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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.
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.
References:
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