Sampling variability of liver biopsy in nonalcoholic fatty liver disease

BACKGROUND & AIMS: In nonalcoholic fatty liver disease (NAFLD), the distinction between steatosis and steatohepatitis (NASH) and the assessment of the severity of the disease rely on liver histology alone. The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH. METHODS: Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the kappa reliability test. RESULTS: No features displayed high agreement; substantial agreement was only seen for steatosis grade; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis; fair agreement for Mallory bodies; acidophilic bodies and lobular inflammation displayed only slight agreement. Overall, the discordance rate for the presence of hepatocyte ballooning was 18%, and ballooning would have been missed in 24% of patients had only 1 biopsy been performed. The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74. Discordance of 1 stage or more was 41%. Six of 17 patients with bridging fibrosis (35%) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy. Intraobserver variability was systematically lower than sampling variability and therefore could not account for most of the sampling error. CONCLUSIONS: Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies.     

Increased hepatic expression is a major determinant of serum alanine aminotransferase elevation in mice with nonalcoholic steatohepatitis

Background: Serum alanine aminotransferase (ALT) is a biomarker for hepatitis of various aetiologies including fatty liver disease. Increased serum ALT is thought to be related to its increased release from dying hepatocytes. Aim: We sought to understand the mechanisms by which serum ALT is elevated in a mouse model of experimental fatty liver disease where hepatocyte death is minimal. Methods: To induce fatty liver disease, female A/J mice were fed a methionine‐choline deficient (MCD) diet for up to 12 weeks. Serum and liver ALT expression and hepatic inflammation, necrosis and apoptosis were assessed and expressed relative to their expressions in control‐diet‐fed mice. Results: Feeding mice the MCD diet produced hepatic steatosis with minimal hepatic inflammation or necrosis. Liver cell apoptosis was not significantly increased by MCD diet treatment. Conversely, serum ALT activity was approximately four‐fold increased at 12 weeks of diet treatment, and ALT protein expressions in serum were correspondingly increased: ALT1 1.7‐fold and ALT2 1.9‐fold at 12 weeks. The expressions of ALT1 and ALT2 protein in liver increased over 2–12 weeks of MCD treatment. At 12 weeks, liver ALT1 protein was 2.27±0.31‐fold increased and ALT2 protein 4.72±0.48‐fold increased relative to their expressions in the mice fed a diet replete with methionine and choline. Liver ALT mRNA expressions were correspondingly increased: ALT1 mRNA 2.58‐fold and ALT2 mRNA 4.97‐fold at 12 weeks. Linear regression analysis showed a strong correlation between serum and liver tissue expressions for both ALT1 and ALT2. Conclusions: These findings suggest that induction of hepatic expression significantly contributes to increased serum ALT in this model of experimental fatty liver disease, whereas cell death appears not to.     

Management and diagnosis of fatty liver disease

Nonalcoholic fatty liver disease is a common cause of chronic liver disease and has been an increasingly studied topic of research as the obesity epidemic has been growing. There is a significant morbidity and mortality with uncontrolled steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. The prevalence of this disease has been estimated to be roughly one-third of the western population, thought to be largely due to diet and sedentary lifestyle. Several treatments have been studied including vitamin E, insulin-sensitizing agents and ursodeoxycholic acid; however, the only treatment shown to improve the histologic changes of nonalcoholic fatty liver disease is weight loss. Given the proven benefit of weight loss, there may be reason to screen at-risk populations; however, limited availability of other disease-modifying treatments may limit the cost–benefit ratios. A better understanding of the diagnosis and management of this condition is required to alter the course of this modifiable disease.     

Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis

BACKGROUND & AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction. METHODS: Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis. RESULTS: TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls. CONCLUSIONS: Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.     

The natural history of nonalcoholic fatty liver disease: a population-based cohort study

BACKGROUND & AIMS: The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. METHODS: Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. RESULTS: Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1-23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003-1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7-2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3-5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2-7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. CONCLUSIONS: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low.     

Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease

BACKGROUND & AIMS: There is a need for more work examining the potential of physical activity and/or weight control as a preventive and/or therapeutic option in the treatment of fatty liver diseases. The purpose of this study was to examine the association between cardiorespiratory fitness, body mass index (BMI), and waist circumference with markers of nonalcoholic fatty liver disease (NAFLD). METHODS: Participants consisted of 218 apparently healthy nonsmoking, nonalcoholic men aged 33-73 years. Cardiorespiratory fitness was assessed by a maximal treadmill test. Liver and spleen density were measured using a computed tomography scan. We defined the presence of NAFLD as the following 3 conditions being met: (1) liver to spleen density of 1.0 or less, (2) serum alanine transaminase level greater than 30 U/L, and (3) serum aspartate transaminase/alanine transaminase level less than 1.0. RESULTS: Twenty-four (11%) of the participants met the NAFLD definition. There was an inverse association between fitness categories, and a positive association for BMI categories (and waist circumference categories) with the prevalence of NAFLD (P for trend <.001 for all). Fitness and BMI were independent of each other in their associations with the prevalence of NAFLD. The addition of waist circumference to the regression model attenuated the association with prevalence of NAFLD for both fitness (P value changed from <.0001 to .06) and BMI (P value changed from <.001 to .22). CONCLUSIONS: Fitness (inversely) and BMI (directly) were associated with the prevalence of NAFLD. However, these associations were attenuated when abdominal obesity was included in the statistical model.     

Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

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Genetic variants in the MTHFR are not associated with fatty liver disease

The common missense sequence variants of methylenetetrahydrofolate reductase (MTHFR), rs1801131 (c.A1298C) and rs1801133 (c.C677T), favour the development of hyperhomocysteinemia and diminished DNA methylation. Previous studies, carried out in small series and with suboptimal characterization of the hepatic phenotype, tested the association of these genetic variants with fatty liver disease (FLD), with conflicting results. Here, we assessed the association of rs1801131 and rs1801133 with hepatic phenotype in the Liver Biopsy Cross‐Sectional Cohort, a large cohort (n=1375 from Italy and 411 from Finland) of European individuals with suspect FLD associated with dysmetabolism. A total of 1786 subjects were analysed by ordinal regression analyses. The rs1801131 and the rs1801133 variants were not associated with steatosis, inflammation, ballooning or fibrosis. The present study suggests that changes in folate and methionine metabolism resulting from these 2 variants are not associated with a clinically significant impact on FLD in Europeans.     

Nonalcoholic Fatty Liver Disease after Liver Transplant

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the world. The rising prevalence of nonalcoholic steatohepatitis (NASH) has led to a 170% increase in NASH cirrhosis as the listing indication for liver transplantation from 2004 to 2013. As of 2018, NASH has overtaken hepatitis C as an indication for liver transplantation in the USA. After liver transplantation, the allograft often develops recurrent NAFLD among patients with known NASH cirrhosis. In addition to recurrent disease, de novo NAFLD has been reported in patients with other indications for liver transplantation. In this review, we will discuss the risk factors associated with recurrent and de novo NAFLD, natural course of the disease, and management strategies after liver transplantation.     

Clinical predictive score for detecting nonalcoholic fatty liver disease with significant fibrosis in patients with metabolic syndrome

Patients with metabolic syndrome are at a higher risk of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis than the general population. Still, accessibility of screening method for NAFLD with significant fibrosis, such as transient elastography (FibroScan) are limited in some settings. This study aimed to develop a simple clinical predictive score for detecting NAFLD with significant fibrosis in patients with metabolic syndrome.A cross-sectional study was designed to obtain the data from medical records of all relevant patients who underwent transient elastography between January 2011 and December 2020 at Siriraj Hospital, Thailand. A liver stiffness cutoff value of 7.0 kilopascal was used to define the presence of significant liver fibrosis. To examine potential predictors, medical history and clinical data commonly assessed in routine practice were selected by following expert opinions and univariable statistical analysis. Backward and forward stepwise logistic regression was performed to acquire a final prediction model. To simplify the model, a weighted score was assigned for each categorized predictor. In addition, eligible cutoff values of the score and their predictive performances were determined.A total of 745 medical records were reviewed. The prevalence of NAFLD with significant fibrosis in patients with metabolic syndrome was 12.6%. Most clinical characteristics of patients with NAFLD with significant fibrosis and those non-NAFLD and NAFLD with no/mild fibrosis were quite disparate. The most practical model comprised globulin, aspartate transaminase, platelet count, and type 2 diabetes. It provided a good predictive performance with an area under the receiver operating characteristic curve of 0.828 (95% confidence interval [CI]: 0.782, 0.874). At the proper cutoff value, sensitivity and specificity were 76.6% (95% CI: 66.7%, 84.7%) and 72.4% (95% CI: 68.7%, 75.8%), respectively. The likelihood ratio of testing positive for NAFLD with significant fibrosis was 2.8 (95% CI: 2.34, 3.27) among patients with scores above the cutoff value.The first score for detecting of NAFLD with significant fibrosis in patients with metabolic syndrome was developed. This practical score, providing a good predictive performance, should be useful to help clinicians prioritize needs for further investigations among high-risk patients, especially in resource-limited settings.     

Non-alcoholic fatty liver disease,obesity and the metabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. This article details the pathogenesis of NAFLD along with the current state of its diagnosis and treatment.