulatory hormone, hepcidin, in response to body iron loading. The aim of this study was to determine in vivo levels of mRNA by quantitative RT-PCR and concentrations of these proteins by quantitative immunoblotting in human liver tissues. The level of TfR2 mRNA was 21- and 63- fold higher than that of TfR1 and HFE, respectively. Molar concentration of TfR2 protein was the highest and determined to be 1.95 nmoles/g protein in whole cell lysates and 10.89 nmoles/g protein in microsomal membranes. Molar concentration of TfR1 protein was 4.5- and 6.1-fold lower than that of TfR2 in whole cell lysates and membranes, respectively. The level of HFE protein was below 0.53 nmoles/g of total protein. HFE is thus present in substoichiometric concentrations with respect to both TfR1 and TfR2 in human liver tissue. This finding supports a model, in which availability of HFE is limiting for formation of complexes with TfR1 or TfR2. PMID:19819738

  20. Screening in liver disease

    PubMed Central

    Poggio, Paolo Del; Mazzoleni, Marzio

    2006-01-01

    A disease is suitable for screening if it is common, if the target population can be identified and reached and if both a good screening test and an effective therapy are available. Of the most common liver diseases only viral hepatitis and genetic hemochromatosis partially satisfy these conditions. Hepatitis C is common, the screening test is good and the therapy eliminates the virus in half of the cases, but problems arise in the definition of the target population. In fact generalized population screening is not endorsed by international guidelines, although some recommend screening immigrants from high prevalence countries. Opportunistic screening (case finding) of individuals with classic risk factors, such as transfusion before 1992 and drug addiction, is the most frequently used strategy, but there is disagreement whether prison inmates, individuals with a history of promiscuous or traumatic sex and health care workers should be screened. In a real practice setting the performance of opportunistic screening by general practitioners is low but can be ameliorated by training programs. Screening targeted to segments of the population or mass campaigns are expensive and therefore interventions should be aimed to improve opportunistic screening and the detection skills of general practitioners. Regarding genetic hemochromatosis there is insufficient evidence for population screening, but individual physicians can decide to screen racial groups with a high prevalence of the disease, such as people in early middle age and of northern European origin. In the other cases opportunistic screening of high risk individuals should be performed, with a high level of suspicion in case of unexplained liver disease, diabetes, juvenile artropathy, sexual dysfunction and skin pigmentation. PMID:16981254

  1. A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression.

    PubMed

    Kawabata, Hiroshi; Uchiyama, Tatsuki; Sakamoto, Soichiro; Kanda, Junya; Oishi, Shinya; Fujii, Nobutaka; Tomosugi, Naohisa; Kadowaki, Norimitsu; Takaori-Kondo, Akifumi

    2015-05-01

    Hepcidin is the central regulator of systemic iron homeostasis; dysregulation of hepcidin expression causes various iron metabolic disorders, including hereditary hemochromatosis and anemia of inflammation. To identify molecules that modulate hepcidin expression, we developed a bioassay system for hepcidin gene (HAMP) promoter activity by stable transfection of Hep3B hepatoma cells with an expression plasmid in which EGFP was linked to a 2.5-kb human HAMP promoter. Interleukin 6, bone morphogenetic protein 6 (BMP-6), and oncostatin M, well-characterized stimulators of the HAMP promoter, strongly enhanced the green fluorescence intensity of these cells. Dorsomorphin, heparin, and cobalt chloride, known inhibitors of hepcidin expression, significantly suppressed green fluorescence intensity, and these inhibitory effects were more prominent when the cells were stimulated with BMP-6. Employing this system, we screened 1,280 biologically active small molecules and found several candidate inhibitors of hepcidin expression. Apomorphine, benzamil, etoposide, CGS-15943, kenpaullone, and rutaecarpine (all at 10 μmol/L) significantly inhibited hepcidin mRNA expression by Hep3B cells without affecting cell viability. CGS-15943 was the strongest suppressor of BMP-6-induced hepcidin-25 secretion in these cells. We conclude that our newly developed hepcidin promoter bioassay system is useful for identifying and evaluating compounds that modulate hepcidin expression.

  2. A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis.

    PubMed

    Gutschow, Patrick; Schmidt, Paul J; Han, Huiling; Ostland, Vaughn; Bartnikas, Thomas B; Pettiglio, Michael A; Herrera, Carolina; Butler, James S; Nemeth, Elizabeta; Ganz, Tomas; Fleming, Mark D; Westerman, Mark

    2015-02-01

    Mice have been essential for distinguishing the role of hepcidin in iron homeostasis. Currently, investigators monitor levels of murine hepatic hepcidin-1 mRNA as a surrogate marker for the bioactive hepcidin protein itself. Here, we describe and validate a competitive, enzyme-linked immunosorbent assay that quantifies hepcidin-1 in mouse serum and urine. The assay exhibits a biologically relevant lower limit of detection, high precision, and excellent linearity and recovery. We also demonstrate correlation between serum and urine hepcidin-1 values and validate the competitive enzyme-linked immunosorbent assay by analyzing plasma hepcidin response of mice to physiological challenges, including iron deficiency, iron overload, acute blood loss, and inflammation. Furthermore, we analyze multiple murine genetic models of iron dysregulation, including β-thalassemia intermedia (Hbb(th3/+)), hereditary hemochromatosis (Hfe(-/-), Hjv(-/-), and Tfr2(Y245X/Y245X)), hypotransferrinemia (Trf(hpx/hpx)), heterozygous transferrin receptor 1 deficiency (Tfrc(+/-)) and iron refractory iron deficiency anemia (Tmprss6(-/-) and Tmprss6(hem8/hem8)). Novel compound iron metabolism mutants were also phenotypically characterized here for the first time. We demonstrate that serum hepcidin concentrations correlate with liver hepcidin mRNA expression, transferrin saturation and non-heme liver iron. In some circumstances, serum hepcidin-1 more accurately predicts iron parameters than hepcidin mRNA, and distinguishes smaller, statistically significant differences between experimental groups.

  3. The dietary flavonoid myricetin regulates iron homeostasis by suppressing hepcidin expression.

    PubMed

    Mu, Mingdao; An, Peng; Wu, Qian; Shen, Xiaoyun; Shao, Dandan; Wang, Hao; Zhang, Yingqi; Zhang, Shenshen; Yao, Hui; Min, Junxia; Wang, Fudi

    2016-04-01

    Hepcidin, a master regulator of iron homeostasis, is a promising target in treatment of iron disorders such as hemochromatosis, anemia of inflammation and iron-deficiency anemia. We previously reported that black soybean seed coat extract could inhibit hepcidin expression. Based on this finding, we performed a screen in cultured cells in order to identify the compounds in black soybeans that inhibit hepcidin expression. We found that the dietary flavonoid myricetin significantly inhibited the expression of hepcidin both in vitro and in vivo. Treating cultured cells with myricetin decreased both HAMP mRNA levels and promoter activity by reducing SMAD1/5/8 phosphorylation. This effect was observed even in the presence of bone morphogenic protein-6 (BMP6) and interleukin-6 (IL-6), two factors that stimulate hepcidin expression. Furthermore, mice that were treated with myricetin (either orally or systemically) had reduced hepatic hepcidin expression, decreased splenic iron levels and increased serum iron levels. Notably, myricetin-treated mice increased red blood cell counts and hemoglobin levels. In addition, pretreating mice with myricetin prevented LPS-induced hypoferremia. We conclude that myricetin potently inhibits hepcidin expression both in vitro and in vivo, and this effect is mediated by altering BMP/SMAD signaling. These experiments highlight the feasibility of identifying and characterizing bioactive phytochemicals to suppress hepcidin expression. These results also suggest that myricetin may represent a novel therapy for treating iron deficiency-related diseases.

  4. Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism.

    PubMed

    Grgurevic, Lovorka; Christensen, Gitte Lund; Schulz, Tim J; Vukicevic, Slobodan

    2016-02-01

    Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target.

  5. Clinical Impact and Cellular Mechanisms of Iron Overload-Associated Bone Loss

    PubMed Central

    Jeney, Viktória

    2017-01-01

    Diseases/conditions with diverse etiology, such as hemoglobinopathies, hereditary hemochromatosis and menopause, could lead to chronic iron accumulation. This condition is frequently associated with a bone phenotype; characterized by low bone mass, osteoporosis/osteopenia, altered microarchitecture and biomechanics, and increased incidence of fractures. Osteoporotic bone phenotype constitutes a major complication in patients with iron overload. The purpose of this review is to summarize what we have learnt about iron overload-associated bone loss from clinical studies and animal models. Bone is a metabolically active tissue that undergoes continuous remodeling with the involvement of osteoclasts that resorb mineralized bone, and osteoblasts that form new bone. Growing evidence suggests that both increased bone resorption and decreased bone formation are involved in the pathological bone-loss in iron overload conditions. We will discuss the cellular and molecular mechanisms that are involved in this detrimental process. Fuller understanding of this complex mechanism may lead to the development of improved therapeutics meant to interrupt the pathologic effects of excess iron on bone. PMID:28270766

  6. Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis

    PubMed Central

    Ulbrich, Friederike; Sticht, Carsten; Demory, Alexandra; Henzler, Thomas; Meyer, Mathias; Zierow, Johanna; Schneider, Sven; Breitkopf-Heinlein, Katja; Gaitantzi, Haristi; Spencer-Dene, Bradley; Arnold, Bernd; Klapproth, Kay; Géraud, Cyrill

    2017-01-01

    Microvascular endothelial cells (ECs) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific ECs control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal endothelial cells (LSECs) are uniquely differentiated to fulfill important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSECs. To study angiocrine Bmp2 signaling in the liver, we conditionally deleted Bmp2 in LSECs using EC subtype-specific Stab2-Cre mice. Genetic inactivation of hepatic angiocrine Bmp2 signaling in Stab2-Cre;Bmp2fl/fl (Bmp2LSECKO) mice caused massive iron overload in the liver and increased serum iron levels and iron deposition in several organs similar to classic hereditary hemochromatosis. Iron overload was mediated by decreased hepatic expression of hepcidin, a key regulator of iron homeostasis. Thus, angiocrine Bmp2 signaling within the hepatic vascular niche represents a constitutive pathway indispensable for iron homeostasis in vivo that is nonredundant with Bmp6. Notably, we demonstrate that organ-specific angiocrine signaling is essential not only for the homeostasis of the respective organ but also for the homeostasis of the whole organism. PMID:27903529

  7. Transformation rate between ferritin and hemosiderin assayed by serum ferritin kinetics in patients with normal iron stores and iron overload.

    PubMed

    Saito, Hiroshi; Hayashi, Hisao

    2015-11-01

    Ferritin iron, hemosiderin iron, total iron stores and transformation rate were determined by serum ferritin kinetics. The transformation rate between ferritin and hemosiderin is motivated by the potential difference between them. The transformer determines transformation rate according to the potential difference in iron mobilization and deposition. The correlations between transformation rate and iron stores were studied in 11 patients with chronic hepatitis C (CHC), 1 patent with treated iron deficiency anemia (TIDA), 9 patients with hereditary hemochromatosis (HH) and 4 patients with transfusion-dependent anemia (TD). The power regression curve of approximation showed an inverse correlation between transformation rate and ferritin iron, hemosiderin iron in part and total iron stores in HH. Such an inverse correlation between transformation rate and iron stores implies that the larger the amount of iron stores, the smaller the transformation of iron stores. On the other hand, a minimal inverse correlation between transformation rate and ferritin iron and no correlation between transformation rate and hemosiderin iron or total iron stores in CHC indicate the derangement of storage iron metabolism in the cells with CHC. Radio-iron fixation on the iron storing tissue in iron overload was larger than that in normal subjects by ferrokinetics. This is consistent with the inverse correlation between transformation rate and total iron stores in HH. The characteristics of iron turnover between ferritin and hemosiderin were disclosed from the correlation between transformation rate and ferritin iron, hemosiderin iron or total iron stores.

  8. Morbidity and mortality of adult patients with congenital dyserythropoietic anemia type I.

    PubMed

    Shalev, Hanna; Al-Athamen, Kaid; Levi, Itai; Levitas, Aviva; Tamary, Hannah

    2017-01-01

    Congenital dyserythropoietic anemia type I (CDAI) is a rare autosomal recessive disease characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. To better define the natural history of the disease among adult patients, we studied 32 Bedouin patients (median age 34 yr; range 21-60) all carrying the same CDAN1 founder mutation. Follow-up studies included complete blood count, blood chemistry, abdominal ultrasound, echocardiography, and T2*MRI. Main complications were due to anemia and ineffective erythropoiesis [osteoporosis (8/9, 89%), cholelithiasis (21/30, 70%), pulmonary arterial hypertension (PAH) (6/25, 24%)] and iron overload [hypothyroidism (9/24, 38%), and diabetes mellitus (6/32, 19%)]. T2* MRI revealed increased liver iron but no cardiac iron (13/13). Anemia improved in the majority of patients who underwent splenectomy (5/6). Three patients died (9%) at the age of 46-56 due to PAH (1) and sepsis (2). All previously underwent splenectomy. Analyzing both our patients and the 21 patients previously described by Heimpel et al. (Blood 107:334, 2006), we conclude that adults with CDA I suffer significant morbidity and mortality. Careful monitoring of iron overload and prompt iron chelation therapy is mandatory. Due to possible complications and inconsistent response to splenectomy α-interferon, transfusion therapy or stem cell transplantation should be considered as alternatives to this procedure in severely affected patients.

  9. The newer hematinics, their use and abuse.

    PubMed

    LUTTGENS, W F

    1952-12-01

    The newer hematinics are merely refinements of preexisting forms of treatment, but they have aided particularly in a better understanding of the deficiency states. The intrinsic factor of Castle has not been isolated from the gastric juice, and the interrelationships of this substance with the extrinsic factor (vitamin B(12)) and folic acid have not been defined at this time. Vitamin B(12) appears to be the active principle of refined liver extract and alone is probably adequate treatment for pernicious anemia. The other varieties of megaloblastic anemia may result from deficiency of vitamin B(12) or folic acid, although generally treatment with the latter brings about complete and lasting remission. The use of multihematinics and multivitamin preparations containing folic acid is to be condemned, particularly because of the possibility of their obscuring anemia and thwarting diagnosis of pernicious anemia until neurologic complications have taken place. Saccharated oxide of iron is a relatively safe preparation for intravenous administration, but the indications for its use are few. Because the body has no mechanism for iron excretion, only the amount of iron necessary to make up a deficiency should be given, although there is no definite evidence that hemochromatosis results from overdosage.

  10. Normal Glucose Metabolism in Carnivores Overlaps with Diabetes Pathology in Non-Carnivores

    PubMed Central

    Schermerhorn, Thomas

    2013-01-01

    Carnivores, such as the dolphin and the domestic cat, have numerous adaptations that befit consumption of diets with high protein and fat content, with little carbohydrate content. Consequently, nutrient metabolism in carnivorous species differs substantially from that of non-carnivores. Important metabolic pathways known to differ between carnivores and non-carnivores are implicated in the development of diabetes and insulin resistance in non-carnivores: (1) the hepatic glucokinase (GCK) pathway is absent in healthy carnivores yet GCK deficiency may result in diabetes in rodents and humans, (2) healthy dolphins and cats are prone to periods of fasting hyperglycemia and exhibit insulin resistance, both of which are risk factors for diabetes in non-carnivores. Similarly, carnivores develop naturally occurring diseases such as hemochromatosis, fatty liver, obesity, and diabetes that have strong parallels with the same disorders in humans. Understanding how evolution, environment, diet, and domestication may play a role with nutrient metabolism in the dolphin and cat may also be relevant to human diabetes. PMID:24348462

  11. Potential applications for cell regulatory factors in liver progenitor cell therapy

    PubMed Central

    Shupe, Thomas; Petersen, Bryon E.

    2010-01-01

    Orthotopic liver transplant represent the state of the art treatment for terminal liver pathologies such as cirrhosis in adults and hemochromatosis in neonates. A limited supply of transplantable organs in relationship to the demand means that many patients will succumb to disease before an organ becomes available. One promising alternative to liver transplant is therapy based on the transplant of liver progenitor cells. These cells may be derived from the patient, expanded in vitro, and transplanted back to the diseased liver. Inborn metabolic disorders represent the most attractive target for liver progenitor cell therapy, as many of these disorders may be corrected by repopulation of only a portion of the liver by healthy cells. Another potential application for liver progenitor cell therapy is the seeding of bio-artificial liver matrix. These ex vivo bioreactors may someday be used to bridge critically ill patients to other treatments. Conferring a selective growth advantage to the progenitor cell population remains an obstacle to therapy development. Understanding the molecular signaling mechanisms and micro-environmental cues that govern liver progenitor cell phenotype may someday lead to strategies for providing this selective growth advantage. The discovery of a population of cells within the bone marrow possessing the ability to differentiate into hepatocytes may provide an easily accessible source of cells for liver therapies. PMID:20851776

  12. Iron-refractory iron deficiency anemia.

    PubMed

    Yılmaz Keskin, Ebru; Yenicesu, İdil

    2015-03-05

    Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the "atypical" microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field.

  13. Genetic defects of iron transport.

    PubMed

    Bannerman, R M

    1976-09-01

    Five genetic traits in man and laboratory animals have major effects on iron transport. The heterogeneous condition, hemochromatosis, in some families appears to segregate as a Mendelian trait, and is associated with defective control of intestinal iron absorption. In the very rare human autosomal recessive trait, atransferrinemia, there is an almost total lack of transferrin and gross maldistribution of iron through the body. In mice, sex-linked anemia (an X-linked recessive trait) causes iron deficiency through defective iron absorption, at the "exit" step; a similar defect probably exists in placental iron transfer. In microcytic anemia of mice, an autosomal recessive trait, iron absorption is also impaired because of a defect of iron entry into cells, which is probably generalized. Belgrade rat anemia, less understood at present, also may involve a major disorder of iron metabolism. Study of these mutations has provided new knowledge of iron metabolism and its genetic control Their phenotypic interaction with nutritional factors, especially the form and quantity of iron in the diet, may provide new insights for the study of nutrition.

  14. Clinical implications of gene polymorphisms in venous leg ulcer: a model in tissue injury and reparative process.

    PubMed

    Zamboni, Paolo; Gemmati, Donato

    2007-07-01

    Wound healing is a multi-step process involving complex pathways at cell and molecular level. Lack of understanding of the molecular mechanisms and pathogenesis of impaired healing in chronic leg ulcers limits clinical assessment and management. In addition, individual genetic background certainly affects the response to treatment and specifically modulates the unfavourable lesion environment. Although the number of actors involved in the aetiology of chronic wounds is extremely high, the ability to find out groups of candidate genes on the basis of clinical and physio-pathological findings is a crucial step. The present review demonstrates how recognition of functional gene variants, mostly single nucleotide polymorphisms (SNPs), significantly involved in wound healing and venous ulcer establishment, extraordinarily helps prognosis, diagnosis and treatment of chronic wounds. We deal with on how one can manage SNPs in coagulation factor XIII (FXIII) and hemochromatosis (HFE) genes as molecular markers or prognostic tools. In this fashion, we could pave the way for strategies aimed to single out in advance categories of patients at increased risk to develop severe complications of chronic venous disorders, or to predict the healing time after surgical intervention. Because of its relevant epidemiology and its easily visualized lesions, venous leg ulcer is an ideal model for investigating, the mechanisms of tissue injury and reparative process, as well as the influence of different genetic backgrounds.

  15. Genetic polymorphisms of vein wall remodeling in chronic venous disease: a narrative and systematic review.

    PubMed

    Bharath, Vighnesh; Kahn, Susan R; Lazo-Langner, Alejandro

    2014-08-21

    Chronic venous disease encompasses a spectrum of disorders caused by an abnormal venous system. They include chronic venous insufficiency, varicose veins, lipodermatosclerosis, postthrombotic syndrome, and venous ulceration. Some evidence suggests a genetic predisposition to chronic venous disease from gene polymorphisms associated mainly with vein wall remodeling. The literature exploring these polymorphisms has not been reviewed and compiled thus far. In this narrative and systematic review, we present the current evidence available on the role of polymorphisms in genes involved in vein wall remodeling and other pathways as contributors to chronic venous disease. We searched the EMBASE, Medline, and PubMed databases from inception to 2013 for basic science or clinical studies relating to genetic associations in chronic venous disease and obtained 38 relevant studies for this review. Important candidate genes/proteins include the matrix metalloproteinases (extracellular matrix degradation), vascular endothelial growth factors (angiogenesis and vessel wall integrity), FOXC2 (vascular development), hemochromatosis (involved in venous ulceration and iron absorption), and various types of collagen (contributors to vein wall strength). The data on associations between these genes/proteins and the postthrombotic syndrome are limited and additional studies are required. These associations might have future prognostic and therapeutic implications.

  16. Molecular epidemiology of HFE gene polymorphic variants (C282Y, H63D and S65C) in the population of Espírito Santo, Brazil.

    PubMed

    Alves, L N R; Santos, E V W; Stur, E; Silva Conforti, A M A; Louro, I D

    2016-04-27

    Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to progressive iron accumulation and may cause cirrhosis, hepatocellular carcinoma, diabetes, and heart failure. Most cases of HH have been linked to mutations in genes associated with iron homeostasis. There have been three major variants in the high Fe (HFE) gene associated with the disease: C282Y, H63D and S65C. In this context, we aimed to evaluate the prevalence of the polymorphic variants (C282Y, H63D and S65C) of the HFE gene in the population of the Espírito Santo State (ES), Brazil by analyzing three different groups: general population (N = 120), Pomeranian descendants (N = 59), and patients with HH (N = 20). Using genomic DNA extracted from peripheral blood, polymorphic variant identification was performed by polymerase chain reaction-restriction fragment length polymorphism. Statistically significant differences were observed for genotype distribution of C282Y (P < 0.001) and H63D (P = 0.013) between the general population and the patients diagnosed with HH. This is the first study to analyze HFE gene allele frequencies for the general population, Pomeranian subpopulation, and patients with HH of ES, Brazil.

