Diagnosis Of Hemochromatosis Research Articles

Is exchange transfusion a possible treatment for neonatal hemochromatosis?

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

Magnetic Resonance Imaging (MRI) Findings of Joints in Young β-Thalassemia Major Patients: Fluid Surrounding the Scaphoid Bone

Beta-thalassemia major is a hereditary disease with developing hemochromatosis as a consequence of repeated blood transfusions. Degenerative arthropathy may be the first manifestation of primary hemochromatosis. The aim of this study is to determine the possible effects of secondary hemochromatosis in joints of beta-thalassemia major patients, and to evaluate the sensitivity of magnetic resonance imaging (MRI) compared with plain x-ray, in the early diagnosis of hemochromatosis of the joints. Thirty beta-thalassemia major patients were randomly enrolled. A questionnaire regarding their history, careful physical examination, the result of their liver biopsies, and other necessary information were completed for these patients. X-ray and MRI of the left hand and wrist were taken in these patients and also in other 30 healthy people with the same age and sex as the case control group. The prevalence of minimal fluid surrounding the scaphoid bone in MRI was 23.3%, which is a novel and significant finding. Other interesting changes included hypo signal intensity (T1 and T2) in carpal, metacarpal, radius, and ulna bones. Regarding the availability of special health services for thalassemia patients, this imaging study can be used for the accurate detection of hemochromatosis in joints of thalassemia patients.

Movement disorder due to aceruloplasminemia and incorrect diagnosis of hereditary hemochromatosis

Movement disorder due to aceruloplasminemia and incorrect diagnosis of hereditary hemochromatosis

Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis

BackgroundHereditary haemochromatosis (HH) is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y) of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D). Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing.MethodsA survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment.ResultsConsensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines.ConclusionAn agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing.

Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis

We recently demonstrated that humans with hereditary haemochromatosis have decreased insulin secretory capacity with a compensatory increase in insulin sensitivity. We therefore determined how these measures change after correction of tissue iron overload. Five non-diabetic subjects who had been studied previously at the time of initial diagnosis by means of the OGTT and frequently sampled intravenous glucose tolerance tests (FSIVGTT) underwent phlebotomy to normalise their serum ferritin. After normalisation of ferritin they were studied again (33+/-4 months after the initial studies) by OGTT and FSIVGTT. Normalisation of tissue iron stores resulted in an average 1.8-fold increase in the integrated area under the insulin curve during OGTT (p<0.0001), but no significant change in the area under the glucose curve (10% decrease, p=0.32). After phlebotomy, there was a 2.2-fold increase in insulin secretory capacity as determined by FSIVGTT (acute insulin response to glucose [AIRg], p<0.02) but a concomitant 70% fall in insulin sensitivity (Si, p<0.05). The disposition index (AIRgxSi) was unchanged (5% increase, p=0.90). BMI and fasting glucose were unchanged. At the time of diagnosis of haemochromatosis, four of the subjects had IGT. After normalisation of ferritin, two achieved NGT and two remained with IGT, despite 2.5- and 3.7-fold increases in insulin secretory capacity. Insulin secretory capacity improves after normalisation of iron stores in subjects with hereditary haemochromatosis. Glucose tolerance status improves incompletely because of decreased insulin sensitivity after phlebotomy. We conclude that tissue iron levels are an important determinant of insulin secretion and insulin action.

Relationships of Serum Ferritin, Transferrin Saturation, and HFE Mutations and Self-Reported Diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

