Iron, hemochromatosis genotypes, and risk of infections: a cohort study of 142 188 general population individuals.

ABSTRACT: It is unclear whether risk of infection is increased in individuals with hereditary hemochromatosis and in individuals with low or high plasma iron, transferrin saturation, or ferritin. Therefore, we tested whether high and low iron, transferrin saturation, and ferritin are associated with risk of infections observationally and genetically through HFE genotypes. We studied 142 188 Danish general population individuals. Iron, transferrin saturation, and ferritin were measured in 136 656, 136 599, and 38 020 individuals, respectively. HFE was genotyped for C282Y and H63D in 132 542 individuals. Median follow-up after study enrollment was 8 years (range, 0-38) for hospital and emergency room admissions with infections (n = 20 394) using the National Patient Register, covering all Danish hospitals. Hazard ratios for any infection were 1.20 (95% confidence interval [CI], 1.12-1.28) and 1.14 (95% CI, 1.07-1.22) in individuals with plasma iron ≤5th or ≥95th percentile compared with individuals with iron from 26th to 74th percentiles. Findings for transferrin saturation were similar, whereas infection risk was not increased in individuals with ferritin ≤5th or ≥95th percentile. Hazard ratios in C282Y homozygotes vs noncarriers were 1.40 (95% CI, 1.16-1.68) for any infection, 1.69 (95% CI, 1.05-2.73) for sepsis, and 2.34 (95% CI, 1.41-3.90) for death from infectious disease. Risk of infection was increased in C282Y homozygotes with normal plasma iron, transferrin saturation, or ferritin, and in C282Y homozygotes without liver disease, diabetes, and/or heart failure. In summary, low and high plasma iron and transferrin saturation were independently associated with increased infection risk. C282Y homozygotes had increased risk of any infection, sepsis, and death from infections. Even C282Y homozygotes with normal iron, transferrin saturation, or ferritin, not currently recommended for genotyping, had increased infection risk.

Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Exploring the Association between Hemochromatosis and Lower-Limb Venous Disease.

OBJECTIVE: Chronic venous disease is a circulatory system dysfunction that has the potential to lead to venous leg ulceration. Although research on the influence of specific gene variants on chronic venous disease has been limited, a few studies have reported an association between hemochromatosis and chronic venous disease. However, no studies have looked at the prevalence of lower-limb venous disease and leg ulcers in people with hemochromatosis. This study aimed to review the existing literature for any association between venous disease and hemochromatosis and investigate the prevalence of venous disease and leg ulcers in people with hemochromatosis. METHODS: Scoping systematic literature review and cross-sectional study surveying people with hemochromatosis. RESULTS: This scoping systematic literature review included nine articles and indicated a link between hemochromatosis and venous disease/leg ulcers, although further studies are needed to support this link. Analysis of survey results from people with hemochromatosis found a 9.2% prevalence of leg ulcers in those with self-reported hemochromatosis, considerably higher than the 1% to 3% expected, suggesting that hemochromatosis gene variants may be associated with the pathogenesis of chronic venous disease and leg ulcers. CONCLUSIONS: This is the first known study to complete a review of the literature regarding hemochromatosis and venous leg ulcers and document the association between hemochromatosis and venous disease/leg ulcers. There is a lack of research in this area and hence limited evidence to guide practice.

Is iron overload associated with worse outcomes in patients with chronic liver disease undergoing liver transplantation?

Background: Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. Methods: We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Results: Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Conclusion: Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.

Non-alcoholic fatty liver disease in hemochromatosis probands with iron overload and HFE p.C282Y/p.C282Y.

