Hereditary Hemochromatosis - HH

Today we discussed an approach to a very classic internal medicine problem, a patient presenting with a new diagnosis of cirrhosis.  One of our former CMR's, recently inducted into the CMR hall of fame, Dr. Isaac Bogoch led the morning report!

Team 1 had a discussion about hereditary hemochromatosis (HH) as a potential cause for this presentation, which is a common genetic condition that is treatable if diagnosed early.

Genetic Features:

HH is an autosomal recessive iron-overload disorder associated with mutation of the HFE-gene on chromosome 6.  This results in a substitution of tyrosine for cysteine at position 282 of the HFE protein (C282Y).

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The original mutation is thought to be approximately 2000 years old, originating in northwestern Europe.  The defect is thought to provide women of child bearing age with some protection related to iron deficiency, and so propagated across northern Europe following the path of the Vikings.

The end result of this mutation in the HFE gene is high levels of iron being absorbed from the GI lumen, and dysregulation of iron storage and metabolism by both the liver and macrophages.  High levels of iron are released into the bloodstream and can deposit in various tissues leading to organ dysfunction.

The frequency of Heterozygotes amongst the caucasian population in the United States and Western Europe is approximately 10%

Ref: Pietrangelo. NEJM 2004. Hereditary Hemochromatosis.

Organs affected:

The main organs that are affected by iron deposition include the liver (leading to hepatits, and potentially cirrhosis), the heart (leading to cardiomyopathy), the pancreas (bronze diabetes), and various endocrine organs (the pituitary and testes).  HH is truly a multi-system disease.

Clinical Features:

The main clinical features include liver function abnormalities (75%), weakness (74%), skin pigmentation (70%), diabetes mellitus (48%), arthralgias (45%), and erectile dysfunction (45%)

Diagnosis:

A transferrin saturation > 45% is 95% specific for HH, and a serum ferritin level > 250 mcg/L is 85% specific in men, and 97% specific in women.  MRI or liver biopsy can also be helpful in making a diagnosis of iron overload states.

Ultimately, we have genetic testing for the HFE gene and other more uncommon genes (H63D) that can cause HH.

Women may have lower than normal ferritin levels because of menstruation, and so often the diagnosis of HH in women is not identified until after menopause.

Management:

The main treatment for HH is the ancient art of phlebotomy.  The target for phlebotomy is a ferritin usually less than 50.  It may take weekly phlebotomy (>500 mL of blood per week) in order to achieve this target.  Each 500 mL of blood contains approximately 250 mg of iron.  A patient with HH may have up to 10 grams (10 000 mg) of excess iron stores, so it may take many phlebotomies (1 per week, for a year) in order to achieve the target end point (ferritin <50 p="">
References:
Hereditary Hemochromatosis - A New Look at an Old Disease. Pietrangelo, A. 2004. New England Journal of Medicine.

UptoDate.