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1
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Bozadjieva-Kramer N, Shin JH, Blok NB, Jain C, Das NK, Polex-Wolf J, Knudsen LB, Shah YM, Seeley RJ. Liraglutide Impacts Iron Homeostasis in a Murine Model of Hereditary Hemochromatosis. Endocrinology 2024; 165:bqae090. [PMID: 39045670 PMCID: PMC11311705 DOI: 10.1210/endocr/bqae090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/18/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients.
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Affiliation(s)
- Nadejda Bozadjieva-Kramer
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Veterans Affairs Ann Arbor Healthcare System, Research Service, Ann Arbor, MI 48105, USA
| | - Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Neil B Blok
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Chesta Jain
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nupur K Das
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | | | - Yatrik M Shah
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
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2
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Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, Ahmed Aboubakr A, AbdelMaqsod A, Sedrak H, Assaad SN, Elwakil R, Esmat G, Salh S, Mostafa T, Mogawer S, Sadek SE, Saber MM, Ezelarab H, Mahmoud AA, Sultan S, El Kassas M, Kamal E, ElSayed NM, Moussa S. Managing diabetes and liver disease association. Arab J Gastroenterol 2018; 19:166-179. [PMID: 30420265 DOI: 10.1016/j.ajg.2018.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/26/2018] [Indexed: 02/05/2023]
Abstract
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
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Affiliation(s)
- Abd Elkhalek Hamed
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt.
| | - Medhat Elsahar
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Police Medical Academy, Egypt
| | | | | | | | | | - Ashraf Ahmed Aboubakr
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | | | - Reda Elwakil
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Ain Shams University, Egypt
| | - Gamal Esmat
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Kasr Al Aini, Egypt
| | - Samira Salh
- Department of Pharmacy, Cairo University, Egypt
| | | | | | - Sameh Emil Sadek
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | - Maha M Saber
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Hanan Ezelarab
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Asem Ashraf Mahmoud
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | - Ehab Kamal
- Medical Department, National Research Centre, Egypt
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3
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Sánchez-Luna SA, Brown KE. Clinical burden of liver disease from hemochromatosis at an academic medical center. Hepatol Commun 2018; 1:453-459. [PMID: 29404472 PMCID: PMC5721419 DOI: 10.1002/hep4.1048] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 04/19/2017] [Accepted: 04/20/2017] [Indexed: 12/02/2022] Open
Abstract
Hereditary hemochromatosis (HH) can cause cirrhosis and hepatocellular carcinoma (HCC), but the frequency of these complications is controversial. To address this question, we reviewed the experience with HH at an academic medical center that is the sole liver transplantation center in a state with a population that is >90% Caucasian. The records of all subjects with International Classification of Diseases, Ninth Revision, code 275, “disorders of iron metabolism” seen at the University of Iowa Hospitals and Clinics between January 1, 2004 and December 31, 2014 were reviewed, and HFE C282Y homozygotes and C282Y/H63D compound heterozygotes were identified. Clinical, pathologic, and laboratory data from these subjects were examined in detail. We identified 118 C282Y homozygotes and 44 compound heterozygotes; 22 of the former and 3 of the latter had advanced hepatic fibrosis (bridging or cirrhosis). Male patients predominated in both groups. Most of the C282Y homozygotes and all compound heterozygotes had causes of chronic liver disease in addition to iron overload. Together, these accounted for 0.42% of cases of cirrhosis seen at the University of Iowa Hospitals and Clinics during this period. Two male patients with cirrhosis attributable solely to iron overload presented with cardiac dysfunction and atrial fibrillation; this classical presentation was rare, representing approximately one per 3,000 cases of cirrhosis. Eight homozygotes were diagnosed with HCC, representing 1.8% of patients with HCC. Conclusion: Despite the expected high prevalence of HH mutations in our state and the referral bias inherent in our study, serious hepatic manifestations of HH were uncommon. These data support claims that the penetrance of frank clinical hemochromatosis is low. (Hepatology Communications 2017;1:453–459)
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Affiliation(s)
- Sergio A Sánchez-Luna
- Department of Internal Medicine Roy J. and Lucille A. Carver College of Medicine, University of IowaIowa City IA.,Iowa City Veterans Administration Medical Center Iowa City IA
| | - Kyle E Brown
- Iowa City Veterans Administration Medical Center Iowa City IA.,Department of Internal Medicine, Division of Gastroenterology-Hepatology.,Free Radical and Radiation Biology Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa Iowa City IA
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4
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El Osta R, Grandpre N, Monnin N, Hubert J, Koscinski I. Hypogonadotropic hypogonadism in men with hereditary hemochromatosis. Basic Clin Androl 2017; 27:13. [PMID: 28694969 PMCID: PMC5501943 DOI: 10.1186/s12610-017-0057-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 06/21/2017] [Indexed: 01/08/2023] Open
Abstract
Hereditary hemochromatosis is a genetic disease that progresses silently. This disease is often diagnosed late when complications appear. Hypogonadotropic hypogonadism (HH) is one of the classical complications of hemochromatosis. Its frequency is declining probably because of earlier diagnosis and better informed physicians. Certain symptoms linked to HH can have an impact on a patient’s sexuality, such as decreased libido, erectile dysfunction, and impairment of ejaculation, as well as on his reproductive capacities. This review is based on an online search in English, French and German language publications found in PubMed/Medline, up to 23 September 2016 using the following key word: Male infertility, Hypogonadotropic Hypogonadism, Hereditary Hemochromatosis. Thirty-four papers met these inclusion criteria. This review describes the impact of iron overload on male fertility, resulting in hypogonadotropic hypogonadism and proposes treatment modalities.
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Affiliation(s)
- Rabih El Osta
- Urology Department of Brabois University Hospital, CHU Nancy, Vandœuvre-lès-Nancy, France
| | | | - Nicolas Monnin
- Laboratoire de Biologie de la Reproduction, CECOS Lorraine, CHU Nancy, Nancy, France
| | - Jacques Hubert
- Urology Department of Brabois University Hospital, CHU Nancy, Vandœuvre-lès-Nancy, France
| | - Isabelle Koscinski
- Laboratoire de Biologie de la Reproduction, CECOS Lorraine, CHU Nancy, Nancy, France
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5
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Orsi E, Grancini V, Menini S, Aghemo A, Pugliese G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017; 37:950-962. [PMID: 27943508 DOI: 10.1111/liv.13337] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent "toxic" effect on pancreatic islets resulting in β-cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes.