BACKGROUND: The aim of this study was to identify characteristics of non-alcoholic fatty liver disease (NAFLD) in adults with HFE p.C282Y/p.C282Y. METHODS: We retrospectively studied non-Hispanic white hemochromatosis probands with iron overload (serum ferritin (SF) > 300 µg/L (M), > 200 µg/L (F)) and p.C282Y/p.C282Y at non-screening diagnosis who did not report alcohol consumption > 14 g/d, have cirrhosis or other non-NAFLD liver disorders, use steatogenic medication, or have diagnoses of heritable disorders that increase NAFLD risk. We identified NAFLD-associated characteristics using univariate and multivariable analyses. RESULTS: There were 66 probands (31 men, 35 women), mean age 49 ± 14 (SD) y, of whom 16 (24.2%) had NAFLD. The following characteristics were higher in probands with NAFLD: median SF (1118 µg/L (range 259, 2663) vs. 567 µg/L (247, 2385); p = 0.0192); prevalence of elevated ALT/AST (alanine/aspartate aminotransferase) (43.8% vs. 10.0%; p = 0.0056); and prevalence of type 2 diabetes (T2DM) (31.3% vs. 10.0%; p = 0.0427). Mean age, sex, and prevalences of human leukocyte antigen-A*03 positivity, body mass index ≥ 30.0 kg/m2, hyperlipidemia, hypertension, and metabolic syndrome in probands with/without NAFLD did not differ significantly. Logistic regression on NAFLD using variables SF, elevated ALT/AST, and T2DM revealed: SF (p = 0.0318; odds ratio 1.0-1.0) and T2DM (p = 0.0342; 1.1-22.3). Median iron removed to achieve iron depletion (QFe) in probands with/without NAFLD did not differ significantly (3.6 g (1.4-7.2 g) vs. 2.8 g (0.7-11.0 g), respectively; p = 0.6862). CONCLUSIONS: NAFLD in hemochromatosis probands with p.C282Y/p.C282Y is associated with higher median SF and greater T2DM prevalence, after adjustment for other factors. NAFLD does not influence QFe significantly.

Risk of Hepatocellular Carcinoma in Patients with Various HFE Genotypes.

BACKGROUND AND AIMS: Hereditary hemochromatosis (HH) is associated with increased risk of hepatocellular carcinoma (HCC). However, HCC risk factors within this population and across various HFE genotypes remain unclear. METHODS: We conducted a retrospective cohort study of patients with ≥ 1 HFE genotype test in the Veterans Health Administration. We followed patients until HCC, death, or 6/30/19. We calculated incidence rates (IRs) and used Cox proportional hazards models to estimate HCC risk. In patients with type-1 HH genotypes (C282Y/C282Y or C282Y/H63D), we examined risk factors for HCC. RESULTS: We identified 5225 patients: 260 were C282Y/C282Y; 227 were C282Y/H63D; 436 were H63D heterozygous; 535 had other HFE mutations; 3767 without mutation. IR for C282Y/C282Y homozygotes (5.59/1000 PYs) and C282Y/H63D compound heterozygotes (4.12/1000 PYs) were significantly higher than controls (0.92/1000 PYs) with adjusted hazard ratio (adj HR), 95% CI 8.80, 4.17-18.54; and 5.25, 2.24-12.32, respectively. HCC risk was higher in H63D heterozygote than controls (adj HR = 2.82, 95% CI 1.21-6.58); cases were related to non-alcoholic fatty liver disease. Among patients with HH, age ≥ 65 (adj HR = 2.2, 95% CI 0.47-10.27), diabetes (adj HR 3.74, 95% CI 1.25-11.20) and high baseline aspartate-aminotransferase to platelet ratio-index (APRI, adj HR = 3.91, 95% CI 1.29-11.89) had higher risk. Among patients with high baseline ferritin, persistent ferritin > 250 ng/mL had higher risk. CONCLUSION: HCC risk was high in C282Y homozygous and C282Y/H63D patients. These HFE genotypes, older age, diabetes, high APRI/ferritin levels were associated with increased risk. While H63D heterozygous genotype was associated with HCC risk, this association might be due to metabolic factors.

Factors associated with serum ferritin levels and iron excess: results from the EPIC-EurGast study.

