Relationship between iron concentration and hepatitis C virus RNA level in liver tissue

Patients with chronic hepatitis C virus (HCV) infection frequently have increased hepatic iron stores. The role of hepatitis C in hepatic iron deposition is unknown. The authors examined whether there is a relation between hepatitis C virus level in liver tissue and hepatic iron concentration. Forty-two paired samples obtained from the liver explants of five patients who underwent transplantation for liver disease due to hepatitis C were studied. Hepatitis C virus levels were measured at multiple sites within each liver by a branched deoxyribonucleic assay. Measurements of hepatic iron concentration were made at adjacent sites by a colorimetric assay. Random effects modeling showed wide intrahepatic variation in hepatic HCV ribonucleic acid (RNA) concentration (variance = 1.2 x 10(4) [mEq/g]2) and hepatic iron concentration (variance = 1.3 x 10(6) [microg/g]2). There was, however, a trend toward an association between the mean HCV level and the mean hepatic iron concentration for each liver (r = 0.30, p = 0.05). In conclusion, HCV level and iron concentration varied within and between cirrhotic livers. Variability in intrahepatic iron concentration was not related to variability in intrahepatic HCV RNA concentration. More studies are needed to determine the cause of variability in hepatic iron and HCV RNA concentration within and between livers in patients with chronic hepatitis C.     

Alcoholic liver injury： Pathological features and models—Role of alcohol in the regulation of iron metabolism

Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.     

Alcoholic liver disease and hepatitis C： A frequently underestimated combination

Alcoholic liver disease （ALD） and hepatitis C virus （HCV） infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world. This review discusses the epidemiology and combined impact of ALD and HCV on the progression of liver disease. ALD and HCV affect the progression of liver disease to liver cirrhosis and hepatocellular carcinoma （HCC） in a synergistic manner. Thus, the risk for HCC increases five times with a daily alcohol consumption of 80 g, in the presence of HCV it is increased 20-fold, and a combination of both risk factors leads to a more than 100-fold risk for HCC development. Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication. Several molecu- lar mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression. They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron. Thus, both HCV and alcohol independently cause hepatic iron accumulation in 〉 50% of patients probably due to suppression of the liver-secreted systemic iron hormone hepcidin. A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future. For now, it can be generally concluded that HCV-infect- ed patients should abstain from alcohol and alcoholics should be encouraged to participate in detoxification programs.     

Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation

It has been suggested that preexisting severe hepatic iron overload may adversely affect outcome after liver transplantation. The pathogenesis of iron overload in cirrhosis in the absence of hemochromatosis gene (HFE) mutations is poorly understood. The relationships between liver disease severity and etiology, degree of hepatic iron overload, and post-liver transplantation outcome were studied in 282 consecutive adult patients with cirrhosis. Thirty-seven percent of patients had stainable hepatic iron. Increased hepatic iron concentration was significantly associated with more severe liver disease (P<.001), male sex (P = .05), the presence of spur cell anemia (P<.0001), and hepatocellular liver disease (P<.0001). The HFE mutations were uncommon in patients with increased hepatic iron stores. Increased hepatic iron concentration was not associated with greater utilization of resources or a lower survival after liver transplantation. Child-Pugh score at the time of liver transplantation was the only independent variable affecting patient survival (P = .0008). In summary, our data suggest that the severity of the liver disease rather than hepatic iron concentration is the most important determinant of outcome after liver transplantation and that, in general, increasing hepatic iron concentration in cirrhosis is a surrogate marker of the severity of the underlying liver disease.     

Iron and non-alcoholic fatty liver disease

The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.     

African iron overload

African iron overload has been recognised in sub-Saharan Africa for seventy years. The condition is distinct from the well-characterised HLA-linked haemochromatosis described in Caucasians. Increased dietary iron intake predisposes to the condition. Recent evidence suggest that African iron overload may be caused by an interaction between increased dietary iron and a genetic defect not associated with the HLA-locus. Iron deposition is prominent both in macrophages and in hepatic parenchymal cells. Iron overload is distinct from alcoholic liver disease, although the excess dietary iron is derived from a traditional beverage that contains alcohol. African iron overload has clinical consequences. It is a cause of hepatic fibrosis and cirrhosis, and associations with diabetes mellitus, peritonitis, scurvy and osteoporosis have been described. African iron overload may be a cause of hepatocellular carcinoma. The disorder is associated with a poor outcome in tuberculosis, an infection that is highly prevalent in sub-Saharan Africa.     

Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.     

Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda

Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, it has been shown that many PCT patients carry mutations in the HFE gene, which is responsible for hereditary hemochromatosis. Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA). Hfe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slower rate. The amount of accumulated URO in the null mutant mice was similar to that in wild-type mice treated with iron carbonyl in the diet, or injected with iron dextran. Iron in both wild-type and Hfe (+/-) mice was mostly in Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT.     

Role of HFE gene mutations in liver diseases other than hereditary hemochromatosis

Heavy iron overload, as occurs in primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, including the heart, liver, and pancreas, and it is a risk factor for the development of hepatocellular carcinoma. Recent evidence indicates that lesser degrees of hepatic iron deposition are also risk factors for nonhemochromatotic liver disease. For example, several recent studies showed extraordinarily high prevalences (about 60% to 75%) of HFE mutations in patients with porphyria cutanea tarda and significantly increased prevalences of these mutations in patients with nonalcoholic steatohepatitis from Australia and the United States. It is less well established that the prevalence of the HFE mutations is increased in alcoholic liver disease and in chronic viral hepatitis, but in both conditions, patients harboring one of these mutations, especially C282Y, are more likely to have advanced hepatic fibrosis or cirrhosis. Thus, these mutations both incite and exacerbate nonhemochromatotic liver disease. In this review, we summarize current knowledge of these associations and emphasize important unresolved questions that require further study     

Association of hepatic iron deposition and serum iron indices with hepatic inflammation and fibrosis stage in nonalcoholic fatty liver disease]

BACKGROUND/AIMS: Nonalcoholic steatohepatitis can develop from nonalcoholic fatty liver and progress to severe liver disease such as cirrhosis. The mechanism determining the progression from fatty liver to steatohepatitis is unknown. Iron is suspected to enhance hepatic damage associated with nonalcoholic fatty liver disease (NAFLD). The aims of this study were to evaluate the relationship of serum iron indices and hepatic iron deposition with hepatic fibrosis or inflammation, and to assess whether the increased hepatic iron deposition is an independent predictor of progression to liver injury. METHODS: The biochemical and histopathological data of thirty-nine patients with NAFLD were analyzed. Liver biopsy findings were graded according to the method described by Brunt, et al. Hepatic iron concentration was available in 29 of 39 patients. RESULTS: The mean hepatic iron concentration and hepatic iron indices were 1,349+/-1,188 microg/g dry weight and 0.9+/-0.7 microg/g/age. Serum ferritin and body mass indices were associated with hepatic inflammation (p=0.001, p=0.006) and fibrosis (p=0.005, p=0.013). Hepatic iron concentration and hepatic iron index were not associated with hepatic inflammation and fibrosis. Multivariate analysis did not identify serum ferritin or body mass index as an independent predictor of liver injury. CONCLUSIONS: Hepatic iron deposition shows no association with the degree of hepatic inflammation or fibrosis. Hepatic iron is not an independent predictor of hepatic injury in patients with NAFLD.     

Iron in nonhemochromatotic liver disorders

Iron is essential for cellular functions, but in excessive amounts it is toxic to cells. The harmful effects are related to increased oxidative stress and production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Heavy iron overload as occurs in primary and secondary hemochromatosis can cause fibrosis of various parenchymal organs such as the liver, heart, and pancreas. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases. Porphyria cutanea tarda is associated with hepatic iron overload and responds to iron-reduction therapy. Other recent evidence indicates that the prevalence of HFE gene mutations is increased in chronic viral hepatitis and that patients with chronic hepatitis C harboring especially the C282Y mutation are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages. In this article we review selected nonhemochromatotic disorders in which iron can play an important comorbid role.     

