Laparoscopic findings in non‐alcoholic steatohepatitis

Background: Non‐alcoholic steatohepatitis (NASH) is prevalent worldwide, but little attention has been paid to the gross visual appearance of NASH. The present study was performed to address the laparoscopic features of NASH and the relationship between laparoscopic and histologicalal findings. Methods: Eleven patients were examined by laparoscopy with liver biopsy. Histological findings were examined according to the criteria of Brunt et al. with minor modification. Mallory bodies were immunohistochemically detected by an antibody to ubiquitin in addition to hematoxylin eosin staining. Results: Laparoscopic features of NASH were swelling of the liver, formation of many depressions, and dull edges of the liver. When steatosis was present in more than one‐third of lobules, yellowish markings appeared on the liver surface. NASH progressed from a smooth liver surface with or without yellowish markings, to formation of depressions on the liver surface, to cirrhosis with or without hepatocellular carcinoma (HCC). Conclusion: Laparoscopy may provide useful information in the diagnosis and progression of NASH.     

Clinicopathological analysis of non‐alcoholic steatohepatitis

OBJECTIVE : Based on liver biopsy samples collected during the past 10 years, the present study aimed to investigate the incidence of fatty liver, the relationship between fatty liver and other underlying liver diseases, and the clinical and pathological characteristics, and the risk factors of fatty liver. METHODS : From a total of 658 liver biopsy specimens collected from 1988 to 1997, there were 71 cases of fatty liver and 68 cases of non‐alcoholic fatty liver. Matched by sex and age, 155 specimens of non‐fatty liver were used as controls. All patients from which the biopsies were taken were tested for liver function, blood lipid profile, blood glucose and hepatitis virus markers. The liver biopsy samples were all investigated by the same pathologist. RESULTS : The prevalence of fatty liver among all the liver biopsies was 10.8%. The alanine aminotransferase, aspartate aminotransferase, total bilirubin and con‐jugated bilirubin levels in the fatty liver group were significantly lower than those in the non‐fatty liver group, whereas the triglyceride levels were higher. Pathologically, steatosis in patients with fatty liver was mainly located around the hepatic lobules, and macrovesicular steatosis was common. Of the 68 cases of non‐alcoholic fatty liver, hepatic cell necrosis was found in 35 cases (51.5%), inflammatory cell infiltration in 46 cases (67.6%) and fibrosis to various degrees in 19 cases (27.9%). CONCLUSION : Non‐alcoholic fatty liver is closely related to hyperlipidemia. In asymptomatic subjects with abnormal liver function, a liver biopsy is the only way to establish the type and severity of liver lesions.     

The challenge of developing novel pharmacological therapies for non‐alcoholic steatohepatitis

Non‐alcoholic fatty liver disease (NAFLD) is an umbrella term for a series of hepatic pathologies that begin with relatively benign steatosis and can, with appropriate triggers, lead to the serious entity of non‐alcoholic steatohepatitis (NASH). This sets the stage for liver fibrosis and finally the development of cirrhosis in up to 20% of patients with NASH. NAFLD, already among the most common diseases in industrialized countries, is increasing in prevalence and roughly affects 30% of US adults and 10% of US children alone. NAFLD is strongly associated with insulin resistance (IR) and represents the hepatic manifestation of the metabolic syndrome. Indeed, treatments aimed at reducing IR are the current mainstay of therapeutic approaches to NAFLD. While lifestyle interventions may produce limited degrees of success, there remains an urgent need for improved pharmacological therapies. Emerging diagnostic and therapeutic opportunities as well as future developments in NAFLD, NASH and liver fibrosis were discussed by a panel of experts and are presented herein. Promising novel therapeutic targets include inhibitors of dipeptidyl peptidase 4 and the renin–angiotensin system. However, improved non‐invasive technologies to diagnose and stage NAFLD are needed. Combined with a better understanding of the pathophysiological processes that underlie the mechanisms of hepatic fibrogenesis in NASH, rapid clinical validation of novel therapies is expected.     

The effect of the metabolic syndrome, hepatic steatosis and steatohepatitis on liver fibrosis in hereditary hemochromatosis.

OBJECTIVES: The variability in phenotypic expression of hereditary hemochromatosis (HH) is not fully understood. We sought to examine whether the metabolic syndrome, hepatic steatosis or steatohepatitis influenced hepatic fibrosis among patients with HH and iron overload. METHODS: We identified 86 patients with C282Y/C282Y or C282Y/H63D HH and iron overload (hepatic iron concentration (HIC) >2,200 microg/g for males, >1,600 microg/g for females). Features of the metabolic syndrome were assessed at the time of liver biopsy. Biopsies were scored by a blinded pathologist. Significant fibrosis was defined as peri-portal fibrosis or greater. RESULTS: The mean (+/-SD) age of the study population was 53+/-12 years and 68 (79%) were male. The median (range) values of ferritin and HIC were 1,125 (253-9,530) microg/l and 9963 (1926-50 887) microg/g, respectively. The metabolic syndrome was present in 23 (27%), hepatic steatosis in 43 (50%), steatohepatitis in 18 (21%) and significant fibrosis in 38 (44%). Overall, neither the metabolic syndrome nor any of its components were associated with significant fibrosis or a higher mean fibrosis stage. Hepatic steatosis but not steatohepatitis was associated with a lower fibrosis stage. C282Y/H63D compound heterozygous individuals who had glucose intolerance had more severe fibrosis compared with those without glucose intolerance (1.0+/-1.0 vs. 0.1+/-0.3, P=0.01). CONCLUSIONS: Overall, the metabolic syndrome and fatty liver were not associated with hepatic fibrosis among individuals with HH and iron overload. However, glucose intolerance may be important risk factor for the development of hepatic fibrosis in subjects with the C282Y/H63D HFE genotype.     