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Affiliation(s)
- Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, A.M. and A. Migliavacca Center for Liver Disease, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
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6
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Scholz B, Crabb S, Wittert GA. "Males Don't Wanna Bring Anything Up To Their Doctor": Men's Discourses of Depression. QUALITATIVE HEALTH RESEARCH 2017; 27:727-737. [PMID: 27055495 DOI: 10.1177/1049732316640294] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Men experiencing depression may present with externalizing behaviors including avoidance, getting angry, or finding distractions rather than seeking help. General practitioners report that depression is harder to diagnose in men than in women. Research has not typically focused on men's accounts of depression; thus, the current study uses an exploratory design to better understand men's subjectivities of depression. A thematic framework informed the analysis of interviews with 10 men who had experienced high levels of depressive symptoms at least once within the prior 5 years, with two overarching discourses of depression discussed. The first relates to links between depression and health, including comorbid illnesses. The second relates to social contexts in which depression is experienced. These findings extend upon previous research suggesting medical practitioners have difficulty with competing biomedical and social discourses of depression, highlighting the importance of continuing to improve understandings of men's depression discourses.
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Affiliation(s)
- Brett Scholz
- 1 University of Canberra, Bruce, Australia
- 2 The University of Adelaide, Adelaide, Australia
- 3 Spur Projects, Brisbane, Queensland, Australia
| | - Shona Crabb
- 2 The University of Adelaide, Adelaide, Australia
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7
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Fabian E, Schiller D, Graninger W, Langner C, Frei J, Schoellnast H, Alibegovic V, Stauber R, Schoefl R, Krejs GJ. Clinical-Pathological Conference Series from the Medical University of Graz : Case No 159: 52-year-old patient with psoriasis and arthralgia of the finger joints. Wien Klin Wochenschr 2016; 128:846-853. [PMID: 27363994 PMCID: PMC5104785 DOI: 10.1007/s00508-016-1010-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/06/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Elisabeth Fabian
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Dietmar Schiller
- Department of Internal Medicine IV, Elisabethinen Hospital, Linz, Austria
| | - Winfried Graninger
- Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Cord Langner
- Department of Pathology, Medical University of Graz, Graz, Austria
| | - Johannes Frei
- Department of Radiology, Elisabethinen Hospital Linz, Linz, Austria
| | - Helmut Schoellnast
- Division of General Diagnostic Radiology, Department of Radiology, Medical University of Graz, Graz, Austria
| | | | - Rudolf Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Rainer Schoefl
- Department of Internal Medicine IV, Elisabethinen Hospital, Linz, Austria
| | - Guenter J Krejs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
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8
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Goldberg DS, Fallon MB. The Art and Science of Diagnosing and Treating Lung and Heart Disease Secondary to Liver Disease. Clin Gastroenterol Hepatol 2015; 13:2118-27. [PMID: 25934564 PMCID: PMC4618073 DOI: 10.1016/j.cgh.2015.04.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/13/2015] [Accepted: 04/14/2015] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at risk of extrahepatic complications related to cirrhosis and portal hypertension, as well as organ-specific complications of certain liver diseases. These complications can compromise quality of life, while also increasing morbidity and mortality before and after liver transplantation. Patients with chronic liver disease are at risk for pulmonary complications of hepatopulmonary syndrome and portopulmonary syndrome; the cardiac complication fall under the general concept of cirrhotic cardiomyopathy, which can affect systolic and diastolic function, as well as cardiac conduction. In addition, patients with certain diseases are at risk of lung and/or cardiac complications that are specific to the primary disease (ie, emphysema in α-1-antitrypsin deficiency) or occur with increased incidence in certain conditions (ie, ischemic heart disease associated with nonalcoholic steatohepatitis). This article focuses on the epidemiology, clinical presentation, pathogenesis, treatment options, and role of transplantation for lung and heart diseases secondary to liver disease, while also highlighting select liver diseases that directly affect the lungs and heart.
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Affiliation(s)
- David S Goldberg
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Michael B Fallon
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
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9
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Aregbesola A, Voutilainen S, Virtanen JK, Aregbesola A, Tuomainen TP. Serum hepcidin concentrations and type 2 diabetes. World J Diabetes 2015; 6:978-982. [PMID: 26185605 PMCID: PMC4499531 DOI: 10.4239/wjd.v6.i7.978] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 12/22/2014] [Accepted: 03/20/2015] [Indexed: 02/05/2023] Open
Abstract
Hepcidin is a peptide hormone with both paracrine and endocrine functions that help in maintaining body iron stores. Type 2 diabetes (T2D) is one of the sequelae of excess body iron stores; thus, iron regulatory hormone hepcidin may have a direct or at least an indirect role in the aetiopathogenesis of T2D. Both human and animal studies at molecular and genetic levels have attempted to establish a role for hepcidin in the development of T2D, and a few epidemiologic studies have also showed a link between hepcidin and T2D at population level, but the findings are still inconclusive. Recent data have suggested different pathways in which hepcidin could be associated with T2D with much emphasis on its primary or secondary role in insulin resistance. Some of the suggested pathways are via transcription modulator of hepcidin (STAT3); ferroportin 1 expression on the cells involved in iron transport; transmembrane protease 6 enzyme; and pro-inflammatory cytokines, interleukin (IL)-1, IL-6, tumor necrosis factor-α and IL-10. This review briefly reports the existing evidence on the possible links between hepcidin and T2D and concludes that more data are needed to confirm or refute hepcidin’s role in the development of T2D. Examining this role could provide a further evidence base for iron in the aetiopathogenesis of T2D.