PURPOSE: Excess iron is involved in the development of non-communicable diseases such as cancer, type 2 diabetes and cardiovascular conditions. We aimed to describe the prevalence of excess iron and its determinants in healthy European adults. METHODS: Sociodemographic, lifestyle, iron status, dietary information, and HFE genotyping were obtained from controls from the nested case-control study EPIC-EurGast study. High sensitivity C-reactive protein (hsCRP) was measured to address possible systemic inflammation. Descriptive and multivariate analyses were used to assess iron status and its determinants. RESULTS: Out of the 828 participants (median age: 58.7 years), 43% were females. Median serum ferritin and prevalence of excess iron were 143.7 µg/L and 35.2% in males, respectively, and 77 µg/L and 20% in females, both increasing with latitude across Europe. Prevalence of HFE C282Y mutation was significantly higher in Northern and Central Europe (~ 11%) than in the South (5%). Overweight/obesity, age, and daily alcohol and heme iron intake were independent determinants for iron status, with sex differences even after excluding participants with hsCRP > 5 mg/L. Obese males showed a greater consumption of alcohol, total and red meat, and heme iron, compared with those normal weight. CONCLUSION: Obesity, higher alcohol and heme iron consumption were the main risk factors for excess iron in males while only age was associated with iron overload in females. Weight control and promoting healthy lifestyle may help prevent iron overload, especially in obese people. Further research is needed to clarify determinants of excess iron in the healthy adult population, helping to reduce the associated comorbidities.

A RETROSPECTIVE STUDY OF HEPATIC HEMOSIDEROSIS AND IRON STORAGE DISEASE IN SEVERAL CAPTIVE AND FREE-RANGING AVIAN SPECIES.

Some wild species of mammals and birds are prone to excessive iron accumulation, especially when maintained in human care. Hemosiderosis is the process of intracellular accumulation of iron without evidence of toxicity, whereas hemochromatosis is characterized by severe iron accumulation with accompanying organ damage. Iron storage disease (ISD) occurs when organ damage is severe and causing clinical signs. This retrospective study investigated the occurrence of hemosiderosis and ISD across a variety of avian taxa, including captive and free-ranging birds. Archived paraffin-embedded hepatic samples from 103 birds from Belo Horizonte Zoo that died naturally in the period of 2008 to 2018 were re-evaluated with histologic and morphometric techniques, focusing on the identification and scoring of iron deposits in hepatocytes and the quantification of total affected hepatic area. The birds represented 13 orders, 22 families, and 52 genera, and 66 (64.0%) had some degree of iron accumulation in their liver. Importantly, no statistical difference was observed in the occurrence of iron accumulation between families, orders, or origin (free-ranging or captive). Direct and positive correlation was observed between the total area affected by the iron deposits and the histologic score. In this study, there were two cases with severe iron accumulation and clinical signs compatible with ISD: a barefaced curassow (Crax fasciolata) and a channel-billed toucan (Ramphastos vitellinus). This study indicates that iron accumulation may occur in a wide range of avian species, with frequencies and intensities that are similar between free-ranging birds and those in human care. It describes for the first time the occurrence of ISD in a Galliform species.

Non-invasive alloimmune risk stratification of long-term liver transplant recipients.

BACKGROUND & AIMS: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. METHODS: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). RESULTS: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. CONCLUSION: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. LAY SUMMARY: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.

Hereditary Hemochromatosis: Rapid Evidence Review.

Hereditary hemochromatosis is an autosomal recessive disorder that disrupts iron homeostasis, resulting in systemic iron overload. It is the most common inherited disorder among people of northern European ancestry. Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance. The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease. The liver, pancreas, joints, heart, skin, and pituitary gland are the most commonly involved organs. Hereditary hemochromatosis is usually diagnosed in the 40s or 50s. Women are often diagnosed later than men, likely because of menstrual blood loss. There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis. Because of increased awareness and earlier diagnosis, the end-organ damage secondary to iron overload is not often seen in clinical practice. A common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation. Ferritin levels greater than 300 ng per mL for men and 200 ng per mL for women and transferrin saturations greater than 45% are highly suggestive of hereditary hemochromatosis. Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications. Liver transplantation may be considered in select patients. Individuals with hereditary hemochromatosis have an increased risk of hepatocellular carcinoma and colorectal and breast cancers. Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition.

Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE.

