Treatment Of Hemochromatosis Research Articles

Primary Non-HFE Hemochromatosis: A Review.

Iron homeostasis is a complex process in which iron uptake and use are tightly balanced. Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator (known as human factors engineering, HFE) protein, a regulator of hepcidin, and makes up approximately 90% of all hemochromatosis cases. However, four types of hemochromatosis do not involve the HFE gene. They are non-HFE hemochromatosis type 2A (HFE2, encoding HJV), type 2B (HAMP, encoding hepcidin), type 3 (TFR2, encoding transferring receptor-2), and types 4A and B (SLC40A1, encoding ferroportin. Non-HFE hemochromatosis is extremely rare. Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A, 20/100,000 for type 2B, 30/100,000 for type 3, and 90/100,000 for type 4 hemochromatosis. Current guidelines recommend that the diagnosis be made by ruling out HFE mutations, history, physical examination, laboratory values (ferritin and transferrin saturation), magnetic resonance or other imaging, and liver biopsy if needed. While less common, non-HFE hemochromatosis can cause iron overload as severe as the HFE type. In most cases, treatment involves phlebotomy and is successful if started before irreversible damage occurs. Early diagnosis and treatment are important because it prevents chronic liver disease. This review updates the mutations and their pathogenetic consequences, the clinical picture, diagnostic guidelines, and treatment of hemochromatosis.

Bloodlettings in Hemochromatosis Result in Increased Blood Lead (Pb) Concentrations

Hemochromatosis is a hereditary disorder, most often associated with mutations of the HFE (High FErrum) gene. If left untreated, it can result in severe parenchymal iron accumulation. Bloodletting is the mainstay treatment. We have previously shown that treatment of hemochromatosis by repeated bloodlettings may induce changes in the serum levels of several trace elements. The aim of this work was to evaluate if whole blood concentrations of the environmental pollutants lead (Pb), mercury (Hg), and cadmium (Cd) could be affected by bloodlettings. We recruited 28 patients and 21 healthy individuals (control group). Whole blood and urine levels of Pb, Hg, and Cd were measured before the start and after the completion of treatment using inductively coupled plasma mass spectrometry, together with serum iron and liver function tests. Concentrations of blood Pb, but not Hg or Cd, were significantly increased after treatment. The increase in Pb was higher in C282Y homozygous patients than in the other patients, and it was positively correlated with the serum concentration of alkaline phosphatase. Bloodlettings in hemochromatosis result in an increase in the blood concentration of Pb. Augmented absorption due to iron loss or Pb mobilization from bone may contribute to the higher blood Pb level.

Hereditary Hemochromatosis: an Inherited Abnormality of Iron Regulation

Hereditary Hemochromatosis (HH) is an autosomal recessive genetic disease characterized by abnormalities in iron regulation, mostly due to mutations in the HFE gene, leading to increased iron absorption due to hepcidin deficiency. The classification of HH is based on the type of mutated gene, which must be distinguished from non-genetic conditions that cause secondary elevations in serum iron levels such as multiple transfusions and increased iron supplementation. Pathophysiological mechanisms of HH include increased absorption of iron in the upper intestine, decreased expression of the iron regulatory hormone hepcidin, altered function of the HFE protein, and tissue damage and fibrogenesis caused by iron overload. The human body is physiologically unable to excrete excess iron load so excess iron in serum will be deposited in various organs, causing organ dysfunction. The clinical manifestations of hemochromatosis vary widely depending on the location of iron deposition in the organ. The classic clinical triad of hemochromatosis is liver cirrhosis, skin pigmentation, and diabetes mellitus. Hemochromatosis can be screened for and diagnosed by examining serum ferritin levels, transferrin saturation, unsaturated iron-binding capacity, total iron-binding capacity, liver biopsy, magnetic resonance imaging, and genetic testing. The main treatment for hemochromatosis at this time is phlebotomy although other therapeutic methods can also be used to help lower iron levels and improve the patient’s clinical course, such as therapy with chelating agents, erythrocytopharesis, and liver transplantation. If hemochromatosis is not treated, the patient can experience progressive liver damage leading to cirrhosis and hepatocellular carcinoma, and complications due to damage to various tissues and organs.

