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PubMed2005

Prolonged hepatitis caused by cytomegalovirus and non-alcoholic steatohepatitis in 16-year-old obese boy.

UNLABELLED: Recently, the prevalence of non-alcoholic steatohepatitis (NASH) has been increasingly reported in patients with type 2 diabetes and obesity. NASH exists not only in adults but also in children. We report on an 16-year-old boy with prolonged hepatitis associated with NASH after cytomegalovirus hepatitis. Increased transaminase levels recovered in parallel to his weight reduction. CONCLUSION: Clinicians should be aware of the possibility that prolonged acute hepatitis might be associated with non-alcoholic steatohepatitis in adolescents.

Adolescent↗

PubMed2006

Nonalcoholic fatty liver disease treated by gastroplasty.

Nonalcoholic steatohepatitis (NASH), which is the most severe histologic form of nonalcoholic fatty liver disease (NAFLD), is emerging as the most common clinically important form of liver disease in obese patients. The prevalence of NASH may increase with the rise in the rate of obesity and metabolic syndrome in affluent communities. The aim of this work is to describe clinical and histopathologic findings and correlate liver tissue damage to the length of duration of the obesity in the group of patients who underwent surgery as obesity treatment. Eighty-seven severely or morbidly obese patients underwent gastroplasty. Each patient was evaluated with complete clinical and laboratory medical assessment together with wedge liver biopsy taken from 59 unselected patients during the surgery. Patients were followed up for 41 months. Repeat liver biopsy was taken from 10 patients. Pathologic analysis recorded the presence and degree of steatosis, portal and lobular inflammation and fibrosis. Age, body mass index (BMI), and laboratory assessment correlated with pathologic data. Male patients showed more pronounced metabolic syndrome and fatty liver damage. Patients who become obese in childhood or as teenagers showed no differences in metabolic syndrome and NAFLD in mature age. There was statistically significant association between BMA, elevated transaminases, NAFLD, and fibrosis. Significant weight reduction was observed within first year after surgery, was slower in the second year, and stabilized within third year. Remarkable improvement followed in biological markers of metabolic syndrome. Ninety-six percent of initial liver biopsies had steatosis; 16% developed steatohepatitis and mild perivenular fibrosis. Significant improvement of the degenerative and inflammatory hepatic lesions in repeated biopsies and liver function readings was noted within 8 months after surgery. Obesity is a major and independent risk factor for the metabolic syndrome, NAFLD, NASH, and fibrosis. Surgical treatment improves metabolic abnormalities and hepatic lesions in long-term observations.

Adult↗

PubMed2006

The restorative effect of taurine on experimental nonalcoholic steatohepatitis.

Our objective was to explore the restorative effect of taurine on experimental nonalcoholic steatohepatitis (NASH). Thirty-six SD rats were randomly divided into three groups, 12 in each group: the normal group was fed standard rat diet; the model group and the treatment group were both fed a high-fat rat diet for 12 weeks, and the rats in the treatment group were simultaneously injected with taurine subcutaneously for 8 weeks. Hepatic histological change was observed; TNF-alpha and TGF-beta(1) protein expression was identified by immunohistochemistry; mRNA expression of TNF-alpha, TGF-beta(1), type I procollagen, and adiponectin was measured by RT-PCR; body weight, weight gain, liver weight, and liver index were measured; and biochemical parameters monitored included serum transaminases, serum lipids, fasting plasma glucose, and hepatic level of oxidative stress. Rats in the model group showed a significant increase in liver weight, liver index, serum transaminase activities, serum triglyceride, fasting plasma glucose, and oxidative stress; the mRNA expression of TNF-alpha, TGF-beta(1), and type I procollagen increased, whereas the expression of adiponectin decreased significantly, compared with that in the normal group. The typical hepatic lesions of NASH were observed histologically in the model group. Taurine treatment resulted in a significant decrease in liver weight, liver index, serum transaminase activities, serum triglyceride, fasting plasma glucose, and oxidative stress; the mRNA expression of TNF-alpha, TGF-beta(1), and type I procollagen decreased, but the expression of adiponectin increased significantly, compared with that in the model group. Histological improvement was observed in the treatment group. In conclusion, taurine could inhibit lipid peroxidation, improve lipid and glucose metabolism, decrease synthesis of TNF-alpha and TGF-beta(1), promote synthesis of adiponectin, and have a restorative effect on experimental NASH.

Adiponectin↗

PubMed2004

Advances in alcoholic liver disease.