BACKGROUND & AIMS: Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment. METHODS: We performed a retrospective analysis of data from 106 patients in France or Australia who were homozygous for the C282Y mutation in HFE with F3 fibrosis (n = 40) or F4 fibrosis (n = 66) at diagnosis and from whom at least 1 liver biopsy was collected during follow up. We collected data from the time of first biopsy and during follow-up period on patient demographics, treatment, smoking habits, alcohol consumption, infection with hepatitis B or C viruses, and other diseases. The median time between first and last liver biopsy was 9.5 years (range, 3.5-15.6 years). We collected results of tests for liver function, markers of iron stores, and platelet levels. Patients were followed for a median 17.6 years (range, 9.8-24.1 years) for development of liver cancer occurrence. RESULTS: At last liver biopsy, 41 patients (38.6%) had fibrosis scores of F2 or less. Liver cancer occurred in 34 patients (52.3%) with F3 or F4 fibrosis at last liver biopsy vs 2 patients (4.8%) with fibrosis scores of F2 or less at last liver biopsy (P < .001). Liver cancer incidences were 32.8 per 1000 person-years (95% CI, 22.7-45.9 per 1000 person-years) in patients with F3 or F4 fibrosis and 2.3 per 1000 person-years (95% CI, 0.2-8.6 per 1000 person-years) in patients with fibrosis scores of F2 or less (P < .001). In multivariate analysis, male sex (hazard ratio [HR], 6.09; 95% CI, 1.21-30.4), age at diagnosis (HR, 1.16; 95% CI, 1.09-1.25), presence of diabetes (HR, 3.07; 95% CI, 1.35-6.97), excess alcohol consumption (HR, 3.1; 95% CI, 1.47-6.35), serum level of ferritin at diagnosis (P < .01), and regression to fibrosis scores of F2 or less (HR, 0.08; 95% CI, 0.01-0.62) were significantly associated with risk of liver cancer. CONCLUSIONS: In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, we found that severe liver fibrosis can regress with treatment. In patients with fibrosis regression to a stage F2 or less, the long-term risk for liver cancer is significantly reduced.

Contemporary Total Hip and Total Knee Arthroplasty Results in Patients with Hemochromatosis.

BACKGROUND: Hemochromatosis can result in metabolic bone pathology (due to excessive iron absorption) and degenerative joint disease, leading to total joint arthroplasties. The aim of this study is to analyze the survivorship, complications, radiographic results, and clinical outcomes of patients with hemochromatosis who received either a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). METHODS: We identified 34 lower extremity arthroplasties in 29 patients with hemochromatosis performed between 2000 and 2016. There were 17 primary THAs in 15 patients and 17 primary TKAs in 14 patients. Mean age at arthroplasty was 63 years with 76% being male. The mean body mass index was 28 kg/m2. Mean follow-up was 5 years. RESULTS: The survivorship free from any revision for THAs was 94% at 10 years. One patient was revised for aseptic loosening of the femoral stem at 6 months. In THA patients, no infections, no other complications, and no radiographic evidence of aseptic loosening were identified. Harris Hip Scores improved from a mean of 55 preoperatively to 94 postoperatively (P < .001). The survivorship free from any revision for TKAs was 100% at 10 years. Two patients (12%) developed acquired idiopathic stiffness postoperatively; no infections were identified. There was no radiographic evidence of aseptic loosening in any TKA. Knee Society Scores improved from a mean of 61 preoperatively to 94 postoperatively (P < .001). CONCLUSION: This study found excellent survivorship, significant improvements in clinical outcomes, and a very low complication profile for both THA and TKA in patients with hemochromatosis.

PATHOLOGIC FINDINGS IN 36 SLOTHS FROM BRAZIL.

Sloths are xenarthrans from Central and South America with a highly adapted morphophysiology. Five of the six known species of sloths are found in Brazil, among which Bradypus torquatus (maned three-toed sloth) is considered a vulnerable species by International Union for Conservation of Nature. Nevertheless, knowledge on health and disease of sloths is very scarce, thus this study aimed to describe macroscopic and microscopic findings in 36 Brazilian sloths. The most common findings included iron storage disorder, probable bacterial pneumonia, gastric and intestinal nematode parasitism, and a presumptive diagnosis of systemic mastocytosis.

Prevalence and characteristics of anti-HCV positivity and chronic hepatitis C virus infection in HFE p.C282Y homozygotes.