Metastatic carcinoma presenting as fulminant hepatic failure.

An unusual cause of fulminant hepatic failure is described. The patient, who presented with symptoms of liver disease, proved to have a small primary oat cell carcinoma of the lung with massive hepatic metastases. The clinical evolution was rapid, with marked elevations of SGOT (this without a prior hypotensive episode) and hepatic coma. Examination of the liver showed two types of necrosis: 1. infarction secondary to multiple tumor emboli in portal vessels and 2. overrunning of hepatic cell plates by expanding masses of tumor cells (somewhat analogous to piecemeal necrosis).     

Computerized measurement of iron in liver biopsies: a comparison with biochemical iron measurement

The measurement of stainable hepatic iron using a microcomputer image analysis system was compared with standard biochemical measurements of liver iron content in 103 liver biopsy specimens--29 of idiopathic hemochromatosis, 51 of alcoholic liver disease and 23 of various nonalcoholic liver diseases. Sections were stained using Perls' method for iron; the mean area staining positively for iron was measured and expressed as a percentage of the area of biopsy measured. Biochemical (biochemical hepatic iron [mumol/gm dry wt]/age) and morphometrical (morphometrical hepatic iron [%]/age x 100) hepatic iron indices were calculated. Patients in the idiopathic hemochromatosis group had significantly higher biochemical hepatic iron concentrations (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 284 (range = 119 to 631), 21 (range = 2 to 65) and 15 (range = 3 to 31) mumol/gm dry wt, respectively. The biochemical hepatic iron index was also significantly higher (p less than 0.001) in the hemochromatosis group compared with the alcoholic liver disease and nonalcoholic liver disease groups: 5.8 (range = 2.1 to 13.7), 0.4 (range = 0 to 1.6) and 0.4 (range = 0 to 1.1), respectively. Computerized measurements were significantly higher in the hemochromatosis group (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 9.72% (range = 1.50% to 29.26%), 0.13% (range = 0% to 1.20%) and 0.03% (range = 0% to 0.40%), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of Kupffer Cell-Derived Reactive Oxygen Intermediates in Alcoholic Liver Disease in Rats In Vivo

The pathophysiology of alcoholic liver disease (ALD) remains largely unknown. In this work, we have developed an experimental rat model to elucidate the mechanism of liver injury, including ALD, in which Kupffer cell-derived reactive oxygen intermediates (ROIs) might be involved. Groups of male Wistar rats were pair-fed on a liquid high-fat diet containing ethanol (36% of total calories) or isocaloric carbohydrate with or without dietary carbonyl iron (0.5% w/v) for 3 weeks. In this rat model, we investigated Kupffer cell-derived ROI generation, which affected hepatocellular injury and hepatic fibrosis in ALD. The production of ROIs in Kupffer cells isolated from the iron-fed, the ethanol-fed, and the ethanol plus iron-fed rats were significantly increased, compared with that in Kupffer cells isolated from control rats (iron > ethanol + iron > ethanol ≫ control). However, hepatic vitamin E content in the ethanol plus iron-fed rats was decreased rather than that in the iron-fed rats. Then, lipid peroxidation of isolated microsomes was assessed as malondialdehyde equivalents determined by thiobarbituric acid assay. Compared with controls, the malondialdehyde equivalents were elevated in experimental groups (ethanol + iron > ethanol > iron > control). Serum ALT levels were greatly elevated in rats fed a diet containing both ethanol and iron (ethanol + iron > iron > ethanol > control). Hepatic content of hydroxyproline was significantly increased in ethanol plus iron-fed rats, compared with rats other than the ethanol plus iron-fed group (ethanol + iron > iron > ethanol > control). These results suggested that the enhanced Kupffer cell-derived ROI generation could itself contribute to the increased susceptibility to lipid peroxidation, which might cause hepatocellular injury and lead to hepatic fibrosis in ALD.     