Cytokines are mediators of cellular communication produced by multiple liver cell types. Cytokines can directly induce either necrosis or apoptosis. They can also recruit such cells as neutrophils and lymphocytes, which can mediate liver damage. Increased levels of hepatotoxic cytokines such as tumor necrosis factor-alpha are documented in alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH) and have been shown to play a mechanistic role in both of these disease processes. Transforming growth factor-beta is a profibrotic cytokine that is critical in hepatic fibrosis. Beneficial cytokines, such as interleukin (IL)-10 and -6, also exist. Such beneficial cytokines as adiponectin are made outside the liver and appear to protect against ALD and NASH. This article reviews the relevance of cytokines in human and experimental forms of liver injury, focusing on modulation of cytokines and the use of beneficial cytokines in treatment and prevention of liver injury in ALD, NASH, and hepatitis C.

Animals↗

PubMed2004

Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is an important medical condition and there is great public health concern related to its increasing incidence and potential implications for the development of end-stage liver disease. NASH represents a progression beyond simple lipid deposition in the liver parenchyma, requiring histologic evidence for hepatocyte injury such as ballooning degeneration, Mallory bodies, and/or pericellular fibrosis that can potentially lead to progressive liver injury and eventually cirrhosis. It is believed that several insults contribute to the evolution of hepatic injury such as insulin dysregulation, lipid deposition, oxidative free radicals, and lipid perioxidation. Initial treatment protocols for NASH focus on various aspects of injury in an attempt to control insulin imbalances, improve lipid regulation, reduce free radicals, and ameliorate the inflammatory process. No therapy is conclusively beneficial in all individuals, but preliminary data suggest several approaches that hold promise.

Journal Article↗

PubMed1986

The peritoneal cell carcinogenicity test.

The peritoneal cell carcinogenicity test, which is a new short-term in vivo-in vitro transformation test invented by Nashed (1981), was evaluated in the present report. The experimental design and materials used were as close as possible to those used by Nashed (1981). Test compounds were the two carcinogenic/non-carcinogenic analog pairs benzo[a]pyrene/pyrene and 2-acetylamidofluorene/4-acetylamidofluorene. All 4 compounds were administered orally. Al(OH)3 was injected intraperitoneally to act as mitogen for peritoneal macrophages. The criterium for transformation was colony growth of macrophages in soft agar. Two transformed cell types formed colonies under the conditions used. Pulmonary and peritoneal macrophages formed colonies when colony-stimulating factor was added. No colony growth was observed on plates with macrophages from 256 animals tested (100 carcinogen treated, 80 treated with noncarcinogenic analogs and 76 untreated controls). Thus we were not able to confirm results published previously by the inventor of this test (Nashed, 1981).

Animals↗

PubMed2006

Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome are reaching epidemic levels worldwide, but data in Asia remain scarce. This cross-sectional study examined the metabolic and adipokine profiles of Chinese patients with biopsy-proven NAFLD and factors associated with severe disease. METHODS: Eighty ethnic Chinese with NAFLD and 41 healthy controls were recruited. Metabolic parameters and fasting adiponectin, tumor necrosis factor-alpha (TNF-alpha), leptin, and resistin levels were measured on the day of liver biopsy. Histology was scored according to Brunt's criteria. Metabolic syndrome was assessed by using both the International Diabetes Federation and Adult Treatment Panel III criteria. RESULTS: Twenty-eight patients had simple steatosis, and 52 patients had nonalcoholic steatohepatitis (NASH), defined as necroinflammatory grade >/=2 and/or fibrosis by Brunt's criteria. The ethnic-specific International Diabetes Federation criteria identified more cases of metabolic syndrome among NAFLD patients than the Adult Treatment Panel III criteria (70% vs 56%, P < .0001). On multivariate analysis, low adiponectin level, increased leptin level, and diabetes mellitus were associated with NAFLD. High TNF-alpha level and high body mass index were independent factors associated with NASH. TNF-alpha level had positive correlation with necroinflammatory grade (R = .35, P = .002) and fibrosis stage (R = .31, P = .005). CONCLUSIONS: Hypoadiponectinemia and elevated TNF-alpha levels are associated with the development of NAFLD and NASH, respectively, independent of other metabolic factors. Ethnic-specific definition of metabolic syndrome is more useful in the assessment of NAFLD patients.