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10
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Phatak PD, Barton JC. Phlebotomy-mobilized iron as a surrogate for liver iron content in hemochromatosis patients. ACTA ACUST UNITED AC 2015; 8:429-32. [PMID: 14668040 DOI: 10.1080/1024533032000158832] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
We sought to establish the relationship of quantitative hepatic iron measurements and phlebotomy-mobilized iron in a large sample of HFE C282Y homozygotes with a hemochromatosis phenotype. Thus, we analyzed data from 79 unrelated C282Y homozygotes from treatment centers in Rochester, NY and Birmingham, AL who had undergone liver biopsy with measurement of hepatic iron content and who had achieved iron depletion (serum ferritin <25 ng/l) with quantitative phlebotomy. The sample consisted of 57 men and 22 women; their median age at diagnosis was 47 years (range 23-76 years). Sixty-three of 79 (79.7%) had hepatic iron index (HII; μmol/g dry weight of liver divided by age in years) ≥1.9, a conventional phenotypic definition of hemochromatosis. The mean quantity of phlebotomy-mobilized iron (± 1 sd) was 6.4 g (±4.0 g) in men (range 2.0-18.0 g) and 6.2 g (±5.8) in women (range 0.7-22.5 g). There was a significant positive correlation of liver iron levels with phlebotomy-mobilized iron in this patient sample (Pearson coefficient 0.75; R<PRE>2</PRE>=55.5%). This relationship was also demonstrable when data from males and females were analyzed separately. We calculated a phlebotomy-mobilized iron index (MII: phlebotomy-mobilized iron in mg divided by age in years) using the corresponding regression equations and evaluated its use as a surrogate for HII. Thus, a phlebotomy-mobilized iron of 3.5 g corresponds to liver iron levels of 80 μmol/g dry weight, and a MII of 80 corresponds to HII of 1.9. Forty-six of 79 subjects met all four phenotypic criteria for hemochromatosis (liver iron levels ≥80 μmol/g, HII≥1.9, phlebotomy-mobilized iron ≥3.5 g and MII≥80). Of the 20 subjects with MII<80, 9 had a HII≥1.9. Conversely, 5 of 16 subjects with HII<1.9 had MII≥80 and 8 had phlebotomy-mobilized iron ≥3.5 g. Most patients with a hemochromatosis phenotype and evidence of moderate or severe iron overload (>80%) are homozygous for the common HFE missense mutation C282Y. Thus, clinicians rely increasingly on HFE mutation analysis to diagnose hemochromatosis and on quantitative phlebotomy to estimate the severity of iron overload in many cases. Liver biopsy is now employed in selected patients to visualize fibrosis or cirrhosis and to identify coincidental hepatic disease. We conclude that the use of the MII permits a retrospective estimation of the age-adjusted severity of iron overload that has a diagnostic value similar to that of the HII in hemochromatosis patients with C282Y homozygosity.
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Affiliation(s)
- Pradyumna D Phatak
- Hematology/Oncology Unit, Rochester General Hospital, Rochester, NY 14621, USA.
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11
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Yun S, Vincelette ND. Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis. Crit Rev Oncol Hematol 2015; 95:12-25. [PMID: 25737209 DOI: 10.1016/j.critrevonc.2015.02.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 01/29/2015] [Accepted: 02/11/2015] [Indexed: 12/14/2022] Open
Abstract
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.
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Affiliation(s)
- Seongseok Yun
- Department of Medicine, University of Arizona, Tucson, AZ 85721, USA.
| | - Nicole D Vincelette
- Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55902, USA
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12
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Gasser B, Courtois F, Hojjat-Assari S, Sauleau E, Buffet C, Brissot P. Hémochromatose héréditaire : circonstances de découverte et délais diagnostiques. Rev Med Interne 2014; 35:160-5. [DOI: 10.1016/j.revmed.2013.02.041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 02/12/2013] [Accepted: 02/25/2013] [Indexed: 01/19/2023]
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13
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14
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García-Compeán D, Jáquez-Quintana JO, González-González JA, Lavalle-González FJ, Villarreal-Pérez JZ, Maldonado-Garza HJ. [Diabetes in liver cirrhosis]. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:473-82. [PMID: 23628170 DOI: 10.1016/j.gastrohep.2013.01.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 01/31/2013] [Indexed: 02/07/2023]
Abstract
The prevalence of overt diabetes mellitus (DM) in liver cirrhosis is about 30%. However, DM or impaired glucose tolerance can be observed in 90% after an oral glucose tolerance test in patients with normal fasting plasma glucose. Type 2 DM may produce cirrhosis, whereas DM may be a complication of cirrhosis. The latter is known as «hepatogenous diabetes». Overt and subclinical DM is associated with liver complications and death in cirrhotic patients. Treating diabetes is difficult in cirrhotic patients because of the metabolic impairments due to liver disease and because the most appropriate pharmacologic treatment has not been defined. It is also unknown if glycemic control with hypoglycemic agents has any impact on the course of the liver disease.
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Affiliation(s)
- Diego García-Compeán
- Servicio de Gastroenterología y Departamento de Medicina Interna, Hospital Universitario Dr. José E. González, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, México.
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Carroll GJ, Breidahl WH, Olynyk JK. Characteristics of the arthropathy described in hereditary hemochromatosis. Arthritis Care Res (Hoboken) 2011; 64:9-14. [PMID: 21584944 DOI: 10.1002/acr.20501] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- G J Carroll
- University of Notre Dame Australia, Australia.
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16
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Carroll GJ, Breidahl WH, Bulsara MK, Olynyk JK. Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load. ACTA ACUST UNITED AC 2010; 63:286-94. [PMID: 20954257 DOI: 10.1002/art.30094] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- G J Carroll
- University of Notre Dame Australia, Fremantle Campus, and Fremantle Hospital, Fremantle, Western Australia, Australia.