  17. Genetic aspects of scurvy and the European famine of 1845-1848.

    PubMed

    Delanghe, Joris R; De Buyzere, Marc L; Speeckaert, Marijn M; Langlois, Michel R

    2013-09-12

    The view of scurvy being exclusively a nutritional disorder needs to be updated. Genetic polymorphisms of HFE and haptoglobin (Hp) may explain the geographic variability of mortality caused by the European famine of the mid-19th century. In this period, potatoes had fallen victim to the potato blight and Ireland was more severely hit than continental Europe. Hereditary hemochromatosis is a genetic disorder with mutations in the HFE gene, characterized by iron overload (with a reduced vitamin C stability) and with a predominance of affected men. The Irish have the world's highest frequency of the C282Y mutation and the particular iron metabolism of the Irish helps to understand the size of the catastrophe and the observed overrepresentation of male skeletons showing scurvy. Hp is a plasma α2-glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin and vitamin C. The relative number of scurvy victims corresponds with the Hp 2-2 frequency, which is associated with iron conservation and has an impact on vitamin C stability. As iron is more abundant in males, males are overrepresented in the group of skeletons showing scurvy signs.

  18. Direct-to-consumer sales of genetic services on the Internet.

    PubMed

    Gollust, Sarah E; Wilfond, Benjamin S; Hull, Sara Chandros

    2003-01-01

    PURPOSE The increasing use of the Internet to obtain genetics information and to order medical services without a prescription, combined with a rise in direct-to-consumer marketing for genetic testing, suggests the potential for the Internet to be used to sell genetic services. METHODS A systematic World Wide Web search was conducted in May 2002 to assess the availability of genetic services sold directly to consumers on the Internet. RESULTS Out of 105 sites that offered genetic services directly, most offered non-health-related services, including parentage confirmation testing (83%), identity testing (56%), and DNA banking (24%); however, health-related genetic tests were offered through 14 sites (13%). The health-related genetic tests available ranged from standard tests, such as hemochromatosis and cystic fibrosis, to more unconventional tests related to nutrition, behavior, and aging. Of these 14 sites, 5 described risks associated with the genetic services and 6 described the availability of counseling. CONCLUSIONS The availability of direct sales of health-related genetic tests creates the potential for inadequate pretest decision making, misunderstanding test results, and access to tests of questionable clinical value.

  19. MTP -493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients.

    PubMed

    Siqueira, E R F; Oliveira, C P M S; Correa-Giannella, M L; Stefano, J T; Cavaleiro, A M; Fortes, M A H Z; Muniz, M T C; Silva, F S; Pereira, L M M B; Carrilho, F J

    2012-01-01

    The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8% of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3% of the patients with fibrosis grade 1+2 (OR = 1.8; 95%CI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95%CI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.

  20. Dolphins as animal models for type 2 diabetes: sustained, post-prandial hyperglycemia and hyperinsulinemia.

    PubMed

    Venn-Watson, Stephanie; Carlin, Kevin; Ridgway, Sam

    2011-01-01

    There is currently no known natural animal model that fully complements type 2 diabetes in humans. Criteria for a true natural animal model include the presence of a fasting hyperglycemia, evidence of insulin resistance, and pathologies matching that reported in humans. To investigate the bottlenose dolphin (Tursiops truncatus) as a comparative model for type 2 diabetes in humans, hourly plasma and urine chemistry changes, including glucose, were analyzed among five healthy, adult dolphins for 24 h following ingestion of 2.5-3.5 kg of mackerel or 2-3 L of 10% dextrose in ionosol. Fasting and 2 h post-prandial insulin levels were also determined among five adult dolphins to assess the presence of hyperinsulinemia. Finally, a case-control study compared insulin and glucagon levels among dolphins with and without iron overload, a condition associated with insulin resistance in humans. Both protein and dextrose meals caused significant increases in plasma glucose during the 0-5 h post-prandial period; dolphins fed dextrose demonstrated a sustained hyperglycemia lasting 5-10 h. Fasting plasma insulin levels among healthy dolphins mimicked those found in humans with some insulin resistance. Dolphins with hemochromatosis had higher post-prandial plasma insulin levels compared to controls. We conclude that bottlenose dolphins can demonstrate metabolic responses consistent with type 2 diabetes, specifically sustained hyperglycemia and hyperinsulinemia. Understanding more about how and why dolphins have a diabetes-like metabolism may provide new research avenues for diabetes in humans.

  1. The effects of okra (Abelmoschus esculentus Linn.) on the cellular events associated with Alzheimer's disease in a stably expressed HFE neuroblastoma SH-SY5Y cell line.

    PubMed

    Mairuae, Nootchanat; Connor, James R; Lee, Sang Y; Cheepsunthorn, Poonlarp; Tongjaroenbuangam, Walaiporn

    2015-08-31

    It has been reported that persons carrying the H63D variant in their hemochromatosis (HFE) gene are at increased risk of Alzheimer's disease (AD). We investigated the possibility that okra (Abelmoschus esculentus) and quercetin could mitigate this risk factor by examining its effect on AD-associated cellular events in HFE stably expressing SH-SY5Y cells. Treatment of H63D HFE cells either with okra or quercetin significantly decreased reactive oxygen species (ROS), hydrogen peroxide (H2O2), and protein oxidation compared to untreated cells. The levels of tau phosphorylation at serine-199, serine-202, and serine-396 sites were also significantly decreased when cells were treated with okra. Exposure of the H63D and wild type (WT) cells to iron increased tau phosphorylation, but this response was decreased significantly when cells were treated with okra. The mechanism responsible for these changes appears to be related to decreased glycogen synthase kinase (GSK)-3β activity, an upstream signaling kinase of tau phosphorylation. We also established that okra treatment dramatically decreases intracellular iron levels in H63D cells compared to untreated cells. Our results provide important in vitro data on the effects of okra on various AD-associated cellular processes in H63D variant HFE cells. These results suggest okra may be beneficial in people expressing the H63D variant to reduce the risk of AD and other neurodegenerative diseases related to oxidative stress. Further in vivo studies would help confirm this.

  2. [Iron deficiency and overload. Implications in oxidative stress and cardiovascular health].

    PubMed

    Toxqui, L; De Piero, A; Courtois, V; Bastida, S; Sánchez-Muniz, F J; Vaquero, Ma P

    2010-01-01

    Although iron is an essential mineral for maintaining good health, excessive amounts are toxic. Nowadays, much interest is focused on the mechanisms and regulation of iron metabolism by down-regulation of the hormone hepcidin. The HAMP gene encodes for hepcidin appears to be exceptionally preserved. Disorders of iron metabolism could lead to iron overload, mainly causing the rare disease hereditary hemochromatosis, or on the other hand, iron deficiency and iron deficiency anaemia. Currently, these alterations constitute an important problem of public health. The genetic variation implicated in iron overload and iron deficiency anaemia, involves mutations in several genes such as HFE, TFR2,HAMP, HJV, Tf and TMPRSS6. Iron has the capacity to accept and donate electrons easily and can catalyze reactions of free radicals production. Therefore, iron overload causes lipid peroxidation and increases cardiovascular risk. Recently, a relationship between iron metabolism and insulin resistance and obesity has been described. In contrast, regarding a possible relationship between iron deficiency anaemia and cardiovascular disease, many aspects remain controversial. This review presents an overview of the most recent information concerning iron metabolism, iron bioavailability and iron overload/deficiency related diseases. The relation between iron and cardiovascular risk, in iron overload and in iron deficiency situations, is also examined. Finally, strategies to modify dietary iron bioavailability in order to prevent iron deficiency or alleviate iron overload are suggested.

  3. Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks

    PubMed Central

    Jones, Nathan R.; Ashmore, Joseph H.; Lee, Sang Y.; Richie, John P.; Lazarus, Philip; Muscat, Joshua E.

    2015-01-01

    Background: Polymorphisms in the hemochromatosis (HFE) gene are associated with excessive iron absorption from the diet, and pro-oxidant effects of iron accumulation are thought to be a risk factor for several types of cancer. Methods: The C282Y (rs1800562) and H63D (rs1799945) polymorphisms were genotyped in 301 oral cancer cases and 437 controls and analyzed in relation to oral cancer risk, and serum iron biomarker levels from a subset of 130 subjects. Results: Individuals with the C282Y allele had lower total iron binding capacity (TIBC) (321.2 ± 37.2 µg/dL vs. 397.7 ± 89.0 µg/dL, p = 0.007) and higher percent transferrin saturation (22.0 ± 8.7 vs. 35.6 ± 22.9, p = 0.023) than wild type individuals. Iron and ferritin levels approached significantly higher levels for the C282Y allele (p = 0.0632 and p = 0.0588, respectively). Conclusions: Iron biomarker levels were elevated by the C282Y allele, but neither (rs1800562) nor (rs1799945) was associated with oral cancer risk in blacks and whites. PMID:26690219

  4. Iron overload patients with unknown etiology from national survey in Japan.

    PubMed

    Ikuta, Katsuya; Hatayama, Mayumi; Addo, Lynda; Toki, Yasumichi; Sasaki, Katsunori; Tatsumi, Yasuaki; Hattori, Ai; Kato, Ayako; Kato, Koichi; Hayashi, Hisao; Suzuki, Takahiro; Kobune, Masayoshi; Tsutsui, Miyuki; Gotoh, Akihiko; Aota, Yasuo; Matsuura, Motoo; Hamada, Yuzuru; Tokuda, Takahiro; Komatsu, Norio; Kohgo, Yutaka

    2017-03-01

    Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5 ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000 ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

  5. Iron oxides in human spleen.

    PubMed

    Kopáni, Martin; Miglierini, Marcel; Lančok, Adriana; Dekan, Július; Čaplovicová, Mária; Jakubovský, Ján; Boča, Roman; Mrazova, Hedviga

    2015-10-01

    Iron is an essential element for fundamental cell functions and a catalyst for chemical reactions. Three samples extracted from the human spleen were investigated by scanning (SEM) and transmission electron microscopy (TEM), Mössbauer spectrometry (MS), and SQUID magnetometry. The sample with diagnosis of hemosiderosis (H) differs from that referring to hereditary spherocytosis and the reference sample. SEM reveals iron-rich micrometer-sized aggregate of various structures-tiny fibrils in hereditary spherocytosis sample and no fibrils in hemochromatosis. Hematite and magnetite particles from 2 to 6 μm in TEM with diffraction in all samples were shown. The SQUID magnetometry shows different amount of diamagnetic, paramagnetic and ferrimagnetic structures in the tissues. The MS results indicate contribution of ferromagnetically split sextets for all investigated samples. Their occurrence indicates that at least part of the sample is magnetically ordered below the critical temperature. The iron accumulation process is different in hereditary spherocytosis and hemosiderosis. This fact may be the reason of different iron crystallization.

  6. Accelerated CCl4-Induced Liver Fibrosis in Hjv-/- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression

    PubMed Central

    Sebastiani, Giada; Gkouvatsos, Kostas; Maffettone, Carmen; Busatto, Graziella; Guido, Maria; Pantopoulos, Kostas

    2011-01-01

    Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/-) mice and wild type (wt) controls were intoxicated with CCl4. Hjv-/- mice developed earlier (by 2-4 weeks) and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv−/− animals. Even though livers of naïve Hjv−/− mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2–3 fold vs. wt, p<0.05) levels of α1-(I)-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis. PMID:21966437

  7. Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management.

    PubMed

    Rider, Nicholas L; Strauss, Kevin A; Brown, Krysta; Finkenstedt, Armin; Puffenberger, Erik G; Hendrickson, Christine L; Robinson, Donna L; Muenke, Nikolas; Tselepis, Chris; Saunders, Lauren; Zoller, Heinz; Morton, D Holmes

    2011-10-01

    Pyruvate kinase deficiency is a chronic illness with age specific consequences. Newborns suffer life-threatening hemolytic crisis and hyperbilirubinemia. Adults are at risk for infections because of asplenia, pregnancy-related morbidity, and may suffer organ damage because of systemic iron overload. We describe 27 Old Order Amish patients (ages 8 months-52 years) homozygous for c.1436G>A mutations in PKLR. Each subject had a predictable neonatal course requiring packed red blood cell transfusions (30 ± 5 mL/kg) to control hemolytic disease and intensive phototherapy to prevent kernicterus. Hemochromatosis affected 29% (n = 4) of adult patients, who had inappropriately normal serum hepcidin (34.5 ± 12.7 ng/mL) and GDF-15 (595 ± 335pg/mL) relative to hyperferritinemia (769 ± 595 mg/dL). A high prevalence of HFE gene mutations exists in this population and may contribute to iron-related morbidity. Based on our observations, we present a strategy for long-term management of pyruvate kinase deficiency.

  8. Iron Absorption in Drosophila melanogaster

    PubMed Central

    Mandilaras, Konstantinos; Pathmanathan, Tharse; Missirlis, Fanis

    2013-01-01

    The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration. PMID:23686013

  9. Repulsive Guidance Molecule is a structural bridge between Neogenin and Bone Morphogenetic Protein

    PubMed Central

    Healey, Eleanor G.; Bishop, Benjamin; Elegheert, Jonathan; Bell, Christian H.; Padilla-Parra, Sergi; Siebold, Christian

    2015-01-01

    Repulsive guidance molecules (RGMs) control crucial processes spanning cell motility, adhesion, immune cell regulation and systemic iron metabolism. RGMs signal via two fundamental signaling cascades: the Neogenin (NEO1) and the Bone Morphogenetic Protein (BMP) pathways. Here, we report crystal structures of the N-terminal domains of all human RGM family members in complex with the BMP ligand BMP2, revealing a novel protein fold and a conserved BMP-binding mode. Our structural and functional data suggest a pH-linked mechanism for RGM-activated BMP signaling and offer a rationale for RGM mutations causing juvenile hemochromatosis. We also determined the ternary BMP2–RGM–NEO1 complex crystal structure, which combined with solution scattering and live-cell super-resolution fluorescence microscopy, indicates BMP-induced clustering of the RGM–NEO1 complex. Our results show how RGM acts as the central hub linking BMP and NEO1 and physically connecting these fundamental signaling pathways. PMID:25938661

  10. Glucose metabolism in the Belgrade rat, a model of iron-loading anemia.

    PubMed

    Jia, Xuming; Kim, Jonghan; Veuthey, Tania; Lee, Chih-Hao; Wessling-Resnick, Marianne

    2013-06-15

    The iron-diabetes hypothesis proposes an association between iron overload and glucose metabolism that is supported by a number of epidemiological studies. The prevalence of type 2 diabetes in patients with hereditary hemochromatosis and iron-loading thalassemia supports this hypothesis. The Belgrade rat carries a mutation in the iron transporter divalent metal transporter 1 (DMT1) resulting in iron-loading anemia. In this study, we characterized the glycometabolic status of the Belgrade rat. Belgrade rats displayed normal glycemic control. Insulin signaling and secretion were not impaired, and pancreatic tissue did not incur damage despite high levels of nonheme iron. These findings suggest that loss of DMT1 protects against oxidative damage to the pancreas and helps to maintain insulin sensitivity despite iron overload. Belgrade rats had lower body weight but increased food consumption compared with heterozygous littermates. The unexpected energy balance was associated with increased urinary glucose output. Increased urinary excretion of electrolytes, including iron, was also observed. Histopathological evidence suggests that altered renal function is secondary to changes in kidney morphology, including glomerulosclerosis. Thus, loss of DMT1 appears to protect the pancreas from injury but damages the integrity of kidney structure and function.

  11. Iron-Refractory Iron Deficiency Anemia

    PubMed Central

    Yılmaz Keskin, Ebru; Yenicesu, İdil

    2015-01-01

    Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the “atypical” microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field. PMID:25805669

  12. [Cardiological follow-up in patients with Fabry disease].

    PubMed

    Pieruzzi, Federico; Pieroni, Maurizio; Chimenti, Cristina; Frustaci, Andrea; Sarais, Cristiano; Cecchi, Franco

    2010-01-01

    Fabry disease is a rare tesaurismosis due to a deficit of the lysosomal enzyme activity of alpha-galactosidase, needed for the normal catabolism of globotriaosylceramides (GL3). Fabry cardiac involvement has several clinical manifestations: concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. Differentiating Fabry disease from similar conditions is often quite straightforward, e.g., cardiac amyloidosis is often associated with low electrocardiographic voltages, and systemic symptoms are usually associated with hemochromatosis and sarcoidosis. However, sometimes second-level (genetic analysis, alpha-galactosidase levels) or invasive investigations are required, which can include endomyocardial biopsy. Diagnostic imaging techniques have been described, but they lack specificity. Echocardiographic imaging with tissue Doppler analysis and/or strain rate analysis can allow diagnosis of Fabry disease even before left ventricular hypertrophy becomes apparent. This review illustrates the techniques for staging cardiac involvement and damage in Fabry disease and for the long-term follow-up of Fabry patients with or without cardiac involvement. Careful cardiac monitoring is especially important in elderly female carriers, who often develop renal disorders and/or left ventricular hypertrophy as the only manifestations of their late Fabry disease. In some clinical series, Fabry disease was diagnosed in 12% of women with adult-onset hypertrophic cardiomyopathy. Cardiological problems and outcomes of enzyme replacement therapy, associated with or without other cardiological treatments, are also discussed.

  13. Gastrins, iron homeostasis and colorectal cancer.

    PubMed

    Kovac, Suzana; Anderson, Gregory J; Baldwin, Graham S

    2011-05-01

    The peptide hormone gastrin has been identified as a major regulator of acid secretion and a potent mitogen for normal and malignant gastrointestinal cells. The importance of gastric acid in the absorption of dietary iron first became evident 50 years ago when iron deficiency anemia was recognized as a long-term consequence of partial gastrectomy. This review summarizes the connections between circulating gastrins, iron status and colorectal cancer. Gastrins bind two ferric ions with micromolar affinity and, in the case of non-amidated forms of the hormone, iron binding is essential for biological activity in vitro and in vivo. The demonstration of an interaction between gastrin and transferrin by biochemical techniques led to the proposal that gastrins catalyze the loading of transferrin with iron. Several lines of evidence, including the facts that the concentrations of circulating gastrins are increased in mice and humans with the iron overload disease hemochromatosis and that transferrin saturation positively correlates with circulating gastrin concentration, suggest the potential involvement of gastrins in iron homeostasis. Conversely, recognition that ferric ions play an unexpected role in the biological activity of gastrins may assist in the development of useful therapies for colorectal carcinoma and other disorders of mucosal proliferation in the gastrointestinal tract. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

  14. Nutrient absorption.

    PubMed

    Rubin, Deborah C

    2004-03-01

    Our understanding of nutrient absorption continues to grow, from the development of unique animal models and from studies in which cutting-edge molecular and cellular biologic approaches have been used to analyze the structure and function of relevant molecules. Studies of the molecular genetics of inherited disorders have also provided many new insights into these processes. A major advance in lipid absorption has been the cloning and characterization of several intestinal acyl CoA:monoacylglycerol acyltransferases; these may provide new targets for antiobesity drug therapy. Studies of intestinal cholesterol absorption and reverse cholesterol transport have encouraged the development of novel potential treatments for hyperlipidemia. Observations in genetically modified mice and in humans with mutations in glucose transporter 2 suggest the importance of a separate microsomal membrane transport pathway for glucose transport. The study of iron metabolism has advanced greatly with the identification of the hemochromatosis gene and the continued examination of the genetic regulation of iron absorptive pathways. Several human thiamine transporters have been identified, and their specific roles in different tissues are being explored.

  15. Iron absorption in Drosophila melanogaster.

    PubMed

    Mandilaras, Konstantinos; Pathmanathan, Tharse; Missirlis, Fanis

    2013-05-17

    The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration.

  16. HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases

    PubMed Central

    Evangelista, Andreia Silva; de Araújo, Thiago Ferreira; Abrantes-Lemos, Clarice Pires; Deguti, Marta Mitiko; Cançado, Eduardo Luiz Rachid

    2015-01-01

    Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS) > 45%, and serum ferritin (SF) > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n = 16) were the HFE hereditary hemochromatosis (HFE-HH) group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n = 92). Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population. PMID:25654085

  17. Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy.

    PubMed

    Das, Subhash K; Wang, Wang; Zhabyeyev, Pavel; Basu, Ratnadeep; McLean, Brent; Fan, Dong; Parajuli, Nirmal; DesAulniers, Jessica; Patel, Vaibhav B; Hajjar, Roger J; Dyck, Jason R B; Kassiri, Zamaneh; Oudit, Gavin Y

    2015-12-07

    Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.

  18. Review of fetal and neonatal immune cytopenias.

    PubMed

    Lewin, Sharon; Bussel, James B

    2015-01-01

    The fetoplacental interface plays a unique role in pathologies of the fetus and neonate, and is increasingly being recognized for effects on fetal and neonatal development that resonate into adulthood. In this review, we will use several exemplary disorders involving each of the 3 types of blood cells to explore the effect of perinatal insults on subsequent development of the affected cell line. We will present new data regarding outcomes of infants treated prenatally for fetal and neonatal alloimmune thrombocytopenia (FNAIT) and contrast these with outcomes of infants affected by hemolytic disease of the fetus and newborn. We also will explore the differences between FNAIT and passively transferred antibodies, as seen in maternal idiopathic thrombocytopenic purpura. Neonatal hemochromatosis is an example of a disease that previously was largely fatal, but whose newly discovered etiology as an immune-mediated perinatal disorder has resulted in development of highly effective treatment. Finally, we will examine the interplay between lymphopoiesis and the placenta in an effort to further explore the phenomenon of neutropenia in preeclampsia, whose etiology remains unknown.

  19. Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis.

