HEREDITARY HAEMOCHROMATOSIS

1. HEREDITARYHAEMOCHROMATOSIS

2. What Is It? • An inherited disease characterised by excess iron deposition in various organs • Leads to eventual fibrosis and functional organ failure

3. Prevalence and Aetiology • Transmitted by an autosomal recessive gene • Caucasian heterozygote ~ 1/10 • Caucasian homozygote ~ 1/400 (ie1/20 x 1/20) • Most common form has been shown to be due to a missense mutation in the HFE gene on the short arm of chromosome 6

4. Mechanism of Damage • Still somewhat unclear but… • There is failure of expression of HFE on the basolateral surface of the crypt cell  the duodenal crypts are unable to incorporate iron from plasma transferrin and are therefore rendered iron deficient  increased expression of DMT-1 protein  increased intestinal iron absorption in relation to body iron stores

5. Mechanism of Damage • Inappropriate iron uptake by the mucosal cells exceeds the capacity of transferrin; excess iron is then taken up by the liver and other tissues • Excessive iron deposition in the tissues can cause serious damage to organs, particularly the heart, liver and endocrine organs

6. Pathogenesis • In symptomatic people the total iron body content is 20-40g compared with 3-4g in a normal person. • Particularly increased in the liver and pancreas (50-100x normal) • In established disease the liver shows extensive iron deposition and fibrosis. Early in the disease, the iron is deposited in the periportal hepatocytes but later it is distributed widely throughout all zones. Cirrhosis is a late feature.

7. Clinical Features • Depends on a number of factors – including sex, diet, presence of associated hepatotoxins (especially alcohol) and genotype • Overt clinical manifestations occur more frequently in men • Most affected individuals present in the 5th decade • Symptoms include weakness/fatigue, arthritis, palpitations, abdo pain and those of diabetes • Classical triad: bronze skin pigmentation (due to excess melanin deposition), hepatomegaly and diabetes mellitus

8. Clinical Features • Hypogonadism secondary to pituitary dysfunction is the most common endocrine feature • Cardiac manifestations, particularly heart failure and arrythmias are common, particularly in young patients • Calcium pyrophosphate is deposited asymmetrically in both large and small joints (chondrocalcinosis) arthopathy

9. Complications • 30% of people with cirrhosis will go on to develop HCC • Diagnosis in the pre-cirrhotic stage  normal life expectancy • Diagnosis once cirrhosis has developed  shortened life expectancy and a high risk of liver cancer, even when iron depletion has been achieved • Various complications of other manifestations eg of diabetes

10. Investigations • Homozygotes: Serum iron elevated TIBC reduced Complete or almost complete transferrin saturation - serum iron/ TIBC x 100. A value greater than 55% (men) or 50% (women) suggests iron accumulation Serum ferritin elevated (usually >500μg/L) Liver biochemistry is often normal, even with established cirrhosis

11. Investigations • Heterozygotes: May have normal biochemistry or may have modest increases in serum iron transferrin saturation or serum ferritin (usually >400μg/L) • Liver biopsy may define the extent of tissue damage, assess tissue iron and the hepatic iron concentration can be measured - >180μmol/g dry weight of liver indicates liver haemochromatosis

12. Investigations • MRI shows dramatic reduction in the signal intensity of the liver and pancreas (paramagnetic effect of ferritin and haemosiderin). In secondary iron overload involving the reticuloendothelial cells (haemosiderosis) the pancreas is spared – allows distinction between these two conditions. Can do quantitative MRI for liver iron.

13. Treatment and Management • Venesection • prolongs life • may reverse tissue damage • may initially need weekly (250-500ml) then only 3-4 per year to prevent re-accumulation of iron • each 500 mL of blood taken removes ~250 mg of iron (Hb). Synthesis of new Hb removes iron from the stores, which are then gradually depleted • monitor serum iron, ferritin and MCV – only fall when available iron is depleted

14. Treatment and Management • In the rare patient who cannot tolerate venesection (because of severe cardiac disease or anaemia) iron chelation therapy via desferrioxamine infusion has been successful in removing iron • Manifestations usually improve or disappear, except for diabetes (insulin requirements may diminish), testicular atrophy and chondrocalcinosis

16. Screening • In all cases of hereditary haemochromatosis, all first-degree family members must be screened to detect early and asymptomatic disease • Serum ferritin is an excellent test for this but genetic markers are also available. • In the general population, the serum iron and transferrin are the best and cheapest tests available

17. Genetic Screening • Confirmation of the diagnosis in cases of suspected iron overload. The genetic test will reduce costs and accelerate the diagnostic process so that effective treatment can be started earlier • Investigation of the families of patients with haemochromatosis if the proband is homozygous for HFE C282Y or is a compound heterozygote

19. Level of Screening? • Genetic screening at a population level cannot be justified at present because it is not yet possible to provide those at risk with a reliable estimate of the likelihood of developing clinical haemochromatosis • If heterozygotes for both C282Y and H63D are included, about 2% of the population would need to be offered regular testing to detect iron overload as well as counselling and family studies.

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