Non-alcoholic Steatohepatitis Activity Score Research Articles

Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice.

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome (MS). Monosodium glutamate (MSG)-treated ICR mice is a useful model of MS and NASH, but it shows the different patterns of steatosis from human NASH. Because inbred aged DIAR (ddY, Institute for Animal Reproduction) mice spontaneously show the similar pattern of steatosis as NASH, we analyzed their liver pathology after administering MSG. MSG-treated DIAR mice (DIAR-MSG) and untreated DIAR mice (DIAR-controls) were sacrificed and assessed histopathologically at 29, 32, 40, 48, and 54 weeks of age. The NASH activity score, body mass index, blood glucose level, and oral glucose tolerance test were also assessed. The body mass index and blood glucose levels of DIAR-MSG were significantly higher than controls. The oral glucose tolerance test revealed a type 2 diabetes pattern in DIAR-MSG. The livers of DIAR-MSG mice showed macrovesicular steatosis, lobular inflammation with neutrophils, and ballooning degeneration after 29 weeks. At 54 weeks, mild fibrosis was observed in 5/6 DIAR-MSG and 2/5 DIAR-control mice. In imaging mass spectrometry analysis, cholesterol as well as triglyceride accumulated in the liver of DIAR-MSG mice. Atypical liver nodules were also observed after 32 weeks in DIAR-MSG, some with cellular and structural atypia mimicking human hepatocellular carcinoma. The NASH activity score of DIAR-MSG after 29 weeks was higher than that of control mice, suggesting the development of NASH. DIAR-MSG had NASH-like liver pathology and liver nodules typically associated with MS symptoms. DIAR-MSG provides a valuable animal model to analyze NASH pathogenesis and carcinogenesis.

Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J).

Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle-related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon-like peptide-1 receptor agonist that affects the histological findings in patients with non-alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy-proven NASH. After lifestyle modification intervention for 24 weeks, subjects whose hemoglobin A1c levels failed to improve to less than 6.0% and/or whose alanine aminotransferase levels were not lower than baseline, received liraglutide at 0.9 mg/body per day for 24 weeks. Of 27 subjects, 26 completed the lifestyle modification intervention. Nineteen subjects received liraglutide therapy for 24 weeks. Body mass index, visceral fat accumulation, aminotransferases and glucose abnormalities improved significantly. Repeated liver biopsy was performed in 10 subjects who continued liraglutide therapy for 96 weeks. Six subjects showed decreased histological inflammation as determined by NASH activity score and stage determined by Brunt classification. We saw no significant adverse events during therapy with liraglutide. Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance.

The relationship between advanced oxidation protein products (AOPP) and biochemical and histopathological findings in patients with nonalcoholic steatohepatitis

To investigate the correlation between advanced oxidation protein products (AOPP) levels and biochemical and histopathological findings in patients with nonalcoholic steatohepatitis (NASH). Sixty biopsy-proven NASH patients and 60 individuals with ultrasonographically healthy liver (the control group) were included in the study. AOPP levels were determined in all the participants and liver histopathological examination based on liver biopsy was performed in NASH patients. The NASH activity score (NAS), hepatosteatosis, liver inflammation and fibrosis were evaluated. Serum AOPP level was significantly higher in the NASH group than that in the control group (461.8 ± 201.9 μmol/L vs 191.7 ± 152.5 μmol/L, P < 0.001). The receiver operating characteristic (ROC) curve revealed a sensitivity of 73.3% and a specificity of 88.3% for the diagnosis of NASH with an AOPP cut-off value of 332 μmol/L (the area under ROC curve 0.88, 95% confidence interval 0.82-0.94, P < 0.01). AOPP levels were positively correlated with NAS (r = 0.27, P = 0.035), fibrosis (r = 0.27, P = 0.037) and inflammation (r = 0.34, P = 0.008), but not the grade of steatosis (r = 0.02, P = 0.83) or ballooning (r = 0.02, P = 0.55). AOPP levels are significantly higher in patients with NASH than in those with ultrasonographically healthy liver. AOPP levels are positively correlated with biochemical and histopathological findings (NAS, liver inflammation and fibrosis), indicating that AOPP may play a role in the development of liver fibrosis and inflammation and may predict liver histopathology in NASH.

