Clinical penetrance of C282Y homozygous HFE hemochromatosis

Following the discovery of the HFE gene, it became apparent that C282Y homozygous HFE hemochromatosis is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately 1 in 200. Cross-sectional studies have revealed that the clinical penetrance of symptoms of iron-loading disease is relatively low and highly variable. Although there is no standard definition of clinical penetrance, large studies of newly diagnosed C282Y homozygotes that have specifically assessed liver disease have obtained data showing that penetrance occurs in between 24 and 43% of males and 1 and 14% of females. This relatively low clinical penetrance is largely unexplained. Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of HFE hemochromatosis. Currently, the single most important environmental and genetic variables promoting penetrance are alcohol consumption and male gender, respectively. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis await identification.     

Phenotypic Expression of Hereditary Hemochromatosis: What Have We Learned from the Population Studies?

Profound advances in our knowledge of hereditary hemochromatosis (HH) during the past 150 years have resulted in two distinct “iron ages”: the pre-HFE gene era and the post-HFE gene era. During these periods, family studies, HLA association studies, and ultimately HFE gene studies in various populations informed us of the genotypic prevalence as well as the clinical and biochemical penetrance of HH. We learned that HH has a highly variable clinical penetrance in susceptible individuals of Northern European ancestry. Further, we now recognize that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH.     

Diagnosis and management of iron deficiency anaemia: a clinical update

Iron deficiency anaemia (IDA) remains prevalent in Australia and worldwide, especially among high-risk groups. IDA may be effectively diagnosed in most cases by full blood examination and serum ferritin level. Serum iron levels should not be used to diagnose iron deficiency. Although iron deficiency may be due to physiological demands in growing children, adolescents and pregnant women, the underlying cause(s) should be sought. Patients without a clear physiological explanation for iron deficiency (especially men and postmenopausal women) should be evaluated by gastroscopy/colonoscopy to exclude a source of gastrointestinal bleeding, particularly a malignant lesion. Patients with IDA should be assessed for coeliac disease. Oral iron therapy, in appropriate doses and for a sufficient duration, is an effective first-line strategy for most patients. In selected patients for whom intravenous (IV) iron therapy is indicated, current formulations can be safely administered in outpatient treatment centres and are relatively inexpensive. Red cell transfusion is inappropriate therapy for IDA unless an immediate increase in oxygen delivery is required, such as when the patient is experiencing end-organ compromise (eg, angina pectoris or cardiac failure), or IDA is complicated by serious, acute ongoing bleeding. Consensus methods for administration of available IV iron products are needed to improve the utilisation of these formulations in Australia and reduce inappropriate transfusion. New-generation IV products, supported by high-quality evidence of safety and efficacy, may facilitate rapid administration of higher doses of iron, and may make it easier to integrate IV iron replacement into routine care.     

Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rsI2979860 polymorphism of the IL28B gene

Objective

HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rsl2979860 C/T polymorphism in the IL28B gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection.

Methods

In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rsl2979860 genotypes were analysed in 84 HCV/H1V co-infected patients. IL28B genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rsl2979860 C/T genotypes over two years.

Results

82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of IL28B genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various IL28B-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047).

Conclusion

Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.     

Prevalence, characteristics, and prognostic significance of HFE gene mutations in type 2 diabetes: the Fremantle Diabetes Study

OBJECTIVE—To examine the relationship between iron status, hereditary hemochromatosis (HFE) gene mutations, and clinical features and outcomes of type 2 diabetes in a well-characterized representative sample of community-based patients.RESEARCH DESIGN AND METHODS—HFE genotype data were available for 1,245 type 2 diabetic patients from the longitudinal observational Fremantle Diabetes Study (FDS), representing 96.2% of the total FDS type 2 diabetes cohort. Data were collected at recruitment between 1993 and 1996 and annually until the end of June 2001. Hospitalization and mortality data were available until the end of June 2006. The presence of the C282Y HFE mutation was determined in all subjects and H63D in C282Y heterozygotes. Fasting serum iron, transferrin, and ferritin were measured in all C282Y homozygotes and C282Y/H63D heterozygotes and in 286 randomly selected wild-type subjects. Multiple logistic regression analysis was performed to determine independent baseline associates of prevalent complications (myocardial infarction, cerebrovascular disease, retinopathy, neuropathy, and nephropathy), as was Cox proportional hazards modeling to determine predictors of incident complications and mortality.RESULTS—Although there were expected positive associations between HFE gene mutations and serum iron and transferrin saturation, there were no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses. HFE gene status did not independently predict cardiac or all-cause mortality. Measures of iron metabolism including serum ferritin were not associated with combined microvascular or macrovascular end points.CONCLUSIONS—Directed screening for iron overload and/or HFE mutations appears unwarranted in patients with type 2 diabetes.Although early reports suggested that hemochromatosis protects against the chronic complications of diabetes (1), recent studies have identified adverse metabolic and vascular effects that could be associated with iron overload (2–11). Serum ferritin correlates positively with insulin resistance and glycated hemoglobin (2) and has been suggested to be an additional component of the metabolic syndrome (3). Hyperglycemia, and other effects of excess tissue iron including oxidant stress, angiogenesis, and fibrosis (4–6), could promote the development of complications such as nephropathy (7,8). The C282Y and H63D variants of the hemochromatosis (HFE) gene product are important determinants of iron storage. HFE-related hemochromatosis is considered to include C282Y homozygous and compound C282Y/H63D heterozygous genotypes (9). H63D and C282Y have been reported to be independent risk factors for diabetic nephropathy (10) and proliferative retinopathy (11), respectively.Because most published studies have been small-scale and cross-sectional, with a restricted number of potentially explanatory variables, there is a need for detailed large-scale longitudinal studies examining the relationship between iron metabolism, HFE mutations, and the clinical features and complications of diabetes (4). Such studies are essential before directed screening for iron overload can be recommended in diabetic patients (12). We have, therefore, analyzed data from the observational Fremantle Diabetes Study (FDS) to assess the effects of iron status and HFE mutations on the characteristics and outcome of type 2 diabetes.     

Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse

BACKGROUND/AIMS: In hereditary hemochromatosis, iron-loading of hepatocytes is associated with increased iron uptake while little is known about iron release. This study aims to characterise iron release and ferroportin expression by Hfe knockout hepatocytes to determine if they contribute to iron overload in haemochromatosis. METHODS: Iron release by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice was measured after incubation with nontransferrin-bound iron as iron-citrate. RESULTS: Iron release and ferroportin expression by hepatocytes from Hfe knockout, non-iron-loaded and in vivo iron-loaded wild-type mice were similar although, nontransferrin-bound iron uptake was significantly increased in Hfe knockout hepatocytes and decreased in iron-loaded wild-type hepatocytes compared with non-iron-loaded wild-type cells. When expressed as a percentage of total iron uptake, iron release was decreased in Hfe knockout hepatocytes (4.6+/-0.7 versus 13.7+/-1.2%, P<0.0001) and increased in iron-loaded wild-type hepatocytes (29.5+/-0.5 versus 13.5+/-0.7%; P<0.0001) compared with wild-type hepatocytes. In contrast, in vitro iron-loading increased iron release and ferroportin expression by both Hfe knockout and wild-type hepatocytes. CONCLUSIONS: Hfe knockout hepatocytes accumulate iron as a result of limited iron export and enhanced iron uptake. The correlation between iron release and ferroportin expression suggests that iron export in hepatocytes is mediated by ferroportin.