Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by increased intestinal absorption of iron with deposition in the liver, pancreas, and multiple other organs. The gene for hemochromatosis was discovered in 1996 and named HFE. Two point mutations were initially described, C282Y and H63D. Approximately 0.5% of Caucasians in the United States are homozygous for C282Y and 10% are heterozygous carriers, confirming that HH is the most common, single-gene inherited disorder in Caucasians.
The initial description of patients with HH was "bronze diabetes" in association with cirrhosis. Currently, most persons diagnosed with HH are asymptomatic. Of those with symptoms, fatigue, arthritis, and impotence are most common. Recent large, population-based screening studies have concluded that most individuals homozygous for C282Y do not develop clinically important disease manifestations. The true penetrance in C282Y homozygotes is unknown.
The diagnosis of HH is based on a combination of clinical, laboratory, and pathological criteria. The best initial test for HH is a fasting, morning transferrin saturation (% saturation). If the transferrin saturation is >45%, it should be repeated along with a serum ferritin. In adults, when both the serum transferrin saturation and ferritin are elevated, the HFE gene test should be performed. Prior to HFE gene testing, a qualified professional should discuss the risks, benefits, and alternatives of genetic testing.
Approximately 85% of US patients with HH are homozygous for C282Y. Absence of the C282Y and H63D mutations does not exclude clinically significant iron overload. HFE gene testing is useful in confirming a diagnosis of HH, screening adult blood relatives of a C282Y homozygous proband, and helping to resolve ambiguous cases of iron overload. A liver biopsy with measurement of the hepatic iron concentration is no longer necessary to confirm the diagnosis in C282Y homozygotes. A liver biopsy also is not necessary in most C282Y homozygotes with serum ferritin values <1,000 mcg/L and normal aspartate aminotransferase values since they have a low risk of having cirrhosis.
Treatment is by phlebotomy. Initially, a pint of blood is removed once per week. The goal is to achieve a serum ferritin of <50 mcg/L. Once depleted of excess iron stores, maintenance phlebotomy approximately every 3 months is usually required. If HH is diagnosed and treated before the development of cirrhosis or diabetes, survival is similar to age- and sex-matched controls without HH. Refer to What's New in Hereditary Hemochromatosis, Mayo Medical Laboratories Communique 2005 April;30(4) for more information regarding diagnostic strategy. See Hereditary Hemochromatosis Algorithm in Special Instructions.
Screening to identify those patients who may have or do have hereditary hemochromatosis and are at risk to develop clinical signs and symptoms of the disease
A transferrin saturation >45% will trigger the determination of a serum ferritin. If the ferritin value is abnormal (males: >336 mcg/L; females: >307 mcg/L) and other causes of an increased value are eliminated (liver disease, etc.) genetic testing for hereditary hemochromatosis (HHEMO/81508 Hemochromatosis HFE Gene Analysis, Blood) should be considered in adults.
See Hereditary Hemochromatosis Algorithm in Special Instructions.
For more information about hereditary hemochromatosis testing, see Update on Hereditary Hemochromatosis and the HFE Gene in Publications.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
No significant cautionary statements.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Males: 50-150 mcg/dL
Females: 35-145 mcg/dL
TOTAL BINDING CAPACITY
Males: 24-336 mcg/L
Females: 11-307 mcg/L
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Tavill AS: Diagnosis and management of hemochromatosis. Hepatology 2001 May;33(5):1321-1328
2. Pietrangelo A: Haemochromatosis. Gut 2003 May;52:23-30