Duration of Hepatic Iron Exposure in Hereditary Hemochromatosis
Duration of Hepatic Iron Exposure in Hereditary Hemochromatosis
Objectives: Hepatic fibrosis is a complication of hereditary hemochromatosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis.
Methods: Receiver-operating characteristic curve analysis to determine the utility of hepatic iron concentration (HIC) and age in the diagnosis of low- or high-grade fibrosis was undertaken retrospectively in 60 subjects who had undergone liver biopsy for assessment of hereditary hemochromatosis. A prospective pilot study was then conducted in 10 additional subjects to evaluate utility of magnetic resonance imaging (MRI) measurements of HIC to predict fibrosis.
Results: Eighteen subjects had high-grade fibrosis while 42 subjects had low-grade fibrosis. Hepatic iron concentration alone was highly sensitive (100%) but of limited specificity (67%) in diagnosis of high-grade fibrosis. The product of [HIC × age] had a sensitivity and specificity of 100% and 86%, respectively, for diagnosis of high-grade fibrosis. Magnetic resonance imaging measurements also provided accurate assignment of subjects into fibrosis severity groups.
Conclusions: Duration of exposure to iron is important in the development of hepatic fibrosis in hereditary hemochromatosis. The product of HIC and age is highly sensitive and specific for diagnosis of high-grade fibrosis and can be obtained using MRI.
Hereditary hemochromatosis (HH) is an inherited disorder of iron metabolism with variable phenotypic expression that in most populations of northern European descent results from a homozygous C282Y mutation in the hemochromatosis ( HFE ) gene. In some HH patients, progressive iron overload can result in end-organ damage such as hepatic fibrosis or cirrhosis, arthritis, diabetes mellitus, or cardiomyopathy. The development of cirrhosis in HH patients is associated with reduced survival and a 20- to 100-fold increased risk of hepatocellular carcinoma compared with the control population. However, survival is normal in those subjects who do not have cirrhosis. It is for this reason that assessment of the liver for the presence of significant fibrosis or cirrhosis is still a consideration in the evaluation of subjects with HH. While subjects with normal biochemical liver function tests and serum ferritin levels less than 1,000 µg/L are unlikely to have significant fibrosis, the remainder are usually recommended to undergo liver biopsy for quantitation of hepatic iron concentration (HIC) and assessment for fibrosis or cirrhosis.
The risk of significant fibrosis or cirrhosis has been associated with the level of HIC and concomitant alcohol consumption. Bassett et al. introduced the concept of a threshold for HIC above which cirrhosis was more likely. The data of Sallie et al. suggest that, in addition to HIC, an age greater than 45 yr may be a risk factor for development of significant fibrosis or cirrhosis in HH. In recent times, it has become apparent that subjects may develop significant fibrosis at a much lower HIC than previously thought. Given the slowly progressive nature of iron deposition and mild submorphological inflammation that occur in HH, we hypothesize that it is the extent of exposure to iron as determined by time and HIC that may be most relevant to the risk of developing significant fibrosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis.
Objectives: Hepatic fibrosis is a complication of hereditary hemochromatosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis.
Methods: Receiver-operating characteristic curve analysis to determine the utility of hepatic iron concentration (HIC) and age in the diagnosis of low- or high-grade fibrosis was undertaken retrospectively in 60 subjects who had undergone liver biopsy for assessment of hereditary hemochromatosis. A prospective pilot study was then conducted in 10 additional subjects to evaluate utility of magnetic resonance imaging (MRI) measurements of HIC to predict fibrosis.
Results: Eighteen subjects had high-grade fibrosis while 42 subjects had low-grade fibrosis. Hepatic iron concentration alone was highly sensitive (100%) but of limited specificity (67%) in diagnosis of high-grade fibrosis. The product of [HIC × age] had a sensitivity and specificity of 100% and 86%, respectively, for diagnosis of high-grade fibrosis. Magnetic resonance imaging measurements also provided accurate assignment of subjects into fibrosis severity groups.
Conclusions: Duration of exposure to iron is important in the development of hepatic fibrosis in hereditary hemochromatosis. The product of HIC and age is highly sensitive and specific for diagnosis of high-grade fibrosis and can be obtained using MRI.
Hereditary hemochromatosis (HH) is an inherited disorder of iron metabolism with variable phenotypic expression that in most populations of northern European descent results from a homozygous C282Y mutation in the hemochromatosis ( HFE ) gene. In some HH patients, progressive iron overload can result in end-organ damage such as hepatic fibrosis or cirrhosis, arthritis, diabetes mellitus, or cardiomyopathy. The development of cirrhosis in HH patients is associated with reduced survival and a 20- to 100-fold increased risk of hepatocellular carcinoma compared with the control population. However, survival is normal in those subjects who do not have cirrhosis. It is for this reason that assessment of the liver for the presence of significant fibrosis or cirrhosis is still a consideration in the evaluation of subjects with HH. While subjects with normal biochemical liver function tests and serum ferritin levels less than 1,000 µg/L are unlikely to have significant fibrosis, the remainder are usually recommended to undergo liver biopsy for quantitation of hepatic iron concentration (HIC) and assessment for fibrosis or cirrhosis.
The risk of significant fibrosis or cirrhosis has been associated with the level of HIC and concomitant alcohol consumption. Bassett et al. introduced the concept of a threshold for HIC above which cirrhosis was more likely. The data of Sallie et al. suggest that, in addition to HIC, an age greater than 45 yr may be a risk factor for development of significant fibrosis or cirrhosis in HH. In recent times, it has become apparent that subjects may develop significant fibrosis at a much lower HIC than previously thought. Given the slowly progressive nature of iron deposition and mild submorphological inflammation that occur in HH, we hypothesize that it is the extent of exposure to iron as determined by time and HIC that may be most relevant to the risk of developing significant fibrosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis.