Hereditary Haemochromatosis (HHC)

At least five different inherited haemochromatosis "iron overload" disorders exist, distinguished by their different clinical, biochemical or genetic features:¹
The prevalence haemochromatosis is greater in European races and may be a high as a 1 in 200-400.

• Classic haemochromatosis (HFE) - usually caused by a mutation of the HFE gene on chromosome 6. The commonest HFE gene variant is designated C282Y and the other is H63D. Classic HFE has also been caused by a mutation of the hemojuvelin gene (HJV) on chromosome 1. All are autosomal recessive.
• Juvenile haemochromatosis (HFE2) is caused by either a mutation in the HJV gene (HFE2A)² on chromosome 1, or in the gene encoding hepcidin antimicrobial peptide (HFE2B) on chromosome 19.³ Both are also autosomal recessive.
• Haemochromatosis type 3 (HFE3) is caused by a mutation in the gene for transferrin receptor-2 on chromosome 7. It is also autosomal recessive.⁴. Clinical picure similar to classical haemochromatosis.
• Haemochromatosis type 4 (HFE4) is autosomal dominant, and the defect is in the gene coding ferroportin (chromosome 2).⁵ Clinical picure similar to classical haemochromatosis (except dominant inheritance) with arthralgias, fatigue, cardiomyopathies, and endocrine disorders. Onset is up to 60 years in males (women on average about 10 years later). Venesection in these patients can result in anaemia inspite of the high ferritin.

These disorders all lead to the accumulation of iron in the body with serious consequences.

It is inherited as an autosomal recessive. In the UK over 90% of patients with haemochromatosis have classic haemochromatosis, and are homozygous for the C282Y gene.⁶
Possession of the homozygous gene does not necessarily mean suffering from the disease. In a population of North European descent the homozygous gene was present in 0.5% but only half of homozygotes had clinical features of haemochromatosis, and a quarter had serum ferritin levels that remained within the reference range over a 4-year period.⁷

Presentation

Symptoms are 3 times as common in men as in women. Some of this may be the benefit of menstrual loss or pregnancy. Women present more often with fatigue and pigmentation but less often have cirrhosis or diabetes.⁸
Women tend to present at a slightly later age than men.
The classical 4 features are:

• Cirrhosis
• Diabetes mellitus
• Hyperpigmentation of the skin
• Cardiac failure from cardiomyopathy.

Presentation has changed in recent years, and its full clinical expression is seen in only a minority of patients.⁹

Symptoms

• Common presentation is chronic fatigue, weakness, lethargy, and apathy.
• Amenorrhoea, loss of libido, erectile dysfunction and symptoms of hypothyroidism are reported.
• The patient may present with features of diabetes, heart failure or cirrhosis.
• Women complain of skin pigmentation more than men. It is due to melanin rather than iron deposition.

Signs

• Hyperpigmentation occurs in over 90% of patients but it may be mild. It is an early sign and is most noticeable on sun-exposed skin, particularly on the face. External genital hyperpigmentation was seen in one third of patients, and one fifth had hyperpigmentation of flexural folds, scars, and nipple areolae. Hyperpigmentation often accentuates during exacerbations and regresses with therapy.¹⁰
• Ichthyosis, skin atrophy, koilonychia, and hair loss may also be evident. Koilonychia is unexpected as it is usually associated with iron deficiency. Partial loss of body hair particularly affects the pubic region.
• The spleen may be palpable.

Many of these signs regress with treatment.

In a series from Germany,¹¹ a total group of 251 patients diagnosed with haemochromatosis from 1959 to 1992 showed the following:

• Abnormal liver function tests (75%)
• Weakness and lethargy (74%)
• Skin hyperpigmentation (70%)
• Diabetes mellitus (48%)
• Arthralgia (44%)
• Erectile dysfunction (45% of males)
• ECG abnormalities (31%).

In recent years about 50% of patients were detected without having liver cirrhosis and 20% of patients did not have any symptoms and pathology except iron overload.

The differential diagnosis depends upon the feature with which the patient presents.

• Hyperpigmentation may resemble Addison's disease.
• Other causes of cirrhosis and iron overload must be considered.

• Serum ferritin level is greater than 500 micrograms/L.
• Transferrin saturation of over 55% in men and 50% in women.
• Skin biopsy can establish the diagnosis. Hyperpigmented areas are not essential but avoid the legs as excess iron can be deposited from venous stasis. Biopsy of eccrine sweat glands is especially useful.¹⁰
• Liver biopsy is not required unless cirrhosis is suspected or ferritin level is over 1000micrograms/L. It used to be the standard investigation. Now a blood test for the 282Y gene is available.¹²
• Echocardiogram may show a restrictive cardiomyopathy. There are often supraventricular arrhythmias.

• Phlebotomy remains the standard treatment. Frequency is dictated by results.
  Each unit of blood is 450ml and contains 220mg Fe. A unit of blood is removed each week until ferritin concentration is less than 20mg/L and transferring saturation is under 16%.
• Desferoximine and dietary restriction are usually unnecessary but iron supplements should be avoided.
• Heterozygotes - The UK Foods Standards Agency has decided that those who are heterozygous for the gene do not need to adjust their diet to reduce iron intake.¹³

• Cirrhosis and subsequent hepatocellular carcinoma.
• Diabetes mellitus
• Cardiomyopathy, cardiac failure and arrhythmias.

If the disease is caught early and treated the outlook is good. Otherwise excess mortality is from cirrhosis, liver cancer and diabetes. ¹⁴About a third died of hepatic failure from cirrhosis and about a quarter died of hepatic carcinoma. These figures are rather old and results should be better now with swifter treatment.

Figures from Germany¹¹ showed also that iron removal halted progression except for established cirrhosis and diabetes. Arthropathy was the one feature than was worse for iron removal. Iron removal in general ameliorated liver disease, weakness and cardiac abnormalities, and also prevented the progression of endocrine alterations. During the follow up there were 60 deaths in the group of 251 with excess deaths from 4 causes. In 19 patients death was due to liver cancer, in 14 due to liver cirrhosis, in 5 due to cardiomyopathy, and in 3 due to diabetes. All liver cancers occurred in cirrhotic livers, but often occurred many years or even decades after complete iron removal.

Figures from the USA¹⁵ showed that deaths from haemochromatosis were 23 times more likely than average to be due to liver neoplasms, 13 times more likely to be due to liver disease and 5 times more likely to be due to cardiomyopathy.

All 1st degree relatives should be screened to allow early treatment. HFE gene testing for the C282Y mutation is a cost effective way.¹⁶ For population screening unbound iron binding capacity¹⁷ can be used. Genetic screening for C282Y has been advocated in Ireland¹⁸ where the incidence of the homozygous form may be as high as 1%.

Algorithms have shown that screening is cost effective if the gene incidence is at least 3 per 1,000.¹⁹ The best screening test is probably unbound iron-binding capacity plus transferrin saturation with genetic testing as the final confirmation.