Role of hepatic iron in non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of clinical entities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) with possible evolution to cirrhosis and hepatocellular carcinoma. Iron is considered a putative element that interacts with oxygen radicals in inducing liver damage and fibrosis. The role of hepatic iron in the progression of NASH remains controversial, but in some patients, iron may have a role in the pathogenesis of NASH. Though genetic factors, insulin resistance, dysregulation of iron-regulatory molecules, erythrophagocytosis by Kupffer cells may be responsible for hepatic iron accumulation in NASH, exact mechanisms involved in iron overload remain to be clarified. Iron reduction therapy such as phlebotomy or dietary iron restriction may be promising in patients with NASH/NAFLD to reduce insulin resistance as well as serum transaminase activities.     

Abnormal liver function tests following bone marrow transplantation: aetiology and role of liver biopsy

INTRODUCTION: Liver dysfunction is common in bone marrow transplant recipients. Common causes are graft-versus-host disease, drugs, veno-occlusive disease, sepsis and iron overload. We studied the prevalence and aetiology of abnormal liver function tests following bone marrow transplantation and the role of liver biopsy. METHODS: All allogeneic and autologous bone marrow transplantations undertaken in our institution over a 2-year period were studied. Subsequent liver function tests, the use and timing of liver biopsy and the final cause of liver dysfunction were determined in each case. RESULTS: We studied 121 patients (58 allogeneic, 63 autologous). Abnormal liver function tests were found in 52% of bone marrow transplant recipients (72% allogeneic and 33% autologous; P = 0.015). The most common causes of liver dysfunction were graft-versus-host disease, drugs and iron overload in the allogeneic group, and drugs and sepsis in the autologous group. Nineteen patients (16%; 18 allogeneic) underwent liver biopsy. The majority of liver biopsies were carried out in the late post-transplant period to exclude or confirm graft-versus-host disease, although only one case was confirmed. Sixteen of the 19 patients who underwent biopsy had significant hepatic iron overload, but no biopsy revealed evidence of fibrosis or cirrhosis. CONCLUSION: Liver dysfunction following bone marrow transplantation is common and most diagnoses can be ascertained without resorting to liver biopsy. In our series, hepatic iron overload was the most common finding in those who underwent liver biopsy.     

Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry.

BACKGROUND: It is unclear whether mild to moderate iron overload in liver diseases other than hereditary haemochromatosis (HH) contributes to hepatocellular carcinoma. This study examined the association between hepatic iron grade and hepatocellular carcinoma in patients with end-stage liver disease of diverse aetiologies. METHODS: The prevalence of hepatic iron overload and hepatocellular carcinoma was examined in 5224 patients undergoing liver transplantation. Explant pathology reports were reviewed for the underlying pathological diagnosis, presence of hepatocellular carcinoma and degree of iron staining. The distribution of categorical variables was studied using chi(2) tests. RESULTS: Both iron overload and hepatocellular carcinoma were the least common with biliary cirrhosis (1.8 and 2.8% respectively). Hepatocellular carcinoma was the most common in patients with hepatitis B (16.7%), followed by those with hepatitis C (15.1%) and HH (14.9%). In the overall cohort, any iron overload was significantly associated with hepatocellular carcinoma (P=0.001), even after adjustment for the underlying aetiology of liver disease. The association between hepatic iron content and hepatocellular carcinoma was the strongest in patients with biliary cirrhosis (P<0.001) and hepatitis C (P<0.001). CONCLUSIONS: Iron overload is associated with hepatocellular carcinoma in patients with end-stage liver disease, suggesting a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease.     

内质网应激在肝脏疾病中的作用研究进展

内质网是细胞内蛋白质、脂类和糖类的重要合成基地,是细胞内钙离子的储存场所,与物质运输、物质交换、解毒作用密切相关。内质网应激是细胞的一种重要自我防御机制,能提高细胞对环境变化的适应能力,但过强过久的内质网应激则会引起不可逆的细胞损伤甚至凋亡。研究发现,内质网应激与多器官多种疾病相关。肝细胞中含有大量的内质网,对内质网应激更为敏感,许多肝脏疾病如肝细胞癌、药物性肝损伤、非酒精性脂肪性肝病、肝胰岛素抵抗等的发病机制均与内质网应激有关。本文就内质网应激对各种肝脏疾病的影响作一概述。