Iron and liver diseases

HEPATITIS B VIRUS AND HEPATITIS C VIRUS CHRONIC LIVER DISEASE In the 1970s, Lustbader et al (1) reported that hemodialysis patients with elevated levels of serum ferritin had a higher likelihood of developing persistent hepatitis B virus (HBV) infection than those with lower levels of serum ferritin. Later, increased values of transferrin saturation, serum ferritin and liver iron concentration (LIC) were found in a high proportion of patients with hepatitis C virus (HCV)and HBV-related chronic liver disease (2-5). These findings motivated the use of phlebotomy in the therapy of patients with chronic hepatitis, because it was thought that iron depletion could improve liver function and possibly the natural history of the patients. However, phlebotomies were followed by a reduction of alanine aminotransferase that, in some cases, reached normal values, but HCV RNA concentration did not appear to be markedly affected by iron depletion (6-9). Iron has been included among the factors that are able to influence the response to alpha-interferon (IFN) therapy. Only 5% to 15% of patients with increased iron parameters have a response to IFN therapy versus 50% of those with normal iron status. A significant difference in LIC values between responders and nonresponders to IFN therapy was found, although the LIC of the majority of the nonresponders was in the upper part of the normal range (10-13). Recently, a correlation between the grade of hepatic iron deposits and histological severity was found (14,15), suggesting that liver iron deposition could facilitate the evolution to cirrhosis.

After the identification of the two mutations of the gene associated with HHC (HFE) (16), several authors analyzed the relationship among HFE mutations, iron status and severity of HCV.An English group studied a large series of patients with HCV-related chronic liver disease and found a significantly higher histological stage in patients positive for the C282Y mutation, the major mutation associated with HHC, than in patients with the wild-type genotype (17).A similar study involving 113 Italian patients with HCV chronic liver disease showed that 43% of patients with iron overload carried HFE mutations.The frequency of C282Y was only marginally increased, while the allelic frequency of H63D, the second mutation associated with HHC that appears to cause a more subtle abnormality of iron metabolism, was significantly increased in HCV patients with iron overload compared with normal controls.The scores of histological grade (activity) and stage (fibrosis) were significantly increased in patients carrying HFE gene mutations compared with patients carrying the wild-type gene (18).In another study performed in Italy, a relation between iron status and progression to fibrosis was observed, and an interplay between genetic and acquired factors was postulated (19).However, no increase in the prevalence of HFE mutations and no correlation between HFE mutations and histology was observed by Shirazi et al (20) in a large series of patients with HCV-related chronic liver disease.

PORPHYRIA CUTANEA TARDA
A liver disease in which the pathogenic role of iron is better defined is porphyria cutanea tarda (PCT), although often several different hepatotoxic factors can be identified, among which the most important are alcohol and HCV (21,22).The majority of patients with PCT have liver siderosis and increased body iron stores (23,24).It has been proposed that increased liver iron may trigger the clinical manifestations of the disease because iron depletion by phlebotomy may induce a remission of cutaneous lesions and an improvement of liver function tests (25).A significantly increased frequency of the C282Y HFE mutation in patients with PCT was reported for the first time by Roberts et al (26) in a British series: the mutation was found on 30% of alleles from patients with PCT versus 5.9% of controls.Similar data were obtained in different countries (Table 1) (27,28); however, Sampietro et al (29) did not confirm an association of PCT with the mutation strongly associated with HHC in northern European countries, but found that the second mutation of HFE, H63D, had a significantly higher frequency, being present in half of the patients with PCT.

ALCOHOL-RELATED LIVER DISEASE
In alcohol-related liver disease, defining iron overload, which in some cases may resemble that found in HHC, is difficult.This is partly due to the fact that the usual iron tests overestimate the iron status of patients with alcohol abuse.An induction of ferritin synthesis occurs during alcohol abuse, while complete alcohol abstinence is followed by normalization of ferritin levels in a few days (30).In addition, a role for iron in facilitating alcohol-induced liver damage has been recently suggested by experimental data from animal models.Tsukamoto et al (31) showed that the histological grading of liver fibrosis of rats fed with ethanol and small amounts of iron was markedly higher than that of rats fed with only ethanol, suggesting a synergistic effect of alcohol and iron that may lead to cirrhosis.The prevalence of HFE mutations was recently studied in alcohol-related liver disease.While Grove et al (32) did not find any correlation between HFE mutations and liver iron content or liver fibrosis, a preliminary study performed in 60 Italian patients with alcohol-related liver disease (33) found that the allelic frequency of both C282Y and H63D mutations was higher in these patients than in normal Italian controls, and that the frequency of mutations was significantly increased in patients with more severe liver damage.These results do not indicate a direct relation between iron and alcohol-related liver disease but suggest a possible role for HFE mutations in the susceptibility to alcohol toxicity.

NONALCOHOLIC STEATOHEPATITIS
Another disease of emerging importance in which iron appears to have a role is nonalcoholic steatohepatitis (NASH).Originally described in middle age, overweight and often diabetic women, more recently it has been recognized in larger groups of patients, often of male sex.Pathognomonic for NASH is the presence of steatosis associated with cellular inflammation in the presence or absence of fibrosis in the liver biopsy (34)(35)(36).Unexpectedly, more than 50% of patients in the different series had hyperferritinemia, whereas increased transferrin saturation was found in a much lower proportion of patients.In addition, patients with increased body iron and carrying the main HFE mutation (C282Y) have more severe liver disease (37).A dysmetabolic iron overload syndrome, partly resembling NASH, has been recently described by Moirand et al (38).In these patients increased serum ferritin was associated with increased LIC but normal transferrin saturation was identified; these typical features are thought to characterize a new iron overload entity.Recently, an increased frequency of HFE gene mutations was observed in Italian patients with NASH and

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Can J Gastroenterol Vol 14 Suppl D November 2000  hyperferritinemia (39), suggesting that the mutations of the HFE gene may affect the natural history of patients with fat accumulation in the liver.
LIVER CANCER Finally, iron has been suggested to facilitate liver cancer occurrence, although its role in cancer development is still a matter of debate.Numerous clinical investigations have suggested that patients with excess iron have a greater than normal risk of developing cancer, and several experimental studies in animals have confirmed a relation between iron and cancer (40).Indirect support of the role of iron in cancer comes from recent findings in French patients who underwent orthotopic liver transplantation for liver cancer.The concentration of iron in extralesion, nonneoplastic tissue was markedly higher than in control patients without liver cancer.Increased liver iron stores were present in both patients with hepatocellular carcinoma that developed on a cirrhotic or noncirrhotic liver (41).In a similar series of Italian patients undergoing orthotopic liver transplantation for liver cancer, the values of LIC compati-ble with a diagnosis of HHC were found in 8% of the patients -a 20-fold higher frequency than expected in the Italian population (42).The absence of severe cirrhosis rules out the possibility that the high LIC could be only secondary to liver cirrhosis, as recently reported (43,44).In addition, in two patients, hepatocellular carcinoma occurred in the absence of a pre-existing cirrhosis.Very recently a high prevalence of the HFE gene mutations has been reported in patients with liver cancer, in those with both normal and cirrhotic livers (45,46).These results suggest that the increased iron in the liver may act as a promoter of neoplastic transformation in the presence of carcinogenic factors.

CONCLUSIONS
Excess iron is present in many patients with chronic liver disease, and mutations of the gene associated with HHC are often found in these patients.Evidence suggests that iron may affect the natural history of different liver diseases independent of etiology.Iron depletion therapy may improve the prognosis of patients with chronic liver disease and possibly reduce the risk of liver cancer.