Haemochromatosis: a clinical update for the practising physician

Abstract

Haemochromatosis is most commonly due to the autosomal recessive inheritance of a C282Y substitution in the HFE protein, whereby both alleles of the corresponding gene are affected. The disease is characterised by an inappropriate increase in intestinal iron absorption due to reduced expression of the iron regulatory protein, hepcidin. Progressive iron deposition in parenchymal tissues may ultimately lead to liver and other organ toxicity. The characteristic biochemical abnormalities are raised serum ferritin and transferrin saturation, which can be used in conjunction with genetic tests and emerging magnetic resonance imaging-based techniques to diagnose patients with the disorder. Progressive iron overload can manifest clinically as advanced fibrosis, cirrhosis and hepatocellular carcinoma. Enigmatically, the penetrance of both raised iron indices and clinically significant disease is incomplete in patients with hereditary haemochromatosis. Regardless, advanced clinical presentations of the disease have become less common due to increased awareness and earlier diagnosis. On the other hand, obesity and alcohol have been identified as major risk factors that can compound the risk of liver injury in people with hereditary (HFE) haemochromatosis. The prospect of modifying genes that may contribute to the clinical expression of the disease is the subject of ongoing research. Treatment with phlebotomy remains the first-line therapy, and if instigated early leads to a normal life expectancy. A healthy, well-balanced diet is recommended to be incorporated as part of the ongoing management of the disease.

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

“…Of these, two were significantly associated with increased cirrhosis prevalence ( P < .05) in MGI: rs738408‐T ( PNPLA3 exon) and rs80215559‐C ( SLC17A2 intron) (Table ). Of note, rs80215559 is in complete linkage with rs1800562 ( r 2 = 1.0 in CEU/GBR), which is also associated with cirrhosis at genome‐wide significance levels ( P = 3.3 × 10 −8 ) and corresponds to the HFE C282Y mutation, the primary cause of hereditary hemochromatosis . Conditional analysis of the effect of rs80215559 on cirrhosis conditional on rs1800562 eliminated its association with cirrhosis (odds ratio 1.61 [95% CI 1.33‐1.84] to 1.00 [95% CI 1.00‐1.00]), suggesting that its effect is because of the HFE C282Y mutation.…”

“…Stage 3 analysis included replicating SNPs as well as SNPs that have been previously reported to associate with cirrhosis in subpopulations, as described in the introduction (Table ) . As above, we included only SNPs with minor allele count >6 in the European populations of UKBB and MGI, which corresponded to minor allele frequency >0.006.…”

“…In hepatitis C virus‐infected patients, rs910049 (in the major histocompatibility complex region) and single nucleotide polymorphisms (SNPs) in MERTK and TULP1 associated with liver fibrosis progression, as does a SNP near PCSK7 in individuals with hereditary hemochromatosis . Finally, two monogenic liver diseases are caused by relatively common variants: hereditary hemochromatosis, which in 80%‐90% of cases is caused by rs1800562‐A ( HFE C282Y), and alpha‐1 antitrypsin deficiency, which is caused by mutations in SERPINA1 , the most common severely deleterious of which is rs28929474‐T (E342K) . However, penetrance is incomplete for all these variants, including those in HFE and SERPINA1 , and whether these variants lead to cirrhosis in the general population remains uncertain.…”

Liver R2* is affected by both iron and fat: A dual biopsy‐validated study of chronic liver disease

“…Excess iron catalyzes the Haber–Weiss reaction leading to reactive oxygen species that are associated with inflammation and fibrosis . Symptoms of iron overload are generally mild and nonspecific and develop gradually . It is therefore important to identify iron overload before organ damage occurs.…”

“…nonspecific and develop gradually. 3,4 It is therefore important to identify iron overload before organ damage occurs.…”