    PubMed

    Koch, Philipp-Sebastian; Olsavszky, Victor; Ulbrich, Friederike; Sticht, Carsten; Demory, Alexandra; Leibing, Thomas; Henzler, Thomas; Meyer, Mathias; Zierow, Johanna; Schneider, Sven; Breitkopf-Heinlein, Katja; Gaitantzi, Haristi; Spencer-Dene, Bradley; Arnold, Bernd; Klapproth, Kay; Schledzewski, Kai; Goerdt, Sergij; Géraud, Cyrill

    2017-01-26

    Microvascular endothelial cells (ECs) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific ECs control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal endothelial cells (LSECs) are uniquely differentiated to fulfill important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSECs. To study angiocrine Bmp2 signaling in the liver, we conditionally deleted Bmp2 in LSECs using EC subtype-specific Stab2-Cre mice. Genetic inactivation of hepatic angiocrine Bmp2 signaling in Stab2-Cre;Bmp2(fl/fl) (Bmp2(LSECKO)) mice caused massive iron overload in the liver and increased serum iron levels and iron deposition in several organs similar to classic hereditary hemochromatosis. Iron overload was mediated by decreased hepatic expression of hepcidin, a key regulator of iron homeostasis. Thus, angiocrine Bmp2 signaling within the hepatic vascular niche represents a constitutive pathway indispensable for iron homeostasis in vivo that is nonredundant with Bmp6. Notably, we demonstrate that organ-specific angiocrine signaling is essential not only for the homeostasis of the respective organ but also for the homeostasis of the whole organism.

  20. Fiber evanescent wave spectroscopy using the mid-infrared provides useful fingerprints for metabolic profiling in humans

    NASA Astrophysics Data System (ADS)

    Anne, Marie-Laure; Le Lan, Caroline; Monbet, Valérie; Boussard-Plédel, Catherine; Ropert, Martine; Sire, Olivier; Pouchard, Michel; Jard, Christine; Lucas, Jacques; Adam, Jean Luc; Brissot, Pierre; Bureau, Bruno; Loréal, Olivier

    2009-09-01

    Fiber evanescent wave spectroscopy (FEWS) explores the mid-infrared domain, providing information on functional chemical groups represented in the sample. Our goal is to evaluate whether spectral fingerprints obtained by FEWS might orientate clinical diagnosis. Serum samples from normal volunteers and from four groups of patients with metabolic abnormalities are analyzed by FEWS. These groups consist of iron overloaded genetic hemochromatosis (GH), iron depleted GH, cirrhosis, and dysmetabolic hepatosiderosis (DYSH). A partial least squares (PLS) logistic method is used in a training group to create a classification algorithm, thereafter applied to a test group. Patients with cirrhosis or DYSH, two groups exhibiting important metabolic disturbances, are clearly discriminated from control groups with AUROC values of 0.94+/-0.05 and 0.90+/-0.06, and sensibility/specificity of 86/84% and 87/87%, respectively. When pooling all groups, the PLS method contributes to discriminate controls, cirrhotic, and dysmetabolic patients. Our data demonstrate that metabolic profiling using infrared FEWS is a possible way to investigate metabolic alterations in patients.

  1. High-speed DNA genotyping using microfabricated capillary array electrophoresis chips

    SciTech Connect

    Woolley, A.T.; Sensabaugh, G.F.; Mathies, R.A.

    1997-06-01

    Capillary array electrophoresis (CAE) chips have been designed and fabricated with the capacity to rapidly (<160 s) analyze 12 different samples in parallel. Detection of all lanes with 0.3 s temporal resolution was achieved using a laser-excited confocal-fluorescence scanner. The operation and capabilities of these CAE microdevices were first determined by performing electrophoretic separations of pBR322 MspI DNA samples. Genotyping of HLA-H, a candidate gene for the diagnosis of hereditary hemochromatosis, was then performed to demonstrate the rapid analysis of biologically relevant samples. Two-color multiplex fluorescence detection of HLA-H genotypes was accomplished by prelabeling the standard pBR322 MspI DNA ladder with a red emitting bisintercalation dye (butyl TOTIN) and on-column labeling of the HLA-H DNA with thiazole orange. This work establishes the feasibility of using CAE chips for high-speed, high-throughput genotyping. 44 refs., 7 figs.

  2. Quantitative imaging of chemical composition using dual-energy, dual-source CT

    NASA Astrophysics Data System (ADS)

    Liu, Xin; Primak, Andrew N.; Yu, Lifeng; McCollough, Cynthia H.; Morin, Richard L.

    2008-03-01

    Dual-energy x-ray material decomposition has been proposed as a noninvasive quantitative imaging technique for more than 20 years. In this paper, we summarize previously developed dual-energy material decomposition methods and propose a simple yet accurate method for quantitatively measuring chemical composition in vivo. In order to take advantage of the newly developed dual-source CT, the proposed method is based upon post reconstruction (image space) data. Different from other post reconstruction methods, this method is designed to directly measure element composition (mass fraction) in a tissue by a simple table lookup procedure. The method has been tested in phantom studies and also applied to a clinical case. The results showed that this method is capable of accurately measuring elemental concentrations, such as iron in tissue, under low noise imaging conditions. The advantage of this method lies in its simplicity and fast processing times. We believe that this method can be applied clinically to measure the mass fraction of any chemical element in a two-material object, such as to quantify the iron overload in the liver (hemochromatosis). Further investigations on de-noising techniques, as well as clinical validation, are merited.

  3. FIB/SEM cell sectioning for intracellular metal granules characterization

    NASA Astrophysics Data System (ADS)

    Milani, Marziale; Brundu, Claudia; Santisi, Grazia; Savoia, Claudio; Tatti, Francesco

    2009-05-01

    Focused Ion Beams (FIBs) provide a cross-sectioning tool for submicron dissection of cells and subcellular structures. In combination with Scanning Electron Microscope (SEM), FIB provides complementary morphological information, that can be further completed by EDX (Energy Dispersive X-ray Spectroscopy). This study focus onto intracellular microstructures, particularly onto metal granules (typically Zn, Cu and Fe) and on the possibility of sectioning digestive gland cells of the terrestrial isopod P. scaber making the granules available for a compositional analysis with EDX. Qualitative and quantitative analysis of metal granules size, amount and distribution are performed. Information is made available of the cellular storing pattern and, indirectly, metal metabolism. The extension to human level is of utmost interest since some pathologies of relevance are metal related. Apart from the common metal-overload-diseases (hereditary hemochromatosis, Wilson's and Menkes disease) it has been demonstrated that metal in excess can influence carcinogenesis in liver, kidney and breast. Therefore protocols will be established for the observation of mammal cells to improve our knowledge about the intracellular metal amount and distribution both in healthy cells and in those affected by primary or secondary metal overload or depletion.

  4. Mapping and characterization of non-HLA multigene assemblages in the human MHC class I region

    SciTech Connect

    Venditti, C.P.; Harris, J.M.; Geraghty, D.E.

    1994-07-15

    The major histocompatibility complex (MHC) class I region has been shown to be associated with a variety of immune and nonimmune disorders. In an effort to initiate steps designed to identify the idiopathic hemochromatosis disease gene (HFE), the authors have cloned and mapped two expressed messages using probes from the HLA-H subregion that lie immediately distal to the HLA-A9 breakpoint. Although the cDNA clones identify distinct multifragment families that are dispersed throughout the MHC, the gene sequences from which the two cDNA clones derive map centromeric to the HLA-B locus and are absent from the genomes of higher nonhuman primates. This suggests that a syntenic coding segment arose within a highly polymorphic region (TNF to HLA-B interval) as the result of an insertion event following the emergence of Homo sapiens. An additional syntenic cluster exists within a peak of linkage disequilibrium with the HFE gene and may define coding sequences that underlie the defect in genetic iron overload. These data generally support the concept that the class I region is potentially gene-rich and further highlight the possibility that these new coding sequences may play a role in the development of a variety of HLA-linked diseases. The observations presented suggest that interlocus exchanges have played a structural role in the genesis of the human class I region. 46 refs., 6 refs.

  5. The role of iron in the skin and cutaneous wound healing

    PubMed Central

    Wright, Josephine A.; Richards, Toby; Srai, Surjit K. S.

    2014-01-01

    In this review article we discuss current knowledge about iron in the skin and the cutaneous wound healing process. Iron plays a key role in both oxidative stress and photo-induced skin damage. The main causes of oxidative stress in the skin include reactive oxygen species (ROS) generated in the skin by ultraviolet (UVA) 320–400 nm portion of the UVA spectrum and biologically available iron. We also discuss the relationships between iron deficiency, anemia and cutaneous wound healing. Studies looking at this fall into two distinct groups. Early studies investigated the effect of anemia on wound healing using a variety of experimental methodology to establish anemia or iron deficiency and focused on wound-strength rather than effect on macroscopic healing or re-epithelialization. More recent animal studies have investigated novel treatments aimed at correcting the effects of systemic iron deficiency and localized iron overload. Iron overload is associated with local cutaneous iron deposition, which has numerous deleterious effects in chronic venous disease and hereditary hemochromatosis. Iron plays a key role in chronic ulceration and conditions such as rheumatoid arthritis (RA) and Lupus Erythematosus are associated with both anemia of chronic disease and dysregulation of local cutaneous iron hemostasis. Iron is a potential therapeutic target in the skin by application of topical iron chelators and novel pharmacological agents, and in delayed cutaneous wound healing by treatment of iron deficiency or underlying systemic inflammation. PMID:25071575

  6. DIAGNOSIS OF ENDOCRINE DISEASE: Expanding the cause of hypopituitarism.

    PubMed

    Pekic, Sandra; Popovic, Vera

    2017-03-03

    Hypopituitarism is defined as one or more pituitary hormone deficits due to a lesion in the hypothalamic-pituitary region. By far, the most common cause of hypopituitarism associated with a sellar mass is a pituitary adenoma. A high index of suspicion is required for diagnosing hypopituitarism in several other conditions such as: other massess in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain injury, vascular lesions, infiltrative/immunological/inflammatory diseases (lymphocytic hypophysitis, sarcoidosis, hemochromatosis), infectious diseases and genetic disorders. Hypopituitarism may be permanent and progressive with sequential pattern of hormone deficiencies (radiation-induced hypopituitarism) or transient after traumatic brain injury with possible recovery occuring years from the initial event. In recent years there is increased reporting of less common and less reported causes of hypopituitarism with its delayed diagnosis. The aim of this review is to summarize the published data and to allow earlier identification of populations at risk of hypopituitarism since optimal hormonal replacement may significantly improve their quality of life and life expectancy.

  7. First cases of animal diseases published since 2000. 1. Dogs.

    PubMed

    Elsinghorst, Th A M

    2003-09-01

    In this first article of a series of papers listing first case reports of animal diseases published since 2000, the following 19 cases of dog diseases are discussed: Blastomycotic granuloma involving the cranial vena cava. Congenital myocardial hamartoma. Discospondylitis: three cases caused respectively by Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus epidermidis. Dystrophin deficient muscular dystrophy in a Labrador Retriever. Emphysematous prostatitis. Erythema multiforme major caused by a Parvovirus infection of keratinocytes. Hemochromatosis due to repeated blood transfusions. Intraspinal synovial cyst. Juvenile nephropathy in the Collie and the Irish Wolfhound. Primary cerebellar cortical degeneration (abiotrophy) in a Scottish terrier. Primary pulmonary artery chondrosarcoma. Renal dysplasia in a Bull Mastiff. Rhabdomyosarcoma (botryoid sarcoma) of the urinary bladder in a Maltese. Spinal mast cell tumor. Spongiform degeneration of the white matter in the central nervous system of Australian Cattle dog. Systemic pasteurellosis caused by Pasteurella canis. Thymic hemorrhage caused by dicumarol intoxication. Undimerized biclonal gammopathy with a single heavy chain class IgA in a dog with multiple myeloma. After a short introduction, the bibliographical data and the abstract of the author(s) and mostly some additional information derived from the article are given. The article will be regularly updated adding overlooked as well as new first reports.

  8. Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

    PubMed Central

    Rodriguez, Libia M; Giraldo, Mabel C; Velasquez, Laura I; Alvarez, Cristiam M; Garcia, Luis F; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

    2015-01-01

    A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH”) and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry. PMID:25983618

  9. Genetic modification of iron metabolism in mice affects the gut microbiota.

    PubMed

    Buhnik-Rosenblau, Keren; Moshe-Belizowski, Shirly; Danin-Poleg, Yael; Meyron-Holtz, Esther G

    2012-10-01

    The composition of the gut microbiota is affected by environmental factors as well as host genetics. Iron is one of the important elements essential for bacterial growth, thus we hypothesized that changes in host iron homeostasis, may affect the luminal iron content of the gut and thereby the composition of intestinal bacteria. The iron regulatory protein 2 (Irp2) and one of the genes mutated in hereditary hemochromatosis Hfe , are both proteins involved in the regulation of systemic iron homeostasis. To test our hypothesis, fecal metal content and a selected spectrum of the fecal microbiota were analyzed from Hfe-/-, Irp2-/- and their wild type control mice. Elevated levels of iron as well as other minerals in feces of Irp2-/- mice compared to wild type and Hfe-/- mice were observed. Interestingly significant variation in the general fecal-bacterial population-patterns was observed between Irp2-/- and Hfe-/- mice. Furthermore the relative abundance of five species, mainly lactic acid bacteria, was significantly different among the mouse lines. Lactobacillus (L.) murinus and L. intestinalis were highly abundant in Irp2-/- mice, Enterococcus faecium species cluster and a species most similar to Olsenella were highly abundant in Hfe-/- mice and L. johnsonii was highly abundant in the wild type mice. These results suggest that deletion of iron metabolism genes in the mouse host affects the composition of its intestinal bacteria. Further studying the relationship between gut microbiota and genetic mutations affecting systemic iron metabolism in human should lead to clinical implications.

  10. Serum ferritin.

    PubMed

    Worwood, M

    1979-01-01

    (1) Brief introduction to iron metabolism and the biochemistry of ferritin. (2) Early studies of circulating ferritin. (3) Methods for measuring serum ferritin concentrations -- immunoradiometric, radioimmuno- and enzyme-linked immuno assays based on liver or spleen ferritin -- an evaluation of these techniques. (4) Serum ferritin concentrations in normal subjects -- definition of normality -- relationship between storage iron and serum ferritin concentrations -- changes during development from birth to old age -- iron deficiency -- variability of serum ferritin concentration -- evaluation of use of ferritin assay for assessment of storage iron levels. (5) Serum ferritin concentrations in disease -- hemochromatosis -- secondary iron overload -- liver damage -- infection and chronic disease -- cancer. (6) Assay of serum ferritin with antibodies to ferritins other than liver or spleen -- ferritinemia and cancer. (7) Properties of serum ferritin -- molecular weight -- iron content -- isoelectric focusing patterns -- carbohydrate content -- immunological properties. (8) Physiology of circulating ferritin -- release of ferritin from tissues -- origin of circulating ferritin -- clearance from the plasma -- iron and protein turnover. (9) Summary -- factors influencing serum ferritin concentrations and clinical use of ferritin estimations.

  11. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

    PubMed Central

    Lakhal-Littleton, Samira; Wolna, Magda; Carr, Carolyn A.; Miller, Jack J. J.; Christian, Helen C.; Ball, Vicky; Santos, Ana; Diaz, Rebeca; Biggs, Daniel; Stillion, Richard; Holdship, Philip; Clarke, Kieran; Davies, Benjamin; Robbins, Peter A.

    2015-01-01

    Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation. PMID:25713362

  12. The second transferrin receptor regulates red blood cell production in mice

    PubMed Central

    Nai, Antonella; Lidonnici, Maria Rosa; Rausa, Marco; Mandelli, Giacomo; Pagani, Alessia; Silvestri, Laura; Ferrari, Giuliana

    2015-01-01

    Transferrin receptor 2 (TFR2) contributes to hepcidin regulation in the liver and associates with erythropoietin receptor in erythroid cells. Nevertheless, TFR2 mutations cause iron overload (hemochromatosis type 3) without overt erythroid abnormalities. To clarify TFR2 erythroid function, we generated a mouse lacking Tfr2 exclusively in the bone marrow (Tfr2BMKO). Tfr2BMKO mice have normal iron parameters, reduced hepcidin levels, higher hemoglobin and red blood cell counts, and lower mean corpuscular volume than normal control mice, a phenotype that becomes more evident in iron deficiency. In Tfr2BMKO mice, the proportion of nucleated erythroid cells in the bone marrow is higher and the apoptosis lower than in controls, irrespective of comparable erythropoietin levels. Induction of moderate iron deficiency increases erythroblasts number, reduces apoptosis, and enhances erythropoietin (Epo) levels in controls, but not in Tfr2BMKO mice. Epo-target genes such as Bcl-xL and Epor are highly expressed in the spleen and in isolated erythroblasts from Tfr2BMKO mice. Low hepcidin expression in Tfr2BMKO is accounted for by erythroid expansion and production of the erythroid regulator erythroferrone. We suggest that Tfr2 is a component of a novel iron-sensing mechanism that adjusts erythrocyte production according to iron availability, likely by modulating the erythroblast Epo sensitivity. PMID:25499454

  13. A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE Hereditary Haemochromatosis

    PubMed Central

    Constantine, C. C.; Anderson, G. J.; Vulpe, C. D.; McLaren, C. E.; Bahlo, M.; Yeap, H. L.; Gertig, D. M.; Osborne, N. J.; Bertalli, N. A.; Beckman, K. B.; Chen, V.; Matak, P.; McKie, A. T.; Delatycki, M. B.; Olynyk, J. K.; English, D. R.; Southey, M. C.; Giles, G. G.; Hopper, J. L.; Allen, K. J.; Gurrin, L. C.

    2009-01-01

    There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample stratified by HFE genotype of 863 from a cohort of 31,192 people of northern European descent provided blood samples for genotyping of 476 SNPs in 44 genes involved in iron metabolism. Single SNP association testing using linear regression models adjusted for sex, menopause and HFE genotype was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 µg/L (N=27) to 387 µg/L (N=16) for male C282Y homozygotes and from 357 µg/L (N=42) to 69 µg/L (N=12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype (p=0.004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0.4%, 22.6%) of the variance in serum ferritin levels of C282Y homozygotes. PMID:19673882

  14. Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism

    PubMed Central

    Zhao, Lu; Xia, Zhidan; Wang, Fudi

    2014-01-01

    Iron, copper, zinc, and eight other minerals are classified as essential trace elements because they present in minute in vivo quantities and are essential for life. Because either excess or insufficient levels of trace elements can be detrimental to life (causing human diseases such as iron-deficiency anemia, hemochromatosis, Menkes syndrome and Wilson's disease), the endogenous levels of trace minerals must be tightly regulated. Many studies have demonstrated the existence of systems that maintain trace element homeostasis, and these systems are highly conserved in multiple species ranging from yeast to mice. As a model for studying trace mineral metabolism, the zebrafish is indispensable to researchers. Several large-scale mutagenesis screens have been performed in zebrafish, and these screens led to the identification of a series of metal transporters and the generation of several mutagenesis lines, providing an in-depth functional analysis at the system level. Moreover, because of their developmental advantages, zebrafish have also been used in mineral metabolism-related chemical screens and toxicology studies. Here, we systematically review the major findings of trace element homeostasis studies using the zebrafish model, with a focus on iron, zinc, copper, selenium, manganese, and iodine. We also provide a homology analysis of trace mineral transporters in fish, mice and humans. Finally, we discuss the evidence that zebrafish is an ideal experimental tool for uncovering novel mechanisms of trace mineral metabolism and for improving approaches to treat mineral imbalance-related diseases. PMID:24639652

  15. Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation

    PubMed Central

    Poli, Maura; Luscieti, Sara; Gandini, Valentina; Maccarinelli, Federica; Finazzi, Dario; Silvestri, Laura; Roetto, Antonella; Arosio, Paolo

    2010-01-01

    Background Impaired regulation of hepcidin in response to iron is the cause of genetic hemochromatosis associated with defects of HFE and transferrin receptor 2. However, the role of these proteins in the regulation of hepcidin expression is unclear. Design and Methods Hepcidin expression, SMAD and extracellular signal-regulated kinase (Erk) phosphorylation and furin expression were analyzed in hepatic HepG2 cells in which HFE and transferrin receptor 2 were down-regulated or expressed, or furin activity specifically inhibited. Furin expression was also analyzed in the liver of transferrin receptor 2 null mice. Results We showed that the silencing of HFE and transferrin receptor 2 reduced both Erk phosphorylation and furin expression, that the exogenous expression of the two enhanced the induction of phosphoErk1/2 and furin by holotransferrin, but that this did not occur when the pathogenic HFE mutant C282Y was expressed. Furin, phosphoErk1/2 and phosphoSMAD1/5/8 were down-regulated also in transferrin receptor 2-null mice. Treatment of HepG2 cells with an inhibitor of furin activity caused a strong suppression of hepcidin mRNA, probably due to the inhibition of bone morphogenic protein maturation. Conclusions The data indicate that transferrin receptor 2 and HFE are involved in holotransferrin-dependent signaling for the regulation of furin which involved Erk phosphorylation. Furin in turn may control hepcidin expression. PMID:20634490

  16. Pharmacological Targeting of the Hepcidin/Ferroportin Axis

    PubMed Central

    Sebastiani, Giada; Wilkinson, Nicole; Pantopoulos, Kostas

    2016-01-01

    The iron regulatory hormone hepcidin limits iron fluxes to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells. Hepcidin insufficiency causes hyperabsorption of dietary iron, hyperferremia and tissue iron overload, which are hallmarks of hereditary hemochromatosis. Similar responses are also observed in iron-loading anemias due to ineffective erythropoiesis (such as thalassemias, dyserythropoietic anemias and myelodysplastic syndromes) and in chronic liver diseases. On the other hand, excessive hepcidin expression inhibits dietary iron absorption and leads to hypoferremia and iron retention within tissue macrophages. This reduces iron availability for erythroblasts and contributes to the development of anemias with iron-restricted erythropoiesis (such as anemia of chronic disease and iron-refractory iron-deficiency anemia). Pharmacological targeting of the hepcidin/ferroportin axis may offer considerable therapeutic benefits by correcting iron traffic. This review summarizes the principles underlying the development of hepcidin-based therapies for the treatment of iron-related disorders, and discusses the emerging strategies for manipulating hepcidin pathways. PMID:27445804

  17. Gastrins, Iron Homeostasis and Colorectal Cancer

    PubMed Central

    Kovac, Suzana; Anderson, Gregory J.; Baldwin, Graham S.