We evaluated the associations of self-reported diabetes with serum ferritin concentration, transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five field centers in the Hemochromatosis and Iron Overload Screening (HEIRS) study. Analyses were conducted on 97,470 participants. Participants who reported a previous diagnosis of diabetes and/or hemochromatosis or iron overload were compared with participants who did not report a previous diagnosis. The overall prevalence of diabetes was 13.8%; the highest prevalence was in Pacific Islanders (20.1%). Of all participants with diabetes, 2.0% reported that they also had hemochromatosis or iron overload. The mean serum ferritin concentration was significantly greater in women with diabetes in all racial/ethnic groups and in Native-American men with diabetes than in those without diabetes. The mean serum ferritin concentration was significantly lower in Asian men with diabetes than in those without diabetes. Mean TfSat was lower in participants with diabetes from all racial/ethnic groups except Native-American women than in those without diabetes. There was no significant association of diabetes with HFE genotype. The mean serum ferritin concentration was greater (P < 0.0001) in women with diabetes than in those without diabetes for HFE genotypes except C282Y/C282Y and C282Y/H63D. Log serum ferritin concentration was significantly associated with diabetes in a logistic regression analysis after adjusting for age, sex, racial/ethnic group, HFE genotype, and field center. Serum ferritin concentration is associated with diabetes, even at levels below those typically associated with hemochromatosis or iron overload.

Disulone et hépatosidérose

Disulone (dapsone + iron oxalate) is a sulfone used in the treatment of numerous skin diseases. We report two cases of hepatosiderosis secondary to long-term administration of Disulone. Case n degrees 1. A 51-year-old man was treated with Disulone for a neutrophilic skin disease. After 17 years of treatment, elevated serum ferritin and free iron with hemolysis were found. Liver biopsy confirmed hepatosiderosis. A diagnosis of genetic hemochromatosis was ruled out by the absence of C282Y mutation of the HFE gene. Case n degrees 2. A 52-year-old man receiving Disulone for dermatitis herpetiformis for 25 years presented elevated serum ferritin and free iron with hemolysis. Hepatic iron overload was confirmed by liver biopsy. The absence of C282Y mutation (HFE gene) ruled out a diagnosis of genetic hemochromatosis. In our two cases, hepatosiderosis was noted after long-term administration of Disulone. This complication has been reported only rarely. In murine models, a relationship was found between prolonged administration of dapsone and hepatic iron overload as revealed by hemolysis. Although it is difficult to extrapolate this relationship to humans with any certainty, our patients had also chronic hemolysis and iron overload secondary to administration of Disulone. Moreover in France, dapsone is marketed in combination with iron oxalate, with the attendant risk of iron overload. These cases raise the question of the need for serum ferritin analysis during Disulone therapy.

Hepatic Iron Overload Associated With a Decreased Serum Ceruloplasmin Level in a Novel Clinical Type of Aceruloplasminemia

Aceruloplasminemia is a novel hereditary iron overload disease caused by a mutation in the ceruloplasmin gene and characterized by a complete deficiency of serum ceruloplasmin and iron accumulation in the liver and brain. We herein studied a novel clinical type of aceruloplasminemia in which a low amount of ceruloplasmin was detected in the serum of a patient. The patient presented with an asymptomatic hepatic iron overload, retinal degeneration, and diabetes mellitus. Magnetic resonance imaging of the liver and basal ganglia showed T2-hypointensity signals associated with parenchymal iron accumulation because of an absence of the ferroxidase activity in ceruloplasmin. A gene analysis showed a novel G969S mutation in the ceruloplasmin gene. A biochemical analysis of the patients' serum and a biogenesis study of G969S mutant ceruloplasmin using mammalian cell culture system resulted in the synthesis and secretion of only apoceruloplasmin without any ferroxidase activity. This novel clinical type of aceruloplasminemia should therefore be considered in the differential diagnosis of unexplained hemochromatosis, which is associated with a decrease in the serum ceruloplasmin level.

Review article: the modern diagnosis and management of haemochromatosis

Haemochromatosis is the most common genetic disease in populations of European ancestry. Despite estimates based on genetic testing in Caucasian populations of 1 in 227, many physicians consider haemochromatosis to be a rare disease. The diagnosis can be elusive because of the non-specific nature of the symptoms. Of all the symptoms, liver disease has the most consistent relationship to haemochromatosis and the prognosis of haemochromatosis is most closely linked to the degree of iron overload. With the discovery of the HFE gene in 1996, comes new insights into the pathogenesis of the disease and new diagnostic strategies. However, a growing number of new iron-related genes have been discovered and linked to other iron overload syndromes.

