Gastroenterology training and education

Explanation :HH is an autosomal recessive iron-overload disorder caused by pathophysiologic predisposition to increased and inappropriate absorption of dietary iron. It is associated with mutation of the HFE gene, located on chromosome 6. In most studies C282Y/C282Y homozygosity has been found in more than 90% of patients with haemochromatosis, while compound heterozygosity (C282Y/H63D) accounts for 3% to 5% of such cases in published series. Other unknown mutations account for the rest of the cases The penetrance of C282Y mutation is variable. In a large population study, full expression as defined by progressive tissue iron overload occurred in only 58 percent of these homozygotes.

Explanation :The iron deposition in HH primarily occurs in parenchymal cells, with reticuloendothelial (RE) cell accumulation occurring very late in the disease. This is in contrast to transfusional iron overload in which iron deposition occurs first in the RE cells and then in parenchymal cells. The second and third MCP joints are characteristically affected. HH can be associated with an arthropathy that displays the full spectrum of calcium pyrophosphate crystal deposition disease (i.e., pseudogout, chondrocalcinosis, and chronic arthropathy). Hypogonadism is due to excess iron deposition in pituitary cells, leading to reduced serum levels of a number of trophic hormones. Secondary hypogonadism causes decreased libido and impotence in men. Other pituitary deficiencies may occur, but are much less frequent. Primary hypogonadism, presumably due to testicular iron deposition, also can occur, but is much less common. The clinical condition of HH evolves in a series of stages beginning with clinically insignificant iron accumulation (0-20 years of age, 0-5 g parenchymal iron storage). This evolves to a stage of iron overload without disease (approximately 20-40 years of age, 10-20 g parenchymal iron storage), which if left untreated, may progress to a stage of iron overload with organ damage (usually more than 40 years of age and more than 20 g parenchymal iron storage). Iron overload states appear to be risk factors for infection with Listeria and Yersinia enterocolitica. Iron overload of macrophages can diminish phagocytosis, while high serum iron levels may increase bacterial virulence. Septicemia from Vibrio vulnificus, another iron-requiring bacterium, is also common in patients with HH who ingest uncooked seafoods

Explanation :Liver biopsy should be offered to document the degree of fibrosis in all homozygotes that are over the age of 40 years or those who have an elevated serum alanine transaminase level, have clinical evidence of liver disease, or have a serum ferritin greater than1,000 ng/mL Liver biopsy and hepatic iron evaluation are also recommended in compound heterozygotes (C282Y/H63D), C282Y heterozygotes, or non-HFE mutated individuals who have indirect markers of iron overload, particularly if they also have abnormal liver enzymes or clinical evidence of liver disease. Serum ferritin is an extremely useful diagnostic threshold test. If the ferritin is less than 1000ng/ml, the patient has essentially no risk of having cirrhosis and thus liver biopsy is optional. By contrast, if the ferritin is above one thousand, there is a fairly high risk that the patient will have cirrhosis and thus liver biopsy is indicated. Documentation of extensive bridging fibrosis or cirrhosis by liver biopsy has a profound impact on the prognosis in HH patients. HH pts have a normal life span in the absence of cirrhosis and diabetes

Explanation :Therapeutic phlebotomy is the most effective way to remove iron. The indication for initiating phlebotomy is ferritin more than 200 in females and more than 300 in males. One phlebotomy (removal of 500ml of blood containing 200 to 250 mg of iron) weekly or biweekly. Check haematocrit prior to each phlebotomy; allow haematocrit to fall by no more than 20% of prior level. Check ferritin level q 10-12 phlebotomies. Stop frequent phlebotomy when ferritin falls below 50ng/ml(takes 2-3 years). Continue phlebotomy at intervals to keep serum ferritin between 25-50ng/ml. The frequency of maintenance phlebotomy varies from monthly to 3-4 times a year. Avoid vitamin C supplements.

Explanation :Normal men have approximately 1 g of iron stores. As a result, 4-5 phlebotomies will produce an iron deficient state (microcytosis or hypochromia with anaemia). In contrast, patients with significant iron loading usually have at least 5-20g of iron stores, requiring at least 20 units of phlebotomy to induce iron deficiency. Screening is recommended in 1st degree relatives (parents, siblings and children). The ideal age of screening is 18-30yrs of age, during which the condition can be detected. Screening tests- TS, Ferritin and HFE gene analysis. The major causes of death are decompensated cirrhosis, hepatocellular carcinoma (HCC), diabetes mellitus, and cardiomyopathy. HCC accounts for about 30% of all deaths in HH, whereas other complications of cirrhosis account for an additional 20%. HCC is exceedingly rare in noncirrhotic HH.