    2011-01-01

    The peptide hormone gastrin has been identified as a major regulator of acid secretion and a potent mitogen for normal and malignant gastrointestinal cells. The importance of gastric acid in the absorption of dietary iron first became evident 50 years ago when iron-deficiency anemia was recognised as a long-term consequence of partial gastrectomy. This review summarises the connections between circulating gastrins, iron status and colorectal cancer. Gastrins bind two ferric ions with micromolar affinity and, in the case of non-amidated forms of the hormone, iron-binding is essential for biological activity in vitro and in vivo. The demonstration of an interaction between gastrin and transferrin by biochemical techniques led to the proposal that gastrins catalyse the loading of transferrin with iron. Several lines of evidence, including the facts that the concentrations of circulating gastrins are increased in mice and humans with the iron-overload disease hemochromatosis and that transferrin saturation positively correlates with circulating gastrin concentration, suggest the potential involvement of gastrins in iron homeostasis. Conversely, recognition that ferric ions play an unexpected role in the biological activity of gastrins may assist in the development of useful therapies for colorectal carcinoma and other disorders of mucosal proliferation in the gastrointestinal tract. PMID:21320535

  18. Mutation analysis of the transferrin receptor-2 gene in patients with iron overload.

    PubMed

    Lee, P L; Halloran, C; West, C; Beutler, E

    2001-01-01

    Three mutations in the transferrin receptor-2 gene have recently been identified in four Sicilian families with iron overload who had a normal hemochromatosis gene, HFE (C. Camaschella, personal communication). To determine the extent to which mutations in the transferrin receptor-2 gene occur in other populations with iron overload, we have completely sequenced this gene in 17 whites, 10 Asians, and 8 African Americans with iron overload and a C282C/C282C HFE genotype, as well as 4 subjects without iron overload and homozygous for the mutant HFE C282Y genotype, 5 patients with iron overload and homozygous for the mutant HFE C282Y genotype, and 5 normal individuals. None of the individuals exhibited the Sicilian mutations, Y250X in exon 6, M172K in exon 4, and E60X in exon 2. One iron-overloaded individual of Asian descent exhibited a I238M mutation which was subsequently found to be a polymorphism present in the Asian population at a frequency of 0.0192. The presence of the I238M mutation was not associated with an increase in ferritin or transferrin saturation levels. Three silent polymorphisms were also identified, nt 1770 (D590D) and nt 1851 (A617A) and a polymorphism at nt 2255 in the 3' UTR. Thus, mutations in the transferrin receptor-2 gene were not responsible for the iron overload seen in our subjects.

  19. Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders.

    PubMed

    de Swart, Louise; Hendriks, Jan C M; van der Vorm, Lisa N; Cabantchik, Z Ioav; Evans, Patricia J; Hod, Eldad A; Brittenham, Gary M; Furman, Yael; Wojczyk, Boguslaw; Janssen, Mirian C H; Porter, John B; Mattijssen, Vera E J M; Biemond, Bart J; MacKenzie, Marius A; Origa, Raffaella; Galanello, Renzo; Hider, Robert C; Swinkels, Dorine W

    2016-01-01

    Non-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrin-bound iron and 4 for labile plasma iron) as part of an international inter-laboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide. Some laboratories provided multiple assays. Overall, highest assay levels were observed for patients with untreated hereditary hemochromatosis and β-thalassemia intermedia, patients with transfusion-dependent myelodysplastic syndromes and patients with transfusion-dependent and chelated β-thalassemia major. Absolute levels differed considerably between assays and were lower for labile plasma iron than for non-transferrin-bound iron. Four assays also reported negative values. Assays were reproducible with high between-sample and low within-sample variation. Assays correlated and correlations were highest within the group of non-transferrin-bound iron assays and within that of labile plasma iron assays. Increased transferrin saturation, but not ferritin, was a good indicator of the presence of forms of circulating non-transferrin-bound iron. The possibility of using non-transferrin-bound iron and labile plasma iron measures as clinical indicators of overt iron overload and/or of treatment efficacy would largely depend on the rigorous validation and standardization of assays.

  20. Raman hyperspectral imaging of iron transport across membranes in cells

    NASA Astrophysics Data System (ADS)

    Das, Anupam; Costa, Xavier Felipe; Khmaladze, Alexander; Barroso, Margarida; Sharikova, Anna

    2016-09-01

    Raman scattering microscopy is a powerful imaging technique used to identify chemical composition, structural and conformational state of molecules of complex samples in biology, biophysics, medicine and materials science. In this work, we have shown that Raman techniques allow the measurement of the iron content in protein mixtures and cells. Since the mechanisms of iron acquisition, storage, and excretion by cells are not completely understood, improved knowledge of iron metabolism can offer insight into many diseases in which iron plays a role in the pathogenic process, such as diabetes, neurodegenerative diseases, cancer, and metabolic syndrome. Understanding of the processes involved in cellular iron metabolism will improve our knowledge of cell functioning. It will also have a big impact on treatment of diseases caused by iron deficiency (anemias) and iron overload (hereditary hemochromatosis). Previously, Raman studies have shown substantial differences in spectra of transferrin with and without bound iron, thus proving that it is an appropriate technique to determine the levels of bound iron in the protein mixture. We have extended these studies to obtain hyperspectral images of transferrin in cells. By employing a Raman scanning microscope together with spectral detection by a highly sensitive back-illuminated cooled CCD camera, we were able to rapidly acquire and process images of fixed cells with chemical selectivity. We discuss and compare various methods of hyperspectral Raman image analysis and demonstrate the use of these methods to characterize cellular iron content without the need for dye labeling.

  1. Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans.

    PubMed

    Wang, Haizhen; Jiang, Xue; Wu, Jieyu; Zhang, Linqiang; Huang, Jingfei; Zhang, Yuru; Zou, Xiaoju; Liang, Bin

    2016-05-01

    The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases.

  2. Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients With Friedreich Ataxia

    PubMed Central

    Kruger, Pamela C.; Yang, Karl X.; Parsons, Patrick J.; Becker, Alyssa B.; Feustel, Paul J.; Koeppen, Arnulf H.

    2016-01-01

    Cardiomyopathy is a frequent cause of death in patients with Friedreich ataxia (FA), and a characteristic pathological feature is the focal accumulation of iron (Fe) in cardiomyocytes. This restricted localization of the metal contrasts with the diffuse cardiac Fe overload in hemochromatosis and transfusion siderosis. Nevertheless, heart Fe in FA contributes to cardiomyocyte necrosis, inflammation, and scarring as the disease progresses. A putative mechanism of cardiomyopathy in FA is Fe-mediated oxidative damage. Two other transition metals zinc (Zn) and copper (Cu), are diffusely distributed throughout normal hearts and the hearts of patients with FA. The myocardium in FA is also prone to deposits of calcium in the form of scattered concretions. In this study, heart tissues (left and right ventricular walls and ventricular septum) of 23 patients with genetically confirmed FA and 8 normal controls were obtained at autopsy and analyzed for Fe, Zn, Cu, and calcium. The principal assay methods were inductively coupled plasma optical emission spectrometry and plasma mass spectrometry. Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA. In conclusion, the decrease of Cu may be important in consideration of the potential benefit of Cu supplements in FA cardiomyopathy. PMID:27189813

  3. Tumour promotion versus tumour suppression in chronic hepatic iron overload.

    PubMed

    Bloomer, Steven A; Brown, Kyle E

    2015-06-01

    Although iron-catalysed oxidative damage is presumed to be a major mechanism of injury leading to cirrhosis and hepatocellular carcinoma in hemochromatosis, these events have been difficult to recapitulate in an animal model. In this study, we evaluated regulators of hepatocarcinogenesis in a rodent model of chronic iron overload. Sprague-Dawley rats were iron loaded with iron dextran over 6 months. Livers were harvested and analysed for markers of oxidative stress, as well as the following proteins: p53, murine double minute 2, the Shc proteins p66, p52, p46; β-catenin, CHOP, C/EBPα and Yes-associated protein. In this model, iron loading is associated with hepatocyte proliferation, and indices of oxidative damage are mildly increased in tandem with augmented antioxidant defenses. Alterations potentially favouring carcinogenesis included a modest but significant decrease in p53 levels and increases in p52, p46 and β-catenin levels compared with control livers. Countering these factors, the iron-loaded livers demonstrated a significant decrease in CHOP, which has recently been implicated in the development of hepatocellular carcinoma, as well as a reciprocal increase in C/EBPα and decrease in Yes-associated protein. Our results suggest that chronic iron overload elicits both tumour suppressive as well as tumour-promoting mechanisms in rodent liver.

  4. Comparative study of the protective effect between deferoxamine and deferiprone on chronic iron overload induced cardiotoxicity in rats.

    PubMed

    Emara, A M; El Kelany, R S; Moustafa, K A

    2006-07-01

    Patients with iron overload frequently suffer from hemochromatosis of major organs, such as the heart and liver. Heart affection is the most common cause of death in patients with iron overload. Although the beneficial effects of deferoxamine (DFO) on iron-associated mortality are well documented, the role of deferiprone in the management of transfusional iron overload is controversial. The aim of this study was to compare the protective effect of iron chelators (DFO and deferiprone) individually and in combination with the anti-oxidant (vitamin C) in the prevention of myocardial damage. Sixty albino rats were divided into six groups: two control groups (noniron-loaded and iron-loaded) and four iron-loaded groups classified as follows: DFO group, DFO combined with vitamin C group, deferiprone group and deferiprone combined with vitamin C group. Heart tissue and blood samples were taken for histopathological examination of the heart, determination of total iron-binding capacity, 8-OH-deoxyguanosine (8-OH-dG), myocardial lipid peroxidation and glutathione (GSH) content. Less histopathological cardiac changes and a significant decrease in all biochemical parameters, except myocardial GSH, were observed in the deferiprone group. The addition of vitamin C improves the biochemical and histopathological changes in comparison to those rats administered DFO or deferiprone individually.

  5. Description and Pilot Results from a Novel Method for Evaluating Return of Incidental Findings from Next Generation Sequencing Technologies

    PubMed Central

    Goddard, Katrina A.B.; Whitlock, Evelyn P.; Berg, Jonathan S.; Williams, Marc S.; Webber, Elizabeth M.; Webster, Jennifer A.; Lin, Jennifer S.; Schrader, Kasmintan A.; Campos-Outcalt, Doug; Offit, Kenneth; Feigelson, Heather Spencer; Hollombe, Celine

    2013-01-01

    Purpose To develop, operationalize, and pilot test a transparent, reproducible, and evidence informed method to qualify when to report incidental findings from next generation sequencing technologies. Methods Using evidence-based principles, we propose a three stage process. Stage I ‘rules out’ incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (Stage III). We used expert opinion to determine the face validity of Stages II and III using three case studies. We evaluated the time and effort for Stages I and II. Results For Stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and α1-Antitrypsin Deficiency were all recommended for routine reporting as incidental findings. The method requires less than three days per topic. Conclusion We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome. PMID:23558254

  6. Hepcidin regulates intrarenal iron handling at the distal nephron.

    PubMed

    Moulouel, Boualem; Houamel, Dounia; Delaby, Constance; Tchernitchko, Dimitri; Vaulont, Sophie; Letteron, Philippe; Thibaudeau, Olivier; Puy, Hervé; Gouya, Laurent; Beaumont, Carole; Karim, Zoubida

    2013-10-01

    Hepcidin, the key regulatory hormone of iron homeostasis, and iron carriers such as transferrin receptor1 (TFR1), divalent metal transporter1 (DMT1), and ferroportin (FPN) are expressed in kidney. Whether hepcidin plays an intrinsic role in the regulation of renal iron transport is unknown. Here, we analyzed the renal handling of iron in hemochromatosis Hepc(-/-) and Hjv(-/-) mouse models, as well as in phenylhydrazine (PHZ)-treated mice. We found a marked medullary iron deposition in the kidneys of Hepc(-/-) mice, and iron leak in the urine. The kidneys of Hepc(-/-) mice exhibited a concomitant decrease in TFR1 and increase in ferritin and FPN expression. Increased FPN abundance was restricted to the thick ascending limb (TAL). DMT1 protein remained unaffected despite a significant decrease of its mRNA level, suggesting that DMT1 protein is stabilized in the absence of hepcidin. Treatment of kidney sections from Hepc(-/-) mice with hepcidin decreased DMT1 protein, an effect confirmed in renal cell lines where hepcidin markedly decreased (55)Fe transport. In the kidneys of Hjv(-/-) mice exhibiting low hepcidin expression, the iron overload was similar to that in the kidneys of Hepc(-/-) mice. However, in PHZ mice, iron accumulation resulting from hemoglobin leak was detected in the proximal tubule. Thus, kidneys exhibit a tissue-specific handling of iron that depends on the extra iron source. Hepcidin may control the expression of iron transporters to prevent renal iron overload.

  7. Iron and hepcidin: a story of recycling and balance.

    PubMed

    Camaschella, Clara

    2013-01-01

    To avoid iron deficiency and overload, iron availability is tightly regulated at both the cellular and systemic levels. The liver peptide hepcidin controls iron flux to plasma from enterocytes and macrophages through degradation of the cellular iron exporter ferroportin. The hepcidin-ferroportin axis is essential to maintaining iron homeostasis. Genetic inactivation of proteins of the hepcidin-activating pathway causes iron overload of varying severity in human and mice. Hepcidin insufficiency and increased iron absorption are also characteristic of anemia due to ineffective erythropoiesis in which, despite high total body iron, hepcidin is suppressed by the high erythropoietic activity, worsening both iron overload and anemia in a vicious cycle. Hepcidin excess resulting from genetic inactivation of a hepcidin inhibitor, the transmembrane protease serine 6 (TMPRSS6) leads to a form of iron deficiency refractory to oral iron. Increased hepcidin explains the iron sequestration and iron-restricted erythropoiesis of anemia associated with chronic inflammatory diseases. In mice, deletion of TMPRSS6 in vivo has profound effects on the iron phenotype of hemochromatosis and beta-thalassemia. Hepcidin manipulation to restrict iron is a successful strategy to improve erythropoiesis in thalassemia, as shown clearly in preclinical studies targeting TMPRSS6; attempts to control anemia of chronic diseases by antagonizing the hepcidin effect are ongoing. Finally, the metabolic pathways identified from iron disorders are now being explored in other human pathologic conditions, including cancer.

  8. METABOLISM OF IRON STORES

    PubMed Central

    SAITO, HIROSHI

    2014-01-01

    ABSTRACT Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953. However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia). We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order (1) labile iron, (2) ferritin and (3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes. We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal. In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects. PMID:25741033

  9. Dietary iron supplements and Moringa oleifera leaves influence the liver hepcidin messenger RNA expression and biochemical indices of iron status in rats.

    PubMed

    Saini, R K; Manoj, P; Shetty, N P; Srinivasan, K; Giridhar, P

    2014-07-01

    In this study, the effects of iron depletion and repletion on biochemical and molecular indices of iron status were investigated in growing male Wistar rats. We hypothesized that iron from Moringa leaves could overcome the effects of iron deficiency and modulate the expression of iron-responsive genes better than conventional iron supplements. Iron deficiency was induced by feeding rats an iron-deficient diet for 10 weeks, whereas control rats were maintained on an iron-sufficient diet (35.0-mg Fe/kg diet). After the depletion period, animals were repleted with different source of iron, in combination with ascorbic acid. Iron deficiency caused a significant (P < .05) decrease in serum iron and ferritin levels by 57% and 40%, respectively, as compared with nondepleted control animals. Significant changes in the expression (0.5- to100-fold) of liver hepcidin (HAMP), transferrin, transferrin receptor-2, hemochromatosis type 2, ferroportin 1, ceruloplasmin, and ferritin-H were recorded in iron-depleted and iron-repleted rats, as compared with nondepleted rats (P < .05). Dietary iron from Moringa leaf was found to be superior compared with ferric citrate in overcoming the effects of iron deficiency in rats. These results suggest that changes in the relative expression of liver hepcidin messenger RNA can be used as a sensitive molecular marker for iron deficiency.

  10. Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy

    PubMed Central

    Kallianpur, Asha R; Hulgan, Todd

    2009-01-01

    Peripheral neuropathy is an important complication of antiretroviral therapy. Nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction, inflammation and nutritional factors are implicated in its pathogenesis. Pharmacogenetic and genomic studies investigating NRTI neurotoxicity have only recently become possible via the linkage of HIV clinical studies to large DNA repositories. Preliminary case–control studies using these resources suggest that host mitochondrial DNA haplogroup polymorphisms in the hemochromatosis gene and proinflammatory cytokine genes may influence the risk of peripheral neuropathy during antiretroviral therapy. These putative risk factors await confirmation in other HIV-infected populations but they have strong biological plausibility. Work to identify underlying mechanisms for these associations is ongoing. Large-scale studies incorporating clearly defined and validated methods of neuropathy assessment and the use of novel laboratory models of NRTI-associated neuropathy to clarify its pathophysiology are now needed. Such investigations may facilitate the development of more effective strategies to predict, prevent and ameliorate this debilitating treatment toxicity in diverse clinical settings. PMID:19374518

  11. Subjects At-Risk for Genetic Diseases in Portugal: Illness Representations.

    PubMed

    Leite, Ângela; Dinis, Maria Alzira P; Sequeiros, Jorge; Paúl, Constança

    2016-02-01

    This study investigates illness representations of subjects at-risk for 3 autosomal dominant late-onset disorders: Familial Amyloid Polyneuropathy (FAP) TTR V30M, Huntington's disease (HD) and Machado-Joseph disease (MJD), comparing them with the illness representations of subjects at-risk for Hemochromatosis (HH). The present study included a clinical group that consisted of 213 subjects at genetic risk (FAP, HD and MJD), comprising 174 subjects at-risk for FAP, 34 subjects at-risk for HD and only 5 subjects at-risk for MJD; and the control group consisting of 31 subjects at genetic risk for HH. All subjects at-risk were undergoing the process of genetic counseling to learn their genetic status (carrier or non-carrier). Subjects were assessed through a semi-structured single interview, in order to obtain sociodemographic data and the answer to an open-ended question relating to the illness representation issue: "What does this illness mean to you?/ What is this disease to you?" It was in the subjects' metaphors that subjects best expressed what they felt regarding the disease and the situation of being at-risk for this disease. Family is their mirror and their source of learning and, therefore, it is inevitable that family is related to the meaning of the disease itself.

  12. Glucose metabolism in the Belgrade rat, a model of iron-loading anemia

    PubMed Central

    Jia, Xuming; Kim, Jonghan; Veuthey, Tania; Lee, Chih-Hao

    2013-01-01

    The iron-diabetes hypothesis proposes an association between iron overload and glucose metabolism that is supported by a number of epidemiological studies. The prevalence of type 2 diabetes in patients with hereditary hemochromatosis and iron-loading thalassemia supports this hypothesis. The Belgrade rat carries a mutation in the iron transporter divalent metal transporter 1 (DMT1) resulting in iron-loading anemia. In this study, we characterized the glycometabolic status of the Belgrade rat. Belgrade rats displayed normal glycemic control. Insulin signaling and secretion were not impaired, and pancreatic tissue did not incur damage despite high levels of nonheme iron. These findings suggest that loss of DMT1 protects against oxidative damage to the pancreas and helps to maintain insulin sensitivity despite iron overload. Belgrade rats had lower body weight but increased food consumption compared with heterozygous littermates. The unexpected energy balance was associated with increased urinary glucose output. Increased urinary excretion of electrolytes, including iron, was also observed. Histopathological evidence suggests that altered renal function is secondary to changes in kidney morphology, including glomerulosclerosis. Thus, loss of DMT1 appears to protect the pancreas from injury but damages the integrity of kidney structure and function. PMID:23599042

  13. Treatment of Nongout Joint Deposition Diseases: An Update

    PubMed Central

    Richette, Pascal; Flipo, René-Marc

    2014-01-01

    This update develops the actual therapeutic options in the management of the joint involvement of calcium pyrophosphate deposition disease (CPPD), basic calcium phosphate (BCP) deposition disease, hemochromatosis (HH), ochronosis, oxalosis, and Wilson's disease. Conventional pharmaceutical treatment provides benefits for most diseases. Anti-interleukine-1 (IL-1) treatment could provide similar results in CPPD than in gout flares. There is only limited evidence about the efficacy of preventive long-term colchicine intake, methotrexate, and hydroxychloroquine in chronic CPPD. Needle aspiration and lavage have satisfactory short and midterm results in BCP. Extracorporeal shockwave therapy has also proved its efficacy for high-doses regimes. Phlebotomy does not seem to have shown real efficacy on joint involvement in HH so far. Iron chelators' effects have not been assessed on joint involvement either, while IL-1 blockade may prove useful. NSAIDs have limited efficacy on joint involvement of oxalosis, while colchicine and steroids have not been assessed either. The use of nitisinone for ochronotic arthropathy is still much debated, but it could provide beneficial effects on joint involvement. The effects of copper chelators have not been assessed either in the joint involvement of Wilson's disease. NSAIDs should be avoided because of the liver affection they may worsen. PMID:24895535

  14. Iron and cancer risk--a systematic review and meta-analysis of the epidemiological evidence.

    PubMed

    Fonseca-Nunes, Ana; Jakszyn, Paula; Agudo, Antonio

    2014-01-01

    Iron has been suggested as a risk factor for different types of cancers mainly due to its prooxidant activity, which can lead to oxidative DNA damage. Furthermore, subjects with hemochromatosis or iron overload have been shown to have a higher risk of developing liver cancer. We have systematically reviewed 59 epidemiologic studies, published between 1995 and 2012, reporting information on total iron, dietary iron, heme iron, and biomarkers of iron status and cancer risk. Furthermore we conducted meta-analysis for colorectal [relative risk (RR), 1.08; 95% confidence interval (CI), 1.00-1.17], colon (RR = 1.12; 95% CI, 1.03-1.22), breast (RR = 1.03; 95% CI, 0.97-1.09), and lung cancer (RR = 1.12; 95% CI, 0.98-1.29), for an increase of 1 mg/day of heme iron intake. Globally, on the basis of the systematic review and the meta-analysis results, a higher intake of heme iron has shown a tendency toward a positive association with cancer risk. Evidence regarding high levels of biomarkers of iron stores (mostly with serum ferritin) suggests a negative effect toward cancer risk. More prospective studies combining research on dietary iron intake, iron biomarkers, genetic susceptibility, and other relevant factors need to be conducted to clarify these findings and better understand the role of iron in cancer development.

