HFE mutations in α-1-antitrypsin deficiency: an examination of cirrhotic explants

Abstract

Increased iron deposition is often seen in liver explants with a-1-antitrypsin deficiency, but it remains unclear if this is a nonspecific effect of end-stage liver disease or if individuals with a-1-antitrypsin deficiency and excess iron are at increased risk for HFE mutations. To further examine this question, 45 liver explants with a-1-antitrypsin deficiency and 33 control livers with chronic hepatitis C were examined for histological iron accumulation, graded on a scale of 0 to 4 þ , and HFE mutations. Interestingly, the a-1-antitrypsin cirrhotic livers showed a bimodal distribution of iron accumulation, with peaks at grades 1 and 3. In contrast, hepatitis C cirrhotic livers showed a unimodal distribution with a peak at grade 2. HFE mutations in livers with a-1-antitrypsin deficiency were as follows: C282Y ¼ 2%, H63D ¼ 42%. H63D mutations were more frequent in a-1-antitrypsin deficiency cases than in controls (42 vs 27%), but was not statistically significant, P ¼ 0.17. However, there was a significant association with HFE mutations in a-1-antitrypsin deficiency livers with grade 3 þ or 4 þ iron, P ¼ 0.02. In contrast, livers with hepatitis C showed a similar frequency of HFE mutations as the general population: C282Y ¼ 15%, H63D ¼ 27%. A rare S65C mutation and a novel A271S mutation were also found in this study; the latter patient had 4 þ iron in the liver and later developed heart failure with cardiac iron. In conclusion, total H63D mutations were high (42%) in cirrhotics with a-1-antitrypsin deficiency and there was a significant association between HFE mutations and high levels of iron accumulation.

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

“…In fact, some previously published work already shown that HFE mutations could modify disease severity in cystic fibrosis [55] as it was already observed for 1ATD [46]. …”

“…Hepatocytes are the main site of synthesis of HFE and play a major role in the pathophysiology of Hemochromatosis [45]. HFE have two common alleles, C282Y and H63D [45], and while clinical hemochromatosis is mostly associated with C282Y homozygosity while the frequency of H63D alleles is higher in 1ATD patients versus in the general population (42 vs 27%) [46]. Further analysis showed that HFE variants were significantly associated with higher liver iron deposits in cases of 1ATD, but not hepatitis C-related cirrhosis.…”

Signal-intensity-ratio MRI accurately estimates hepatic iron load in hemodialysis patients

“…Validation of Scheuer’s classification by comparison with biochemical determination of liver iron content was, until recently, based mainly on a report published in the 1990s by Scheuer’s group in thalassemia major patients treated with the chelator desferrioxamine, but recent publications have also shown its validity in alcoholic liver disease and sickle cell disease [29, 30, 31]. It is also noteworthy that recent publications on the epidemiology of iron-overload diseases in African-American and cirrhotic explants of alpha1-antitrypsin deficiency used Perls’ histological grading as the mainstay of their research [32, 33]. …”

Cryptogenic Chronic Hepatitis and Its Changing Guise in Adults

“…The high frequency of the HFE mutations in the general population can complicate the interpretation of serum and hepatic iron perturbations in chronic liver diseases that have well-defined etiologies [81,149,[154][155][156]. Screening studies for C282Y disclosed its presence in 12% of patients with chronic hepatitis C and 4% of patients with cryptogenic cirrhosis [156].…”