Haemachromatosis

Haemachromatosis is caused by dysregulated iron homeostatis, due to inappropriate increased iron absorption in the duodenum and proximal small intestine. 

It is an autosomal recessive hereditary condition which is associated with homozygous C282Y mutation of the HFE gene in North Europeans. It is located on the short arm of chromosome 6. Some heterozygotes C282Y/H63D have iron overload.
Varients:
C282Y homozygous 80%
compound C282Y/ H63D heterozygous 5%
H63D homozygous
C282Y heterozygous +rare mutation e.g S65C, HAMP

Increased absorption of iron results in its deposition in the organs, notably the liver, pancreas, heart, joints, skin and pituitary. This causes cirrhosis, restrictive cardiomyopathy, diabetes mellitus, arthropathy, skin hyperpigmentation and gonadal failure. 

Males and females are affected equally, but females are often 'protected' from the clinical features by menstrual blood loss.

Iron induced injury:
Activation of Kupffer cells—
Production of profibrogenic cytokines—
Stimulation of Collagen products—
Hepatic Fibrosis and Cirrhosis are the principal pathologic findings in HH

Arthropathy is relatively common. It is chronic and progressive, and mildly inflammatory. There is a predilection for the MCP joints and is often accompanied by chondrocalcinosis. Iron load is probably a major determinant but it does not usually respond to venesection.

Early diagnosis and treatment is critical in haemochromatosis as survival and morbidity are improved if phlebotomy is initiated prior to the development of cirrhosis.

Transferrin saturation is suggested as the initial screening test: a level of more than 45% warrants further investigation (less than 45% usually excludes the diagnosis). 

Genetic screening is then performed. If the usual C282Y HFE mutation is found this makes the diagnosis.  If the C282Y HFE mutation is not present other genotypes should be looked for and if present a liver biopsy is indicated.

Ferritin is measured to help guide further investigation and treatment: if more than 1000 a liver biopsy should be performed and treatment initiated. If the ferritin is within normal range and the liver function tests are normal patients can be followed closely.

The goal of therapy is to remove excess body iron stores, which is commonly done via phlebotomy. Initially this is weekly or twice-weekly (if tolerated) venesections of 500cm3 until the serum ferritin is less than 50ng/mL. Transferritin saturation should also be reduced to less than 50% if possible. 

After these goals are reached maintenance therapy is typically required three to four times per year. 

When iron overload and anaemia are present concomitantly chelation with desferoxamine may be required. 

Patients should be told to avoid vitamin C supplementation as this can enhance iron toxicity.

End-stage liver disease, portal hypertension and hepatocellular carcinoma (which is increased up to 200 fold) may necessitate liver transplantation. This is associated with poorer outcome compared with other indications because of increased incidence of infection and cardiac complications.

Haemochromatosis is classically associated with a non-migratory, rather than migratory, polyarthritis. This particularly affects the hands: in over 50% of patients there is involvement of the 2nd and 3rd MCPs, but the PIPs, knees, feet, wrists, back and neck are also commonly involved.

Skin pigmentation rather than a rash is more typical.

Haemochromatosis can cause hypogonadism, which can also be associated with gynaecomastia but costochondrosis is a more reliable sign.

EASL guidelines:

• Patients with suspected iron overload should first receive measurement of fasting transferrin saturation and serum ferritin, and HFE testing should be performed only in

those with increased transferrin saturation.

• HFE testing for the C282Y and H63D polymorphism should be carried out in all patients with otherwise unexplained increased serum ferritin and increased transferrin saturation.

• Diagnosis of HFE hemochromatosis should not be based on C282Y homozygosity alone, but requires evidence of increased iron stores.

• C282Y/H63D compound heterozygotes and H63D homozygotes presenting with increased serum ferritin (>200 mg/L in females, >300 mg/L in males), increased transferrin saturation (>45% infemales, >50% in males) or increased liver iron should first be investigated for other causes of hyperferritinemia (1 C).

• In C282Y homozygote patients with increased iron stores, liver biopsy is no longer necessary to diagnose hemochromatosis. Liver biopsy could be offered to C282Y homozygous patients with serum ferritin above 1000 mg/L, elevated AST, hepatomegaly, or age over 40 years.

• Genetic testing of ‘other hemochromatosis genes’ (TFR2,SLC40A1, HAMP, HJV) could be considered in patients with increased iron stores after exclusion of C282Y homozygosity

if (i) iron excess has been proven by direct assessment, i.e. by MRI or liver biopsy, and (ii) other hepatic and haematologicaldisorders have been ruled out. 

According to the autosomal recessive transmission of HFE-HC, genetic testing of siblings of individuals with HFE-HC should be carried out. Genetic testing of other 1st degree relatives should be considered . (Practical and cost effective strategies for family screening have been published)