  15. Iron supplementation in athletes--first do no harm.

    PubMed

    Zoller, Heinz; Vogel, Wolfgang

    2004-01-01

    Although it generally does not improve performance, iron is often used by elite athletes. The physiologic changes induced by exercise can mimic iron deficiency and decrease hemoglobin and ferritin concentrations. Determination of serum transferrin receptor concentrations may identify true iron deficiency, which occurs particularly in young athletes. In contrast, increased iron stores in the body are a frequent finding in elite athletes who have used long-term iron supplementation. Elite runners have increased intestinal blood loss, but this usually can be compensated by enhanced absorption of dietary iron. The combination of exercise-induced hemolysis with enhanced intestinal blood loss in various endurance sports leads to severe abnormalities of routine tests, and extreme physical activity may be responsible for positive fecal occult blood determinations. Indiscriminate iron supplementation carries the risk of inducing hemochromatosis in individuals homozygous for the widespread C282Y allele of the HFE gene. This polymorphism is common and can be found in about 1% of individuals of Northern European descent; moreover, iron supplementation can modify the presentation of important underlying diseases such as celiac disease or colon carcinoma. In conclusion, iron supplements should be prescribed for athletes with iron-deficiency anemia and carefully monitored if given for prophylaxis; unless a therapeutic response occurs, investigations to establish the cause of iron deficiency should be initiated.

  16. Neonatal Liver Failure and Congenital Cirrhosis due to Gestational Alloimmune Liver Disease: A Case Report and Literature Review

    PubMed Central

    Rostirola Guedes, Renata; Kieling, Carlos Oscar; Rossato Adami, Marina; Cerski, Carlos Thadeu Schmidt

    2017-01-01

    Neonatal liver failure (NLF) is a major cause of neonatal morbidity and mortality, presenting as acute liver failure and/or congenital cirrhosis. Many affected patients show antenatal signs of fetal injury. There are several causes of NLF and early diagnosis is mandatory to elucidate the etiology and determine a specific treatment or the best management strategy. Gestational alloimmune liver disease associated with neonatal hemochromatosis (GALD-NH) is a rare but potentially treatable cause of NLF. It should be considered in any neonate with fetal signs of disease and postnatal signs of liver failure with no other identifiable causes. GALD-NH is often diagnosed late and patients are therefore referred late to specialized centers, delaying treatment. This case highlights the consequences of late diagnosis and treatment of GALD-NH and emphasizes the importance of a high grade of suspicion of this disease in order to refer the patient to a specialized center soon enough to perform the appropriate treatment. PMID:28251010

  17. Population genetic screening programmes: principles, techniques, practices, and policies.

    PubMed

    Godard, Béatrice; ten Kate, Leo; Evers-Kiebooms, Gerry; Aymé, Ségolène

    2003-12-01

    This paper examines the professional and scientific views on the principles, techniques, practices, and policies that impact on the population genetic screening programmes in Europe. This paper focuses on the issues surrounding potential screening programmes, which require further discussion before their introduction. It aims to increase, among the health-care professions and health policy-makers, awareness of the potential screening programmes as an issue of increasing concern to public health. The methods comprised primarily the review of the existing professional guidelines, regulatory frameworks and other documents related to population genetic screening programmes in Europe. Then, the questions that need debate, in regard to different types of genetic screening before and after birth, were examined. Screening for conditions such as cystic fibrosis, Duchenne muscular dystrophy, familial hypercholesterolemia, fragile X syndrome, hemochromatosis, and cancer susceptibility was discussed. Special issues related to genetic screening were also examined, such as informed consent, family aspects, commercialization, the players on the scene and monitoring genetic screening programmes. Afterwards, these questions were debated by 51 experts from 15 European countries during an international workshop organized by the European Society of Human Genetics Public and Professional Policy Committee in Amsterdam, The Netherlands, 19-20, November, 1999. Arguments for and against starting screening programmes have been put forward. It has been questioned whether genetic screening differs from other types of screening and testing in terms of ethical issues. The general impression on the future of genetic screening is that one wants to 'proceed with caution', with more active impetus from the side of patients' organizations and more reluctance from the policy-makers. The latter try to obviate the potential problems about the abortion and eugenics issues that might be perceived as a

  18. Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data

    PubMed Central

    Zhang, Bo; Liu, Dajiang J.; Muscat, Joshua E.; Langan, Sara T.; Connor, James R.

    2017-01-01

    Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119–0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474–0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients’ survival in the TCGA data set of GBM. PMID:28358914

  19. Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

    PubMed Central

    2011-01-01

    Background Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. Methods Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. Results Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research. Conclusions Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements. PMID:22074419

  20. Monogenic diseases that can be cured by liver transplantation.

    PubMed

    Fagiuoli, Stefano; Daina, Erica; D'Antiga, Lorenzo; Colledan, Michele; Remuzzi, Giuseppe

    2013-09-01

    While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management

  1. Performance of the U.S. Office of Management and Budget’s Revised Race and Ethnicity Categories in Asian Populations*

    PubMed Central

    Holup, Joan L.; Press, Nancy; Vollmer, William M.; Harris, Emily L.; Vogt, Thomas M.; Chen, Chuhe

    2007-01-01

    Objectives The U.S. Office of Management and Budget (OMB) guidelines for collecting and reporting race and ethnicity information recently divided the “Asian or Pacific Islander” category into “Asian” and “Native Hawaiian or Other Pacific Islander”. The OMB’s decision to disaggregate the “Asian or Pacific Islander” category was the first step toward providing these communities with information to better serve their needs. However, whether individuals who formerly made up the combined group categorize themselves as the new guidelines intend is a question analyzed in this report. Methods A subset of adults participating in the Hemochromatosis and Iron Overload Screening Study completed both the OMB-minimum and the expanded race and ethnicity measure used in the National Health Interview Survey. We compared responses on the expanded measure contained within the OMB “Asian” definition (Filipino, Korean, Vietnamese, Japanese, Asian Indian, Chinese, and/or Other Asian) to “Asian” responses on the OMB-minimum measure. Results Mixed heritage Asians less often marked “Asian”. Among mixed heritage Japanese, Chinese, and Filipinos, 27%, 49%, and 52% did not mark “Asian” on the OMB measure, respectively. Eleven percent of single-heritage Filipinos did not mark “Asian.” Conclusions Many individuals formerly making up the combined “Asian or Pacific Islander” group do not categorize themselves as the revised OMB guidelines intend. This is particularly evident among Filipinos and among Asians of mixed heritage. This research illuminates the reliability and utility of the broad “Asian” category and points to possible consequences of collapsing groups into a single category, i.e., missed information and/or erroneous generalization. PMID:18037976

  2. Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms.

    PubMed

    Eum, Ki-Do; Seals, Ryan M; Taylor, Kathryn M; Grespin, Matthew; Umbach, David M; Hu, Howard; Sandler, Dale P; Kamel, Freya; Weisskopf, Marc G

    2015-03-01

    Our objective was to examine whether functional polymorphisms in hemochromatosis (HFE; H63D and C282Y), transferrin (TfC2), and glutathione-s-transferase Pi1 (GSTP1; Ile105Val) genes modify any lead-ALS association. We measured blood lead using atomic absorption spectroscopy and bone lead - a biomarker of cumulative lead exposure - using K-shell-X-ray fluorescence in 100 neurologist-confirmed ALS cases and 194 controls, the latter recruited as part of two separate studies; all subjects lived in New England. Participants were considered variant carriers or wild-type for each polymorphism. To assess effect modification, we included cross-product terms between lead biomarkers and each polymorphism in separate adjusted polytomous logistic regression models. Compared with wild-type, the odds ratio (OR) per 15.6 μg/g patella lead (interquartile range; IQR) was 8.24 (95% CI 0.94-72.19) times greater among C282Y variant carriers, and 0.34 (95% CI 0.15-0.78) times smaller among H63D variant carriers. Results were weaker for tibia lead. Compared with wild-type the OR per 2 μg/dl blood lead (IQR) was 0.36 (95% CI 0.19-0.68) times smaller among H63D variant carriers, and 1.96 (95% CI 0.98-3.92) times greater among GSTP1 variant carriers. In conclusion, we found that HFE and GSTP1 genotypes modified the association between lead biomarkers and ALS. Contrasting modification by the HFE polymorphisms H63D and C282Y may suggest that the modification is not simply the result of increased iron.

  3. Gender and iron genes may modify associations between brain iron and memory in healthy aging.

    PubMed

    Bartzokis, George; Lu, Po H; Tingus, Kathleen; Peters, Douglas G; Amar, Chetan P; Tishler, Todd A; Finn, J Paul; Villablanca, Pablo; Altshuler, Lori L; Mintz, Jim; Neely, Elizabeth; Connor, James R

    2011-06-01

    Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

  4. Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study

    PubMed Central

    Weisskopf, Marc G.; Sparrow, David; Schwartz, Joel; Hu, Howard; Park, Sung Kyun

    2016-01-01

    Background Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. Objectives We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. Methods We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Results Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50–3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Conclusions Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data. PMID:27584680

  5. Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.

    PubMed

    Alfred, Tamuno; Ben-Shlomo, Yoav; Cooper, Rachel; Hardy, Rebecca; Deary, Ian J; Elliott, Jane; Harris, Sarah E; Hyppönen, Elina; Kivimaki, Mika; Kumari, Meena; Maddock, Jane; Power, Chris; Starr, John M; Kuh, Diana; Day, Ian N M

    2013-05-01

    Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on Z-score for carriers vs. noncarriers: -0.05 (95% CI: -0.09, -0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D-raising allele of rs2282679 [pooled β per T allele: -0.03 (95% CI: -0.05, -0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.

  6. Mössbauer Spectra of Mouse Hearts reveal age-dependent changes in mitochondrial and ferritin iron levels.

    PubMed

    Wofford, Joshua D; Chakrabarti, Mrinmoy; Lindahl, Paul Alan

    2017-02-15

    Cardiac function requires continuous high levels of energy, and so iron, a critical player in mitochondrial respiration, is an important component of the heart. Hearts from (57)Fe-enriched mice were evaluated by Mossbauer spectroscopy. Spectra consisted of a sextet and two quadrupole doublets. One doublet was due to residual blood while the other was due to [Fe4S4](2+) clusters and Fe(II) hemes, most of which were associated with mitochondrial respiration. The sextet was due to ferritin; there was no evidence of hemosiderin, a ferritin decomposition product. Iron from ferritin was nearly absent in young hearts, but increased steadily with age. EPR spectra exhibited signals similar to those of brain, liver, and human cells. No age-dependent EPR trends were apparent. Hearts from HFE(-/-) mice with hemochromatosis contained slightly more iron overall than controls, including more ferritin and less mitochondrial iron; these differences typify slightly older hearts, perhaps reflecting the burden due to this disease. HFE(-/-) livers were overloaded with ferritin but had low mitochondrial iron levels. IRP2(-/-) hearts contained less ferritin than controls but normal levels of mitochondrial iron. Hearts of young mice born to an iron-deficient mother contained normal levels of mitochondrial iron and no ferritin; the mothers heart contained low ferritin and normal levels of mitochondrial iron. High-spin Fe(II) ions were nearly undetectable in heart samples; these were evident in brains, livers, and human cells. Previous Mossbauer spectra of unenriched diseased human hearts lacked mitochondrial and blood doublets, and included hemosiderin features. This suggests degradation of iron-containing species during sample preparation.

  7. IRon Overload screeNing tool (IRON): development of a tool to guide screening in primary care.

    PubMed

    Mainous, Arch G; Diaz, Vanessa A; Everett, Charles J; Knoll, Michele E; Hulihan, Mary M; Grant, Althea M; McLaren, Christine E; McLaren, Gordon D

    2011-09-01

    Iron overload is associated with significant morbidity and mortality yet is easily treated. The objective of this study was to create a tool that could be easily adapted to clinical practice that indicates the likelihood of a patient having undetected iron overload. We used the National Health and Nutrition Examination Survey (NHANES) 1999-2002 for US adults aged 20 years and older to build a model (unweighted n=8,779). We chose potential variables for inclusion that could be gathered by self-report or measured without laboratory data and were suggested by past literature on hemochromatosis and iron overload. We computed logistic regressions to create the scores by initially evaluating the variables' relationship with elevated ferritin and elevated transferrin saturation and then using odds ratios to correspond to scores. The resulting score on the IRon Overload ScreeNing Tool (IRON) was then validated with data on 13,844 adults in the NHANES III, 1988-94. Predictors in the final tool were age, gender, previous diagnoses of liver condition, osteoporosis or thyroid disease. The IRON score yielded an area under the curve (AUC) in the NHANES 1999-02 of 0.720 and an AUC of 0.685 in the NHANES III validation sample. The IRON score is a tool to assist in identification of patients with iron overload that has several qualities that make it attractive for use in clinical practice with an undifferentiated patient population including brevity, easily collected information and predictive ability comparable to other tools that help in directing screening.

  8. Iron Replacement Therapy in the Routine Management of Blood Donors

    PubMed Central

    Bryant, Barbara J.; Yau, Yu Ying; Arceo, Sarah M.; Daniel-Johnson, Jennifer; Hopkins, Julie A.; Leitman, Susan F.

    2013-01-01

    Background Iron depletion/deficiency in blood donors frequently results in deferrals for low hemoglobin, yet blood centers remain reluctant to dispense iron replacement therapy to donors. Study Design and Methods During a 39-month period, 1236 blood donors deferred for hemoglobin <12.5 g/dL and 400 non-deferred control donors underwent health history screening and laboratory testing (CBC, iron studies). Iron depletion and deficiency were defined as ferritin of 9–19 mcg/L and <9 mcg/L in females and 18–29 mcg/L and <18 mcg/L in males. Deferred donors and iron-deficient control donors were given a 60-pack of ferrous sulfate 325 mg tablets, and instructed to take one tablet daily. Another 60-pack was dispensed at all subsequent visits. Results In the low hemoglobin group, 30% and 23% of females and 8% and 53% of males had iron depletion or deficiency, respectively, compared with 29% and 10% of females and 18% and 21% of males in the control group. Iron depleted/deficient donors taking iron showed normalization of iron-related laboratory parameters, even as they continued to donate. Compliance with oral iron was 68%. Adverse gastrointestinal effects occurred in 21% of donors. The study identified 13 donors with serious medical conditions, including eight with GI bleeding. No donors had malignancies or hemochromatosis. Conclusion Iron depletion or deficiency was found in 53% of female and 61% of male low hemoglobin donors, and in 39% of female and male control donors. Routine administration of iron replacement therapy is safe, effective, and prevents the development of iron depletion/deficiency in blood donors. PMID:22211316

  9. Design and validation of a high-throughput matrix-assisted laser desorption ionization time-of-flight mass spectrometry method for quantification of hepcidin in human plasma.

    PubMed

    Anderson, Damon S; Kirchner, Marc; Kellogg, Mark; Kalish, Leslie A; Jeong, Jee-Yeong; Vanasse, Gary; Berliner, Nancy; Fleming, Mark D; Steen, Hanno

    2011-11-01

    Disorders of iron metabolism affect over a billion people worldwide. The circulating peptide hormone hepcidin, the central regulator of iron distribution in mammals, holds great diagnostic potential for an array of iron-associated disorders, including iron loading (β-thalassemia), iron overload (hereditary hemochromatosis), and iron deficiency diseases. We describe a novel high-throughput matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry assay for quantification of hepcidin in human plasma. This assay involves enrichment using a functionalized MALDI chip, a novel solvent-detergent precipitation buffer, and quantification using a stable isotope labeled internal standard. The linear range of hepcidin in plasma was 1-120 nM, with a low limit of quantification (LOQ) (1 nM), high accuracy (<15% relative error (RE)), and high precision (intraday average 5.52-18.48% coefficient of variation (CV) and interday 9.32-14.83% CV). The assay showed strong correlation with an established hepcidin immunoassay (Spearman; R(2) = 0.839 n = 93 ethylenediaminetetraacetic acid (EDTA) plasma). A collection of normal healthy pediatric samples (range 3.8-32.5 ng/mL; mean 12.9 ng/mL; n = 119) showed significant differences from an adult collection (range 1.8-48.7 ng/mL; mean 16.1 ng/mL; n = 95; P = 0.0096). We discuss these preliminary reference ranges and correlations with additional parameters in light of the utility and limitations of hepcidin measurements as a stand-alone diagnostic and as a tool for therapeutic intervention.

  10. The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda

    PubMed Central

    Farrell, Colin P.; Overbey, Jessica R.; Naik, Hetanshi; Nance, Danielle; McLaren, Gordon D.; McLaren, Christine E.; Zhou, Luming; Desnick, Robert J.; Parker, Charles J.

    2016-01-01

    Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT. PMID:27661980

  11. Conditional Deletion of Ferritin H in Mice Reduces B and T Lymphocyte Populations

    PubMed Central

    Vanoaica, Liviu; Richman, Larry; Jaworski, Maike; Darshan, Deepak; Luther, Sanjiv A.; Kühn, Lukas C.

    2014-01-01

    The immune system and iron availability are intimately linked as appropriate iron supply is needed for cell proliferation, while excess iron, as observed in hemochromatosis, may reduce subsets of lymphocytes. We have tested the effects of a ferritin H gene deletion on lymphocytes. Mx-Cre mediated conditional deletion of ferritin H in bone marrow reduced the number of mature B cells and peripheral T cells in all lymphoid organs. FACS analysis showed an increase in the labile iron pool, enhanced reactive oxygen species formation and mitochondrial depolarization. The findings were confirmed by a B-cell specific deletion using Fthlox/lox; CD19-Cre mice. Mature B cells were strongly under-represented in bone marrow and spleen of the deleted mice, whereas pre-B and immature B cells were not affected. Bone marrow B cells showed increased proliferation as judged by the number of cells in S and G2/M phase as well as BrdU incorporation. Upon in vitro culture with B-cell activating factor of the tumor necrosis factor family (BAFF), ferritin H-deleted spleen B cells showed lower survival rates than wild type cells. This was partially reversed with iron-chelator deferiprone. The loss of T cells was also confirmed by a T cell-specific deletion in Fthlox/lox;CD4-Cre mice. Our data show that ferritin H is required for B and T cell survival by actively reducing the labile iron pool. They further suggest that natural B and T cell maturation is influenced by intracellular iron levels and possibly deregulated in iron excess or deprivation. PMID:24586648

  12. Zinc protoporphyrin, a useful parameter to address hyperferritinemia.

    PubMed

    Metzgeroth, Georgia; Schultheis, Beate; Dorn-Beineke, Alexandra; Hehlmann, Rüdiger; Hastka, Jan

    2007-05-01

    Zinc protoporphyrin (ZPP) is produced instead of heme as soon as iron support to erythropoiesis becomes insufficient. In iron deficiency the intra-erythrocytic ZPP concentration is increased. The aim of this study was to investigate whether ZPP is influenced by increased iron levels in hereditary hemochromatosis (HE) and is useful in the clarification of hyperferritinemia. Twenty HE patients and 160 patients with hyperferritinemic caused by anemia of chronic disorders, liver diseases, transfusional iron overload and hematologic or solid malignancies were enrolled. ZPP was measured using the Aviv front-face hematofluorometer (normal

  13. Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis

    PubMed Central

    Xiong, Shigang; She, Hongyun; Zhang, An-Sheng; Wang, Jiaohong; Mkrtchyan, Hasmik; Dynnyk, Alla; Gordeuk, Victor R.; French, Samuel W.; Enns, Caroline A.; Tsukamoto, Hidekazu

    2008-01-01

    One prime feature of alcoholic liver disease (ALD) is iron accumulation in hepatic macrophages/Kupffer cells (KC) associated with enhanced NF-κB activation. Our recent work demonstrates a peroxynitrite-mediated transient rise in intracellular labile iron (ILI) as novel signaling for endotoxin-induced IKK and NF-κB activation in rodent KC. The present study investigated the mechanism of KC iron accumulation and its effects on ILI response in experimental ALD. We also tested ILI response in human blood monocytes. Chronic alcohol feeding in rats results in increased expression of transferrin (Tf) receptor-1 and hemochromatosis gene (HFE), enhanced iron uptake, an increase in nonheme iron content, and accentuated ILI response for NF-κB activation in KC. Ex vivo treatment of these KC with an iron chelator abrogates the increment of iron content, ILI response, and NF-κB activation. The ILI response is evident in macrophages derived from human blood monocytes by PMA treatment but not in vehicle-treated monocytes, and this differentiation-associated phenomenon is essential for maximal TNF-α release. PMA-induced macrophages load iron dextran and enhance ILI response and TNF-α release. These effects are reproduced in KC selectively loaded in vivo with iron dextran in mice and more importantly aggravate experimental ALD. Our results suggest enhanced iron uptake as a mechanism of KC iron loading in ALD and demonstrate the ILI response as a function acquired by differentiated macrophages in humans and as a priming mechanism for ALD. PMID:18599584

  14. HFE Gene Variants Modify the Association between Maternal Lead Burden and Infant Birthweight: A Prospective Birth Cohort Study in Mexico City, Mexico

    PubMed Central

    2010-01-01

    Background Neonatal growth is a complex process involving genetic and environmental factors. Polymorphisms in the hemochromatosis (HFE) iron regulatory genes have been shown to modify transport and toxicity of lead which is known to affect birth weight. Methods We investigated the role of HFE C282Y, HFE H63 D, and transferrin (TF) P570 S gene variants in modifying the association of lead and infant birthweight in a cohort of Mexican mother-infant pairs. Subjects were initially recruited between 1994-1995 from three maternity hospitals in Mexico City and 411 infants/565 mothers had archived blood available for genotyping. Multiple linear regression models, stratified by either maternal/infant HFE or TF genotype and then combined with interaction terms, were constructed examining the association of lead and birthweight after controlling for covariates. Results 3.1%, 16.8% and 17.5% of infants (N = 390) and 1.9%, 14.5% and 18.9% of mothers (N = 533) carried the HFE C282Y, HFE H63D, and TF P570 S variants, respectively. The presence of infant HFE H63 D variants predicted 110.3 g (95% CI -216.1, -4.6) decreases in birthweight while maternal HFE H63 D variants predicted reductions of 52.0 g (95% CI -147.3 to 43.2). Interaction models suggest that both maternal and infant HFE H63 D genotype may modify tibia lead's effect on infant birthweight in opposing ways. In our interaction models, maternal HFE H63 D variant carriers had a negative association between tibia lead and birthweight. Conclusions These results suggest that the HFE H63 D genotype modifies lead's effects on infant birthweight in a complex fashion that may reflect maternal-fetal interactions with respect to the metabolism and transport of metals. PMID:20659343

  15. Hepatic porphyria: A narrative review.

    PubMed

    Arora, Sumant; Young, Steven; Kodali, Sudha; Singal, Ashwani K

    2016-11-01

    Porphyrias are a group of metabolic disorders, which result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway. These have been subdivided based on the predominant site of enzyme defect into hepatic and erythropoietic types and based on clinical presentation into acute neurovisceral and cutaneous blistering porphyrias. This review focuses on hepatic porphyrias, which include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), aminolevulinic acid dehydratase deficiency porphyria (ADP), and porphyria cutanea tarda (PCT). Of these, AIP and ADP are classified as acute porphyria, PCT as cutaneous, while VP and HCP present with both acute and cutaneous clinical manifestations. Porphobilinogen levels in a spot urine sample is the initial screening test for the diagnosis of acute hepatic porphyria, and plasma with spot urine porphyrin levels is the initial screening test to approach patients suspected of cutaneous porphyria. Specific biochemical porphyrin profile for each porphyria helps in determining the specific diagnosis. Pain relief and elimination of triggering agents are the initial steps in managing a patient presenting with an acute attack. Intravenous glucose administration terminates the mild episode of acute porphyria, with intravenous hemin needed for management of moderate to severe episodes. Liver transplantation is curative and may be needed for patients with a life-threatening acute porphyria attack or for patients with recurrent acute attacks refractory to prophylactic treatment. Of the cutaneous porphyrias, PCT is the most common and is frequently associated with a combination of multiple susceptibility factors such as alcohol use, smoking, hepatitis C virus infection, HIV infection, estrogen use, and mutations of the hemochromatosis gene. Regular phlebotomy schedule and low-dose hydroxychloroquine are effective and safe treatment options for management of PCT.