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17
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The effect of dietary iron intake on the development of iron overload among homozygotes for haemochromatosis. Public Health Nutr 2009; 12:1823-9. [DOI: 10.1017/s1368980008004631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AbstractObjectiveTo quantify the role of dietary Fe in total body Fe (TBI) accumulation among homozygotes for theHFEgene associated with haemochromatosis.DesignA Monte Carlo model was built to simulate Fe accumulation based on findings from human feeding experiments and national dietary surveys. A hypothetical cohort of 1000 homozygotes with starting age 25 years was used in 39-year simulations. The impact of reducing dietary Fe intake on Fe accumulation was tested.ResultsIn the baseline model without any dietary intervention, by age 64, the percentage of males with TBI > 10 g, >15 g and >20 g was 93·2 %, 49·6 % and 14·7 %, respectively. When the Fe intake of individuals in the cohort was reduced to ≤200 % of the recommended dietary allowance (RDA), the corresponding percentages were 92·0 %, 40·5 % and 10·2 %, respectively. The corresponding figures were 91·0 %, 40·0 % and 9·3 % for Fe defortification and 70·3 %, 21·3 % and 4·1 % when Fe intake was capped at 100 % RDA. Similar trends were seen with sexes combined, although the impact of interventions was less. Sensitivity analysis revealed that the rate of Fe accumulation and the impact of dietary interventions are highly dependent on assumptions concerning Fe absorption rates.ConclusionsVariation in Fe intake as currently observed in the USA contributes to variation in Fe accumulation among homozygotes, when continued over an extended period. Lifelong dietary habits and national fortification policy can affect the rate of Fe accumulation, although the magnitude of the effect varies by gender, the TBI level of interest and factors affecting the Fe absorption rate.
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18
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Distante S. Genetic predisposition to iron overload: Prevalence and phenotypic expression of hemochromatosis‐associated HFE‐C282Y gene mutation. Scandinavian Journal of Clinical and Laboratory Investigation 2009; 66:83-100. [PMID: 16537242 DOI: 10.1080/00365510500495616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- S Distante
- Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.
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19
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Hip involvement in hereditary hemochromatosis: A clinical-pathologic study. Joint Bone Spine 2009; 76:412-5. [DOI: 10.1016/j.jbspin.2008.11.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2008] [Indexed: 11/20/2022]
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Abstract
Haemochromatosis should currently refer to hereditary iron overload disorders presenting with a definite and common phenotype characterised by normal erythropoiesis, increased transferrin saturation and ferritin and primarily parenchymal iron deposition related to innate low (but normally regulated) production of the hepatic peptide hormone hepcidin. Since the discovery of the haemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron overload diseases. Overall, at least four main types of hereditary haemochromatosis (HH) have been identified. This review describes the systematic diagnostic and therapeutic strategy and pitfalls for patients suspected for HH and their relatives.
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Affiliation(s)
- M C H Janssen
- Radboud University Medical Centre, Department of General Internal Medicine 463, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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21
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Kell DB. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics 2009; 2:2. [PMID: 19133145 PMCID: PMC2672098 DOI: 10.1186/1755-8794-2-2] [Citation(s) in RCA: 376] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Accepted: 01/08/2009] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. REVIEW We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation).The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible.This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles.Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here. CONCLUSION Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach that may lead to novel therapeutic targets.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess St, Manchester, M1 7DN, UK.
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22
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Montané de la Roque P, Lyon-Dubreuille G, Rochet N, About I, Gallardo J, Denat S. Des douleurs cervicales fébriles. Rev Med Interne 2008; 29:660-1. [DOI: 10.1016/j.revmed.2007.10.407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Accepted: 10/05/2007] [Indexed: 11/28/2022]
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Cooper K, Bryant J, Picot J, Clegg A, Roderick PR, Rosenberg WM, Patch C. A decision analysis model for diagnostic strategies using DNA testing for hereditary haemochromatosis in at risk populations. QJM 2008; 101:631-41. [PMID: 18522976 DOI: 10.1093/qjmed/hcn070] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND New techniques for diagnosing hereditary haemochromatosis (HHC) have become available alongside traditional tests such as liver biopsy and serum iron studies. AIM To evaluate DNA tests in people suspected of having haemochromatosis at clinical presentation compared to liver biopsy, and in family members of those diagnosed with haemochromatosis compared to phenotypic iron studies in UK. METHODS Decision analytic models were constructed to compare the costs and consequences of the diagnostic strategies for a hypothetical cohort of people with suspected haemochromatosis. For each strategy, the number of cases of haemochromatosis identified and treated and the resources used were estimated. RESULTS For diagnostic strategies in people suspected clinically of having haemochromatosis, the DNA strategy is cost saving compared to liver biopsy (cost saved per case detected, 123 pounds) and continues to be so across all ranges of parameters. For family testing, the DNA strategy is cost saving for the offspring of the proband but not for siblings. If the DNA test cost were to reduce by 40% to 60 pounds or, if in the phenotypic model, those with initially normal iron indices were retested twice instead of once, the DNA strategy would be the cheaper one. CONCLUSION Diagnostic strategies involving DNA testing are likely to be cost saving in clinical cases with iron overload and in the offspring of index cases. This study supports the UK guideline recommendations for the use of DNA testing in UK.
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Affiliation(s)
- K Cooper
- Southampton Health Technology Assessments Centre, Boldrewood, University of Southampton, Southampton, SO16 7PX.
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Rajpathak SN, Crandall JP, Wylie-Rosett J, Kabat GC, Rohan TE, Hu FB. The role of iron in type 2 diabetes in humans. Biochim Biophys Acta Gen Subj 2008; 1790:671-81. [PMID: 18501198 DOI: 10.1016/j.bbagen.2008.04.005] [Citation(s) in RCA: 251] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2008] [Revised: 04/22/2008] [Accepted: 04/25/2008] [Indexed: 01/11/2023]
Abstract
The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.
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Affiliation(s)
- Swapnil N Rajpathak
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx NY, NY 10461, USA.