Chelating Polymers for Hereditary Hemochromatosis Treatment

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

Hemochromatosis International: therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr homozygous genotype

Hereditary hemochromatosis is a kind of hereditary metabolic liver disorders. It is caused by mutations in genes related to hemochromatosis, which leads to over deposition of iron in the liver, pancreas, skin, hypophysis, gonad and other organs and tissues of the whole body and is manifested as cirrhosis, diabetes, skin pigmentation, and low libido. Physicians of our country have inadequate understanding and familiarity with this disorder. Both the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases have issued guidelines for the diagnosis and treatment of hemochromatosis, but these two guidelines are complicated and difficult for Chinese clinical physician to comprehend. In 2018, Hepatology International published therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr homozygous genotype developed by Hemochromatosis International, these recommendations were objective, simple, and practical. We believe the above-mentioned guideline is understandable and helpful for clinicians and patients without medical education background. Therefore, herein the recommendations are translated into Chinese language, with a view to being able to be clinical work guide for the majority of Chinese hepatologists.

PF501 HOMOZYGOUS I281T MUTATION IN HJV CAUSING INDOLENT JUVENILE HEMOCHROMATOSIS WITH A MIDDLE TO LATE ONSET

Background:Juvenile hemochromatosis (JH; hemochromatosis type 2A) is a rare autosomal recessive disorder of systemic iron overload due to homozygous mutations of HJV (HFE2) which encodes hemojuvelin, an essential regulator of hepcidin expression, leading to intestinal iron hyperabsorption because of hepcidin deficiency. JH usually occurs younger than 30 years old, and causes liver fibrosis, hepatocellular carcinoma, diabetes, hypogonadism and heart failure with fatal outcomes.Aims:Here we report two Japanese siblings with JH caused by a homozygous I281T mutation in HJV, who unusually showed an indolent clinical course with a middle to late onset.Methods:After obtaining a written informed consent from each individual, blood samples were collected, followed by genomic DNA purification, and the coding regions of HFE, HFE2 (HJV), HAMP, TFR2, and SLC40A1 were sequenced. Genetic mutation was then evaluated by comparing the sequencing results to open access genetic information on the NCBI websites.Results:Patient #1 is a 38‐year‐old woman, who was referred to us due to 1‐year history of amenorrhea, thirst and weight loss. The patient's laboratory findings showed high levels of transferrin saturation (93%) and serum ferritin (2274 ng/mL), insulin‐dependent diabetes, iron deposition of the anterior pituitary gland by nuclear magnetic resonance (NMR) with hypogonadism, and massive iron deposition in hepatocytes by liver biopsy. Phlebotomy effectively improved iron overload as a treatment of hemochromatosis and has been continued for more than 15 years on an outpatient basis. Patient #2, aged 55, is an elder sister of the patient #1, who referred to us because due to liver dysfunction, dyslipidemia and hyperglycemia for 3 years and thirst for 1 year. She was also found to have high levels of transferrin saturation (92%) and serum ferritin (4340 ng/mL), insulin‐dependent diabetes, iron deposition of the pituitary gland by NMR with hypogonadism, massive iron deposition in hepatocytes by liver biopsy, and cardiomyopathy with congestive heart failure. Phlebotomy successfully improved organ damages associated with iron overload and has been continued for more than 4 years on an outpatient basis. It was later found that serum levels of hepcidin were below the measurement sensitivity in both patients.To identify the causative genetic defect responsible for the iron overload in these two siblings (probands), we screened them for mutations in the genes involved in hereditary hemochromatosis as well as their healthy brother, and two healthy sons of the patient #1. Both probands were homozygous for a missense mutation in HJV exon 4 (842 T>C; I281T). Both of the patient #1's sons were heterozygous for I281T of HJV, and the brother had no mutations related with hemochromatosis.Summary/Conclusion:We have reported two Japanese siblings (onset, 37 and 52 years) with the homozygous mutation of HJV I281T in middle to late onset with an indolent clinical course. HJV mutations, which are the cause of JH, have been widely identified mainly in a Caucasian population. However, the homozygous mutation of HJV I281T as observed in the current study has only been identified in one Greek patient (Papanikolaou G. Nature genet. 2004), whose JH notably occurred at the age of 39 years and was diagnosed at the age of 49 years. Therefore, together with the current findings, it was suggested that the homozygous mutation of I281T may be associated with an indolent clinical course and a middle to late onset of JH.