INTRODUCTION AND AIM: Observations of hepatitis C virus (HCV) infection in adults with hemochromatosis are limited. MATERIALS AND METHODS: We determined associations of serum ferritin (SF) with anti-HCV in non-Hispanic white North American adults in a post-screening examination. Cases included p.C282Y homozygotes (regardless of screening transferrin saturation (TS) and SF) and participants (regardless of HFE genotype) with high screening TS/SF. Controls included participants without p.C282Y or p.H63D who had normal screening TS/SF. Participants with elevated alanine aminotransferase underwent anti-HCV testing. We determined prevalence of chronic HCV infection in consecutive Alabama and Ontario referred adults with HFE p.C282Y homozygosity. RESULTS: In post-screening participants, anti-HCV prevalence was 0.3% [95% CI: 0.02, 2.2] in 294 p.C282Y homozygotes, 9.5% [7.2, 12.3] in 560 Cases without p.C282Y homozygosity, and 0.7% [0.2, 2.3] in 403 Controls. Anti-HCV was detected in 7.2% of 745 participants with and 0.8% of 512 participants without elevated SF (odds ratio 9.9 [3.6, 27.6]; p<0.0001). Chronic HCV infection prevalence in 961 referred patients was 1.0% (10/961) [95% confidence interval (CI): 0.5, 2.0]. Ten patients with chronic HCV infection had median age 45y (range 29-67) and median SF 1163µg/L (range 303-2001). Five of eight (62.5%) patients had biopsy-proven cirrhosis. CONCLUSIONS: Odds ratio of anti-HCV was increased in post-screening participants with elevated SF. Prevalence of anti-HCV in post-screening participants with HFE p.C282Y homozygosity and chronic HCV infection in referred adults with HFE p.C282Y homozygosity in North America is similar to that of Control participants with HFE wt/wt and normal screening TS/SF.

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

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

Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes.

Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.

Gender differences in liver disease and the drug-dose gender gap.

Although gender-based medicine is a relatively recent concept, it is now emerging as an important field of research, supported by the finding that many diseases manifest differently in men and women and therefore, might require a different treatment. Sex-related differences regarding the epidemiology, progression and treatment strategies of certain liver diseases have long been known, but most of the epidemiological and clinical trials still report results only about one sex, with consequent different rate of response and adverse reactions to treatment between men and women in clinical practice. This review reports the data found in the literature concerning the gender-related differences for the most representative hepatic diseases.

Haemochromatosis: unexplained metacarpophalangeal or ankle arthropathy should prompt diagnostic tests: findings from two UK observational cohort studies.

OBJECTIVES: To examine demographic and clinical features leading to the diagnosis of hereditary haemochromatosis and assess factors that might enhance earlier diagnosis, with particular attention to arthritic symptoms. METHOD: Diagnostic features were captured directly from patients with haemochromatosis attending a specialist rheumatology clinic (group 1) and from analysis of a specifically designed questionnaire circulated to members of the UK Haemochromatosis Society (group 2). RESULTS: In groups 1 (n = 62) and 2 (n = 470), respectively, the diagnosis of haemochromatosis was made at a mean age of 52.8 and 56.4 years with 77% and 76% reporting joint symptoms with a mean duration of 8.3 and 8.1 years. The first joints to be affected in group 1 were the metacarpophalangeal (MCP; 38.5%) and ankle (29.5%) followed by the knee, hip, and proximal interphalangeal (PIP) joints. At the time of clinical assessment or questionnaire completion, the most prevalent regions with arthropathy in group 1 were PIP (64.5%), knee (64%), ankle (61%), and MCP (60%) and in group 2 the most prevalent joint regions self-reported were the first carpometacarpal (CMC; 59%), wrist (52%), PIP (47%), MCP (46%), knee (42%), and ankle (35%). CONCLUSIONS: Data from both cohorts confirm the high prevalence of joint symptoms in haemochromatosis predating the diagnosis by many years. Discriminatory features of the arthropathy include the involvement of MCP joints and ankles at a relatively young age in the absence of trauma, all of which are unusual features of primary osteoarthritis (OA). The finding of this presentation should prompt diagnostic tests for haemochromatosis.