HEMOCHROMATOSIS

I. Pathophysiology

1. Iron overload causing tissue damage
2. Can be hereditary (mostly Caucasian), in which case excess intestinal absorption of iron occurs

1. In the hereditary form, clinical manifestations occur after years of excess absorption
2. Women homozygous for the hereditary defect express the disease 1/10 as often as men, prob. b/c of menstrual loss of iron
3. Ethanol abuse or hepatitis accelerates liver and pancreatic damage, prob. due to high serum levels of ferritin after hepatocyte injury
4. A candidate gene has been identified: HFE--see below

3. Or secondary, caused by

1. Chronic anemias, e.g. homozygous beta-thal
2. Multiple transfusions
3. Porphyria cutanea tarda
4. Portocaval shunt, etc.

4. Iron accumulation-ubiquitous, as ferritin and hemosiderin

1. Liver

1. All Fe absorbed from intestine passes through liver; any Fe that exceeds binding capacity of transferrin is deposited

2. Pancreas, heart, gonads, thyroid, hypothalamus, pituitary, and joints, causing dysfunction in all these organs

II. Clinical manifestations

1. Symptomatic presentation is most common in men over 20 and postmenopausal women
2. Common presenting sx:

1. Fatigue, often severe
2. Arthralgias
3. Abdominal discomfort
4. Arrhythmia (atrial or ventricular)
5. Erectile dysfunction in men
6. Amenorrhea
7. Skin hyperpigmentation (like suntan) on both exposed and nonexposed areas; slate gray in late stages

3. Other manifestations

1. Hepatosplenomegaly and hepatic dysfunction, including cirrhosis
2. Ascites
3. Pleural effusion
4. Arthritis (most commonly 2nd and 3rd MCP joints, knees, and hips; treatable with salicylates or NSAIDS)
5. Cardiac involvement can cause restrictive cardiomyopathy with CHF and/or arrhythmia
6. Thyroid involvement can cause hypothyroidism
7. Testicular atrophy
8. Pancreatic involvement can cause diabetes
9. Hair loss
10. Acute peritonitis or septicemia, often fatal

III. Diagnosis

1. Laboratory abnormalities

1. Fe studies

1. Transferrin saturation (Fe/TIBC) > 60% (nl 20-50%)
2. This can also occur with taking exogenous Fe or OC's

2. If % Sat is elevated and confounding factors ruled out, check ferritin

1. In advanced hemochromatosis will be >500ug/l, often much higher
2. But it's also an acute phase reactant so will be high in chronic disease, malignancy, etc., as well as alcohol abuse

3. Often get macrocytosis ("due to liver dysfunction"-?)
4. Genetic screens (for hereditary hemochromatosis)

1. The gene known as HLA-H (aka HFE) is probably responsible
2. Most common mutation is known as Cys282Tyr (aka C282Y)
3. Less common mutation is His63Asp (aka H63D)
4. Genetic screening is useful in testing relatives in families known to carry mutant alleles of HLA-H, to distinguish homozygotes from heterozygotes in families with hereditary hemochromatosis, or when hereditary hemochromatosis is suspected.

2. Liver biopsy gives semiquantitative estimation of Fe overload (Hepatic Iron Concentration; us. divided by age to give "Hepatic Iron Index"); HII 1.9 or higher seems to be highly sensitive & specific for homozygous hereditary hemochromatosis diagnosed according to clinical & biochemical criteria (Gastroenterology 113:1270, 1997-JW)
3. Bone marrow examination not helpful; may or may not show increased hemosiderin content
4. X-rays show joint changes which may be confused with osteoarthritis or rheumatoid arthritis, e.g. small cysts and osteophytes
5. SCREEN SIBLINGS OF ANY CONFIRMED CASES with %sat and serum ferritin
6. Screening not yet advised in general population as of 2006 by ACP-ASIM or USPSTF

IV. Treatment and prognosis

1. Median survival 2y after dx without tx; if tx begins before onset of signs/sx, survival is same as general population
2. Treatment of choice is repeated phlebotomy; us. 1-2x/wk initially, then 4-6/yr; monitor tx with ferritin concentration.
3. Must abstain completely from alcohol
4. Liver transplant may be necessary in advanced cases
5. Usually die from complications of liver disease (SBP, bleeding from varices, hepatocellular Ca
6. In general, organ dysfunction is not reversed by tx but progression may be halted; the exception is cardiac dysfunction, which often substantially improves

(Source: Cecil's 20th ed.)