Hepatology Highlights

Hepatology Highlights

Obstructive Sleep Apnea Syndrome Affects Liver Histology and Inflammatory Cell Activation in Pediatric Nonalcoholic Fatty Liver Disease, Regardless of Obesity/Insulin Resistance

Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown. To assess the relationship of OSAS with liver injury in pediatric NAFLD. Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h. Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.

Cholecystectomy is a Predictor of Taking Liver Biopsy in Patients with Steatohepatitis-Related Liver Disease

Purpose: Steatohepatitis (SH)-related liver disease due to either alcohol use (ASH) or non-alcoholic steatohepatitis (NASH) is a common cause of cirrhosis and liver transplantation in the US. Although imperfect, liver biopsy is a definitive method of diagnosing SH and assessing its severity. However, liver biopsy is not always performed in clinical practice, and often, a diagnosis of SH is made clinically by exclusion of other causes of liver disease and history of alcohol use. We performed retrospective analysis to determine factors predictive of taking a liver biopsy among SH-related liver disease patients. Methods: Patients with SH-related liver disease, including ASH and NASH, managed at a single tertiary care center (2007-2011) were stratified based on receipt of liver biopsy for confirming diagnosis. Chisquare and t-tests were used for comparing categorical and continuous variables, respectively. Logistic regression model was built to assess factors associated with taking liver biopsy for diagnosing SH, its etiology, and assess its severity. Data were reported as odds ratio (OR) with 95% confidence interval (CI). Results: ASH patients (N=226) presented more often to clinician with symptoms of cirrhosis or its complications compared to NASH (69 vs. 27%; P<0.0001). Comparing 110 (22%) patients receiving liver biopsy to 391 non-biopsied cases, those undergoing liver biopsy differed for: female gender (53 vs. 42%; P=0.03), history of cholecystectomy (49 vs. 29%; P=0.0001), NASH diagnosis (73 vs. 50%; P<0.0001), asymptomatic presentation (71 vs. 49%; P<0.0001), median ALT (61 vs. 48; P=0.03), and MELD score (8 vs. 11; P=0.005). Age, race, and proportion of metabolic syndrome components, steatosis on imaging, cirrhosis, and HCC were similar. After controlling for significantly different and clinically relevant variables, patients undergoing liver biopsy were over two-fold more likely to have had cholecystectomy: OR [95% CI] of 2.1 [1.3-3.5]. Histology details available on 95 (70 NASH) biopsies showed NASH patients to differ from ASH for: steatosis >33% of hepatocytes (62 vs. 41%; P=0.03), lobular inflammation (94 vs. 72%; P=0.03), trend for higher NASH activity score (3.7±1.5 vs. 2.8±1.9; P=0.058), and lower stage 3 or 4 fibrosis (54 vs. 72%; P=0.15). Conclusion: About 2/3 of biopsies in SH-related liver disease is taken at the time of cholecystectomy. Most of these biopsies are taken for NASH patients. Studies are needed to examine whether taking routine liver biopsy at laparotomy for alcoholics is helpful in improving patient adherence to alcohol abstinence and in early diagnosis of liver disease related to ASH.

Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder in developed countries in the context of the global obesity epidemic. A two-stage metabolic screening of human liver biopsies (discovery set: N=33; replication set: N=66) including the range from normal liver histology to severe non-alcoholic steatohepatitis (NASH) analysed the correlation of 252 metabolites to the histological NASH activity score. Six metabolites passed correction for multiple testing in the discovery set and two of those, namely hydroquinone (HQ, pcombined=3.0×10–4) and nicotinic acid (NA, pcombined=3.9×10–9) were confirmed in the replication set to be inversely correlated with histological NASH activity. Upon evaluation of these two substances in a murine high-fat diet model of NAFLD, NA showed a significant hepatoprotective effect by reducing liver fat content by 75% (p=0.001) and serum liver enzyme levels (p=0.009), whereas hydroquinone reduced only liver steatosis (p=0.0004), without improvements of serum liver enzyme levels (p=0.24) upon sacrifice after six weeks. Global analysis of gene expression in the sacrificed mice revealed involvement of the hepatocyte nuclear factor 4, alpha (HNF4A), a key regulator of hepatic metabolic transcripts and bax inhibitor 1 (TMBIM6), which is involved in the unfolded protein response and fibroblast growth factor 19 (FGF19), a key regulator of energy metabolism as pathways in the mechanism of action of NA. In summary, targeting these pathways through the use of NA or other compounds may be a promising mode to treating or preventing human NAFLD.

