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Hereditary Haemochromatosis (Pathophysiology (Excess iron is then…
Hereditary Haemochromatosis
Epidemiology
More common in MALES than females since menstrual blood is protective
Middle-aged men are more frequently and severely affected than women
Most common single gene disorder in caucasians
Main cause
There are other gene mutations responsible and one is autosomal dominant
High intake of iron and chelating agents (ascorbic acid)
HFE gene mutation on chromosome 6, this is an AUTOSOMAL RECESSIVE gene - most common cause
Alcoholic may have iron overload
Risk Factors
Family history since autosomal recessive disease
Alcoholic
Pathophysiology
Excess iron is then gradually taken up by the liver and other tissue over a long period
The iron itself precipitates fibrosis
Hepatic expression of the hepcidin gene is decreased in HFE haemochromatosis thereby facilitating iron overload
In symptomatic patients, the total body iron content is 20-40g (compared to 3-4g in a normal person)
Hepcidin, a protein synthetic in the liver, is central to the control of iron absorption; it is increased in iron deficiency states and decreased with iron overload
The iron content is particularly increased in the liver and pancreas but also in other organs
Iron is taken up by the mucosal cells of the small intestine inappropriately, EXCEEDING the binding capacity of transferrin
In established cases, the liver shows extensive iron deposition and fibrosis
The HFE gene protein interacts with the transferrin receptor 1, which is a mediator in intestinal iron absorption
Cirrhosis is a late feature
Clinical Presentation
Hypogonadism secondary to pituitary dysfunction is the most common endocrine dysfunction
Later there is slate-grey skin pigmentation, signs of chronic liver disease, hepatomegaly, cirrhosis, dilated cardiomyopathy and osteoporosis
Early on there is tiredness and arthralgia
Cardiac manifestations such as heart failure and arrhythmias are common, especially in younger patients
Most affected individuals present in their 50s
In gross iron overload there is a classic triad:
Hepatomegaly
Diabetes mellitus
Bronze skin pigmentation (due to melanin deposition)
Men affected more than women due to menstrual blood loss and lower dietary intake of men
Diagnosis
MRI
Detects iron overload
Heterozygotes e.g. other genes
May have normal biochemical tests
Slightly raised serum iron transferrin saturation or serum ferritin
If iron studies are abnormal can do genetic testing to confirm
Liver biopsy
Can establish extent of tissue damage and disease severity
Homozygous e.g. HFE
Raised serum ferritin (but note an inflammatory process can raise ferritin)
Liver biochemistry is often normal even with established cirrhosis
Raised serum iron
ECG/ECHO is cardiomyopathy suspected
Treatment
In patients who can't tolerate venesection, chelation therapy is used. Desferrioxamine is effective.
Diet low in iron - tea, coffee and red wine
Testosterone replacement
Avoid fruit/fruit juice and white wine as these increase iron absorption
Treat diabetes
Screening - all first-degree relatives should be screened to detect early and asymptomatic disease
Venesection
Prolongs life and may reverse tissue damage
Required lifelong - done 3-4 times a year
Regular removal of blood, then body can use some of the excess iron to make new RBCs - effective at reducing iron excess
Monitor serum iron and ferritin (should remain in normal range) during venesection