Adiponectin↗

PubMed2006

Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a frequent liver disease that can progress to cirrhosis and for which there is no recognized therapy. UDCA and vitamin E have been considered separately as therapeutic options and have not been shown to be effective. This study tested their combination. METHODS: Patients with elevated aminotransferase levels and drinking less than 40 g alcohol/week with biopsy-proven NASH were randomly assigned to receive UDCA 12-15 mg.kg-1.day-1 with vitamin E 400 IU twice a day (UDCA/Vit E), UDCA with placebo (UDCA/P), or placebo/placebo (P/P). After 2 years, they underwent a second liver biopsy. Biopsy specimens were collected, blinded, and scored by a single liver pathologist. RESULTS: Forty eight patients were included, 15 in the UDCA/Vit E group, 18 in the UDCA/P group, and 15 in the P/P group; 8 patients dropped out, none because of side effects. Baseline parameters were not significantly different between the 3 groups. Body mass index remained unchanged during the study. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels diminished significantly in the UDCA/Vit E group. Neither the AST nor the ALT levels improved in the P/P group and only the ALT levels in the UDCA/P group. Histologically, the activity index was unchanged at the end of the study in the P/P and UDCA/P groups, but it was significantly better in the UDCA/Vit E group, mostly as a result of regression of steatosis. CONCLUSIONS: Two years of treatment with UDCA in combination with vitamin E improved laboratory values and hepatic steatosis of patients with NASH. Larger trials are warranted.

Adolescent↗

PubMed2004

The potential role of genes in nonalcoholic fatty liver disease.

Although most people with obesity and type 2 diabetes will have steatosis, only a minority will ever develop nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Family studies suggest that genetic factors are important in disease progression, although dissecting genetic factors playing a role in NASH and fibrosis from those influencing the development established risk factors is difficult. Several approaches can be used to look for genetic factors playing a role in nonalcoholic fatty liver disease (NAFLD). In the future, genome-wide single nucleotide polymorphism (SNP) scanning of cases and controls may become feasible. To date, however,studies have relied on candidate gene, case control, allele association methodology. Recent, and as yet preliminary, studies have reported associations between steatosis severity, NASH, and fibrosis with genes whose products are involved in lipid metabolism,oxidative stress, and endotoxin-cytokine interactions. If confirmed,these associations will enhance understanding of disease pathogenesis,and accordingly, the ability to design effective therapies.

Alleles↗

PubMed2004

The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease in the United States. The histologic spectrum of NAFLD ranges from steatosis liver alone to nonalcoholic steatohepatitis (NASH), which is the most serious form of NAFLD. NASH is a progressive fibrotic disease, in which cirrhosis and liver-related death occur in up to 20% and 12%, respectively, over a 10-year period. NASH-associated cirrhosis also can develop into subacute liver failure, progress to hepatocellular carcinoma, and reoccur post-transplantation. In contrast, steatosis alone has a more benign clinical course, although progression to cirrhosis has occurred in 3% of these patients. The major risk factors for fibrosis include diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio of greater than 1, age older than 50, and hepatic histology.

Adult↗

PubMed2004

Lipid metabolism in hepatic steatosis.

Hepatic steatosis is a consequence of both obesity and ethanol use. Nonalcoholic steatosis (NASH) resemble alcoholic steatosis and steatohepatitis. Both exhibit increased hepatocellular triglycerides(TG), reflecting an increase in long chain fatty acids (LCFA). LCFA enter cells by both facilitated transport and passive diffusion. A driving force for both is the plasma unbound LCFA concentration ([LCFAu]). In both obese rodents and obese patients, adipocyte LCFA uptake via both facilitated transport and diffusion is increased. However, the LCFA uptake Vmax in hepatocytes is not increased in obese animals. Nevertheless, total LCFA uptake in obese rodents is increased ~3-fold, reflecting increased plasma LCFA concentrations. With advancing obesity, resistance to the antilipolytic effects of insulin results in increased lipolysis within the omental fat depot, a consequent further rise in portal venous LCFA, and an even greater rise in portal [LCFAu]. This causes a further increase in hepatocellular LCFA uptake, increased intracellular generation of reactive oxygen species (ROS), and transition from simple steatosis to NASH. By contrast, in rodent hepatocytes and in human hepatoma cell lines, ethanol up-regulates the LCFA uptake Vmax. Consequently, although plasma LCFA are unaltered, hepatocellular LCFA uptake in ethanol-fed rats is also increased~3-fold, leading to increased ROS generation and evolution of alcoholic hepatitis. Thus, while increased hepatic LCFA uptake contributes to the pathogenesis of both NASH and alcoholic hepatitis,the underlying mechanisms differ. Recognizing these mechanistic differences is important in developing strategies for both prevention and treatment of these conditions.

Animals↗

PubMed2005

Clinical and pathological features of non-alcoholic steatohepatitis.

