Terese Haaland

Hepatitis C Infection in Patients with Primary Hypogammaglobulinemia after Treatment with Contaminated Immune Globulin

BACKGROUND In Scandinavia many patients with primary hypogammaglobulinemia contracted non-A, non-B hepatitis after intravenous treatment with an immune globulin product that was later found to contain a non-A, non-B hepatitis virus. METHODS We studied the prevalence and clinical course of hepatitis C virus (HCV) infection in a group of 55 Norwegian patients with primary hypogammaglobulinemia and investigated its association with the use of contaminated immune globulin. We used the polymerase chain reaction to detect HCV RNA and performed HCV genotyping. We also analyzed the responses to treatment with interferon. RESULTS Of 20 patients who received the contaminated immune globulin, 17 were seropositive for HCV RNA: In addition, 1 of 35 patients not exposed to the contaminated immune globulin was HCV RNA--positive. HCV genotype V was found in all 12 patients for whom genotyping was performed, but 8 patients also had genotype II or III, or both. All HCV RNA--positive patients had abnormal results on biochemical liver tests. All liver-biopsy specimens (from 15 patients) were abnormal, with portal inflammation, bile-duct damage, and focal necrosis. In six patients there was cirrhosis. Two patients died of liver failure. In 4 of the 10 patients treated with interferon there were complete, though transient, biochemical responses, but the follow-up biopsy specimens showed evidence of histologic progression. The poorest responses to interferon were among the patients with multiple HCV genotypes. All but one patient remained positive for HCV RNA: CONCLUSIONS In patients with primary hypogammaglobulinemia there was a high rate of HCV infection after treatment with contaminated immune globulin. In these immunocompromised patients HCV infection has a severe and rapidly progressive course, and responses to interferon are poor.

Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial

Objective. The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease. Material and methods. Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers. Results. No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p<0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p<0.001), glucose (p=0.032) and on HbA1c (p=0.020). Conclusions. Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537)

Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies

OBJECTIVE Fetuin A has been associated with insulin resistance and the metabolic syndrome. We therefore explored the role of fetuin A in nonalcoholic fatty liver disease (NAFLD). DESIGN Cross-sectional and intervention studies. METHODS We included 111 subjects with histologically proven NAFLD of whom 44 participated in a randomized, controlled trial with metformin. One hundred and thirty-one healthy subjects and 13 subjects undergoing hepatic surgery for metastatic cancer served as controls. Main outcome variables were circulating levels of fetuin A according to the presence of NAFLD, hepatic gene expression of fetuin A and key enzymes in glucose and lipid metabolism, and the effect of metformin on fetuin A levels in vivo and in vitro (HepG2 cells). RESULTS Fetuin A levels were significantly higher in NAFLD patients compared with controls (324 ± 98 vs 225 ± 75 mg/l, P<0.001). NAFLD was a significant predictor of elevated fetuin A levels (β=174 (95% confidence interval: 110-234)) independent of body mass index, age, sex, fasting glucose, and triglycerides. Hepatic fetuin A mRNA levels correlated significantly with hepatic mRNA levels of key enzymes in lipid (sterol regulatory element-binding protein 1c, carnitine palmitoyltransferase 1) and glucose (phosphoenol pyruvate kinase 1, glucose-6-phosphatase) metabolism. Plasma fetuin A levels decreased significantly after metformin treatment compared with placebo (-40 ± 47 vs 15 ± 82 mg/l, P = 0.008). Metformin induced a dose-dependent decrease in fetuin A secretion in vitro. CONCLUSIONS Fetuin A levels were elevated in NAFLD. Hepatic expression of fetuin A correlated with key enzymes in glucose and lipid metabolism. Metformin decreased fetuin A levels in vitro.

Abnormal glucose tolerance is a predictor of steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease.

Objective. The majority of patients with non-alcoholic fatty liver disease (NAFLD) have simple steatosis. A minority, however, present with non-alcoholic steatohepatitis (NASH), a condition that can lead to advanced fibrosis and cirrhosis. The frequencies of NASH and fibrosis among patients with NAFLD and sustained elevation of liver function tests (LFT) are uncertain. Our aim was to estimate these frequencies. We characterize a population with NAFLD, with special emphasis on insulin resistance and the metabolic syndrome, and study possible predictors for different stages of the disease. Material and methods. All referred patients with sustained elevation of LFT, radiological evidence or clinical suspicion of fatty liver, and absence of other liver disease, were invited to participate in our study in the period June 2002 to December 2004. Results. Of 129 patients who met the inclusion criteria, 88 underwent liver biopsy. NAFLD was verified in 83 of them. Among these patients, 59 (71%) had the metabolic syndrome, 41 (49%) had NASH and 36 (43%) had fibrosis. Abnormal glucose tolerance (T2DM or impaired glucose tolerance) was the only independent risk factor for NASH (OR: 3.14; 95% CI: 1.20–8.23). Independent predictors for fibrosis were abnormal glucose tolerance (OR: 3.83; 95% CI: 1.29–11.40) and body mass index (OR: 1.20; 95% CI: 1.06–1.36) per kg/m2. Conclusions. Both NASH and fibrosis are frequently present among patients with NAFLD and sustained elevation of LFT. The probability of these potentially progressive stages of NAFLD increases with the presence of abnormal glucose tolerance.