Abnormal Hematologic Screening in an Elite Athlete

HISTORY: The patient is a 21-year-old male, elite level athlete who competes in a sprinting sport. He has no medical concerns other than some low back pain (common in his sport). Routine laboratory testing had documented elevated hemoglobin and hematocrit levels since he was first tested about 4 years previously. He was in the process of obtaining a Blood Passport from his athletic governing body which grants permission to compete based upon documentation of elevated hematocrit levels from adolescence to present time. His latest screening also demonstrated an elevated total serum iron and iron saturation for the first time. He has a family history of some relatives with elevated blood counts who were thought to be otherwise healthy. PHYSICAL EXAMINATION: Routine yearly physical examinations had previously revealed no abnormalities. Laboratory screening examinations were performed several times a year to monitor blood levels consisting of Complete Blood Count (CBC), Ferritin, Serum Iron, and Total Iron Binding Capacity. The following values were obtained during the above mentioned screening exam (abnormal levels are in bold): RBC - 5.96 (n 4.5–5.9), Hgb - 19.3 (n 13.5–17.5), Hct -55.8 (n 41.0–53.0), Ferritin- 211 (n 20–300), Total Serum Iron - 200 (n 49–181), Total Iron Binding Capacity - 389 (n 250–450), Iron Percent Saturation - 51 (n 20–50). DIFFERENTIAL DIAGNOSIS: Constitutionally high hemoglobin Polycythemia Hemochromatosis Altitude induced hematopoesis Erythropoetin (EPO) usage TEST AND RESULTS: Given a change in the the previously normal iron parameters, coupled with an elevated Hgb and Hct, a fasting serum transferrin saturation was ordered and found to be 45%. Genetic testing for hemochromatosis was obtained via Polymerase Chain Reaction (PCR), which showed: C282Y Hemochromatosis Mutation: Heterozygous H63D Hemochromatosis Mutation: Heterozygous S65C Hemochromatosis Mutation: Negative Final/Working diagnosis: Hereditary Hemochromatosis TREATMENT AND OUTCOMES: The diagnosis of hemochromatosis in an elite athlete in an Olympic year played an important part in this athlete's management process. Further testing, including liver biopsy to determine the extent of end organ iron deposition, was deemed safe to delay until after Olympic competition. No phlebotomizing was started. Most importantly, notification and further evaluation of several of the athlete's family members was initiated, including a grandmother who additional history revealed had both diabetes and a “dark complexion.” This is a rare event when “routine blood screening” has revealed significant abnormalities, with implications for both the athlete and his family.

Gastric Siderosis

Recently, we encountered 2 cases of diffuse iron deposition in gastric antral and fundic glandular epithelium, which in 1 patient eventually led to the diagnosis of hemochromatosis. Gastric mucosal siderosis (GS) has previously been described in hemochromatosis patients, alcoholics, and in association with iron medications. However, the prevalence of various patterns of iron deposition in the gastric mucosa and their clinical significance have not been studied in detail. The 2 index cases mentioned above and 500 additional consecutive gastric biopsies examined over a period of 8 months at our institution were stained for iron by the Prussian blue method. In addition, all patients with genetic hemochromatosis diagnosed by liver biopsy in our department between 1998 and 2003 who also had gastric biopsies were identified from the surgical pathology files and included in the study (n = 3). The location of iron deposition [stromal cells (endothelium, fibroblasts, macrophages), glandular epithelium, or extracellular] was recorded and subjectively graded as 1+ to 3+ according to the severity of deposition within the mucosa. Relevant histologic changes (inflammation, presence of H. pylori, ulceration) and clinical features were reviewed. Three patterns of GS were identified: A) "nonspecific GS" with predominant iron deposition in the stromal cells including macrophages, and focally in epithelium; B) "iron-pill gastritis" with often mild gastritis and reactive gastropathy type changes, and mostly extracellular deposition with focal stromal cells and epithelial deposition; and C) predominant deposition in antral and fundic glandular epithelium. Of the 500 cases studied, a total of 18 (3.6%) cases were found to have GS. Of these 18 cases, 11 (2.2%) showed pattern A, 4 (0.8%) showed pattern B, and 3 (0.6%) showed pattern C. The GS in patterns A and B was always focal or patchy (1+ to 2+), whereas in pattern C it was generally diffuse and strong (2+ to 3+). A history of oral iron medication was present in 2 (n = 11, 0.4%) patients with pattern A, in all patients with pattern B (n = 4, 100%), and in none of patients with pattern C (n=3, 0%). Varying degrees of mucosal inflammation were noted in patients with pattern A cases, and 2 had evidence of active Helicobacter pylori infection. Of the 3 cases with known hemochromatosis, only one gastric biopsy showed pattern C GS (1+). In conclusion, gastric mucosal siderosis is relatively uncommon (3%) but is important to look for as it may lead to a diagnosis of hemochromatosis in some cases. Three patterns are recognized: A) a "nonspecific" stromal cell predominant pattern, which may be associated with gastric inflammation, possibly prior mucosal hemorrhages or iron medications; B) extracellular coarse clumps of crystalline iron deposition associated with oral iron medications, mild gastritis, and reactive gastropathy type changes ("Iron-pill gastritis"); and C) gastric glandular siderosis, which may be associated with systemic iron overload/hemochromatosis.