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25
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Hickman IJ, Macdonald GA. Impact of diabetes on the severity of liver disease. Am J Med 2007; 120:829-34. [PMID: 17904449 DOI: 10.1016/j.amjmed.2007.03.025] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2006] [Revised: 02/27/2007] [Accepted: 03/13/2007] [Indexed: 01/07/2023]
Abstract
The prevalence of type 2 diabetes is higher in patients who have liver diseases, such as nonalcoholic fatty liver disease, chronic viral hepatitis, hemochromatosis, alcoholic liver disease, and cirrhosis. The development of diabetes in patients with cirrhosis is well recognized, but evidence is emerging that the development of chronic liver disease and progression to cirrhosis may occur after the diagnosis of diabetes and that diabetes plays a role in the initiation and progression of liver injury. This article provides an overview of the evidence for an increased prevalence of diabetes in a range of liver diseases; the effect of diabetes on the severity of disease; the potential mechanisms whereby coexistent diabetes exacerbates progression of hepatic fibrosis; and the impact of obesity, insulin resistance, and type 2 diabetes on clinical outcomes.
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Affiliation(s)
- Ingrid J Hickman
- Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
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26
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Guggenbuhl P, Albert JD, Chalès G. Manifestations rhumatologiques de l'hémochromatose génétique. Presse Med 2007; 36:1313-8. [PMID: 17531432 DOI: 10.1016/j.lpm.2006.12.036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2006] [Accepted: 12/31/2006] [Indexed: 10/22/2022] Open
Abstract
Rheumatic manifestations of genetic hemochromatosis are frequent. These manifestations are characterized by articular damage and osteoporosis. Clinicians must be aware of these presentations because they are sometimes the initial manifestation of hemochromatosis. Moreover, rheumatic pain causes substantial discomfort for patients and diminishes their quality of life.
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27
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Reid R, Hutchins R. Medical causes of abdominal pain. Br J Hosp Med (Lond) 2007; 68:M52-5. [PMID: 17419467 DOI: 10.12968/hmed.2007.68.sup3.22866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Richard Reid
- Department of Surgery, St Bartholomew's and the Royal London Hospital NHS Trust, London
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28
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Abstract
BACKGROUND Genetic hemochromatosis is a relatively common disease that may present as an arthropathy. In particular, arthropathy of the ankle is invariably bilateral and occurs in young men. However, the orthopaedic management of this condition has been poorly documented. METHODS Four patients with hemochromatic ankle arthropathy were treated with unilateral mobile bearing total ankle arthroplasty. RESULTS All four patients had good relief of symptoms after arthroplasty. CONCLUSIONS Hemochromatosis should be considered when symmetrical ankle arthropathy occurs in a young man. Early diagnosis is necessary to prevent extra-articular progression of the disease and inappropriate management.
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Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med 2006; 119:391-9. [PMID: 16651049 DOI: 10.1016/j.amjmed.2005.10.041] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2005] [Revised: 10/22/2005] [Accepted: 10/22/2005] [Indexed: 12/14/2022]
Abstract
Originally regarded as a rare affliction notable for its distinctive evolution to "bronze diabetes," hereditary hemochromatosis is now recognized as the most common genetic disorder in populations of European ancestry. Recent advances in our understanding of iron metabolism, the identification of the gene responsible for hemochromatosis, and large epidemiologic studies have changed the diagnostic approach toward patients with hereditary hemochromatosis and other forms of iron overload. This article reviews the pathophysiology, epidemiology, clinical features, diagnostic testing, and management of hemochromatosis for the primary care provider.
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Affiliation(s)
- Andrew W Yen
- University of California, Davis Medical Center, Department of Internal Medicine, Sacramento, Calif 95817, USA.
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30
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Carroll GJ. Polyarticular osteoarthritis – Two major phenotypes hypothesized. Med Hypotheses 2006; 66:315-8. [PMID: 16213101 DOI: 10.1016/j.mehy.2005.08.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Accepted: 08/15/2005] [Indexed: 11/27/2022]
Abstract
Osteoarthritis is the commonest form of arthritis, at least amongst Caucasians and is frequently polyarticular. Genetic factors are now considered pivotal in the aetiopathogenesis of polyarticular osteoarthritis (POA). This document proposes a nexus between the gene most commonly mutated amongst Caucasian peoples, notably the HFE gene and an appreciable subset of POA patients who have a clinically recognisable OA phenotype. It is hypothesised that there are at least 2 major POA phenotypes each of which is associated with discrete genotypes. Type 1 POA characterized by Heberden's or Bouchard's nodes with prominent DIP, PIP, knee joint (medial compartment) and Great toe MTP joint involvement corresponds to the putative nodal generalized form of OA or NGOA (proposed Type 1 POA phenotype). As yet no genetic marker has been defined for this POA subset. The second is a hitherto less well recognized phenotype characterized by involvement of the index and/or middle finger metacarpophalangeal (MCP2,3) joints and the elbows, ankles and possibly the intertarsal and tarsometatarsal joints. The hip and knee joints may sometimes also be involved. This different joint distribution corresponds closely to the pattern observed in the arthropathy that often accompanies hereditary haemochromatosis. It is predicted that mutations in the HFE gene will associate strongly with the proposed Type 2 POA phenotype and serve as a genetic marker for this clinically recognisable subset.
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Affiliation(s)
- Graeme J Carroll
- ArthroCare Pty Ltd, P.O. Box 6, Mount Lawley, and Department of Medicine, University of Western Australia, Australia.
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31
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Scotet V, Le Gac G, Mérour MC, Mercier AY, Chanu B, Ka C, Mura C, Nousbaum JB, Férec C. Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data. BMC MEDICAL GENETICS 2005; 6:24. [PMID: 15929798 PMCID: PMC1180708 DOI: 10.1186/1471-2350-6-24] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2004] [Accepted: 06/01/2005] [Indexed: 12/26/2022]
Abstract
Background Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH. Methods We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France. Results In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10-5), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004). Conclusion This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients.
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Affiliation(s)
- Virginie Scotet
- INSERM U 613 "Génétique moléculaire et génétique épidémiologique", Brest, France
| | - Gérald Le Gac
- Etablissement Français du Sang, Site de Brest, Brest, France
| | | | | | - Brigitte Chanu
- Etablissement Français du Sang, Site de Brest, Brest, France
| | - Chandran Ka
- Etablissement Français du Sang, Site de Brest, Brest, France
- Université de Bretagne Occidentale, Brest, France
| | | | - Jean-Baptiste Nousbaum
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire La Cavale Blanche, Brest, France
| | - Claude Férec
- INSERM U 613 "Génétique moléculaire et génétique épidémiologique", Brest, France
- Etablissement Français du Sang, Site de Brest, Brest, France
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Abstract
Hemochromatosis is a common genetic disease with a wide range of clinical expression: from no symptoms to cirrhosis of the liver. The discovery of the gene has led to a genetic blood test useful in the diagnosis of hemochromatosis. Treatment by phlebotomy is simple and efficient and can prevent the development of cirrhosis, leading to a normal life expectancy.