A Red Herring in a College Track and Field Thrower

HISTORY: 18 year old male track and field thrower, who was previously healthy, presented to the training room clinic 2 months after being diagnosed with mono by his PCP. The symptoms at the time of presentation to his PCP were fatigue and palpitations, and his labs showed elevated liver enzymes. The patient continued to have the same symptoms at the time of presentation to us. He had been on long term (>1 yr) Bactrim for acne, denied taking Tylenol regularly, but did occasionally drink ETOH. At the time of presentation to the training room, he had been scheduled for a stress treadmill and cardiac evaluation for work up of the palpitations. PHYSICAL EXAMINATION: Constitutional: Well developed. Eyes: B/L No injection. Neck: Inspection reveals symmetry. Respiratory: Lungs clear to auscultation. Normal effort Cardiovascular: No murmurs RRR No edema is present. Vascular: Pulses Capillary refill less than 2 sec. Abd: Symmetric - no distention. BS +, no bruits. NT, no RRG. No hepatic enlargement. Integumentary: No impressive skin lesions present. Ext: No edema. Neurological: Memory: Intact . Psychiatric: OA x 3 demonstrates the appropriate mood and affect. DIFFERENTIAL DIAGNOSIS: - Drug-induced hepatitis from multiple years of Bactrim use -ETOH abuse - Viral hepatitis - Gallbladder polyp/stones - Hemochromatosis - Mono TEST AND RESULTS: Hepatitis panel negative, CMP- Normal except for ALT 211 AST 87 Negative treadmill stress test FU lab 9 m later showed- Negative mono test, but ferritin was 5172, Total iron binding capacity 317, % of iron sat 91 %, iron 289, genetic testing for hemochromatosis was negative. FINAL WORKING DIAGNOSIS: Hemochromatosis TREATMENT AND OUTCOMES: Patient is doing much better at this time. Patient started out getting phlebotomies every 2 weeks and then was increased to twice weekly. His last ferritin was 750 and he continues now with once weekly phlebotomies. He is currently participating without restrictions in track and field at the NCAA level.

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

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 11.5nmol/L, serum Cu 16.2–17.6μmol/L, Ni increased from 50.0 to 52.6nmol/L and Sb from 13.2 to 16.3nmol/L. Average serum Mn concentration declined from 30.2 to 28.3nmol/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.

Target TMPRSS6 for the Treatment of Hereditary Hemochromatosis

Abstract 1047Hereditary hemochromatosis (HH) is a genetic disorder in which hyperabsorption of dietary iron leads to accumulation of iron in multiple tissues including liver and heart. A common clinical manifestation in HH patients is cirrhosis and hepatocellular carcinoma as a result of iron-mediated injury in liver. The most prevalent genetic defect for HH is the failure to up-regulate hepcidin, a peptide hormone that inhibits the absorption of iron in duodenum and the release of iron from intracellular iron storage such as macrophages. Mutations in a number of genes have been identified as the cause for HH, including hepcidin itself. However, the most common mutation is C282Y mutation in HFE, which is a positive regulator for hepcidin expression. C282Y mutation represents about 85% of the HH population. HFE C282Y HH is an autosomal recessive disease with a ∼50% penetrance. Currently, the only treatment available for iron overload is phlebotomy which will continue throughout the patient’s life.Hepcidin is mainly expressed and secreted by the liver and its expression is regulated predominantly at the transcription level. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor for hepcidin expression. It’s been demonstrated that hepcidin expression is significantly elevated in Tmprss6−/− mice and reduction of TMPRSS6 in Hfe−/− mice could ameliorate the iron overload phenotype (Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg KE et al., Blood, 2011).Using second generation antisense technology, we identified antisense oligonucleotides (ASOs) targeting mouse TMPRSS6 for the treatment of HH. These compounds were first identified through in vitro screens in mouse primary hepatocytes. After 4 weeks of treatment in C57BL/6 mice on normal chow, we observed an 80% to 90% reduction of liver TMPRSS6 mRNA with a subsequent 2–3 fold induction of liver hepcidin mRNA. Serum iron and transferrin saturation levels were reduced by ∼50%. These ASOs are currently being evaluated in a diet-induced iron overload model and an Hfe−/− iron overload model. Our preliminary results demonstrate that targeting TMPRSS6 is a viable approach for the treatment of hereditary hemochromatosis and possibly other iron-loading diseases associated with suppressed hepcidin levels. Disclosures:Booten:Isis Pharmaceuticals: Employment. Knox:Isis Pharmaceuticals: Summer Intern. Alvarado:Isis Pharmaceuticals: Employment. Guo:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment.

