IM Quiz: Hemochromatosis

Hereditary hemochromatosis, once thought to be rare, is the most common genetic disorder in the United States. Recent estimates place the prevalence of the homozygous genotype at 1 in 250 persons, and about one in nine is a carrier, making hereditary hemochromatosis the most common known genetic disorder in the United States (4,5,6,7). Serum iron and transferrin saturation, ferriten level, and desferrioxamine challenge are comparably sensitive, noninvasive tests of iron stores (1,2). They may all be normal in the early stages of iron overload, such as in precirrhotic affected family members of persons with idiopathic hemochromatosis. The most sensitive test for detecting early iron overload is a quantitative iron analysis, usually determined by atomic absorption spectrometry, of a liver biopsy specimen.

Table 1. Common tests used in assessment of iron status and detection of iron overload (3)
Test	Description	Normal values	Value indicating overload	Interpretation of results

Transferrin saturation	Most sensitive test for detecting hemochromatosis. Iron is transported in the body by the protein transferrin. Saturation (the extent to which transferrin has vacant hereditary hemochromatosis have elevated levels but not iron-binding sites) is calculated by dividing serum iron concentration by total iron-binding capacity. High saturation indicates high level of body iron.	>15% to 40%	>60% in men; >50% in women	A fasting test eliminates short-term effects of diet on saturation. Infection and inflammation can depress saturation. Compared with normal population, heterozygotes for hereditary hemochromatosis have elevated levels but not as high as those in homozygotes. Saturation <15% indicates iron deficiency.

Serum ferritin concentration	Ferritin is an intracellular iron storage protein. Its concentration in serum indicates the level of iron stored in the body (concentration 1 ng/mL equals 10 mg of stored iron).	20 to 400 ng/mL in men; 20 to 200 ng/mL in in women of childbearing age; 20 to 300 ng/mL in postmenopausal women	>400 ng/mL in men; >200 ng/mL in in women of childbearing age; >300 ng/mL in postmenopausal women	A high concentration may also indicate infection or inflammation, especially liver disease. Level of <20 ng/mL indicates iron deficiency; <12 ng/mL indicates iron depletion.

Hemoglobin	Hemoglobin content in circulating red blood cells	13.6 g/dL in men; 12 g/dL in women	Normal or low	High levels do not occur with iron overload. Iron deficiency may result from anemia due to chronic inflammation and illness.

Quantitative phlebotomy	Removal of blood until iron deficiency develops. The amount of blood removed indicates total body iron load.	Variable; usually >2 to 3 U in 2 wk results in drop in hemoglobin level.	About 10 U whole blood	Also used to treat iron overload

Liver biopsy	The amount of iron in the liver (hepatic iron concentration) is measured by atomic absorption spectrophotometry of hepatic parenchymal cells or estimated histologically with Perls' stain.	Hepatic iron concentration <80 mol/g dry weight	Hepatic iron concentration >80 mol/g dry weight	Biopsy used to evaluate prognosis on the basis of extent of iron infiltration in tro tissues and damage to tissues ( fibrosis and cirrhosis).
	Hepatic iron index equals the hepatic iron concentration divided by the patient's age.	Hepatic iron index < 1.1	Hepatic iron index > 1.9	Used to differentiate hemochromatosis from other liver diseases. Liver iron levels are affected by age, menstruation, blood donation, and pathologic blood losses.
	Perls' staining uses a grading system to describe the amount of parenchymal iron on a scale from 0 to 4.	Perls' stain grades 0 or 1 stainable hepatic in parenchymal iron	Perls' stain grades 2 to 4 in hepatocytes	Young homozygotes have normal or near-normal stainable iron levels.

The usual manifestations described for hemochromatosis are cirrhosis (hepatomegaly with normal LFT's in 50%), diabetes mellitus (65%), arthritis (25-50%), cardiomyopathy (15%) with congestive heart failure occurring in about 10% of young adults and hypogonadotrophic hypogonadism (loss of libido common) .