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Affiliation(s)
- Paul C Adams
- Department of Medicine, University of Western Ontario, London Health Sciences Centre, University Campus, P.O. Box 5339, London, Ontario N6A 5A5, Canada
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Abstract
Hereditary haemochromatosis is a very common genetic defect in the Caucasian population, with an autosomal recessive inheritance. It is characterized by inappropriately increased iron absorption from the duodenum and upper intestine, with consequent deposition in various parenchymal organs, notably the liver, pancreas, joints, heart, pituitary gland and skin, with resultant end-organ damage. Clinical features may be non-specific and include lethargy and malaise, or reflect target organ damage and present with abnormal liver tests, cirrhosis, diabetes mellitus, arthropathy, cardiomyopathy, skin pigmentation and gonadal failure. Early recognition and treatment (phlebotomy) is essential to prevent irreversible complications such as cirrhosis and hepatocellular carcinoma. The history of this condition dates as far back as 1865, but in the last decade great advances have been made. We discuss the genetics, pathophysiology, clinical features, diagnosis and management of a condition that could easily present to a generalist, and is an important diagnosis not to miss.
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Affiliation(s)
- J K Limdi
- Hope Hospital, Salford, Manchester, UK.
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34
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Jiang R, Ma J, Ascherio A, Stampfer MJ, Willett WC, Hu FB. Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: a prospective cohort study. Am J Clin Nutr 2004; 79:70-5. [PMID: 14684399 DOI: 10.1093/ajcn/79.1.70] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Excessive iron stores may promote insulin resistance and lead to the development of type 2 diabetes. However, prospective data relating iron intake and blood donations (determinants of body iron stores) to diabetes incidence are limited. OBJECTIVE We examined iron intake and blood donations in relation to the incidence of type 2 diabetes. DESIGN We followed men aged 40-75 y who participated in the Health Professionals' Follow-up Study; were free of diabetes, cardiovascular disease, and cancer in 1986; and provided dietary data (n = 38 394). Of those participants, 33 541 also provided a history of blood donation during the past 30 y in 1992. RESULTS During 12 y of follow-up, we ascertained 1168 new cases of type 2 diabetes. After adjustment for age, body mass index, and other diabetes risk factors, total iron intake was not associated with the risk of type 2 diabetes. Intakes of total heme iron [multivariate relative risk (RR) for extreme quintiles: 1.28; 95% CI: 1.02, 1.61; P for trend = 0.045] and of heme iron from red meat (RR: 1.63; 1.26, 2.10; P for trend < 0.001) were associated with an increased risk. However, heme-iron intake from sources other than red meat was not associated with diabetes risk (RR: 0.99; 0.81, 1.22). No significant associations were found between blood donation and the risk of type 2 diabetes. CONCLUSIONS Heme-iron intake from red meat sources is positively associated with the risk of type 2 diabetes. Total iron intake, heme-iron intake from non-red meat sources, and blood donations are not related to the risk of type 2 diabetes.
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Affiliation(s)
- Rui Jiang
- Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
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Canturk Z, Cetinarslan B, Tarkun I, Canturk NZ. Serum ferritin levels in poorly- and well-controlled diabetes mellitus. Endocr Res 2003; 29:299-306. [PMID: 14535631 DOI: 10.1081/erc-120025037] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Serum ferritin level is related to body iron stores and is influenced by several diseases. We aimed to evaluate the association between serum ferritin concentration and the complications and nature of diabetes mellitus (DM). We examined association of ferritin concentration, fasting and post-prandial glucose levels and glycated hemoglobin in 329 patients with type 2 diabetes mellitus and 269 healthy controls. In the present study, 41 of 150 poorly controlled diabetic patients and 31 of 119 cases had hyperferritinemia. We confirmed that serum ferritin was increased in diabetic patients as long as glycemic control is not achieved. There was also a correlation between ferritin level and diabetic retinopathy. In conclusion, this study showed an independent positive association between serum ferritin concentration and markers of glucose homeostasis.
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Affiliation(s)
- Zeynep Canturk
- Department of Endocrinology and Metabolism, Kocaeli University, Medical School, Derince, Kocaeli, Turkey.
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36
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Abstract
Hemochromatosis is the clinical expression of iron overload and occurs as hereditary and secondary variants. In hereditary hemochromatosis, an inborn error in iron metabolism results in excess absorption of dietary iron, which gradually accumulates in the liver, pancreas, and heart. The most common form of hereditary hemochromatosis is related to homozygosity for the C282Y mutation in the HFE gene. Early diagnosis is essential because hereditary hemochromatosis is common, severe, and treatable. Early manifestations consist of asthenia, arthralgia, and serum transferrin saturation elevation. The C282Y mutation should be looked for to confirm the diagnosis in the patient and family members. Measurement of serum transferrin saturation followed by genetic testing in individuals with values above 45% is a reasonable screening strategy.
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Affiliation(s)
- Gérard Chalès
- Rheumatology department, Hôpital Sud, 16, boulevard de Bulgarie, BP 59129, 35065 Rennes, cedex 2, France.
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Decreasing prevalence of hypogonadism in hereditary haemochromatosis. Ir J Med Sci 2002. [DOI: 10.1007/bf03170255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Affiliation(s)
- Richard M Green
- Division of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Waalen J, Felitti V, Gelbart T, Ho NJ, Beutler E. Prevalence of hemochromatosis-related symptoms among individuals with mutations in the HFE gene. Mayo Clin Proc 2002; 77:522-30. [PMID: 12059121 DOI: 10.4065/77.6.522] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the HFE mutation C282Y compared with controls without HFE mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and HFE wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D HFE mutations were also assessed by questionnaire. RESULTS The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other HFE genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS Results of this study indicate that many of the symptoms associated with hemochromatosis are common among HFE wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low.