The iron-chelating potential of silybin in patients with hereditary haemochromatosis

Milk thistle contains silybin, which is a potential iron chelator. We aimed to determine whether silybin reduced iron absorption in patients with hereditary haemochromatosis. In this crossover study, on three separate occasions, 10 patients who were homozygous for the C282Y mutation in the HFE gene (and fully treated) consumed a vegetarian meal containing 13.9 mg iron with: 200 ml water; 200 ml water and 140 mg silybin (Legalon Forte); or 200 ml tea. Blood was drawn once before, then 0.5, 1, 2, 3 and 4 h after the meal. Consumption of silybin with a meal resulted in a reduction in the postprandial increase in serum iron (AUC±s.e.) compared with water (silybin 1726.6±346.8 versus water 2988.8±167; P<0.05) and tea (silybin 1726.6±346.8 versus tea 2099.3±223.3; P<0.05). In conclusion, silybin has the potential to reduce iron absorption, and this deserves further investigation, as silybin could be an adjunct in the treatment of haemochromatosis.

Iron overload measurements by CMR in patients with suspected hemochromatosis - comparison of methods for T2* calculation in myocardium and liver

Introduction Iron tissue overload can be detected non-invasively by CMR using T2* measurements techniques. Hemochromatosis is a disorder of iron metabolism that results in excess iron accumulation in tissues and organs. If left undiagnosed and untreated, iron overload can cause serious, sometimes fatal health problems. Early detection of iron overload and hemochromatosis treatment can prevent complications and prolong life.

HFE C282Y Homozygosity Is Associated With Lower Total and Low-Density Lipoprotein Cholesterol

Background— Previous studies have suggested a positive association of coronary heart disease risk and both serum ferritin concentrations and C282Y heterozygosity. Relationships between serum lipids, C282Y homozygosity, and serum ferritin have not been well established. Methods and Results— The Hemochromatosis and Iron Overload Screening study screened 101 168 participants in primary care from 5 field centers in the United States and Canada with serum ferritin, transferrin saturation, and HFE genotyping for C282Y and H63D mutations. Serum lipids were measured in a subset of 176 C282Y homozygotes (63 male, 113 female whites) without a prior diagnosis of, family history, or treatment for hemochromatosis and a matched sample of participants with normal transferrin saturation and serum ferritin without C282Y or H63D mutations (wild-type, 123 male, 189 female whites). The proportion of subjects who reported using prescription cholesterol-lowering medications was ≈3 times higher in HFE wild-type subjects than C282Y homozygotes among men (22% versus 7%; P =0.02) and, in women, 2 times higher (16% versus 8%; P =0.07). After excluding subjects taking cholesterol medications, C282Y homozygotes had significantly lower mean total and low-density lipoprotein cholesterol concentrations than wild-type subjects, with larger genotypic differences for low-density lipoprotein in men (−0.62 mmol/L; 95% CI, −0.93 to −0.33) than in women (−0.28 mmol/L; 95%, CI −0.52 to −0.08). Conclusions— Total mean serum cholesterol and low-density lipoprotein levels were lower in C282Y homozygotes than in HFE wild-type participants. Further studies are required to determine whether this is related to iron overload, HFE alleles, or other factors on C282Y-positive chromosome 6p haplotypes.

