Biopsy rate and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD)

Abstract

Background: Licensed therapies for nonalcoholic fatty liver disease (NAFLD) do not yet exist, but clinical trials are testing treatment options. Inclusion criteria often require liver biopsy showing fibrosis (F2/3) or cirrhosis (F4) and nonalcoholic steatohepatitis (NASH). However, histological criteria pose a serious obstacle for recruitment.

Aims: Characterize the relevance of liver biopsies in the selection of patients with NAFLD.

Methods: Patients between 2013 and 2018 with the ICD-10 code K76.0 were analyzed. Fibrosis was defined by the NASH clinical research network (CRN) fibrosis staging system, NASH by a NAFLD activity score (NAS) ≥4. Predictive factors were determined by logistic regression.

Results: Liver biopsy was performed in 87/638 (13.6%) patients (49% female, age 52.5?±?14.0, BMI 30.4?±?5.9?kg/m²). Fibrosis stage F0/F1/F2/F3/F4 was observed in N?=?7/47/7/17/9, an NAS ≥4 in N?=?27. Fibrosis stage F2/F3 and F4 along with NAS ≥4 was found in 1.7% and 0.5% of cases. Liver stiffness measurement, LSM (OR 2.3 per doubling of value; CI 1.3–4.4, p?=?.005) and FIB-4 (OR 2.3 per doubling of value; CI 1.2–4.4, p?=?.012) were significant predictors for fibrosis?≥?F2. Predictive factors for NASH were not identified.

Conclusion: The biopsy rate in NAFLD patients is low and fibrosis?≥?F2 along with NAS ≥4 only present in a few cases. Transient elastography and FIB-4 are useful to select patients at risk for fibrosis for liver biopsy.     

Microbiota and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH)

Genetic predisposition, the intestinal microbiota (IM) and environmental factors, such as sedentary lifestyle and inadequate diet, should be considered as critical factors for the development of nonalcoholic fatty liver disease (NAFLD). Recently, some studies have demonstrated an association between dysbiosis and NAFLD; however, the exact mechanisms that lead to intestinal membrane damage, bacterial translocation and inflammation are not well elucidated. Due to the relevance of this theme, the IM and its metabolites have received special attention in recent years in an attempt to better understand the mechanisms related to the prevention, physiopathology, and treatment of NAFLD. In this paper, we provide a review of the human IM and its role in diet, obesity, and the development/progression of NAFLD/NASH, as well as the use of prebiotics and probiotics in the modulation of IM.     

Disease severity predicts higher healthcare costs among hospitalized nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients in Spain

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) presents many public health challenges, including a substantial impact on healthcare resource utilization and costs. There are important regional differences in the burden of NAFLD/NASH, and Spain-specific data are lacking. This retrospective, observational study examined the impact of liver disease severity, comorbidities, and demographics on healthcare resource utilization and costs in Spain.NAFLD/NASH patients in the Spanish National Health System''s Hospital Discharge Records Database (1/1/2006 to 4/30/2017) were categorized into disease severity cohorts as NAFLD/NASH overall, NAFLD/NASH non-progressors, compensated cirrhosis (CC), decompensated cirrhosis (DCC), liver transplant (LT), or hepatocellular carcinoma (HCC). Patients were followed from index date until the earliest of 6 months, disease progression, end of coverage, death, or end of study. Within each cohort, pre- and post-index healthcare resource utilization and costs per patient per month (PPPM) were calculated.A total of 8,205 patients (mean age 58.4; 54% male) were identified; 5,984 (72.9%) were non-progressors, 139 (1.7%) progressed to CC, 2,028 (24.7%) to DCC, 115 (1.4%) to LT, and 61 (0.7%) to HCC. Pre-index comorbidity burden was high across disease cohorts, and the frequency of comorbidities increased with disease severity. From pre- to post-index, average length of stay (LOS) increased significantly (23%–41%) as did all-cause PPPM costs (44%–46%), with significantly longer LOS and costs in patients with increasing disease severity.Progression of NAFLD/NASH was associated with significantly higher costs and longer LOS. A coordinated approach is needed to manage resources and costs in Spain.     