Clinical and pathological features were reviewed in 76 Japanese patients with non-alcoholic steatohepatitis (NASH). Forty-one were male and 35 were female with the mean age of 49.7 years old (range 15-75 years old, males; 46.3, females; 53.7 years old). Fifty-four percent of patients were preobese with a body mass index (BMI) between 25 and 30, while 16% of the patients were non-obese, and only 30% of the cases were morbidly obese, indicating that Japanese have a greater tendency to develop insulin-resistance and fatty liver disease than Western people. Hyperlipidemia was found in 51%, diabetes mellitus in 38%, and hypertension in 33% of the patients. Abnormally elevated liver function tests were found in one-third to two-thirds of the patients and were characteristically mild with 2- to 3-fold elevation from the normal range in the majority of the cases. Histological features of the liver were similar or identical to those reported in English literature and were characterized by fatty change, perivenular and pericellular fibrosis in zone 3, hepatocyte ballooning and necrosis with occasional Mallory's body formation and polymorphonuclear leukocyte infiltration. Mallory's bodies were found in 39% of patients and were characteristically small and poorly formed compared with those in alcoholic hepatitis. Eosinophilic granular or dirty foggy aggregated, not sufficient to be identified as Mallory's bodies, were a rather characteristic cytoplasmic expression in NASH patients. Portal inflammation and fibrosis were not found in the early stage of NASH, but were found as the disease progresses with formation of C-C and/or P-C bridging fibrosis, and eventually resulting in liver cirrhosis.

Journal Article↗

PubMed2005

The role of leptin in progression of non-alcoholic fatty liver disease.

Since non-alchoholic steatohepatitis (NASH) is often accompanied with metabolic syndrome comprising obesity, type-2 diabetes and hypertension, it is hypothesized that adipocytokines, insulin resistance and autonomic nervous system play crucial roles in disease progression of NASH. On the other hand, hepatic stellate cells (HSCs) have been shown to produce leptin when they get activated during hepatic fibrogenesis. Therefore, we investigated the role of leptin in fibrogenesis in the liver. Xenobiotics-induced liver fibrosis was extremely diminished in ob/ob mice and Zucker (fa/fa) rats, an inborn leptin- and leptin receptor (Ob-R)-deficient animal, respectively. Further, leptin increased transforming growth factor (TGF)-beta mRNA in isolated sinusoidal endothelial cells and Kupffer cells, suggesting that leptin promotes hepatic fibrogenesis through up-regulation of TGF-beta in the liver. Moreover, leptin augmented PDGF-dependent proliferation of HSCs by enhancing downstream intracellular signaling pathways via mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/Akt. Taken together, it is postulated that leptin acts as a profibrogenic cytokine in sinusoidal microenvironment. These findings indicate that leptin is one of the key regulators for inflammation and progression of fibrosis in various chronic liver diseases including NASH.

Journal Article↗

PubMed2005

Hepatocyte-specific Pten-deficient mice as a novel model for nonalcoholic steatohepatitis and hepatocellular carcinoma.

Phosphatase and tensin homolog (PTEN) is a multifunctional phosphatase whose substrate is phosphatidylinositol-3,4,5-triphosphate (PIP3), and it is also a ubiquitously expressed tumor suppressor gene that down-regulates phosphatidylinositol-3-kinases (PI3Ks). Although there are a few reports about PTEN related to hepatocellular carcinoma, the role of PTEN in the liver remains unclear. Therefore, to clarify the role of PTEN in the liver, we generated and analyzed hepatocyte-specific Pten-deficient mice (Pten-deficient mice). The liver of 40-week-old Pten-deficient mice revealed macrovesicular steatosis, ballooning hepatocytes, lobular inflammatory cell infiltration, and perisinusoidal fibrosis that are characteristic of human nonalcoholic steatohepatitis (NASH). By 80 weeks of age, 100% of Pten-deficient livers showed adenomas and 66% had hepatocellular carcinomas. Thus, PTEN is important for the prevention of adipogenic and tumorigenic transformation, and Pten-deficient mice are a novel model for NASH and hepatocellular carcinoma. Our results suggest that the controlled blocking of molecules acting downstream of PI3K might provide significant therapeutic benefit to patients predisposed to NASH and hepatocellular carcinoma.

Journal Article↗

PubMed2005

Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.