Late onset of Wilson??s disease in a family with genetic haemochromatosis

We report the coexistence of Wilson's disease and genetic haemochromatosis in one family. The diagnosis of genetic haemochromatosis was established in a 52-year-old man. Among his siblings, one 57-year-old sister and one 55-year-old brother had decreased copper and ceruloplasmin levels in serum and increased urinary copper excretion. The sister shared the same human leucocyte antigen haplotypes and was homozygous for the HFE mutation C282Y, like the propositus. However, she had normal liver iron content and increased liver copper content. Her dietary copper intake was probably excessive. The association of Wilson's disease and genetic haemochromatosis is rare and has only been described twice. The onset of Wilson's disease after 50 years of age is rare; Wilson's disease should be considered in any patient with unexplained chronic liver disease; an excess in liver copper content might be induced by excessive dietary input in a susceptible individual.

Prognostic Factors and Survival in Patients with Hereditary Hemochromatosis and Cirrhosis

The survival of treated, noncirrhotic patients with hereditary hemochromatosis is similar to that of the general population. Less is known about the outcome of cirrhotic hereditary hemochromatosis patients. The present study evaluated the survival of patients with hereditary hemochromatosis and cirrhosis. From an established hereditary hemochromatosis database, all cirrhotic patients diagnosed from January 1972 to August 2004 were identified. Factors associated with survival were determined using univariate and multivariate regression. Survival differences were assessed using the Kaplan-Meier life table method. Ninety-five patients were identified. Sixty patients had genetic testing, 52 patients (87%) were C282Y homozygotes. Median follow-up was 9.2 years (range 0 to 30 years). Nineteen patients (20%) developed hepatocellular carcinoma, one of whom was still living following transplantation. Cumulative survival for all patients was 88% at one year, 69% at five years and 56% at 20 years. Factors associated with death on multivariate analysis included advanced Child-Pugh score and hepatocellular carcinoma. Patients with hepatocellular carcinoma were older at the time of diagnosis of cirrhosis (mean age 61 and 54.6 years, respectively; P=0.03). The mean age at the time of diagnosis of hepatocellular carcinoma was 70 years (range 48 to 79 years). No other differences were found between the groups. Patients with hereditary hemochromatosis and cirrhosis are at significant risk of developing hepatocellular carcinoma. These patients are older when diagnosed with carcinoma and may have poorer survival following transplantation than patients with other causes of liver disease. Early diagnosis and treatment of hereditary hemochromatosis by preventing the development of cirrhosis may reduce the incidence of hepatocellular carcinoma in the future.