A Prospective Evaluation of Transient Elastography in Non-Alcoholic Fatty Liver Disease - BMI and Subcutaneous Fat Thickness Do Not Affect Accuracy

Purpose: Transient elastography (TE) has emerged as an important non-invasive technique of evaluating hepatic fibrosis. However, recent data suggest that greater hepatic steatosis may downgrade TE values relative to the degree of hepatic fibrosis on biopsy in nonalcoholic fatty liver disease (NAFLD) patients. This prospective study evaluates the relationship between TE values and hepatic steatosis as measured on magnetic resonance imaging (MRI) of the liver. Other variables which may affect TE accuracy in NAFLD were also investigated, including higher patient body mass index (BMI) and greater subcutaneous fat overlying the liver. Methods: All adult patients at a tertiary care centre in London, Canada, who met diagnostic criteria for NAFLD were invited to participate in this study. All patients underwent liver biopsy, TE and had anthropomorphic measurements, liver transaminases and measures of metabolic dysfunction measured. Liver biopsies were read by a single, blinded pathologist and scored according to the validated nonalcoholic steatohepatitis activity score (NAS). The FibroScan 502 system (Echosens) was used to conduct TE measurements for all study patients. Subcutaneous fat and hepatic steatosis measured as hepatic fat fraction was measured using Magnetic Resonance Imaging with Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL-MRI), a computer-based quantification method separating fat and water signals in MRI images allowing accurate, validated and reproducible measurement of subcutaneous fat thickness. Linear regression analysis was used to evaluate the correlation between BMI and TE values; subcutaneous fat thickness and TE values; and degree of fibrosis on liver biopsy and TE values. Results: Linear regression demonstrated a positive correlation between TE values and the degree of fibrosis on liver biopsy (P<0.001). There was no correlation between subcutaneous fat thickness and TE values (P=0.699), between BMI and TE values (P=0.883), between subcutaneous fat thickness and liver fibrosis score (p=0.183), nor between BMI and liver fibrosis score (p=0.057). There was no correlation between hepatic fat fraction and TE values (p=0.152), nor hepatic fat fraction and liver fibrosis score (p=0.0118). Conclusion: This study demonstrates that TE correlates well with the degree of hepatic fibrosis on liver biopsy in NAFLD patients, and suggests that common anthropomorphic features of such patients such as increased hepatic steatosis, increased BMI, and peri-hepatic subcutaneous fat does not adversely affect the reliability of TE. This finding supports the continued use of this important diagnostic modality in a population that is becoming increasingly prevalent.

Noninvasive Assessment of Nonalcoholic Fatty Liver Disease in Obese or Overweight Patients

Reliable noninvasive tools are needed for staging nonalcoholic fatty liver disease (NAFLD). Published scoring systems have not been validated in prospective assessments of unselected patients. We aimed to identify factors that predicted development of nonalcoholic steatohepatitis (NASH) in a large group of overweight or obese patients and compared these with established factors. We performed a prospective analysis of factors associated with the development and severity of NAFLD in patients at a single obesity center. We evaluated liver involvement in 542 patients by a large set of routine and non-routine parameters, including ultrasound and genetic testing. Those suspected of having NAFLD underwent liver biopsy (57.7%). Patients were divided into design cohort (n = 200) and validation cohort (n = 113) to identify factors associated with the presence and severity of NAFLD and NASH. Factors independently associated with development of NASH included increased levels of alanine aminotransferase (ALT), fasting levels of C-peptide, and ultrasound steatosis scores (USSs), with area under the receiver operating curve (AUROC) values of 0.854 in the design cohort and 0.823 in the validation cohort. NASH activity scores also correlated with level of ALT, USS, and fasting level of C-peptide (R(2) = 0.491). Independent predictors of advanced fibrosis included waist circumference and level of aspartate aminotransferase (AUROC values of 0.839 and 0.846 for design and validation cohorts, respectively; negative predictive values of 98% and 97%, respectively, for a cutoff of -2.14). Previously published scoring systems had significantly lower AUROC values. Levels of CK18 and PNPLA3 polymorphisms correlated with development of NASH but did not add value. Parameters routinely analyzed in assessing obese patients can be used to determine the presence of NASH and advanced fibrosis. Non-routine tests do not increase diagnostic accuracy. Previously published scores are significantly less accurate.