The clinical utility of biomarkers and the nonalcoholic steatohepatitis CRN liver biopsy scoring system in patients with nonalcoholic fatty liver disease

Background and Aims:  We identified patients with nonalcoholic fatty liver disease (NAFLD) to determine the predictive value of serum markers to diagnose histological steatohepatitis (NASH).
Methods:  Demographic, serological, radiological and histological variables on 95 consecutive patients with NAFLD were recorded. The serum markers studied were CK18, Hyaluronic acid, TIMP 1 and YKL 40. The NAS score and the metavir score were the histological scoring systems used.
Results:  CK18 levels were higher in the NASH group compared to the simple steatosis group (394 ± 53 µ/L vs 194 ± 26 µ/L; P  < 0.05). In assessing clinical effectiveness, CK18 yielded an AUC of 0.8 for NASH (cut-off value 300 µ/L gives PPV 81% and NPV 85%).The fibrosis markers showed no differences between groups. We stratified the same cohort according to liver fibrosis (F0 vs F1–F4). Fibrosis was associated with advanced age, high body mass index and type 2 diabetes. The biomarkers performed relatively poorly at identifying liver fibrosis (F1–F4), with HA performing the best (AUC 0.73); performance improved for advanced fibrosis (F3/F4) - (HA: AUC 0.77). The NAS score performed the best overall at identifying liver fibrosis (AUC 0.79).
Discussion:  CK18 is the only biomarker studied that can identify NASH. Additionally, liver biopsy should be performed in all high risk patients to determine the standardised NAS score to identify patients at high risk of disease progression.     

Circulating microRNAs in nonalcoholic fatty liver disease

Liver biopsy is currently recognized as the most accurate method for diagnosing and staging nonalcoholic fatty liver disease (NAFLD). However, this procedure is typically performed when disease has progressed to clinically significant stages, thereby limiting early diagnosis of patients who are at high risk for development of liver- and cardiovascular-related morbidity and mortality. Recently, microRNAs (miRNAs), short, noncoding RNAs that regulate gene expression, have been associated with histological features of NAFLD and are readily detected in the circulation. As such, miRNAs are emerging as potentially useful noninvasive markers with which to follow the progression of NAFLD. In this article, we present the evidence linking circulating miRNAs with NAFLD and discuss the potential value of circulating miRNA profiles in the development of improved methods for NAFLD diagnosis and clinical monitoring of disease progression.     

Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses both simple steatosis and nonalcoholic steatohepatitis (NASH). Differentiation of these two entities requires histopathologic evaluation. The aim of this study was to establish a reliable diagnostic model for differentiating steatosis from steatohepatitis utilizing both clinical characteristics and a panel of biochemical markers of lipid peroxidation and fibrosis. Eighty subjects with biopsy proven NAFLD were enrolled, 39 with simple steatosis and 41 with histopathologic evidence of NASH. Demographic and laboratory data to include serologic testing for 8-epi-PGF(2alpha), transforming growth factor-beta (TGF-beta), adiponectin, and hyaluronic acid (HA) were obtained and compared between the two groups. There were significant differences between the two groups with respect to age (P=0.004), female gender (P=0.024), aspartate aminotransferase (AST) (P=0.028), body mass index (BMI) (P=0.003), fasting insulin (0.018), AST/alanine aminotransferase (ALT) ratio (AAR) (P=0.017), quantitative insulin sensitivity check index (QUICKI) (P=0.002), and HA (P=0.029). A composite index for distinguishing steatosis from NASH was calculated by summing the risk factors of age >or=50 years, female gender, AST>or=45 IU/l, BMI >or=30 mg/kg2, AAR>or=0.80, and HA>or=55 microg/l, and its accuracy was determined by receiver operating characteristic (ROC) analysis to be 0.763 (95% CI: 0.650-0.876). The presence of three or more risk factors had a sensitivity, specificity, PPV, and NPV of 73.7%, 65.7%, 68.2%, and 71.4%, respectively. In addition, HA at a cutoff of 45.3 microg/l was a good predictor of advanced fibrosis. In conclusion, we propose a noninvasive screening model for distinguishing simple steatosis from NASH. Identifying patients at risk for NASH will allow clinicians to more accurately determine who may benefit from liver biopsy.     

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.     