Intracellular Nicotinamide Phosphoribosyltransferase Protects against Hepatocyte Apoptosis and Is Down-Regulated in Nonalcoholic Fatty Liver Disease

CONTEXT Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western and non-Western countries, but its pathogenesis is not fully understood. OBJECTIVE Based on the role of nicotinamide phosphoribosyltransferase (NAMPT) in fat and glucose metabolism and cell survival, we hypothesized a role for NAMPT/visfatin in the pathogenesis of NAFLD-related disease. DESIGN AND SETTING We conducted clinical studies at a referral medical center in well-characterized NAFLD patients (n = 58) and healthy controls (n = 27). In addition we performed experimental in vitro studies in hepatocytes. MAIN OUTCOME MEASURES We examined 1) the hepatic and systemic expression of NAMPT/visfatin in patients with NAFLD and control subjects, 2) the hepatic regulation of NAMPT/visfatin, and 3) the effect of NAMPT/visfatin on hepatocyte apoptosis. RESULTS Our main findings were as follows. 1) Patients with NAFLD had decreased NAMPT/visfatin expression both systemically in serum and within the hepatic tissue, with no difference between simple steatosis and nonalcoholic steatohepatitis. 2) By studying the hepatic regulation of NAMPT/visfatin in wild-type and peroxisome proliferators-activated receptor (PPAR)alpha(-/-) mice as well as in hepatocytes, we showed that PPARalpha activation and glucose may be involved in the down-regulation of hepatic NAMPT/visfatin expression in NAFLD. 4) Within the liver, NAMPT/visfatin was located to hepatocytes, and our in vitro studies showed that NAMPT/visfatin exerts antiapoptotic effects in these cells, involving enzymatic synthesis of nicotinamide adenine dinucleotide. CONCLUSION Based on these findings, we suggest a role for decreased NAMPT/visfatin levels in hepatocyte apoptosis in NAFLD-related disease.

Hepatobiliary disease in ulcerative colitis. An analysis of 18 patients with hepatobiliary lesions classified as small-duct primary sclerosing cholangitis.

BACKGROUND The aim of the present study was to describe the characteristics of patients with ulcerative colitis (UC) and hepatobiliary disease that does not satisfy the diagnostic cholangiographic criteria of primary sclerosing cholangitis (PSC) and to compare this group with PSC patients. METHODS Among 199 patients with UC admitted to our department during 1986-91, 64 patients had major hepatobiliary disease considered to be associated with the colitis. Biochemical tests, colonoscopy, endoscopic retrograde cholangiography (ERC), and liver biopsy were performed in these 64 patients and in 5 patients from our outpatient clinic. RESULTS PSC was diagnosed in 51 patients (group I; 80%). The other 13 patients (20%) and the additional 5 patients (n = 18; group II) all had normal extrahepatic bile ducts. Five patients in group II also had normal intrahepatic ducts, whereas 13 patients had intrahepatic abnormalities. The male to female ratio in group II was 2.0:1. All of them had extensive colitis. The clinical symptoms and the biochemical and histologic findings were quite similar in groups I and II. CONCLUSIONS The patients in group II of this study constitute a major group with hepatobiliary lesions associated with UC, amounting to one-fourth the number of PSC patients. They have several similarities with classical PSC of the large bile ducts, and we suggest that they be classified as having small-duct PSC.

A Complex Role of Activin A in Non-Alcoholic Fatty Liver Disease

OBJECTIVES:Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD).METHODS:Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes.RESULTS:Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A–follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-β1, promoted matrix metalloproteinase activity, induced mitochondrial β-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs.CONCLUSIONS:Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation.

Combining transient elastography with FIB4 enhances sensitivity in detecting advanced fibrosis of the liver

Abstract Objective. To evaluate the predictive value of transient elastography (TE), easy available biochemical scores and a combination of these to detect advanced liver fibrosis (i.e. fibrosis stage ≥F3) in patients with chronic liver disease of different etiologies. Material and methods. A valid TE was obtained in 418 patients with chronic liver disease of mixed etiologies during the period of 2007–2010. Reliable fibrosis staging and biochemical data for calculation of APRI, FIB4, and AST/ALT-ratio (AAR) were available in 187 cases of which 50 had clinical obvious cirrhosis. Logistic regression analyses were performed to investigate if biochemical scores were significant predictors of advanced fibrosis independent of TE. Results. In the whole group, TE correlated significantly with APRI and FIB4 but not with AAR. In patients with TE ≥7 kPa, a new formula combining TE and FIB4 improved the accuracy for detecting advanced fibrosis. Area under the receiver operating characteristic curve (AUROC) and sensitivity for the combined formula was 0.94 and 0.92, respectively, as opposed to 0.90 and 0.87 for TE alone. After exclusion of cases with clinical obvious cirrhosis, only FIB4 was a significant predictor of advanced liver fibrosis independent of TE. A combined formula gave a marginally improved AUROC in this group. Conclusions. Our findings suggest that the combination of TE and FIB4 is useful in the prediction of advanced fibrosis. The effect of this combination was marginal when only asymptomatic patients were included. Larger studies are needed to see if this effect is statistically significant and to detect possible differences according to etiology.

Liver transplantation for endstage hepatitis C cirrhosis in a patient with primary hypogammaglobulinaemia.

Liver transplantation was performed in a patient with primary hypogammaglobulinaemia, chronic hepatitis C and hepatic failure. The immediate posttransplant period was uncomplicated. Owing to a stricture of the choledochojejunostomy the patient was reoperated with construction of a hepaticojejunostomy 11 months posttransplant. The patient remained hepatitis C virus (HCV) RNA-positive, with high and increasing levels of HCV. Liver biopsies demonstrated the recurrence of HCV. 14 months after the transplantation the patient developed severe diarrhoea caused by Cryptosporidium parvum. The infection did not respond to available therapeutic measures. He deteriorated with development of liver failure and died 18 months after the transplantation. The present case report illustrates the difficulties associated with organ transplantation in patients with primary hypogammaglobulinaemia.