Hereditary iron and copper deposition: Diagnostics, pathogenesis and therapeutics

Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about 200 times higher than the prevalence of Wilson's disease. The two diseases are characterized by homozygous occurrences of mutations in the HFE gene on chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13 (Wilson's disease). Unlike most other inherited conditions, these diseases can be successfully treated, emphasizing the importance of early diagnosis. Serum ferritin values, transferrin saturation and genetic analysis are used when diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the use of urinary copper values, serum ceruloplasmin and liver biopsy. If untreated, both of these genetic diseases result in rapidly progressing multiorgan damage and early death. The key treatment for haemochromatosis is phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present treatments considerably improve the prognosis of patients, they may be inadequate in patients diagnosed so late that extensive body deposits of metal have been developed. The main research needs in this field are to further clarify molecular mechanisms of disease progression and to develop new chelators that are more effective and less toxic than those presently available.

Inherited metabolic liver disease

The purpose of this review is to identify and discuss recent findings related to inherited metabolic disorders of the liver that increase our understanding of the pathophysiology and treatment for hemochromatosis and other iron overload disorders, Wilson disease and alpha one antitrypsin deficiency. The main theme in the recent discoveries for both iron overload disorders and Wilson disease is our increasing understanding that the phenotypic expression of these disorders are greatly influenced by genes involved in the metabolic pathways for these metals, or influence the progression of liver disease independent of metal metabolism. For example, the role of hepcidin dysregulation in hemochromatosis has been a surprising discovery that provides some mechanistic understanding for the increased iron absorption that is present in this disorder. Given the recent explosion of information on iron and copper metabolism and the cellular processing of alpha one antitrypsin, the highlights reviewed in this article will help the reader keep up to date with the current understanding of these diseases and potential future approaches to their treatment.

Successful combined heart-liver transplantation in a patient with hemochromatosis

Hemochromatosis is a disorder of excess iron deposition in tissues that may cause multiorgan dysfunction. Because the early symptoms of hemochromatosis are nonspecific, the diagnosis is frequently overlooked until significant organ failure has developed. The primary cause of death in these patients is usually liver cancer related to cirrhosis. Patients who are candidates for liver transplantation should be referred for evaluation. For patients with severe cardiomyopathy, in addition to end-stage liver disease, combined transplantation may be performed. Although there is a limited number of combined heart-liver transplantations that have been performed, successful outcomes can be achieved with close monitoring and a multidisciplinary team approach. In this case report, we will discuss the prevalence, pathophysiology, and treatment of hemochromatosis and potential complications of combined heart-liver transplantation.

Inherited metabolic liver disease

Division of Liver Diseases and The Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, New York, USA. Correspondence to Michael L. Schilsky, MD, Division of Liver Diseases and The Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029, USA; e-mail: [email protected]