Successful pregnancy outcome following maternal intravenous immunoglobulin treatment in a woman with recurrent perinatal haemochromatosis

We report a case of successful pregnancy outcome following maternal intravenous immunoglobulin treatment in a woman with previous history of recurrent fetal hydrops secondary to perinatal haemochromatosis. A 32-year old woman had two successive pregnancies complicated by fetal hydrops and perinatal deaths. Pathological examination of the fetus showed severe liver destruction with siderosis of hepatocytes at extrahepatic sites, but sparing of the reticulo-endothelial elements, consistent with the diagnosis of perinatal haemochromatosis. In the subsequent pregnancy, maternal intravenous immunoglobulin was administered weekly from the 18th week of gestation until delivery by elective caesarean section at 38 weeks. The infant was treated with desferrioxamine, N-acetylcysteine, vitamins K and E. The infant was born in good health, but had high serum ferritin levels, markedly elevated percent transferrin saturation, and mild transient derangement of liver and coagulation function. The infant made an excellent recovery and the treatment was stopped at 7 weeks of age. The liver and coagulation parameters and the serum ferritin levels returned to normal values. Haemochromatosis should be considered in the differential diagnosis of hydrops fetalis. The recurrence risk is high, and immunomodulation with intravenous immunoglobulin treatment appears to alter the course of the disease with better infant survival.

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

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

Initial Screening Transferrin Saturation Values, Serum Ferritin Concentrations, and HFE Genotypes in Native Americans and Whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

There are few reports of transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes in native Americans. We compared initial screening data of 645 native American and 43,453 white HEIRS Study participants who reported a single race/ethnicity and who did not report a previous diagnosis of hemochromatosis or iron overload. Each underwent TfSat and SF measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat >50% (men), >45% (women); and SF >300 ng/mL (men), >200 ng/mL (women). Mean TfSat was lower in native American men than in white men (31% vs. 32%, respectively; p = 0.0337), and lower in native American women than in white women (25% vs. 27%, respectively; p <0.0001). Mean SF was similar in native American and white men (153 μg/L vs. 151 μg/L; p = 0.8256); mean SF was lower in native American women than in white women (55 μg/L vs. 63 μg/L, respectively; p = 0.0015). The respective percentages of native American men and women with elevated TfSat or elevated SF were similar to those of white men and women. The respective mean TfSat and SF values of native American and white participants with genotype HFE wt/wt were similar. The C282Y allele frequency was 0.0340 in native Americans and 0.0683 in whites (p <0.0001). The H63D allele frequency was 0.1150 in native Americans and 0.1532 in whites (p = 0.0001). We conclude that the screening TfSat and SF phenotypes of native Americans do not differ greatly from those of whites. The respective allele frequencies of HFE C282Y and H63D are significantly lower in native Americans than in whites.

Screening for Hereditary Hemochromatosis: A Clinical Practice Guideline from the American College of Physicians

Hereditary hemochromatosis is a genetic disorder of iron metabolism. Diagnosis of hereditary hemochromatosis is usually based on a combination of various genetic or phenotypic criteria. Decisions regarding screening are difficult because of the variable penetrance of mutations of the HFE gene and the absence of any definitive trials addressing the benefits and risks of therapeutic phlebotomy in asymptomatic patients or those with only laboratory abnormalities. The purpose of this guideline is to increase physician awareness of hereditary hemochromatosis, particularly the variable penetrance of genetic mutations; aid in case finding; and explain the role of genetic testing. This guideline provides recommendations based on a review of evidence in the accompanying background paper by Schmitt and colleagues. The target audience for this guideline is internists and other primary care physicians. The target patient population is all persons who have a probability or susceptibility of developing hereditary hemochromatosis, including the relatives of individuals who already have the disease.

