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
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)
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.