Clinical haemochromatosis in HFE mutation carriers

Sir—Ernest Beutler and co-workers (Jan 19, p 211) calculate that fewer than 1% of C282Y homozygotes develop frank clinical haemochromatosis, a penetrance much lower than previously thought. We believe their conclusion is flawed. The prevalence of symptomatic haemochromatosis is not the same as the penetrance of the C282Y/C282Y genotype. Penetrance is the proportion of people who have the genotype that develops the phenotype. Definition of the phenotype is central. Four stages are recognised in haemochromatosis; end-organ damage and severe fibrosis or cirrhosis define stage 4. In Beutler and co-workers’ study, only three of 119 patients had serum ferritin higher than 1000 g/L and raised aspartate aminotransferase; only one had bronzed diabetes. This number would underestimate the proportion of people with the C282Y/C282Y genotype who had stage 4 disease, and their data suggest that the proportion of patients with stage 2–3 is more than 1% (stage 1 is genetic predisposition without phenotypic abnormality). Stage 4 liver disease can be predicted by measurement of serum ferritin, aspartate aminotransferase, and presence of hepatomegaly. Beutler and coworkers misquote Guyarder’s conclusion as saying that only haemochromatosis patients with serum ferritin concentrations of more than 1000 g/L and with raised aspartate aminotransferase concentrations develop severe liver fibrosis. Guyarder and colleagues noted that 30 of 68 patients with serum ferritin higher than 1000 g/L and normal aspartate aminotransferase had severe hepatic fibrosis. No information on hepatic fibrosis is available from Beutler and co-workers’ study. However, 57% of patients had raised serum transferrin saturation, and 65% raised serum ferritin. 30% had been previously diagnosed with haemochromatosis. Most (28 of 45) of these patients were excluded from the analysis of symptoms, lowering the estimate of penetrance based on symptoms. If an agreed definition of phenotype is used, Beutler and coworkers’ study suggests a penetrance much higher than 1%, perhaps as high as 50% if based on serum transferrin saturation. We have found screening of liver clinic referrals with serum transferrin saturation to be a reliable predictor of haemochromatosis (figure). This approach identified 11 C282Y homozygous over a 3-year period, of whom nine had phenotypic haemochromatosis. On screening of people with late-onset diabetes mellitus, undiagnosed C282Y homozygosity is five times as common as in controls. All eight homozygotes detected had phenotypic haemochromatosis with cirrhosis (four with hepatocellular carcinoma). Beutler and co-workers note no loss of C282Y homozygotes from the population with increasing age, and conclude that this supports low penetrance. However, they took no account of demographic changes in southern California in the past few decades. Immigration of younger Hispanic and Asian populations, in which there is a lower prevalence of C282Y homozygosity, would have a confounding effect by diluting the prevalence in younger agegroups. Population screening for the mutation in the hereditary haemochromatosis (HFE) protein is controversial since the penetrance of the HFE mutation is unclear. We believe Beutler and co-workers underestimate the penetrance. Based on liver-biopsy findings of screendetected homozygotes, the penetrance of the HFE mutation is far higher than they suggest. *A Poullis, S J Moodie, J D Maxwell

This month in J Lab Clin Med: Issue highlights for February 2000

This month in J Lab Clin Med: Issue highlights for February 2000

Iron overload, public health, and genetics: evaluating the evidence for hemochromatosis screening.

Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease. The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes. Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures a family history of hemochromatosis, or consistent early signs and symptoms of the disease.

Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data.

Hemochromatosis, which can lead to serious chronic diseases resulting from iron overload, has an estimated prevalence of 50 to 80 cases per 10000 persons. However, little population-based information is available on the impact of hemochromatosis on morbidity and mortality. To evaluate trends over 14 years in deaths and medical conditions associated with hemochromatosis in the United States. We searched Multiple-Cause Mortality Files compiled by the National Center for Health Statistics for the years 1979 to 1992 for all records listing hemochromatosis. We used these data to calculate age-adjusted and age-specific mortality rates, identify medical conditions associated with a known diagnosis of hemochromatosis at death, and calculate proportionate mortality ratios for these medical conditions. The listing of hemochromatosis on death certificates increased 60% from 1979 to 1992. Decedents with hemochromatosis were 23, 13, and 5 times more likely to have liver neoplasms, liver disease, and cardiomyopathy, respectively, than were decedents without hemochromatosis. Conversely, decedents with liver neoplasms, liver disease, and cardiomyopathy were 26, 14, and 5 times more likely, respectively, to have hemochromatosis than were decedents without these conditions. Hemochromatosis was 82 times more likely in persons with the combination of liver neoplasms and diabetes and 43 times more likely in those with the combination of liver disease and diabetes than in those without these conditions. Comparison of the reported prevalence of hemochromatosis among decedents with estimates of prevalence in the general U.S. population suggests that either the penetrance or the recognition of hemochromatosis, or both, is low. Nevertheless, substantial mortality resulting from liver disease, liver neoplasms, cardiomyopathy, and a combination of liver disease and diabetes in patients with hemochromatosis argues for the improved diagnosis and treatment of hemochromatosis in persons with these conditions.