Ezetimibe reduces fatty acid quantity in liver and decreased inflammatory cell infiltration and improved NASH in medaka model

PurposeWe previously developed medaka non-alcoholic steatohepatitis (NASH) model. The model showed similar histology with human NASH so we analyzed the effect of drug using medaka NASH activity score (MNAS). In this study we analyzed the effect of ezetimibe, a small intestine cholesterol transporter inhibitor, on NASH. MethodsMedaka NASH model showed steatohepatits with infiltration of D-PAS positive inflammatory cell. In this study we induced medaka NASH and compared the effect of ezetimibe on medaka NASH by HFD. ResultsAs compared with the HFD group, ezetimibe reduced total cholesterol and triacyglycerol in the blood. But concerning with liver quantity of fatty acids in the liver were significantly decreased by ezetimibe. Genes related with fatty acid metabolism in liver was also decreased by ezetimibe administration. On histological observations of the liver, increases in the number of inflammatory cells and MNAS were inhibited. With this decrease of fatty acid in liver, medaka NASH was improved by ezetimibe. ConclusionEzetimibe was clarified as a useful drug to improve NASH.

PPARα Expression Protects Male Mice from High Fat–Induced Nonalcoholic Fatty Liver1–3

Emerging evidence suggests that the lack of PPARα enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD). Thus, the aim of this study was to determine whether Ppara-null mice are more susceptible to nonalcoholic steatohepatitis (NASH) than their wild-type (WT) counterparts following short-term feeding with a HFD. Age-matched male WT and Ppara-null mice were randomly assigned to consume ad libitum a standard Lieber-DeCarli liquid diet (STD) (35% energy from fat) or a HFD (71% energy from fat) for 3 wk. Liver histology, plasma transaminase levels, and indicators of oxidative/nitrosative stress and inflammatory cytokines were evaluated in all groups. Levels of lobular inflammation and the NASH activity score were greater in HFD-exposed Ppara-null mice than in the other 3 groups. Biochemical analysis revealed elevated levels of ethanol-inducible cytochrome P450 2E1 and TNFα accompanied by increased levels of malondialdehyde as well as oxidized and nitrated proteins in Ppara-null mice. Elevated oxidative stress and inflammation were associated with activation of c-Jun-N-terminal kinase and p38 kinase, resulting in increased hepatocyte apoptosis in Ppara-null mice fed a HFD. These results, with increased steatosis, oxidative stress, and inflammation observed in Ppara-null mice fed a HFD, demonstrate that inhibition of PPARα functions may increase susceptibility to high fat-induced NASH.

Telmisartan improves nonalcoholic steatohepatitis in medaka (Oryzias latipes) by reducing macrophage infiltration and fat accumulation

We investigated the efficacy of the antihypertensive drug telmisartan (Tel) and the mechanisms underlying the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) in a medaka (Oryzias latipes) NASH model. We used the NASH activity score (NAS) developed in humans to assess the histology of the medaka NASH model and found that NAS increased with time. Further, TUNEL-positive apoptosis hepatocytes were found in the medaka NASH model. Tel administration resulted in the increased expression of liver peroxisome proliferator-activated receptor-γ, carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 and decreased the number of 8-hydroxydeoxyguanosine-positive hepatocytes and the migration of macrophages positive for diastase-periodic-acid-Schiff. Medaka NAS was improved by Tel administration but fatty acid content was not affected. Tel reduced the infiltration of macrophages into the liver and ameliorated NASH pathology.

Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial

Short-term trials of glitazones in nonalcoholic steatohepatitis (NASH) yielded controversial histological results. Longer treatment might result in additional improvement. After a 1-year randomized trial, 53 patients underwent a control liver biopsy and were enrolled in an open-label extension trial of rosiglitazone (RSG), 8 mg/day for 2 additional years. In all, 44 completed the extension phase including 40 with a third liver biopsy. Of these, 22 received placebo (PLB) in the randomized phase (PLB-RSG), and 18 RSG (RSG-RSG). During the 2-year extension phase serum insulin decreased by 26%, homeostasis model assessment (HOMA) by 30%, and alanine aminotransferase (ALT) by 24%. However, there was no significant change in the mean NASH activity score (NAS) (3.8 +/- 2.11 versus 3.68 +/- 1.8), ballooning score, fibrosis stage (1.76 +/- 1.18 versus 1.85 +/- 1.19), or area of fibrosis by micromorphometry (4.43% +/- 0.68 to 5.54% +/- 0.68). In the PLB-RSG group steatosis significantly decreased after 2 years of RSG (median decrease of 15%); in the RSG-RSG group, after an initial decline in the first year of 20%, 2 additional years of RSG did not result in further improvement. Likewise, there was no improvement in the NAS score, ballooning, intralobular inflammation, fibrosis stage, or area of fibrosis with 2 additional years of RSG in the RSG-RSG group. Rosiglitazone has a substantial antisteatogenic effect in the first year of treatment without additional benefit with longer therapy despite a maintained effect on insulin sensitivity and transaminase levels. This suggests that improving insulin sensitivity might not be sufficient in NASH and that additional targets of therapy for liver injury should be explored.

The Histologic Spectrum of Liver Disease in African-American, Non-Hispanic White and Hispanic Obesity Surgery Patients

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease in African Americans, non-Hispanic whites, and Hispanics. The aim of this study was to evaluate ethnic differences in the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH) and to compare the severity of histologic features of NASH in obesity surgery patients. Subjects consisted of 238 patients who had a routine liver biopsy at the time of obesity surgery. Demographic and clinical variables pertaining to the metabolic syndrome were collected retrospectively. Liver biopsies were evaluated according to the scoring system proposed by the Nonalcoholic Steatohepatitis Clinical Research Network and NASH was defined as a NASH activity score > or =5. African Americans had lower rates of steatosis than non-Hispanic whites (P<0.001) and Hispanics (P=0.03). Among patients with steatosis, African Americans had lower rates of NASH than non-Hispanic whites (P=0.05) and Hispanics (P=0.02) and lower rates of fibrosis score > or =F2 than non-Hispanic whites (P=0.002) and Hispanics (P=0.04). Ethnic differences in rates of NAFLD, NASH, and fibrosis > or =F2 persisted when controlling for demographic variables and features of the metabolic syndrome in logistic regression analysis. There were no significant differences in steatosis, NASH, or fibrosis > or =F2 between non-Hispanic whites and Hispanics. African-American obesity surgery patients have a lower rate of NAFLD, NASH, and less severe fibrosis than non-Hispanic whites and Hispanics.

Increased Expression and Activity of the Transcription Factor FOXO1 in Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver, affecting 34% of the U.S. population, is characterized by hepatic insulin resistance, which is more marked in the presence of steatohepatitis, and frequently precedes hyperglycemia. The molecular mechanisms underlying the relationship between fatty liver and insulin resistance are still undergoing definition and have not been evaluated in humans. Our aim was to evaluate the relationship between insulin resistance and the expression and regulation of forkhead box-containing protein O subfamily-1 (FOXO1), a transcription factor that mediates the effect of insulin on the gluconeogenic genes PEPCK and glucose-6-phosphatase catalytic subunit (G6PC). FOXO1, PEPCK, and G6PC mRNA levels were evaluated in 84 subjects: 26 with steatohepatitis, 28 with steatosis alone, 14 with normal liver histology without metabolic alterations, and 16 with hepatitis C virus chronic hepatitis, of whom 8 were with and 8 were without steatosis. Protein expression and regulation of FOXO1 and upstream insulin signaling were analyzed in a subset. RESULTS; Expression of PEPCK was higher in steatohepatitis compared with steatosis alone and normal liver, and it was correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) index. FOXO1 mRNA levels were higher in steatohepatitis, correlated with PEPCK and G6PC mRNA and with HOMA-IR. FOXO1 upregulation was confirmed at protein levels in steatohepatitis and, in the presence of oxidative stress, was associated with decreased Ser(256) phosphorylation, decreased Akt1, and increased Jun NH(2)-terminal kinase-1 activity. Consistently, immunohistochemistry showed increased FOXO1 expression and nuclear localization in steatohepatitis. FOXO1 mRNA levels correlated with nonalcoholic steatohepatitis activity score and were modulated by drugs counteracting hepatic lipogenesis. FOXO1 expression and activity are increased in patients with steatohepatitis, and mRNA levels are correlated with hepatic insulin resistance.

Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations

Equitani et al. (1) reported on the effect of iron depletion by phlebotomy on insulin resistance and release in 17 carriers of mutations of hereditary hemochromatosis HFE gene with nonalcoholic fatty liver disease (NAFLD). They found that iron depletion ameliorated insulin sensitivity and secretion and reduced hepatic iron stores and nonalcoholic steatohepatitis activity score, and they concluded that results justify glucose tolerance testing and preventive iron depletion in asymptomatic carriers …

Combination of N‐acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non‐alcoholic steatohepatitis

There is no proven medical therapy for the treatment of non-alcoholic steatohepatitis (NASH). Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. The aim of our study was to evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) in improving the aminotransferases and histological parameters (steatosis, inflammation, hepatocellular ballooning, and fibrosis) after 12 months of treatment. Twenty consecutive patients (mean age 53 +/- 2 years [36-68] and body mass index [BMI] 29 [25-35]) with biopsy-proven NASH were enrolled in the study. NAC (1.2 g/day) and MTF (850-1000 mg/day) were given orally for 12 months. All patients underwent evaluation of serum aminotransferases, fasting lipid profile and serum glucose, anthropometric parameters, and nutritional status at 0 and 12 months. A low calorie diet was prescribed for all patients. Serum alanine aminotransferase, high-density lipoprotein, insulin, and glucose concentrations and thehomeostasis model assessment-insulin resistance (HOMA-IR) index were reduced significantly at the end of study (P < 0.05). The BMI declined, but without statistical significance. Aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, cholesterol, and triglycerides levels were not altered with the treatment. Liver steatosis and fibrosis decreased (P < 0.05), but no improvement was noted in lobular inflammation or hepatocellular ballooning. The NASH activity score was significantly improved after treatment. Based on the biochemical and histological evidence in this pilot study, NAC in combination with MTF appears to ameliorate several aspects of NASH, including fibrosis. Further studies of this form of combination therapy are warranted to assess its potential efficacy.

Metabolic Syndrome Is Associated with Greater Histologic Severity, Higher Carbohydrate, and Lower Fat Diet in Patients with NAFLD

Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. Insulin resistance (IR) is a key component of metabolic syndrome. The aim was to determine the dietary composition, physical activity, and histologic severity between NAFLD patients with and without metabolic syndrome. Ninety-one patients with NAFLD completed the Block Food Frequency Questionnaire and the Paffenbarger Physical Activity Questionnaire. IR was assessed by the homeostasis model assessment (HOMA) index. Metabolic syndrome was defined by the ATP III clinical definition. Nonalcoholic steatohepatitis (NASH) Clinical Network Scoring System was used to determine the histologic severity of NAFLD. Thirty-one patients (34%) had metabolic syndrome. Patients with metabolic syndrome had a higher HOMA index (7.66 vs 4.45, p = 0.04), and consumed more carbohydrates (51%vs 45%, p = 0.03) and less fat (34%vs 40%, p = 0.01) compared with those without metabolic syndrome; total daily calorie, protein consumption, and physical activity were similar between the two groups. Patients with metabolic syndrome had higher scores for steatosis (2.0 +/- 0.8 vs 1.37 +/- 1, p = 0.02), NASH activity (4.13 +/- 1.4 vs 3.13 +/- 1.7, p = 0.004), and global NASH score (5.9 +/- 1.7 vs 4.4 +/- 2.3, p = 0.0006) compared with those without metabolic syndrome. When controlled for other factors including dietary composition and physical activity, the presence of metabolic syndrome was a significant risk factor for global NASH severity in addition to HOMA index and female gender. Metabolic syndrome in patients with NAFLD is associated with a diet containing more carbohydrate and less fat and greater histologic severity. The role of a carbohydrate-restricted diet in decreasing the risk for metabolic syndrome and histologic severity should be assessed in patients with NAFLD.