Journal Article↗

PubMed2004

Pathologic features associated with fibrosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopatholologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis. Although steatosis alone seems to be nonprogressive, some patients with NASH can progress. This study focuses on the clinical and pathological characteristics of patients with NAFLD associated with the development of histological fibrosis. Patients with an established diagnosis of nonalcoholic fatty liver were identified through our NAFLD database containing extensive clinical, demographic, and laboratory data. Liver biopsy specimens were read blindly by one hepatopathologist using a 19-item pathological protocol and by another hepatopathologist using a second pathological protocol. Clinical and pathological data were matched to the presence of different types of histological fibrosis. Univariate and multivariate analyses helped determine all of the variables independently associated with histological fibrosis. Of 132 NAFLD patients, 21.2% had advanced fibrosis (septal/bridging fibrosis or well-established cirrhosis). Sinusoidal fibrosis was present in 20.3% of patients, whereas perivenular fibrosis was seen in 17.2%. Ballooning degeneration and Mallory bodies were independently associated with both sinusoidal fibrosis and perivenular fibrosis. Aspartate aminotransferase/alanine aminotransferase ratio and ballooning degeneration were also independently associated with periportal-portal fibrosis. We conclude that the presence of hepatocyte injury in NAFLD is associated with fibrosis. These pathological features can be used to establish the pathological criteria for diagnosis of the progressive form of NAFLD or NASH.

Adult↗

PubMed2005

Effects of calibration on L-THIA GIS runoff and pollutant estimation.

Urbanization can result in alteration of a watershed's hydrologic response and water quality. To simulate hydrologic and water quality impacts of land use changes, the Long-Term Hydrologic Impact Assessment (L-THIA) system has been used. The L-THIA system estimates pollutant loading based on direct runoff quantity and land use based pollutant coefficients. The accurate estimation of direct runoff is important in assessing water quality impacts of land use changes. An automated program was developed to calibrate the L-THIA model using the millions of curve number (CN) combinations associated with land uses and hydrologic soil groups. L-THIA calibration for the Little Eagle Creek (LEC) watershed near Indianapolis, Indiana was performed using land use data for 1991 and daily rainfall data for six months of 1991 (January 1-June 30) to minimize errors associated with use of different temporal land use data and rainfall data. For the calibration period, the Nash-Sutcliffe coefficient was 0.60 for estimated and observed direct runoff. The calibrated CN values were used for validation of the model for the same year (July 1-December 31), and the Nash-Sutcliffe coefficient was 0.60 for estimated and observed direct runoff. The Nash-Sutcliffe coefficient was 0.52 for January 1, 1991 to December 31, 1991 using uncalibrated CN values. As shown in this study, the use of better input parameters for the L-THIA model can improve accuracy. The effects on direct runoff and pollutant estimation of the calibrated CN values in the L-THIA model were investigated for the LEC. Following calibration, the estimated average annual direct runoff for the LEC watershed increased by 34%, total nitrogen by 24%, total phosphorus by 22%, and total lead by 43%. This study demonstrates that the L-THIA model should be calibrated and validated prior to application in a particular watershed to more accurately assess the effects of land use changes on hydrology and water quality.

Calibration↗

PubMed1999

Insulin resistance-associated hepatic iron overload.

BACKGROUND & AIMS: Hepatic iron overload has been reported in various metabolic conditions, including the insulin-resistance syndrome (IRS) and nonalcoholic steatohepatitis (NASH). The aim of this study was to show that such hepatic iron overload is part of a unique and unrecognized entity. METHODS: A total of 161 non-C282Y-homozygous patients with unexplained hepatic iron overload were included. We determined the age; sex; presence of IRS (1 or more of the following: body mass index of >25, diabetes, or hyperlipidemia); serum iron tests and liver iron concentration (LIC; reference value, <36 micromol/g); liver function test results; C282Y and H63D HFE mutations; and liver histological status. RESULTS: Patients were predominantly male and middle-aged. Most (94%) had IRS. Transferrin saturation was increased in 35% (median, 42%; range, 13%-94%). LIC ranged from 38 to 332 micromol/g (median, 90 micromol/g), and LIC/age ratio ranged from 0.5 to 4.8 (median, 1.8). Allelic frequencies of both HFE mutations were significantly increased compared with values in normal controls (C282Y, 20% vs. 9%; H63D, 30% vs. 17%), only because of a higher prevalence of compound heterozygotes. Patients with no HFE mutations had similar degrees of iron overload as those with other genotypes, except for compound heterozygotes, who had slightly more iron burden. Steatosis was present in 25% of patients and NASH in 27%. Portal fibrosis (grades 0-3) was present in 62% of patients (grade 2 or 3 in 12%) in association with steatosis, inflammation, and increased age. Sex ratio, IRS, transferrin saturation, and LIC did not vary with liver damage. Serum ferritin concentration, liver function test results, and fibrosis grade were more elevated in patients with steatosis and NASH than in others, but LIC and allelic frequencies of HFE mutations were similar. CONCLUSIONS: This study shows that patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and the nearly constant association of an IRS irrespective of liver damage.

Adult↗