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Affiliation(s)
- Jill Waalen
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
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Lecoules S, el Maghraoui A, Damiano J, Lechevalier D, Magnin J, Eulry F. [Hip arthroplasty in genetic hemochromatosis. Report of 5 cases]. Rev Med Interne 2002; 23:454-9. [PMID: 12064217 DOI: 10.1016/s0248-8663(02)00593-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Half of the patients with genetic hemochromatosis will have arthritis. Two of these articular involvements are well-known: the arthropathy involving the phalangeal and the metacarpophalangeal joints of the hand, useful for diagnosis, and hip arthropathy. Iron deposits seem to be involved in articular cartilage destruction. EXEGESIS We report five cases of patients with hemochromatosis hip involvement. Hip arthropathy revealed hemochromatosis in one case and appeared despite efficient phlebotomies in another case. Three of these patients required hip arthroplasty. CONCLUSION Hip arthropathy remains a frequent but unknown event in genetic hemochromatosis (12.5%) and it involves the functional prognosis.
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Affiliation(s)
- S Lecoules
- Service de rhumatologie, hôpital d'instruction des armées Bégin, 69, avenue de Paris, 94160 Saint-Mandé, France.
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Abstract
BACKGROUND Hereditary hemochromatosis is the most common autosomal recessive disorder in populations of northern European descent. ISSUES Many experts consider hemochromatosis to be an almost ideal disease for population screening because it essentially fulfills almost all the criteria for screening proposed by the WHO. However, others disagree and suggest that more data are required particularly with regard to the natural history and penetrance of the disease. There is also disagreement about the best diagnostic/screening test for the disease and the performance of these tests in the context of screening. Other concerns are the variability and lack of standardization in screening test measurements, the selection of screening threshold values and the identification of false positive cases. The advent of a genetic test for the condition has brought other worries with regard to informed consent and the ethical, legal and social implications of screening particularly in relation to medical and general discrimination. Other important issues include compliance, cost effectiveness and the evidence that screening has lessened the burden of disease in the community. CONCLUSIONS At the present time, we believe that further data regarding both the exact disease burden and the outcomes of screening studies particularly in the general community are required before widespread population screening is introduced.
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Affiliation(s)
- Mark A McCullen
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia
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Hachiya M, Watanabe H, Tsukimoto I, Fujisawa T. Hereditary hemochromatosis not associated with common HFE gene mutation in Japanese siblings. J Pediatr Gastroenterol Nutr 2001; 32:501-3. [PMID: 11396825 DOI: 10.1097/00005176-200104000-00024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- M Hachiya
- First Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan.
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Brissot P, Guyader D, Loréal O, Lainé F, Guillygomarc'h A, Moirand R, Deugnier Y. Clinical aspects of hemochromatosis. TRANSFUSION SCIENCE 2000; 23:193-200. [PMID: 11099895 DOI: 10.1016/s0955-3886(00)00088-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Hemochromatosis is one of the most frequent genetic diseases among the white populations, affecting one in three hundred persons. Its diagnosis has been radically transformed by the discovery of the HFE gene. In a given individual, the diagnosis can, from now on, be ascertained on the sole association of a plasma transferrin saturation (TS) over 45% and homozygosity for the C282Y mutation. Liver biopsy is only required to search for cirrhosis whenever there is hepatomegaly and/or serum ferritin >1000 ng/ml and/or elevated serum AST. Family screening is mandatory, primarily centered on the siblings. The treatment remains based on venesection therapy which improves many features of the disease (one of the most refractory, however, being the joint signs) and permits normal life expectancy provided the diagnosis is established prior to the development of cirrhosis or of insulin-dependent diabetes. In view of the prevalence, the non-invasive diagnosis, the spontaneous severity and the efficacy of a very simple therapy, hemochromatosis should benefit from population screening. This screening could be based, first, on the assessment of transferrin saturation, followed - when elevated - by the search for the C282Y mutation. The discovery of the HFE gene has also paved the road for the individualization of other types of iron overload syndromes which are not HFE-related.
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Affiliation(s)
- P Brissot
- Clinique des Maladies du Foie and Liver Research Unit INSERM U-522, University Hospital Pontchaillou, Rue H. Le Guilloux, 35033 Rennes, France.
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Bulaj ZJ, Ajioka RS, Phillips JD, LaSalle BA, Jorde LB, Griffen LM, Edwards CQ, Kushner JP. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med 2000; 343:1529-35. [PMID: 11087882 DOI: 10.1056/nejm200011233432104] [Citation(s) in RCA: 139] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Hemochromatosis occurs in approximately 5 white people per 1000 and is usually due to homozygosity for mutations in the HLA-linked HFE gene. Although screening has been proposed, the proportion of homozygotes with conditions related to hemochromatosis is uncertain. METHODS We studied the prevalence of disease-related conditions among relatives of probands with hemochromatosis. We identified probands who presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. We identified homozygous relatives, mainly siblings, on the basis of HLA identity with the proband and by HFE genotyping. Disease-related conditions were cirrhosis, hepatic fibrosis, elevated amino-transferase values, and hemochromatotic arthropathy. RESULTS We identified 214 homozygous relatives of 291 homozygous probands. Of the 113 men in this group (mean age, 41 years), 96 (85 percent) had iron overload, and 43 (38 percent) had at least one disease-related condition. Of the 52 men over 40 years of age, 27 (52 percent) had at least one disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68 percent) had iron overload, and 10 (10 percent) had at least one disease-related condition. Of the 43 women over 50 years of age, 7 (16 percent) had at least one disease-related condition. If the proband had a disease-related condition, relatives who were men were more likely to have morbidity than if the proband had no disease-related condition. CONCLUSIONS A substantial number of homozygous relatives of patients with hemochromatosis--more commonly men than women--have conditions related to hemochromatosis that have yet to be detected clinically.