Systematic review of performance of non‐invasive biomarkers in the evaluation of non‐alcoholic fatty liver disease

This systematic review evaluates the many studies carried out to discover and evaluate non‐invasive markers of non‐alcoholic fatty liver disease (NAFLD). Many different strategies and methods have been used in this task, from the discovery of new markers by global ‘shotgun’ studies to hypothesis‐driven approaches, to the development of algorithm tests based on routinely available clinical and biochemical parameters. We examined the various different approaches, summarising the findings in an attempt to give an overview of the field of non‐invasive markers in NAFLD, encompassing markers of steatosis, necro‐inflammation and fibrosis. The body of literature surrounding this topic is complex and varied, encompassing not only different methodologies but also different patient characteristics, different disease definitions, as well as different end points. This reflects the heterogeneity of NAFLD, which, however, introduces considerably difficulty when trying to draw a conclusion between studies. We have divided this review into three main chapters based on the characteristics of the studies. The Genomics/Proteomics chapter reviews studies using a non‐hypothesis‐driven approach to biomarker discovery. Thereafter, we evaluate studies of association – studies that target‐specific markers, comparing levels between disease and control groups. Finally, we examine the algorithm tests – mathematical systems developed on the basis of previously described markers and assessed, usually, by receiver operator curve analysis. While radiological examination and investigations offer important diagnostic information, such studies are not discussed in this review – the body of literature surrounding blood and anthropological markers is complex and varied, demanding close attention.     

Measurement of spleen volume is useful for distinguishing between simple steatosis and early‐stage non‐alcoholic steatohepatitis

Aim: Although non‐alcoholic fatty liver disease (NAFLD) is now a common cause of chronic liver disease, discriminating between simple steatosis and non‐alcoholic steatohepatitis (NASH), especially early‐stage NASH, remains difficult. We investigated the clinical usefulness of measuring the spleen volume as a marker of early‐stage NASH. Methods: We evaluated computed tomography (CT) images obtained in 84 patients with histologically diagnosed NAFLD (22 with simple steatosis, 62 with NASH with mild fibrosis [stages 1–2]). We defined the data obtained by the following formula as a spleen‐body index (SBI): SBI = maximal CT axial section area of the spleen (cm²)/body surface area (BSA) (cm²) × 10⁴. We compared the SBI between patients with simple steatosis and those with NASH with mild fibrosis. Results: The mean SBI of the simple steatosis group was 15.8 ± 3.9, while that of the NASH with mild fibrosis group was 18.7 ± 5.7. This difference between the two groups was significant (P = 0.0314). A multiple logistic regression analysis showed that the SBI was significantly correlated with the discrimination of simple steatosis and NASH with mild fibrosis. The area under the receiver–operator curve was 0.661 for distinguishing between simple steatosis and NASH with mild fibrosis (P = 0.026, 95% confidence interval = 0.532–0.789). Conclusion: Spleen enlargement may be a distinct feature of NASH, especially early‐stage NASH. SBI might be a non‐invasive and simple method of differentiating NASH and simple steatosis.     

Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non‐alcoholic steatohepatitis

Introduction: One of the proposed second hit mechanisms in the pathophysiology of non‐alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia – disruption of intestinal barrier integrity. Methods: We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5‐h lactulose/mannitol (L/M) ratio and 24‐h sucralose. Permeability testing was repeated after aspirin challenge. Results: Groups had similar baseline urinary 0–5 h L/M ratio (small bowel permeability) and 0–24 h sucralose (whole‐gut permeability). Aspirin increased 0–5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole‐gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6–24 h samples, which points towards the colon as the major site responsible for aspirin‐induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects. Discussion: Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity‐induced abnormal lipid homoeostasis.     

Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non‐alcoholic fatty liver disease patients

Introduction: Differentiation between steatosis and non‐alcoholic steatohepatitis (NASH) in non‐alcoholic fatty liver disease (NAFLD) is important as NASH progress to cirrhosis. No specific laboratory/imaging technique exists either to diagnose NASH or to select patients for liver biopsy. Patients and methods: We evaluated serum ferritin and the features of metabolic syndrome with respect to histological inflammation and/or fibrosis in NAFLD patients. The Kleiner scoring system was used to classify NAFLD in consecutive liver biopsies. One hundred and eleven patients: median age 52.6, 64 males, obesity 62, diabetes mellitus (DM) 58, arterial hypertension 26 and hyperlipidaemia 40%. Results: Histologically, 40.7 had fatty liver, 30.6% had borderline NASH, 28.7% had NASH and 11% had cirrhosis. Multivariate regression showed that diabetes, serum ferritin concentrations, body mass index (BMI) and AST were independently associated with NASH: together, the areas under the receiver operating characteristic (AUROC) was 0.91 (95% confidence interval 0.86–0.96); fibrosis was associated with ferritin concentrations and BMI: AUROC 0.87, portal inflammation with ferritin and DM: AUROC 0.82, while lobular inflammation was associated with BMI, DM and ferritin: AUROC 0.85. Conclusion: Serum ferritin concentrations and BMI are strongly associated with fibrosis, portal and lobular inflammation in NAFLD patients. Both ferritin and BMI are potential discriminant markers to select patients for liver biopsy and are associated with inflammation and fibrosis.