Calculation and interpretation of the hepatic iron index: A brief summary.
Contributed by Michael Torbenson, M.D., Michael Nalesnik, M.D. and Robert Bourne
Hereditary hemochromatosis (HH) is one of the most common inherited disease in individuals of Northern European ancestry, with an estimated carrier rate of 1 in 10 and an estimated frequency of homozygosity of approximately 1:200 to 1:400 (1). Populations of Celtic origin may have the highest gene frequency of HH (2). The gene responsible for a large percent of the cases of HH has been termed HFE. The two major mutations discovered to date are C282Y and H63D. A number of studies have shown that C282Y accounts for 60-100% of cases, H63D accounts for between 3-7% of cases, with compound heterozygotes accounting for another 1 to 4% of patients (1). The penetrance of the HH is unknown but is clearly not 100% (3).
The clinical manifestations are a direct result of iron overload with iron deposition involving principally the liver, pancreas, heart, and joints. Hepatic iron overload can lead to fibrosis and eventual cirrhosis. Historically, the diagnosis of HH was based on finding evidence for significant iron overload, including the classic triad of liver cirrhosis, diabetes mellitus, and skin "bronzing", along with laboratory testing showing elevated body stores of iron. The diagnosis could be further supported by demonstrating increased body iron stores through quantitative phlebotomy, increased urine iron following chelation therapy, an increase in iron staining on a liver biopsy, or by measuring the liver iron content in a quantitative fashion using atomic absorption spectrophotometry. The interpretation of quantitative iron levels in liver tissue are complicated by the observation that other liver diseases such as ethanol related cirrhosis and viral hepatitis can also lead to significant hepatic iron deposition. The hepatic iron index was then introduced to aid in separating HH from other, secondary, causes of significant siderosis (4).
Liver biopsy and Calculation of hepatic iron index
Liver biopsies in patients with suspected HH are important in both confirming the clinical impression of iron overload as well as in determining the extent of hepatic fibrosis. Hepatic fibrosis appears to develop when iron accumulation in the liver exceeds approximately 400 mmols of iron per gram of dry liver, although patients with both HH and ethanol use may develop fibrosis at lower levels of hepatic iron (4). Substantial hepatic fibrosis is generally not seen before the age of 40(5).
The hepatic iron index is calculated as follows:
[Iron concentration (mg iron per gram dry weight of liver) / 55.846 (atomic weight of iron)] / patient's age = HII in mmol iron/gram liver/year.
A HII greater than 1.9 in a non-cirrhotic liver is considered strongly suggestive of HH. The theoretical basis for the HII is that iron accumulation increases steadily with age in patients with HH resulting in a correlation between age and hepatic iron content in patients with HH but not in patients who have secondary iron overload (4). Several studies have found a weak to moderate correlation between the patient's age and the HII (4, 6), but other studies have not been able to confirm this observation (7). In time, the hepatic iron concentration may plateau as the storage capacity of the liver is exceeded (8).
Interpretation (including caveats)
1. A HII of greater than 1.9 in a non-cirrhotic liver is strongly suggestive of HH.
2. Not all patients with HH have a HII greater than 1.9. In one study of an ethnically diverse US population, 7% of patients with HH (n=55) had a HII of less than 1.9. The authors suggested adding a threshold hepatic iron concentration of 71 mmol/g as an adjunct to the HII in diagnosing HH, as it was able to detect all but one of their patients with HH (7). In another study of 55 patients with HH, 7% of patients with HH also had a HII of less than 1.9(9).
3. A HII in a cirrhotic liver should be interpreted with a great deal of caution as several studies have emphasized that the HII lacks specificity in cirrhotic livers (10-12). Apparently, cirrhotic livers can rapidly accumulate iron in some cases of non-HH liver disease and lead to an HII of greater than 1.9(10). One study suggested that a new HII cut-off of approximately 4.2 was useful in diagnosing HH in patients with cirrhosis (12), though further studies are needed to validate this new cut-off point.
4. Iron is not uniformly distributed in the liver and sampling variation can be significant. In six cases with the hepatic iron in the hemochromatosis range, intentional sampling to show the greatest range in iron accumulation resulted in iron indices that varied from 2.6 vs 1.3 (in the same liver); 3.0 vs. 1.1; 2.2 vs 0.3; 2.2 vs 0.4; 2.3 vs 0.7; and 3.4 vs 1(10).
5. The correlation between the HII, phenotypic HH, and genotypic HH is not 100%. HH is not 100% penetrant: not all patients with HH develop clinical evidence of iron overload. There are patients with clinical HH who do not have known mutations in the HFE gene (13). Because of these observations, the "gold-standard" for defining HH is not entirely clear at this time(9, 14). An elevated HII in a non-cirrhotic liver is probably best considered as identifying patients with significant iron overload, most of who are homozygous HH.
- Burke W, Thomson E, Khoury MJ, et al. Hereditary hemochromatosis: gene discovery and its implications for population-based screening. Jama 1998; 280 (2): 172.
- Smith BN, Kantrowitz W, Grace ND, et al. Prevalence of hereditary hemochromatosis in a Massachusetts corporation: is Celtic origin a risk factor? Hepatology 1997; 25 (6): 1439.
- Adams PC, Campion ML, Gandon G, LeGall JY, David V, Jouanolle AM. Clinical and family studies in genetic hemochromatosis: microsatellite and HFE studies in five atypical families. Hepatology 1997; 26 (4): 986.
- Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 1986; 6 (1): 24.
- Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK. HFE genotype in patients with hemochromatosis and other liver diseases [see comments]. Ann Intern Med 1999; 130 (12): 953.
- Summers KM, Halliday JW, Powell LW. Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index [see comments]. Hepatology 1990; 12 (1): 20.
- Kowdley KV, Trainer TD, Saltzman JR, et al. Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study. Gastroenterology 1997; 113 (4): 1270.
- Mandelli C, Cesarini L, Piperno A, et al. Saturability of hepatic iron deposits in genetic hemochromatosis. Hepatology 1992; 16 (
- Adams PC, Bradley C, Henderson AR. Evaluation of the hepatic iron index as a diagnostic criterion for genetic hemochromatosis. J Lab Clin Med 1997; 130 (5): 509.
- Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers [see comments]. Gastroenterology 1997; 112 (3): 882.
- Cotler SJ, Bronner MP, Press RD, et al. End-stage liver disease without hemochromatosis associated with elevated hepatic iron index. J Hepatol 1998; 29 (2): 257.
- Press RD, Flora K, Gross C, Rabkin JM, Corless CL. Hepatic iron overload: direct HFE (HLA-H) mutation analysis vs quantitative iron assays for the diagnosis of hereditary hemochromatosis [see comments]. Am J Clin Pathol 1998; 109 (5): 577.
- Sham RL, Ou CY, Cappuccio J, Braggins C, Dunnigan K, Phatak PD. Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases. Blood Cells Mol Dis 1997; 23 (2): 314.
- Franks AL, Burke W. Will the real hemochromatosis please stand up? [editorial; comment]. Ann Intern Med 1999; 130 (12): 1018.
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