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Affiliation(s)
- Z J Bulaj
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, USA
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Durupt S, Durieu I, Nové-Josserand R, Bencharif L, Rousset H, Vital Durand D. [Hereditary hemochromatosis]. Rev Med Interne 2000; 21:961-71. [PMID: 11109593 DOI: 10.1016/s0248-8663(00)00252-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Hereditary hemochromatosis is a fairly common disease in the Caucasian population, with a prevalence estimated at between 1.5 to 3/1,000 inhabitants. Over the past few years, its symptomatology has altered; at present, its clinical aspect with diabetes mellitus, cirrhosis, and darker skin pigmentation only constitutes 10% of new cases of this disease. CURRENT KNOWLEDGE AND KEY POINTS In 1996, the discovery of the C282Y mutation in the HFE gene radically altered the diagnostic approach to hereditary hemochromatosis. At present, any patient admitted with an isolated case of asthenia, or with arthralgia or hypertransaminasemia should be examined via transferrin-saturation testing: if the transferrin saturation coefficient is > 45%, then the presence of the C282Y mutation should be investigated to confirm the diagnosis of hemochromatosis. A liver biopsy is no longer necessary to establish the diagnosis, but this is still useful in cases of possible cirrhosis, which is the main risk factor for hepatocellular carcinoma. Phlebotomy remains the sole recommended treatment, and should be undertaken in a case-specific manner. Family screening should be carried out for all first-degree relatives for every new case that is diagnosed. FUTURE PROSPECTS AND PROJECTS The discovery of the HFE gene has permitted hereditary hemochromatosis to be easily differentiated from other forms of hepatic iron overload including a new syndrome, dysmotabolic hepatosiderosis. Casos of homozygotic C282Y without hepatic iron overload have been described, but the clinical outcome of some of these cases requires further study, and adds to the controversy on whether systematic population screening should be made available.
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Affiliation(s)
- S Durupt
- Service de médecine interne, centre hospitalier Lyon-Sud, France
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Affiliation(s)
- P Adams
- University of Western Ontario, London, Canada
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Abstract
The recent cloning of the hemochromatosis gene (HFE) and the demonstration that a single missense mutation is responsible for 90% or more of patients with the disease, have stimulated renewed interest in all aspects of this common disease. The molecular tests for identifying mutations in HFE provide improved means for diagnosis, family screening, and population screening. Moreover, the elucidation of the role of the HFE gene product will provide new insights into the regulation of normal iron absorption and iron metabolism. In addition, it is now apparent that iron, even in the modest tissue concentrations, can act as a co-factor in potentiating cell injury in other liver diseases.
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Affiliation(s)
- L W Powell
- Department of Medicine, University of Queensland, Brisbane, Australia.
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Florkowski CM, George PM, Willis JA, Stott MK, Burt MJ, Upton JD, Nesbit J, Walmsley TA, Scott RS. Haemochromatosis gene mutations Cys282Tyr and His63Asp are not increased in Type 2 diabetic patients compared with the Canterbury (New Zealand) general population. Diabetes Res Clin Pract 1999; 43:199-203. [PMID: 10369430 DOI: 10.1016/s0168-8227(98)00129-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Genetic predisposition to haemochromatosis may be an important aetiological factor in some cases of Type 2 diabetes. Our aim was therefore to test the hypothesis that the haemochromatosis gene mutations Cys282Tyr and His63Asp are more prevalent in Type 2 diabetic patients compared with the Canterbury, New Zealand general population. We studied 230 consecutive patients referred to the Diabetes Services with age > or = 30 years and considered to have Type 2 diabetes. DNA was extracted from whole blood and amplified by polymerase chain reaction prior to restriction fragment length polymorphism analysis. The frequency of the mutations was compared with that observed previously in 1064 subjects from the Canterbury general population by chi2 testing. Iron was measured by a colorimetric method, transferrin by rate nephelometry and ferritin by immunoassay. There were 2/230 (0.8%) Cys282Tyr homozygous subjects in the diabetic group compared with 5/1064 (0.5%) NS in the general population. Although there was a trend to lower incidence of Cys282Tyr heterozygosity in the diabetic group, there was no significant difference for any of the six genotype frequencies between the two groups. Haemochromatosis gene mutations Cys282Tyr and His63Asp are therefore not increased in Type 2 diabetics compared with the general population. Transferrin saturation was a sensitive marker (100%) of genetic haemochromatosis, although ferritin had low specificity (77.8%). Genetic susceptibility to haemochromatosis is not an important aetiological factor for diabetes, and targeted screening of diabetic patients for haemochromatosis is not indicated.
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Affiliation(s)
- C M Florkowski
- Lipid and Diabetes Research Group, Christchurch Hospital, New Zealand.
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Abstract
HHC is a common inherited disorder, characterized by iron accumulation in the liver, heart, pancreas, and other organs. The clinical consequences of systemic iron loading are diverse and not always improved with iron reduction therapy. The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis. Those without significant hepatic fibrosis may be expected to have a normal life expectancy with phlebotomy therapy. The availability of genetic testing for HHC has significantly changed the diagnostic approach to this disorder. Although liver biopsy remains vital to determining prognosis, genetic testing is increasingly used in the diagnosis and family screening of patients with HHC.
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Affiliation(s)
- B Y Tung
- Division of Gastroenterology, University of Washington School of Medicine, Seattle, USA
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Abstract
Hereditary hemochromatosis (HH) is a human leukocyte antigen-linked inherited disease that is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The spectrum of disease presentation is changing with more and more patients now being identified before they are symptomatic with complications of iron overload. A candidate gene for HH, called HFE, was identified in 1996, and a test for the gene is commercially available. A review of the recent identification of the gene and its implications for clinical diagnosis and therapy is presented. We also propose an algorithm for evaluation of patients for HH. Early diagnosis and appropriate therapy can prevent significant morbidity and mortality associated with the development of end-organ complications of HH. The understanding of the C282Y and H63D mutations is still evolving, and the algorithm and the contribution of various heterozygous mutations to the diagnosis and management of iron overload need to be confirmed by further clinical and genetic studies.
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Affiliation(s)
- S Ramrakhiani
- Department of Internal Medicine, Saint Louis University School of Medicine, MO 63110-0250, USA
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