  16. The sweet thing about Type 1 diabetes: a cryoprotective evolutionary adaptation.

    PubMed

    Moalem, S; Storey, K B; Percy, M E; Peros, M C; Perl, D P

    2005-01-01

    The reasons for the uneven worldwide distribution of Type 1 diabetes mellitus have yet to be fully explained. Epidemiological studies have shown a higher prevalence of Type 1 diabetes in northern Europe, particularly in Scandinavian countries, and Sardinia. Recent animal research has uncovered the importance of the generation of elevated levels of glucose, glycerol and other sugar derivatives as a physiological means for cold adaptation. High concentrations of these substances depress the freezing point of body fluids and prevent the formation of ice crystals in cells through supercooling, thus acting as a cryoprotectant or antifreeze for vital organs as well as in their muscle tissue. In this paper, we hypothesize that factors predisposing to elevated levels of glucose, glycerol and other sugar derivatives may have been selected for, in part, as adaptive measures in exceedingly cold climates. This cryoprotective adaptation would have protected ancestral northern Europeans from the effects of suddenly increasingly colder climates, such as those believed to have arisen around 14,000 years ago and culminating in the Younger Dryas. When life expectancy was short, factors predisposing to Type 1 diabetes provided a survival advantage. However, deleterious consequences of this condition have become significant only in more modern times, as life expectancy has increased, thus outweighing their protective value. Examples of evolutionary adaptations conferring selection advantages against human pathogens that result in deleterious effects have been previously reported as epidemic pathogenic selection (EPS). Such proposed examples include the cystic fibrosis mutations in the CFTR gene bestowing resistance to Salmonella typhi and hemochromatosis mutations conferring protection against iron-seeking intracellular pathogens. This paper is one of the first accounts of a metabolic disorder providing a selection advantage not against a pathogenic stressor alone, but rather against

  17. Measurement of liver iron overload by magnetic induction using a planar gradiometer: preliminary human results.

    PubMed

    Casañas, R; Scharfetter, H; Altes, A; Remacha, A; Sarda, P; Sierra, J; Merwa, R; Hollaus, K; Rosell, J

    2004-02-01

    The measurement of hepatic iron overload is of particular interest in cases of hereditary hemochromatosis or in patients subject to periodic blood transfusion. The measurement of plasma ferritin provides an indirect estimate but the usefulness of this method is limited by many common clinical conditions (inflammation, infection, etc). Liver biopsy provides the most quantitative direct measurement of iron content in the liver but the risk of the procedure limits its acceptability. This work studies the feasibility of a magnetic induction (MI) low-cost system to measure liver iron overload. The excitation magnetic field (B0, frequency: 28 kHz) was produced by a coil, the perturbation produced by the object (deltaB) was detected using a planar gradiometer. We measured ten patients and seven volunteers in supine and prone positions. Each subject was moved in a plane parallel to the gradiometer several times to estimate measurement repeatability. The real and imaginary parts of deltaB/B0 were measured. Plastic tanks filled with water, saline and ferric solutions were measured for calibration purposes. We used a finite element model to evaluate the experimental results. To estimate the iron content we used the ratio between the maximum values for real and imaginary parts of deltaB/B0 and the area formed by the Nyquist plot divided by the maximum imaginary part. Measurements in humans showed that the contribution of the permittivity is stronger than the contribution of the permeability produced by iron stores in the liver. Defined iron estimators show a limited correlation with expected iron content in patients (R < or = 0.56). A more precise control of geometry and position of the subjects and measurements at multiple frequencies would improve the method.

  18. Identification and characterization of a new multigene family in the human MHC: A candidate autoimmune disease susceptibility element (3.8-1)

    SciTech Connect

    Harris, J.M.; Venditti, C.P.; Chorney, M.J.

    1994-09-01

    An association between idiopathic hemochromatosis (HFE) and the HLA-A3 locus has been previously well-established. In an attempt to identify potential HFE candidate genes, a genomic DNA fragment distal to the HLA-A9 breakpoint was used to screen a B cell cDNA library; a member (3.8-1) of a new multigene family, composed of five distinct genomic cross-reactive fragments, was identified. Clone 3.8-1 represents the 3{prime} end of 9.6 kb transcript which is expressed in multiple tissues including the spleen, thymus, lung and kidney. Sequencing and genome database analysis indicate that 3.8-1 is unique, with no homology to any known entries. The genomic residence of 3-8.1, defined by polymorphism analysis and physical mapping using YAC clones, appears to be absent from the genomes of higher primates, although four other cross-reactivities are maintained. The absence of this gene as well as other probes which map in the TNF to HLA-B interval, suggest that this portion of the human HMC, located between the Class I and Class III regions, arose in humans as the result of a post-speciation insertional event. The large size of the 3.8-1 gene and the possible categorization of 3.8-1 as a human-specific gene are significant given the genetic data that place an autoimmune susceptibility element for IDDM and myasthenia gravis in the precise region where this gene resides. In an attempt to isolate the 5{prime} end of this large transcript, we have constructed a cosmid contig which encompasses the genomic locus of this gene and are progressively isolating coding sequences by exon trapping.

  19. Comparison of CT scanning and radionuclide imaging in liver disease

    SciTech Connect

    Friedman, M.L.; Esposito, F.S.

    1980-01-01

    Early experience with body CT suggested its usefulness in many diagnostic problems; jaundice, renal and pancreatic masses, and in the evaluation of relatively inaccessible parts of the body, such as the retroperitineum, mediastinum, and pelvis. Investigation of hepatic disease by CT was not unexpectedly compared to radionuclide liver scanning, the major preexisting modality for imaging the liver. In the evaluation of the jaundiced patient, CT rapidly assumed a major role, providing more specific information about the liver than the RN liver scan, as well as demonstrating adjacent organs. CT differentiate obstructive from non-obstructive jaundice. With respect to mass lesions of the liver, the RN liver scan is more sensitive than CT but less specific. The abnormalities on an isotope image of the liver consist of normal variants in configuration, extrinsic compression by adjacent structures, cysts, hemangiomata, abscesses, and neoplasms. These suspected lesions may then be better delineated by the CT image, and a more precise diagnosis made. The physiologic information provided by the RN liver scan is an added facet which is helpful in the patient with diffuse hepatic disease. The CT image will be normal in many of these patients, however, hemochromatosis and fatty infiltration lend themselves especially to density evaluation by CT. The evaluation of lymphoma is more thorough with CT. Structures other than the liver, such as lymph nodes, are visualized. Gallium, however, provides additional isotopic information in patients with lymphoma, and in addition, is known to be useful in the investigation of a febrile patient with an abscess. Newer isotopic agents expand hepatic imaging in other directions, visualizing the biliary tree and evaluating the jaundiced patient.

  20. In vivo time-harmonic multifrequency elastography of the human liver

    NASA Astrophysics Data System (ADS)

    Tzschätzsch, Heiko; Ipek-Ugay, Selcan; Guo, Jing; Streitberger, Kaspar-Josche; Gentz, Enno; Fischer, Thomas; Klaua, Robert; Schultz, Michael; Braun, Jürgen; Sack, Ingolf

    2014-04-01

    Elastography is capable of noninvasively detecting hepatic fibrosis by imposing mechanical stress and measuring the viscoelastic response in the liver. Magnetic resonance elastography (MRE) relies on time-harmonic vibrations, while most dynamic ultrasound elastography methods employ transient stimulation methods. This study attempts to benefit from the advantages of time-harmonic tissue stimulation, i.e. relative insensitivity to obesity and ascites and mechanical approachability of the entire liver, and the advantages of ultrasound, i.e. time efficiency, low costs, and wide availability, by introducing in vivo time-harmonic elastography (THE) of the human liver using ultrasound and a broad range of harmonic stimulation frequencies. THE employs continuous harmonic shear vibrations at 7 frequencies from 30 to 60 Hz in a single examination and determines the elasticity and the viscosity of the liver from the dispersion of the shear wave speed within the applied frequency range. The feasibility of the method is demonstrated in the livers of eight healthy volunteers and a patient with cirrhosis. Multifrequency MRE at the same drive frequencies was used as elastographic reference method. Similar values of shear modulus and shear viscosity according the Kelvin-Voigt model were obtained by MRE and THE, indicating that the new method is suitable for in vivo quantification of the shear viscoelastic properties of the liver, however, in real-time and at a fraction of the costs of MRE. In conclusion, THE may provide a useful tool for fast assessment of the viscoelastic properties of the liver at low costs and without limitations in obesity, ascites or hemochromatosis.

  1. Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population

    PubMed Central

    Gordeuk, Victor R.; Reboussin, David M.; McLaren, Christine E.; Barton, James C.; Acton, Ronald T.; McLaren, Gordon D.; Harris, Emily L.; Reiss, Jacob A.; Adams, Paul C.; Speechley, Mark; Phatak, Pradyumna D.; Sholinsky, Phyliss; Eckfeldt, John H.; Chen, Wen-Pin; Passmore, Leah; Dawkins, Fitzroy W.

    2013-01-01

    How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores. PMID:18429050

  2. Shigella sonnei Bacteremia Presenting with Profound Hepatic Dysfunction

    PubMed Central

    Rettew, Andrew; Shaikh, Bilal; Abdulkareem, Abdullateef

    2017-01-01

    Worldwide, Shigellosis is a significant public health issue, associated with nearly one million deaths annually. About half a million cases of Shigella infection are reported annually in the United States. Shigella bacteremia is uncommon and generally seen in children and immunocompromised adults. We present a case of a Shigella sonnei bacteremia with marked hepatic derangement in a 27-year-old previously healthy homosexual male with history of Roux-en-Y gastric bypass, who presented to the emergency room with a 4-day history of loose watery stool, abdominal cramps, nausea and vomiting, and yellow skin of 2-day duration. He reports similar diarrhea illness in two close contacts in preceding days. On examination, he was fully oriented but dehydrated, icteric, and febrile. Laboratory data revealed WBC of 2200/μL, elevated AST and ALT (201 IU/L, 73 IU/L resp.), normal alkaline phosphatase, elevated total and direct bilirubin of 8.2 mg/dL and 4.4 mg/dL, albumin of 3.2 g/dL, INR of 2.9, prothrombin time of 31.7, and platelet of 96,000/μL. Workup for infectious, autoimmune and medication-induced hepatitis, Wilson's disease, and hemochromatosis was negative. Abdominal ultrasound and computed tomography of the abdomen showed hepatic steatosis and right-sided colitis. Stool and blood cultures were positive for Shigella sonnei. He was treated with ciprofloxacin with improvement in liver function. Follow-up blood test 4 months later was within normal limits. PMID:28326205

  3. Incident acute pseudogout and prior bisphosphonate use: Matched case–control study in the UK-Clinical Practice Research Datalink

    PubMed Central

    Roddy, Edward; Muller, Sara; Paskins, Zoe; Hider, Samantha L.; Blagojevic-Bucknall, Milisa; Mallen, Christian D.

    2017-01-01

    Abstract Oral bisphosphonates are the most commonly used drugs to treat postmenopausal osteoporosis. Acute pseudogout is anecdotally reported to occur following bisphosphonate initiation but empirical data are lacking. We investigated whether treatment with oral bisphosphonates is a risk factor for incident acute pseudogout. A matched case–control study was undertaken using data from the UK-Clinical Practice Research Datalink. Adults who consulted for incident acute pseudogout between 1987 and 2012 were each matched for gender, age at pseudogout diagnosis, and general practice to up to 4 control subjects without pseudogout. The exposure of interest was a prescription for an oral bisphosphonate issued within the 60-day period prior to the date of incident acute pseudogout. Associations between incident acute pseudogout and prior bisphosphonate prescription were examined using conditional logistic regression, adjusting for hyperparathyroidism, osteoarthritis, rheumatoid arthritis, hemochromatosis, hypophosphatasia, and prescriptions for diuretics and oral corticosteroids. Two thousand eleven acute pseudogout cases were compared with 8013 matched controls without acute pseudogout (mean age [standard deviation] 72 years [14]; 52% male). One hundred twenty-three cases (6.1%) had received an oral bisphosphonate prescription in the 60-day exposure period compared with 305 controls (3.8%) (adjusted incidence rate ratio [IRR] 1.33; 95% confidence interval [CI] 1.05–1.69). This association was stronger in females (adjusted IRR 1.49; 95% CI 1.15–1.94) and was nonsignificant in males (0.83; 0.48–1.44). Incident acute pseudogout was associated with prescription of an oral bisphosphonate in the preceding 60 days. Prescribers should be aware of acute pseudogout as a possible side effect of bisphosphonate treatment. Further research is needed to explore the risks conferred by different bisphosphonates and the mechanism underlying this association. PMID:28328803

  4. Hypogonadotropic Hypogonadism Revisited

    PubMed Central

    Fraietta, Renato; Zylberstejn, Daniel Suslik; Esteves, Sandro C

    2013-01-01

    Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Hypogonadotropic hypogonadism can be congenital or acquired. Congenital hypogonadotropic hypogonadism is divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and congenital normosmic isolated hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism). The incidence of congenital hypogonadotropic hypogonadism is approximately 1-10:100,000 live births, and approximately 2/3 and 1/3 of cases are caused by Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism, respectively. Acquired hypogonadotropic hypogonadism can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X. The clinical characteristics of hypogonadotropic hypogonadism are androgen deficiency and a lack/delay/stop of pubertal sexual maturation. Low blood testosterone levels and low pituitary hormone levels confirm the hypogonadotropic hypogonadism diagnosis. A prolonged stimulated intravenous GnRH test can be useful. In Kallmann syndrome, cerebral MRI can show an anomalous morphology or even absence of the olfactory bulb. Therapy for hypogonadotropic hypogonadism depends on the patient's desire for future fertility. Hormone replacement with testosterone is the classic treatment for hypogonadism. Androgen replacement is indicated for men who already have children or have no desire to induce pregnancy, and testosterone therapy is used to reverse the symptoms and signs of hypogonadism. Conversely, GnRH or gonadotropin therapies are the best options for men wishing to have children. Hypogonadotropic hypogonadism is one of the rare conditions in which specific

  5. Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and a polyclonal antiserum.

    PubMed

    Deaglio, Silvia; Capobianco, Andrea; Calì, Angelita; Bellora, Francesca; Alberti, Federica; Righi, Luisella; Sapino, Anna; Camaschella, Clara; Malavasi, Fabio

    2002-11-15

    Human transferrin receptor-2 (TFR-2) is a protein highly homologous to TFR-1/CD71 and is endowed with the ability to bind transferrin (TF) with low affinity. High levels of TFR-2 mRNA were found in the liver and in erythroid precursors. Mutations affecting the TFR-2 gene led to hemochromatosis type 3, a form of inherited iron overload. Several issues on distribution and function of the receptor were answered by raising a panel of 9 monoclonal antibodies specific for TFR-2 by immunizing mice with murine fibroblasts transfected with the human TFR-2 cDNA. A polyclonal antiserum was also produced in mice immunized with 3 peptides derived from the TFR-2 sequence, exploiting an innovative technique. The specificity of all the reagents produced was confirmed by reactivity with TFR-2(+) target cells and simultaneous negativity with TFR-1(+) cells. Western blot analyses showed a dominant chain of approximately 90 kDa in TFR-2 transfectants and HepG2 cell line. Analysis of distribution in normal tissues and in representative cell lines revealed that TFR-2 displays a restricted expression pattern--it is present at high levels in hepatocytes and in the epithelial cells of the small intestine, including the duodenal crypts. Exposure of human TFR-2(+) cells to TF-bound iron is followed by a significant up-regulation and relocalization of membrane TFR-2. The tissue distribution pattern, the behavior following exposure to iron-loaded TF, and the features of the disease resulting from TFR-2 inactivation support the hypothesis that TFR-2 contributes to body iron sensing.

  6. Results of an international round robin for the quantification of serum non-transferrin-bound iron: Need for defining standardization and a clinically relevant isoform.

    PubMed

    Jacobs, Esther M G; Hendriks, Jan C M; van Tits, Berry L J H; Evans, Patricia J; Breuer, William; Liu, Ding Yong; Jansen, Eugene H J M; Jauhiainen, Katri; Sturm, Brigitte; Porter, John B; Scheiber-Mojdehkar, Barbara; von Bonsdorff, Leni; Cabantchik, Z Ioav; Hider, Robert C; Swinkels, Dorine W

    2005-06-15

    Non-transferrin-bound iron (NTBI) appears in the circulation of patients with iron overload. Various methods to measure NTBI were comparatively assessed as part of an international interlaboratory study. Six laboratories participated in the study, using methods based on iron mobilization and detection with iron chelators or on reactivity with bleomycin. Serum samples of 12 patients with hereditary (n=11) and secondary (n=1) hemochromatosis were measured during a 3-day analysis using 4 determinations per sample per day, making a total of 144 measurements per laboratory. Bland-Altman plots for repeated measurements are presented. The methods differed widely in mean serum NTBI level (range 0.12-4.32mumol/L), between-sample variation (SD range 0.20-2.13mumol/L and CV range 49.3-391.3%), and within-sample variation (SD range 0.02-0.45mumol/L and CV range 4.4-193.2%). The results obtained with methods based on chelators correlated significantly (R(2) range 0.86-0.99). On the other hand, NTBI values obtained by the various methods related differently from those of serum transferrin saturation (TS) when expressed in terms of both regression coefficients and NTBI levels at TS of 50%. Recent studies underscore the clinical relevance of NTBI in the management of iron-overloaded patients. However, before measurement of NTBI can be introduced into clinical practice, there is a need for more reproducible protocols as well as information on which method best represents the pathophysiological phenomenon and is most pertinent for diagnostic and therapeutic purposes.

  7. Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain.

    PubMed

    Aranda, Núria; Viteri, Fernando E; Montserrat, Carme; Arija, Victoria

    2010-08-01

    Mutations in the HFE gene result in iron overload and can produce hereditary hemochromatosis (HH), a disorder of iron metabolism characterized by increased intestinal iron absorption. Dietary quality, alcoholism and other life-style factors can increase the risk of iron overload, especially among genetically at risk populations. Polymorphisms of the HFE gene (C282Y, H63D and S65C) were measured together with serum ferritin (SF), transferrin saturation (TS) and hemoglobin, to measure iron status, in randomly-selected healthy subjects living in the Spanish Mediterranean coast (n = 815; 425 females, 390 males), 18 to 75 years of age. The intake of dietary components that affect iron absorption was calculated from 3-day dietary records. The presence of C282Y/H63D compound heterozygote that had a prevalence of 2.8% in males and 1.2% in females was associated with an elevated TS and SF. No subject was homozygous for C282Y or S65C. The C282Y heterozygote, H63D heterozygote and homozygote and H63D/S65C compound heterozygote genotypes were associated with increased TS relative to the wild type in the general population. These genotypes together with the alcohol and iron intake increase the indicators of iron status, while calcium intake decreases them. We did not observe any affect of the S65C heterozygote genotype on these levels. All the HFE genotypes except for the S65C heterozygote together with the alcohol, iron and calcium intake affect the indicators of iron status. The C282Y/H63D compound heterozygote genotype has the higher phenotypic expression in our Spanish Mediterranean population.