Reversible cardiomyopathy in a patient with juvenile hemochromatosis

Cardiac involvement in juvenile hemochromatosis is a very rare cause of heart failure in young patients associated with a serious prognosis [1,2]. We herein report normalization of severely impaired left ventricular systolic function following iron chelating therapy in a patient with juvenile hemochromatosis. In September 2001, a 25-year-old man was referred because of infertility that was found to be due to hypogonadotropic hypogonadism. Markedly elevated levels of plasma ferritin (3800 Ag/l; normal <400 Ag/l) and a transferrin saturation index of 106% (normal <50%) led to the diagnosis of hemochromatosis. Regarding the patient’s young age, the negative family history, and negative genetic testing for typical mutations seen in inherited hemochromatosis, the disease was classified as juvenile hemochromatosis. Therapy with repeated phlebotomies was started. In May 2002, the patient was admitted in cardiogenic shock. Transthoracic echocardiography showed a hyperechogenic myocardium and dilatation of all heart chambers, the systolic left ventricular function being severely impaired (left ventricular ejection fraction 20%; Fig. 1). Heart failure medication including angiotensin-converting-enzyme inhibitor, loop diuretic, and betablocker was started, iron chelation treatment with desferrioxamine was introduced, and phlebotomies were continued. After a two-week hospital stay the patient was discharged, and thereafter his condition improved continuously. In January 2003, when he presented to the outpatient clinic, transthoracic echocardiography showed dramatic improvement of systolic left ventricular function (left

Comparison of the Unsaturated Iron-Binding Capacity with Transferrin Saturation as a Screening Test to Detect C282Y Homozygotes for Hemochromatosis in 101 168 Participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

The diagnosis of hemochromatosis was previously based on a combination of clinical and laboratory assessments that included history and physical examination, increased transferrin saturation (TS) and serum ferritin, liver biopsy, the amount of iron removed by phlebotomy, and pedigree studies identifying other family members with iron overload (1). Since the discovery of the hemochromatosis gene (HFE) in 1996 (2), most studies from referral centers have shown that >90% of typical hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene (3). Before the availability of DNA-based testing, it was assumed that most hemochromatosis patients have increased TS. However, recent population screening studies incorporating HFE genotyping have now shown that many C282Y homozygotes will have a normal TS and may never develop clinical signs and symptoms related to iron overload (4)(5)(6)(7)(8). TS has been recommended in many studies as the most clinically useful screening test for hemochromatosis because it is widely available and may be increased even in young adults with a genetic predisposition to hemochromatosis. Another potential advantage over DNA-based testing as an initial screening test is that TS may detect many types of iron overload other than those associated with HFE mutations. In addition, screening for iron overload instead of performing DNA-based testing may reduce the risks of potential genetic discrimination that some authors suggest is associated with identification of a C282Y homozygote with normal serum iron tests (9)(10)(11). The TS is a 2-step assay in which serum iron is the numerator and the denominator is either total iron-binding capacity (TIBC), [serum iron + unsaturated iron-bonding capacity (UIBC)] or an adjusted serum transferrin. The UIBC is a 1-step automated colorimetric assay that has been reported to have similar or better operating characteristics than TS for …

Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study.

BackgroundAlthough most patients with hereditary haemochromatosis have HFE C282Y mutations, the lifetime risk to HFE C282Y homozygotes of developing fatal diseases such as hepatocellular carcinoma is uncertain. We have carried out a cross-sectional study to determine the proportion of diagnosed hepatocellular carcinoma patients who are homozygous for the HFE C282Y mutation; and to estimate the penetrance of this genotype with respect to hepatocellular carcinoma in East Anglia.MethodsTissue biopsies were analysed from 144 cases of hepatocellular carcinoma for HFE C282Y mutations; the data produced were compared with the frequency of HFE mutations in a large sample of the local population. Data were also retrieved from the East Anglian Cancer Intelligence Unit to determine the annual incidence of hepatocellular carcinoma; and from appropriate life tables.ResultsEight out of 144 of the cases were homozygous for the HFE C282Y mutation, all 8 cases were male. 6 of these 8 cases had a previous diagnosis of hereditary haemochromatosis. Male HFE C282Y homozygotes were more likely to be diagnosed with hepatocellular carcinoma (odds ratio [OR] = 14, 95% confidence interval [CI] = 5–37). For this population, we estimate that the penetrance of the HFE C282Y homozygous genotype, with respect to hepatocellular carcinoma, was between 1.31 % and 2.1% for males and was zero for females.ConclusionIn this population, we found that only a very small proportion of homozygotes for the HFE C282Y mutation developed hepatocellular carcinoma. However, individuals with this genotype have a significantly increased risk of this rare disease relative to those who do not carry the mutations.