  8. Plague Gives Surprises in the First Decade of the 21st Century in the United States and Worldwide

    PubMed Central

    Butler, Thomas

    2013-01-01

    Plague is an ancient disease caused by the bacterium Yersinia pestis and transmitted by rodent flea bites that continues to surprise us with first-ever events. This review documents plague in human cases in the 1st decade of the 21st century and updates our knowledge of clinical manifestations, transmission during outbreaks, diagnostic testing, antimicrobial treatment, and vaccine development. In the United States, 57 persons were reported to have the disease, of which seven died. Worldwide, 21,725 persons were affected with 1,612 deaths, for a case-fatality rate of 7.4%. The Congo reported more cases than any other country, including two large outbreaks of pneumonic plague, surpassing Madagascar, which had the most cases in the previous decade. Two United States scientists suffered fatal accidental exposures: a wildlife biologist, who carried out an autopsy on a mountain lion in Arizona in 2007, and a geneticist with subclinical hemochromatosis in Chicago, who was handling an avirulent strain of Y. pestis in 2009. Antimicrobial drugs given early after the onset of symptoms prevented many deaths; those recommended for treatment and prophylaxis included gentamicin, doxycycline, and fluoroquinolones, although fluoroquinolones have not been adequately tested in humans. Fleas that do not have their guts blocked by clotted blood meals were shown to be better transmitters of plague than blocked fleas. Under development for protection against bioterrorist use, a subunit vaccine containing F1 and V antigens of Y. pestis was administered to human volunteers eliciting antibodies without any serious side effects. These events, although showing progress, suggest that plague will persist in rodent reservoirs mostly in African countries burdened by poverty and civil unrest, causing death when patients fail to receive prompt antimicrobial treatment. PMID:24043686

  9. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

    PubMed Central

    Yin, Wei-Li; Wang, Feng-Mei; Han, Tao

    2016-01-01

    Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation<0.05). However, no significant difference between liver cirrhosis cases and the control group was observed for HFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. PMID:27657935

  10. Glutamyl cysteine dipeptide suppresses ferritin expression and alleviates liver injury in iron-overload rat model.

    PubMed

    Salama, Samir A; Al-Harbi, Mohammad S; Abdel-Bakky, Mohamed S; Omar, Hany A

    2015-08-01

    Despite its biological importance, iron is a pro-oxidant element and its accumulation results in tissue injury. Iron overload diseases such as thalassemia and hereditary hemochromatosis are commonly associated with liver tissue injury. Glutamyl cysteine (GC) is a dipeptide with antioxidant properties owing to its cysteine residue. The aim of the current work was to investigate the hepatoprotective effect of GC against iron overload-induced liver injury. Rats were distributed into five groups; normal control, GC control, iron-treated (150 mg/kg ip injection) and both iron and GC-treated (total iron: 150 mg/kg ip and GC: 50 mg or 100 mg/kg/day ip for 30 days). Our results showed that treatment with GC at the two-dose levels attenuated iron-induced liver tissue injury as evidenced by significant reduction in serum activity of liver enzymes ALT and AST, amelioration of iron-induced histopathological alteration, suppression of iron-induced oxidative stress as demonstrated by significant reduction of malondialdehyde and protein carbonyl content beside elevation of total antioxidant capacity, reduced glutathione and the antioxidant enzymes GPx and SOD in liver tissue. In addition, GC significantly reduced levels of the proinflammatory cytokines TNF-α, IL-6 and IL-1β and activity of the apoptotic marker caspase-3 in liver tissues. To our surprise, GC reduced liver iron content and ferritin expression, denoting the possible iron chelation competency. Collectively our results highlight evidence for the hepatoprotective effect of GC against iron overload-induced liver injury that is potentially mediated through suppression of oxidative tissue injury, attenuation of inflammatory response, amelioration of hepatocellular apoptosis and possibly through iron chelation.

  11. Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century.

    PubMed

    Rostoker, Guy; Vaziri, Nosratola D; Fishbane, Steven

    2016-05-01

    Iron overload used to be considered rare in hemodialysis patients but its clinical frequency is now increasingly realized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosideroses and genetic hemochromatosis. Magnetic resonance imaging is now the gold standard method for LIC estimation and monitoring in non-renal patients. Studies of LIC in hemodialysis patients by quantitative magnetic resonance imaging and magnetic susceptometry have demonstrated a strong relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Three long-term observational studies have recently suggested that excessive IV iron doses may be associated with an increased risk of cardiovascular events and death in hemodialysis patients. We postulate that iatrogenic iron overload in the era of erythropoiesis-stimulating agents may silently increase complications in dialysis patients without creating frank clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It is therefore tempting to postulate that the main pathophysiological pathway leading to these events may involve the pleiotropic master hormone hepcidin (synergized by fibroblast growth factor 23), which regulates iron metabolism. Oxidative stress as a result of IV iron infusions and iron overload, by releasing labile non-transferrin-bound iron, might represent a 'second hit' on the vascular bed. Finally, iron deposition in the myocardium of patients with severe iron overload might also play a role in the pathogenesis of sudden death in some patients.

  12. Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome.

    PubMed

    Cassidy, Lara M; Martiniano, Rui; Murphy, Eileen M; Teasdale, Matthew D; Mallory, James; Hartwell, Barrie; Bradley, Daniel G

    2016-01-12

    The Neolithic and Bronze Age transitions were profound cultural shifts catalyzed in parts of Europe by migrations, first of early farmers from the Near East and then Bronze Age herders from the Pontic Steppe. However, a decades-long, unresolved controversy is whether population change or cultural adoption occurred at the Atlantic edge, within the British Isles. We address this issue by using the first whole genome data from prehistoric Irish individuals. A Neolithic woman (3343-3020 cal BC) from a megalithic burial (10.3× coverage) possessed a genome of predominantly Near Eastern origin. She had some hunter-gatherer ancestry but belonged to a population of large effective size, suggesting a substantial influx of early farmers to the island. Three Bronze Age individuals from Rathlin Island (2026-1534 cal BC), including one high coverage (10.5×) genome, showed substantial Steppe genetic heritage indicating that the European population upheavals of the third millennium manifested all of the way from southern Siberia to the western ocean. This turnover invites the possibility of accompanying introduction of Indo-European, perhaps early Celtic, language. Irish Bronze Age haplotypic similarity is strongest within modern Irish, Scottish, and Welsh populations, and several important genetic variants that today show maximal or very high frequencies in Ireland appear at this horizon. These include those coding for lactase persistence, blue eye color, Y chromosome R1b haplotypes, and the hemochromatosis C282Y allele; to our knowledge, the first detection of a known Mendelian disease variant in prehistory. These findings together suggest the establishment of central attributes of the Irish genome 4,000 y ago.

  13. Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane.

    PubMed

    Sousa, Leilismara; Garcia, Israel J P; Costa, Tamara G F; Silva, Lilian N D; Renó, Cristiane O; Oliveira, Eneida S; Tilelli, Cristiane Q; Santos, Luciana L; Cortes, Vanessa F; Santos, Herica L; Barbosa, Leandro A

    2015-01-01

    Iron is an essential chemical element for human life. However, in some pathological conditions, such as hereditary hemochromatosis type 1 (HH1), iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload interferes with the Na,K-ATPase activity of the plasma membrane by studying erythrocytes that were obtained from the whole blood of patients suffering from iron overload. Additionally, we treated erythrocytes of normal subjects with 0.8 mM H2O2 and 1 μM FeCl3 for 24 h. We then analyzed the lipid profile, lipid peroxidation and Na,K-ATPase activity of plasma membranes derived from these cells. Iron overload was more frequent in men (87.5%) than in women and was associated with an increase (446%) in lipid peroxidation, as indicated by the amount of the thiobarbituric acid reactive substances (TBARS) and an increase (327%) in the Na,K-ATPase activity in the plasma membrane of erythrocytes. Erythrocytes treated with 1 μM FeCl3 for 24 h showed an increase (132%) in the Na,K-ATPase activity but no change in the TBARS levels. Iron treatment also decreased the cholesterol and phospholipid content of the erythrocyte membranes and similar decreases were observed in iron overload patients. In contrast, erythrocytes treated with 0.8 mM H2O2 for 24 h showed no change in the measured parameters. These results indicate that erythrocytes from patients with iron overload exhibit higher Na,K-ATPase activity compared with normal subjects and that this effect is specifically associated with altered iron levels.

  14. Inborn anemias in mice: (Annual report, 1983-1984)

    SciTech Connect

    Bernstein, S.E.

    1984-09-01

    The hypotranserrinemic-hemochromatosis mutation in mice discovered in our laboratory is an almost exact duplicate of human atransferrinemia. Just as in man, the condition is inherited as a recessive lethal. The disease appears to stem from a congenital deficiency in transferrin. The new mutation arose spontaneously in BALB/c mice and results in death before 12 days of age. It is characterized by stunted growth, low numbers of erythrocytes, hypochromia, and in the absence of jaundice. Treatments with Imferon or other iron preparations were uniformly unsuccessful, but the use of normal mouse serum proved successful as a therapeutic measure. We find that we are able to keep these afflicted mice alive for more than a year with small amounts of normal serum, and transferrin bands are missing on cellulose acetate electrophoresis of serum proteins from affected individuals receiving no treatment. Genetic tests indicated that the new mutation was not an allele of any of the other known iron deficiency anemias in the mouse: sex linked anemia (sla), microcytic anemia (mk), or flexed anemia (f) or any of the members of the hemolytic disease group (sph, sph/sup ha/, nb, or ja). Biochemical and genetic analyses carried out during the past year indicate that the new mutation, tentatively designated hpx is not likely to be a mutation at the transferrin (Trf) locus on Chromosome 9. We observed no unusual serum proteins on cellulose acetate electrophoresis, such as might be expected if the Trf gene had mutated. Moreover, radial immunodiffusion examination and Ouchterlony analysis did not show the presence of smaller molecules (or fragments) with transferrin antigenic specificities. Instead they showed a total loss in serum transferrin. 14 refs., 5 tabs.

  15. Frequency of common HFE variants in the Saudi population: a high throughput molecular beacon-based study

    PubMed Central

    Alsmadi, Osama A; Al-Kayal, Fadi; Al-Hamed, Mohamed; Meyer, Brian F

    2006-01-01

    Background Hereditary Hemochromatosis (HH) is an autosomal recessive disorder highlighted byiron-overload. Two popular mutations in HFE, p.C282Y and p.H63D, have been discovered and found to associate with HH in different ethnic backgrounds. p.C282Y and p.H63D diagnosis is usually made byrestriction enzyme analysis. However, the use of this technique is largelylimited to research laboratories because they are relativelyexpensive, time-consuming, and difficult to transform into a high throughput format. Methods Single nucleotide variations in target DNA sequences can be readily identified using molecular beacon fluorescent probes. These are quenched probes with loop and hairpin structure, and they become fluorescent upon specific target recognition. We developed high throughput homogeneous real-time PCR assays using molecular beacon technology, to genotype p.C282Y and p.H63D variants. Representative samples of different genotypes for these variants were assayed by restriction enzyme analysis and direct sequencing as bench mark methods for comparison with the newly developed molecular beacon-based real-time PCR assay. Results Complete concordance was achieved by all three assay formats. Homozygotes (mutant and wildtype) and heterozygotes were readily differentiated by the allele specific molecular beacons as reported by the associated fluorophore in the real-time assay developed in this study. Additionally, these assays were used in a high throughput format to establish the allele frequency of C282Y and H63D in Saudis for the first time. Conclusion These assays may be reliably applied as a diagnostic test or large scale method for population screening. PMID:16672055

  16. Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

    PubMed Central

    Sousa, Leilismara; Garcia, Israel J. P.; Costa, Tamara G. F.; Silva, Lilian N. D.; Renó, Cristiane O.; Oliveira, Eneida S.; Tilelli, Cristiane Q.; Santos, Luciana L.; Cortes, Vanessa F.; Santos, Herica L.; Barbosa, Leandro A.

    2015-01-01

    Iron is an essential chemical element for human life. However, in some pathological conditions, such as hereditary hemochromatosis type 1 (HH1), iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload interferes with the Na,K-ATPase activity of the plasma membrane by studying erythrocytes that were obtained from the whole blood of patients suffering from iron overload. Additionally, we treated erythrocytes of normal subjects with 0.8 mM H2O2 and 1 μM FeCl3 for 24 h. We then analyzed the lipid profile, lipid peroxidation and Na,K-ATPase activity of plasma membranes derived from these cells. Iron overload was more frequent in men (87.5%) than in women and was associated with an increase (446%) in lipid peroxidation, as indicated by the amount of the thiobarbituric acid reactive substances (TBARS) and an increase (327%) in the Na,K-ATPase activity in the plasma membrane of erythrocytes. Erythrocytes treated with 1 μM FeCl3 for 24 h showed an increase (132%) in the Na,K-ATPase activity but no change in the TBARS levels. Iron treatment also decreased the cholesterol and phospholipid content of the erythrocyte membranes and similar decreases were observed in iron overload patients. In contrast, erythrocytes treated with 0.8 mM H2O2 for 24 h showed no change in the measured parameters. These results indicate that erythrocytes from patients with iron overload exhibit higher Na,K-ATPase activity compared with normal subjects and that this effect is specifically associated with altered iron levels. PMID:26197432

  17. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells.

    PubMed

    Liuzzi, Juan P; Aydemir, Fikret; Nam, Hyeyoung; Knutson, Mitchell D; Cousins, Robert J

    2006-09-12

    Zip14 is a member of the SLC39A zinc transporter family, which is involved in zinc uptake by cells. Up-regulation of Zip14 by IL-6 appears to contribute to the hepatic zinc accumulation and hypozincemia of inflammation. At least three members of the SLC39A family transport other trace elements, such as iron and manganese, in addition to zinc. We analyzed the capability of Zip14 to mediate non-transferrin-bound iron (NTBI) uptake by overexpressing mouse Zip14 in HEK 293H cells and Sf9 insect cells. Zip14 was found to localize to the plasma membrane, and its overexpression increased the uptake of both (65)Zn and (59)Fe. Addition of bathophenanthroline sulfonate, a cell-impermeant ferrous iron chelator, inhibited Zip14-mediated iron uptake from ferric citrate, suggesting that iron is taken up by HEK cells as Fe(2+). Iron uptake by HEK and Sf9 cells expressing Zip14 was inhibited by zinc. Suppression of endogenous Zip14 expression by using Zip14 siRNA reduced the uptake of both iron and zinc by AML12 mouse hepatocytes. Zip14 siRNA treatment also decreased metallothionein mRNA levels, suggesting that compensatory mechanisms were not sufficient to restore intracellular zinc. Collectively, these results indicate that Zip14 can mediate the uptake of zinc and NTBI into cells and that it may play a role in zinc and iron metabolism in hepatocytes, where this transporter is abundantly expressed. Because NTBI is commonly found in plasma of patients with hemochromatosis and transfusional iron overload, Zip14-mediated NTBI uptake may contribute to the hepatic iron loading that characterizes these diseases.

  18. Genetic testing behavior and reporting patterns in electronic medical records for physicians trained in a primary care specialty or subspecialty

    PubMed Central

    Li, Cheng; Lester, William T

    2012-01-01

    Objective To characterize important patterns of genetic testing behavior and reporting in modern electronic medical records (EMRs) at the institutional level. Materials and methods Retrospective observational study using EMR data of all 10 715 patients who received genetic testing by physicians trained in a primary care specialty or subspecialty at an academic medical center between January 1, 2008 and December 31, 2010. Results Patients had a mean±SD age of 38.3±15.8 years (median 36.1, IQR 30.0–43.8). The proportion of female subjects in the study population was larger than in the general patient population (77.2% vs 55.0%, p<0.001) and they were younger than the male subjects in the study (36.5±13.2 vs 44.6±21.2 years, p<0.001). Approximately 1.1% of all patients received genetic testing. There were 942 physicians who ordered a total of 15 320 genetic tests. By volume, commonly tested genes involved mutations for cystic fibrosis (36.7%), prothrombin (13.7%), Tay–Sachs disease (6.7%), hereditary hemochromatosis (4.4%), and chronic myelogenous leukemia (4.1%). EMRs stored reports as free text with categorical descriptions of mutations and an average length of 269.4±153.2 words (median 242, IQR 146–401). Conclusions In this study, genetic tests were often ordered by a diverse group of physicians for women of childbearing age being evaluated for diseases that may affect potential offspring. EMRs currently serve primarily as a storage warehouse for textual reports that could potentially be transformed into meaningful structured data for next-generation clinical decision support. Further studies are needed to address the design, development, and implementation of EMRs capable of managing the critical genetic health information challenges of the future. PMID:22511017

  19. Polychlorinated Biphenyls, Lead, and Mercury Are Associated with Liver Disease in American Adults: NHANES 2003–2004

    PubMed Central

    Cave, Matt; Appana, Savitri; Patel, Mihir; Falkner, Keith Cameron; McClain, Craig J.; Brock, Guy

    2010-01-01

    Background High-level occupational exposures to some industrial chemicals have been associated with liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, the potential role of low-level environmental pollution on liver disease in the general population has not been evaluated. Objective We determined whether environmental pollutants are associated with an elevation in serum alanine aminotransferase (ALT) activity and suspected NAFLD in U.S. adults. Methods This cross-sectional cohort study evaluated adult participants without viral hepatitis, hemochromatosis, or alcoholic liver disease from the National Health and Nutrition Examination Survey (NHANES) for 2003–2004. ALT elevation was defined in men as ≥ 37 IU/L (age18–20 years) and ≥ 48 IU/L (age ≥ 21 years) and in women as ≥ 30 IU/L (age 18–20 years) and ≥ 31 IU/L (age ≥ 21 years). Adjusted odds ratios (ORs) for ALT elevation were determined across exposure quartiles for 17 pollutant subclasses comprising 111 individual pollutants present with at least a 60% detection rate. Adjustments were made for age, race/ethnicity, sex, body mass index, poverty income ratio, and insulin resistance. Individual pollutants from subclasses associated with ALT elevation were subsequently analyzed. Results The overall prevalence of ALT elevation was 10.6%. Heavy metals and polychlorinated biphenyls (PCBs) were associated with dose-dependent increased adjusted ORs for ALT elevation. Within these subclasses, increasing whole-blood levels of lead and mercury and increasing lipid-adjusted serum levels of 20 PCBs were individually associated with ALT elevation. Conclusions PCB, lead, and mercury exposures were associated with unexplained ALT elevation, a proxy marker of NAFLD, in NHANES 2003–2004 adult participants. PMID:21126940

  20. Estimation of liver iron concentration by dual energy CT images: influence of X-ray energy on sensitivity.

    PubMed

    Malvarosa, I; Massaroni, C; Liguori, C; Paul, J; Beomonte Zobel, B; Saccomandi, P; Vogl, T J; Silvestri, S; Schena, E

    2014-01-01

    In hemochromatosis an abnormal accumulation of iron is present in parenchymal organs and especially in liver. Among the several techniques employed to diagnose the iron overload, magnetic resonance imaging (MRI) and Computed Tomography (CT) are the most promising non-invasive ones. MRI is largely used but shows limitation including an overestimation of iron and inability to quantify iron at very high concentrations. Therefore, some research groups are focusing on the estimation of iron concentration by CT images. Single X-ray CTs are not able to accurately perform this task in case of the presence of confounding factors (e.g., fat). A potential solution to overcome this concern is the employment of Dual-Energy CT (DECT). The aim of this work is to investigate influence of the kVp and mAs on CT number sensitivity to iron concentration. A phantom with test tubes filled with homogenized porcine liver at different iron concentrations, has been scanned with DECT at different mAs. The images have been analyzed using an ad-hoc developed algorithm which allows minimizing the influence of air bubbles present in the homogenized. Data show that the sensitivity is strongly influenced by kVp (its value almost halves from 80 kVp to 140 kVp; e.g. 0.41 g·μmol(-1) and 0.19 g·μmol(-1) at 80 kVp/120 mAs and 140 kVp/60 mAs respectively), on the other hand the influence of mAs value is negligible.

  1. Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome

    PubMed Central

    Cassidy, Lara M.; Martiniano, Rui; Murphy, Eileen M.; Teasdale, Matthew D.; Mallory, James; Hartwell, Barrie; Bradley, Daniel G.

    2016-01-01

    The Neolithic and Bronze Age transitions were profound cultural shifts catalyzed in parts of Europe by migrations, first of early farmers from the Near East and then Bronze Age herders from the Pontic Steppe. However, a decades-long, unresolved controversy is whether population change or cultural adoption occurred at the Atlantic edge, within the British Isles. We address this issue by using the first whole genome data from prehistoric Irish individuals. A Neolithic woman (3343–3020 cal BC) from a megalithic burial (10.3× coverage) possessed a genome of predominantly Near Eastern origin. She had some hunter–gatherer ancestry but belonged to a population of large effective size, suggesting a substantial influx of early farmers to the island. Three Bronze Age individuals from Rathlin Island (2026–1534 cal BC), including one high coverage (10.5×) genome, showed substantial Steppe genetic heritage indicating that the European population upheavals of the third millennium manifested all of the way from southern Siberia to the western ocean. This turnover invites the possibility of accompanying introduction of Indo-European, perhaps early Celtic, language. Irish Bronze Age haplotypic similarity is strongest within modern Irish, Scottish, and Welsh populations, and several important genetic variants that today show maximal or very high frequencies in Ireland appear at this horizon. These include those coding for lactase persistence, blue eye color, Y chromosome R1b haplotypes, and the hemochromatosis C282Y allele; to our knowledge, the first detection of a known Mendelian disease variant in prehistory. These findings together suggest the establishment of central attributes of the Irish genome 4,000 y ago. PMID:26712024

  2. Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling.

    PubMed

    Zhang, Miao; Liu, Jing; Guo, Wenli; Liu, Xin; Liu, Sijin; Yin, Huijun

    2016-05-01

    Systemic iron homeostasis is strictly controlled under normal conditions to ensure a balance between the absorption, utilization, storage and recycling of iron. The hepcidin-ferroportin (FPN) axis is of critical importance in the maintenance of iron homeostasis. Hepcidin deficiency gives rise to enhanced dietary iron absorption, as well as to increased iron release from macrophages, and this in turn results in iron accumulation in the plasma and organs, and is associated with a range of tissue pathologies. Low hepcidin levels have been demonstrated in most forms of hereditary hemochromatosis (HH), as well as in β-thalassemia. Therapies that increase hepcidin concentrations may potentially play a role in the treatment of these iron overload-related diseases. To date, natural compounds have not been extensively investigated for this purpose, to the best of our knowledge. Thus, in the present study, we screened natural compounds that have the potential to regulate hepcidin expression. By performing hepcidin promoter-luciferase assay, RT-qPCR and animal experiments, we demonstrated that icariin and berberine were potent stimulators of hepcidin transcription. Mechanistic experiments indicated that icariin and berberine increased hepcidin expression by activating the signal transducer and activator of transcription 3 (Stat3) and Smad1/5/8 signaling pathways. The induction of hepcidin was confirmed in mice following icariin administration, coupled with associated changes in serum and tissue iron concentrations. In support of these findings, the icariin analogues, epimedin A, B and C, also increased hepatic hepcidin expression. However, these changes were not observed in hepcidin-deficient [Hamp1-/- or Hamp1‑knockout (KO)] mice following icariin administration, thereby verifying hepatic hepcidin as the target of icariin. Although berberine exhibited a robust capacity to promote hepcidin expression in vitro, it failed to alter hepcidin expression in mice. Taken together

  3. Treatment of hepatocellular carcinoma using percutaneous radiofrequency thermoablation: results and outcomes in 56 patients.

    PubMed

    Giovannini, Marc; Moutardier, Vincent; Danisi, Carcline; Bories, Erwan; Pesenti, Christian; Delpéro, Jean-Robert

    2003-01-01

    The aim of this study was to evaluate the efficacy of and tolerance for radiofrequency thermoablation (RFTA) in patients with hepatocellular carcinoma (HCC). From March 1999 to September 2001, a total of 56 patients (46 men and 10 women) whose mean age was 67.8 years (range 51 to 76 years) underwent RFTA for 71 HCCs at our institution. RFTA was carried out in 45 patients with one lesion less than 6 cm in diameter, in seven patients with two lesions less than 4 cm in diameter each, and in four patients with three lesions less than 3 cm in diameter each. The mean diameter of the lesions was 4.1 cm (range 0.8 to 6.0 cm). The etiology of the cirrhosis was alcoholism in 31 patients, post-hepatitis C in 19 patients, post-hepatitis B in four patients, and hemochromatosis in two patients. Forty-five patients were classified as Child stage A and 11 were Child stage B. No ascites, prothrombin time >60%, and platelet count <60,000/mm(3) were needed. Two types of cooled needles were used depending on the size of the lesion (a needle 15 cm in length was used for 2 or 3 cm tumors, and a cluster of needles was used for tumors larger than 4 cm). Helical computed tomography was performed 8 weeks after treatment. The main criterion for a complete response was the presence of a hypodense lesion without contrast enhancement. Mean follow-up was 14 months. Complete tumor destruction was achieved in 50 (89.2%) of 56 patients after one session and in 52 (92.8%) of 56 after two sessions. Twelve months later, a complete response was confirmed in 45 patients (80.3%), four patients had a local recurrence and new liver nodules, and three patients had died (one of bone metastasis, one of acute alcoholic hepatitis, and one of bronchial carcinoma). Thirty-nine patients (69.6%) were still in complete remission 36 months later, and a new HCC had developed in six patients. At 36 months 49 of 56 patients were alive and 39 of 56 were free of disease. Patients with HCCs that developed following viral

  4. Incidence and Risks of Congenital Anomalies of Kidney and Urinary Tract in Newborns: A Population-Based Case-Control Study in Taiwan.

    PubMed

    Tain, You-Lin; Luh, Hsing; Lin, Ching-Yuang; Hsu, Chien-Ning

    2016-02-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) are 1 of the major factors in young adults needing renal replacement therapy, but there is little extensive assessment of their incidence and risk factors. This study aimed to evaluate trends in the incidence of and risk factors for CAKUT among all births in Taiwan.This population-based case-control study design was conducted using the Taiwan national births registry, which contains detailed information about maternal health and characteristics of newborns, supplied by health professionals. Of 1,603,794 newborns registered between 2004 and 2014, 668 infants were reported to have CAKUT. Newborns without congenital anomalies were matched with CAKUT cases by birth year, month, and Apgar score in a ratio of 5:1. Odds ratio (OR) and 95% confidence interval (CI) for developing CAKUT were calculated using a conditional multivariate logistic regression model.The incidence of CAKUT was approximately 4.2 per 10,000 births. The adjusted ORs for CAKUT in newborns associated with maternal age of 20 to 29 (OR, 2.18; 95% CI, 1.11-4.28), or 30 to 39 (OR, 2.29; 95% CI, 1.17-4.51), maternal gestational diabetes (OR, 2.22, 95% CI, 1.06-4.67), maternal thalassemia/hemochromatosis (OR, 2.67; 95% CI, 1.35-5.27), polyhydramnios or oligohydramnios (OR, 9.16; 95% CI, 5.46-15.37), birth parity >1 (OR, 0.27; 95% CI, 0.15-0.50), having a gestational age <37 weeks (OR, 1.48; 95% CI, 1.23-1.78), and being a boy (OR, 1.83; 95% CI, 1.53-2.19). Infants of mother with gestational diabetes were more likely to have congenital anomalies, small gestational age (<37 weeks) and low birth weight.CAKUT are associated with several maternal health risk factors. As Taiwan has the highest prevalence and incidence rates of end-stage renal disease in the world, these findings strongly support the need to develop professional guidelines for prenatal counseling and management of women at risk of adverse birth outcomes, to prevent kidney disease

  5. Inborn errors of metabolism in infancy: a guide to diagnosis.

    PubMed

    Burton, B K

    1998-12-01

    group of inborn errors of metabolism including galactosemia, hereditary tyrosinemia, neonatal hemochromatosis, and a number of other conditions. A subset of lysosomal storage disorders may present very early with coarse facial features, organomegaly, or even hydrops fetalis. Specific patterns of dysmorphic features and congenital anomalies characterize yet another group of inherited metabolic disorders, such as Zellweger syndrome and the Smith-Lemli-Opitz syndrome. Each of these symptom complexes, and the appropriate evaluation of the affected infants, is discussed in more detail in this review.

  6. Plasmatic higher levels of homocysteine in Non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    2013-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD. Methods Thirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson’s, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies. Results The plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005). Conclusion Our results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17

  7. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association.

    PubMed

    Pennell, Dudley J; Udelson, James E; Arai, Andrew E; Bozkurt, Biykem; Cohen, Alan R; Galanello, Renzo; Hoffman, Timothy M; Kiernan, Michael S; Lerakis, Stamatios; Piga, Antonio; Porter, John B; Walker, John Malcolm; Wood, John

    2013-07-16

    This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a

  8. Alcoholic liver disease: pathologic, pathogenetic and clinical aspects.

    PubMed

    Ishak, K G; Zimmerman, H J; Ray, M B

    1991-02-01

    Alcoholic liver disease includes steatosis, alcoholic hepatitis and cirrhosis. Other liver diseases of genetic origin, but with a curious association with alcohol intake, are hemochromatosis and porphyria cutanea tarda. The attribution of chronic hepatitis to alcohol intake remains speculative, and the association may reflect hepatitis C infection. Hepatic injury attributed to alcohol includes the changes reported in the fetal alcohol syndrome. Steatosis, the characteristic consequence of excess alcohol intake, is usually macrovesicular and rarely microvesicular. Acute intrahepatic cholestasis, which in rare instances accompanies steatosis, must be distinguished from other causes of intrahepatic cholestasis (e.g., drug-induced) and from mechanical obstruction of the intrahepatic bile ducts (e.g., pancreatitis, choledocholithiasis) before being accepted. Alcoholic hepatitis (steatonecrosis) is characterized by a constellation of lesions: steatosis, Mallory bodies (with or without a neutrophilic inflammatory response), megamitochondria, occlusive lesions of terminal hepatic venules, and a lattice-like pattern of pericellular fibrosis. All these lesions mainly affect zone 3 of the hepatic acinus. Other changes, observed at the ultrastructural level, are of importance in progression of the disease. They include widespread cytoplasmic shedding, and capillarization and defenestration of sinusoids. Progressive fibrosis complicating alcoholic hepatitis eventually leads to cirrhosis that is typically micronodular but can evolve to a mixed or macronodular pattern. Hepatocellular carcinoma occurs in 5 to 15% of patients with alcoholic liver disease. The clinical syndrome of alcoholic liver disease is the result of three factors--parenchymal insufficiency, portal hypertension and the clinical consequences of extrahepatic damage produced by alcohol. At the several phases of the life history of alcoholic liver disease, the individual factors play a different role. The clinical

  9. Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.

    PubMed

    Pronicka, Ewa; Węglewska-Jurkiewicz, Anna; Taybert, Joanna; Pronicki, Maciej; Szymańska-Dębińska, Tamara; Karkucińska-Więckowska, Agnieszka; Jakóbkiewicz-Banecka, Joanna; Kowalski, Paweł; Piekutowska-Abramczuk, Dorota; Pajdowska, Magdalena; Socha, Piotr; Sykut-Cegielska, Jolanta; Węgrzyn, Grzegorz

    2011-02-01

    Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii

  10. Quantitating Iron in Serum Ferritin by Use of ICP-MS

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Gillman, Patricia L.

    2003-01-01

    A laboratory method has been devised to enable measurement of the concentration of iron bound in ferritin from small samples of blood (serum). Derived partly from a prior method that depends on large samples of blood, this method involves the use of an inductively-coupled-plasma mass spectrometer (ICP-MS). Ferritin is a complex of iron with the protein apoferritin. Heretofore, measurements of the concentration of serum ferritin (as distinguished from direct measurements of the concentration of iron in serum ferritin) have been used to assess iron stores in humans. Low levels of serum ferritin could indicate the first stage of iron depletion. High levels of serum ferritin could indicate high levels of iron (for example, in connection with hereditary hemochromatosis an iron-overload illness that is characterized by progressive organ damage and can be fatal). However, the picture is complicated: A high level of serum ferritin could also indicate stress and/or inflammation instead of (or in addition to) iron overload, and low serum iron concentration could indicate inflammation rather than iron deficiency. Only when concentrations of both serum iron and serum ferritin increase and decrease together can the patient s iron status be assessed accurately. Hence, in enabling accurate measurement of the iron content of serum ferritin, the present method can improve the diagnosis of the patient s iron status. The prior method of measuring the concentration of iron involves the use of an atomic-absorption spectrophotometer with a graphite furnace. The present method incorporates a modified version of the sample- preparation process of the prior method. First, ferritin is isolated; more specifically, it is immobilized by immunoprecipitation with rabbit antihuman polyclonal antibody bound to agarose beads. The ferritin is then separated from other iron-containing proteins and free iron by a series of centrifugation and wash steps. Next, the ferritin is digested with nitric acid

  11. Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)

    PubMed Central

    Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G.; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

    2015-01-01

    Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations– c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family’s HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40−2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins—the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C

  12. The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice

    PubMed Central

    Nai, Antonella; Pellegrino, Rosa M.; Rausa, Marco; Pagani, Alessia; Boero, Martina; Silvestri, Laura; Saglio, Giuseppe; Roetto, Antonella; Camaschella, Clara

    2014-01-01

    Transferrin receptor 2 (TFR2) is a transmembrane glycoprotein expressed in the liver and in the erythroid compartment, mutated in a form of hereditary hemochromatosis. Hepatic TFR2, together with HFE, activates the transcription of the iron-regulator hepcidin, while erythroid TFR2 is a member of the erythropoietin receptor complex. The TMPRSS6 gene, encoding the liver-expressed serine protease matriptase-2, is the main inhibitor of hepcidin and inactivation of TMPRSS6 leads to iron deficiency with high hepcidin levels. Here we evaluate the phenotype resulting from the genetic loss of Tmprss6 in Tfr2 total (Tfr2−/−) and liver-specific (Tfr2LCKO) knockout mice. Tmprss6−/−Tfr2−/− and Tmprss6−/−Tfr2LCKO mice have increased hepcidin levels and show iron-deficiency anemia like Tmprss6−/−mice. However, while Tmprss6−/−Tfr2LCKO are phenotypically identical to Tmprss6−/− mice, Tmprss6−/−Tfr2−/− mice have increased red blood cell count and more severe microcytosis than Tmprss6−/− mice. In addition hepcidin expression in Tmprss6−/−Tfr2−/− mice is higher than in the wild-type animals, but lower than in Tmprss6−/− mice, suggesting partial inhibition of the hepcidin activating pathway. Our results prove that hepatic TFR2 acts upstream of TMPRSS6. In addition Tfr2 deletion causes a relative erythrocytosis in iron-deficient mice, which likely attenuates the effect of over-expression of hepcidin in Tmprss6−/− mice. Since liver-specific deletion of Tfr2 in Tmprss6−/− mice does not modify the erythrocyte count, we speculate that loss of Tfr2 in the erythroid compartment accounts for the hematologic phenotype of Tmprss6−/−Tfr2−/− mice. We propose that TFR2 is a limiting factor for erythropoiesis, particularly in conditions of iron restriction. PMID:24658816

  13. Text Mining Genotype-Phenotype Relationships from Biomedical Literature for Database Curation and Precision Medicine

    PubMed Central

    Simmons, Michael; Lu, Zhiyong

    2016-01-01

    The practice of precision medicine will ultimately require databases of genes and mutations for healthcare providers to reference in order to understand the clinical implications of each patient’s genetic makeup. Although the highest quality databases require manual curation, text mining tools can facilitate the curation process, increasing accuracy, coverage, and productivity. However, to date there are no available text mining tools that offer high-accuracy performance for extracting such triplets from biomedical literature. In this paper we propose a high-performance machine learning approach to automate the extraction of disease-gene-variant triplets from biomedical literature. Our approach is unique because we identify the genes and protein products associated with each mutation from not just the local text content, but from a global context as well (from the Internet and from all literature in PubMed). Our approach also incorporates protein sequence validation and disease association using a novel text-mining-based machine learning approach. We extract disease-gene-variant triplets from all abstracts in PubMed related to a set of ten important diseases (breast cancer, prostate cancer, pancreatic cancer, lung cancer, acute myeloid leukemia, Alzheimer’s disease, hemochromatosis, age-related macular degeneration (AMD), diabetes mellitus, and cystic fibrosis). We then evaluate our approach in two ways: (1) a direct comparison with the state of the art using benchmark datasets; (2) a validation study comparing the results of our approach with entries in a popular human-curated database (UniProt) for each of the previously mentioned diseases. In the benchmark comparison, our full approach achieves a 28% improvement in F1-measure (from 0.62 to 0.79) over the state-of-the-art results. For the validation study with UniProt Knowledgebase (KB), we present a thorough analysis of the results and errors. Across all diseases, our approach returned 272 triplets (disease

  14. Text Mining Genotype-Phenotype Relationships from Biomedical Literature for Database Curation and Precision Medicine.

    PubMed

    Singhal, Ayush; Simmons, Michael; Lu, Zhiyong

    2016-11-01

    The practice of precision medicine will ultimately require databases of genes and mutations for healthcare providers to reference in order to understand the clinical implications of each patient's genetic makeup. Although the highest quality databases require manual curation, text mining tools can facilitate the curation process, increasing accuracy, coverage, and productivity. However, to date there are no available text mining tools that offer high-accuracy performance for extracting such triplets from biomedical literature. In this paper we propose a high-performance machine learning approach to automate the extraction of disease-gene-variant triplets from biomedical literature. Our approach is unique because we identify the genes and protein products associated with each mutation from not just the local text content, but from a global context as well (from the Internet and from all literature in PubMed). Our approach also incorporates protein sequence validation and disease association using a novel text-mining-based machine learning approach. We extract disease-gene-variant triplets from all abstracts in PubMed related to a set of ten important diseases (breast cancer, prostate cancer, pancreatic cancer, lung cancer, acute myeloid leukemia, Alzheimer's disease, hemochromatosis, age-related macular degeneration (AMD), diabetes mellitus, and cystic fibrosis). We then evaluate our approach in two ways: (1) a direct comparison with the state of the art using benchmark datasets; (2) a validation study comparing the results of our approach with entries in a popular human-curated database (UniProt) for each of the previously mentioned diseases. In the benchmark comparison, our full approach achieves a 28% improvement in F1-measure (from 0.62 to 0.79) over the state-of-the-art results. For the validation study with UniProt Knowledgebase (KB), we present a thorough analysis of the results and errors. Across all diseases, our approach returned 272 triplets (disease

  15. Ratiometric Measurements of Adiponectin by Mass Spectrometry in Bottlenose Dolphins (Tursiops truncatus) with Iron Overload Reveal an Association with Insulin Resistance and Glucagon

    PubMed Central

    Neely, Benjamin A.; Carlin, Kevin P.; Arthur, John M.; McFee, Wayne E.; Janech, Michael G.

    2013-01-01

    High molecular weight (HMW) adiponectin levels are reduced in humans with type 2 diabetes and insulin resistance. Similar to humans with insulin resistance, managed bottlenose dolphins (Tursiops truncatus) diagnosed with hemochromatosis (iron overload) have higher levels of 2 h post-prandial plasma insulin than healthy controls. A parallel reaction monitoring assay for dolphin serum adiponectin was developed based on tryptic peptides identified by mass spectrometry. Using identified post-translational modifications, a differential measurement was constructed. Total and unmodified adiponectin levels were measured in sera from dolphins with (n = 4) and without (n = 5) iron overload. This measurement yielded total adiponectin levels as well as site specific percent unmodified adiponectin that may inversely correlate with HMW adiponectin. Differences in insulin levels between iron overload cases and controls were observed 2 h post-prandial, but not during the fasting state. Thus, post-prandial as well as fasting serum adiponectin levels were measured to determine whether adiponectin and insulin would follow similar patterns. There was no difference in total adiponectin or percent unmodified adiponectin from case or control fasting animals. There was no difference in post-prandial total adiponectin levels between case and control dolphins (mean ± SD) at 763 ± 298 and 727 ± 291 pmol/ml, respectively (p = 0.91); however, percent unmodified adiponectin was significantly higher in post-prandial cases compared to controls (30.0 ± 6.3 versus 17.0 ± 6.6%, respectively; p = 0.016). Interestingly, both total and percent unmodified adiponectin were correlated with glucagon levels in controls (r = 0.999, p  < 0.001), but not in cases, which is possibly a reflection of insulin resistance. Although total adiponectin levels were not significantly different, the elevated percent unmodified adiponectin follows a trend similar to

  16. The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis

    PubMed Central

    2013-01-01

    Background Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). Methods To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. Results Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the “high hepcidin” 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02). Conclusions The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients

  17. Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

    PubMed Central

    Meienberg, Janine; Rohrbach, Marianne; Neuenschwander, Stefan; Spanaus, Katharina; Giunta, Cecilia; Alonso, Sira; Arnold, Eliane; Henggeler, Caroline; Regenass, Stephan; Patrignani, Andrea; Azzarello-Burri, Silvia; Steiner, Bernhard; Nygren, Anders OH; Carrel, Thierry; Steinmann, Beat; Mátyás, Gábor

    2010-01-01

    Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys–Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers–Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3 408 306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene. PMID:20648054

  18. Kinetics of iron removal by phlebotomy in patients with iron overload after allogeneic hematopoietic cell transplantation

    PubMed Central

    Eisfeld, Ann-Kathrin; Krahl, Rainer; Jaekel, Nadja; Niederwieser, Dietger; Al-Ali, Haifa Kathrin

    2012-01-01

    Excess body iron could persist for years after allogeneic hematopoietic cell transplantation (HCT) with possible deleterious sequels. An iron depletive therapy with phlebotomy seems rational. Kinetics of iron removal by phlebotomy without erythropoietin support in non-thalassemic adult patients with iron overload after HCT and the impact of pre- and post-HCT hemochromatosis (HFE) genotype on iron mobilization were investigated. Patients and methods: Phlebotomy was initiated in 61 recipients of allografts due to hematologic malignancies (median age 48 years) after a median of 18 months. The prephlebotomy median serum ferritin (SF) was 1697ng/ml and the median number of blood transfusions 28 units. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphates (AP), and bilirubin were elevated in 55.7%, 64% and 11.5% patients respectively. HFE-genotype was elucidated by polymerase chain reaction using hybridization probes and melting curve analysis. Results: Phlebotomy was well-tolerated irrespective of age or conditioning. A negative iron balance in 80% of patients (median SF 1086 ng/ml) and a rise in hemoglobin were observed (p<0.0001). Higher transfusional burden and SF were associated with a greater iron mobilization per session (p=0.02). In 58% of patients, a plateau after an initial steady decline in SF was followed by a second decline under further phlebotomy. The improvement in ALT (p=0.002), AST (p=0.03), AP (p=0.01), and bilirubin (p<0.0001) did not correlate with the decline in SF. Mutant HFE-gene variants were detected in 14/55 (25%) pre-HCT and 22/55 (40%) patients post-HCT. Overall, dissimilar pre- and posttransplantational HFE-genotypes were detected in 20/55 (40%) patients. Posttransplantational mutant HFE variants correlated with a slower decline in SF (p=0.007). Conclusions: Phlebotomy is a convenient therapy of iron overload in survivors of HCT. A negative iron balance and a rise in hemoglobin were observed in the majority of

  19. Syndromic (phenotypic) diarrhea in early infancy.

    PubMed

    Goulet, Olivier; Vinson, Christine; Roquelaure, Bertrand; Brousse, Nicole; Bodemer, Christine; Cézard, Jean-Pierre

    2008-02-28

    diarrhea - Phenotypic diarrhea - Tricho-hepato-enteric syndrome - Intractable diarrhea of infancy with facial dysmorphism - Trichorrhexis nodosa and cirrhosis - Neonatal hemochromatosis phenotype with intractable diarrhea and hair abnormalities - Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency.

  20. Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: the Normative Aging Study

    PubMed Central

    Grashow, Rachel; Sparrow, David; Hu, Howard; Weisskopf, Marc G.

    2015-01-01

    Introduction Olfactory dysfunction has been identified as an early warning sign for Alzheimer’s disease, Parkinson’s disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone. Methods Olfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-Ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE). Results The average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD = 5.7) years. Mean tibia lead was 16.3 (SD = 12.0) μg/g bone, mean patella lead was 22.4 (SD = 14.4) μg/g bone, and mean UPSIT score was 26.9 out of 40 (SD = 7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15 μg/g tibia lead: β = −1.57; 95% CI: −2.93, −0.22; p = 0.02) in models adjusted for smoking and age. Additional adjustment for education did not