Evidence‐based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non‐alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non‐invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence‐based therapeutic options, although the clinical evidence for long‐term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.     

Association between thrombotic risk factors and extent of fibrosis in patients with non-alcoholic fatty liver diseases

AIM: To evaluate the prevalence of genetic and acquired prothrombotic risk factors and their association with the extent of fibrosis and fatty infiltration in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: Forty-four patients with chronic hepatitis (28 men and 16 women, with mean age of 45±11 and 49±12 years, respectively) constituted the patient population of this study. The groups were divided as follows: 15 patients with fatty liver (FL); 15 with non-alcoholic steatohepatitis (NASH); 14 with chronic viral hepatitis (CH) diagnosed by histology and liver technetium scan or ultrasound; and 10 healthy individuals. Thrombophilic, coagulation factors and genetic mutations were diagnosed by standard hemostatic and molecular coagulation assays. RESULTS: Activated protein C (APC) resistance and protein S were the most prevalent thrombotic risk factors (6% and 10% in NAFLD vs 21% and 14% in CH; P<0.01 and P<0.05, respectively). One thrombotic risk factor was identified in 41% of patients (23% mild fibrosis, 18% severe fibrosis) and two thrombotic risk factors in 6% of patients with NAFLD and severe fibrosis. While no differences in APC ratio, lupus anticoagulant, fibrinogen, factor V Leiden, prothrombin, and MTHFR mutation were found. Protein S levels were significantly lower in NASH patients than in patients with FL alone (92±19 vs 106±2, P<0.01). Protein C levels were markedly higher in patients with NAFLD and mild or severe fibrosis as compared to the patients with CH, respectively (128±40 vs 96±14, P<0.001 or 129±36 CONCLUSION: Up to 46% of patients with NAFLD may have thrombotic risk factors, and the presence of thrombotic risk factors is correlated with the extent of hepatic fibrosis, suggesting a crucial role of the coagulation system in the pathogenesis of hepatic fibrosis.     

Smoking is associated with severity of liver fibrosis but not with histological severity in nonalcoholic fatty liver disease. Results from a cross-sectional study

Objectives: To assess the influence of smoking on histological disease severity and fibrosis in real-world NAFLD patients.

Material and methods: Consecutive NAFLD patients were identified with liver biopsies performed between 2008 and 2015. Characteristics such as smoking status and total number of pack years were collected. Biopsies were revised and BRUNT fibrosis and NAFLD activity score (NAS) determined. Patients with a high NAS (≥5) were compared to patients with a low NAS (<5) and with advanced fibrosis (stage 3–4) to patients with no-early fibrosis (stage 0–2). Patients with a history of smoking (current or past smoker) were defined ever smokers.

Results: Fifty-six patients were included (mean age 49?±?14.3, 68.9% males and 39.3% history of smoking). Ever smokers had a higher fibrosis score than never smokers; two (IQR 0–3) versus one (IQR 1–1.5) (p?=?.040). Patients with advanced fibrosis smoked significantly more pack years than patients with no-early fibrosis; 10.6 (IQR 0–25.8) versus 0 (IQR 0–7) (p?=?.011). There is a weak to moderate correlation between fibrosis stage and number of pack years (Spearman’s Rho?=?0.341, p?=?.012). There was no difference in NAS between never and ever smokers; 2.8?±?1.5 versus 3.3?±?1.4 (p?=?.205). Patients with NAS <5 had a median number of pack years of 0 (IQR 0–9) versus a median of 10.3 pack years (IQR 0–24) in patients with NAS ≥5 (p?=?.127).

Conclusion: Smoking is associated with severity of NAFLD-related liver fibrosis but not with histological disease severity. This supports the recommendation to cease smoking for NAFLD patients.     

非酒精性脂肪性肝病显著肝纤维化的无创诊断

目的:通过对非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)患者多个肝纤维化非创伤性诊断模型的验证和分析比较,评价其诊断价值.方法:选取29例NAFLD患者,进行肝组织活检和病理学分期,并检测血清指标,用受试者操作特征(ROC)曲线等方法评估APRI指数、AST/ALT比率、BARD评分等模型的诊断价值.结果:29例病例中17例(58.9%)为男性,平均年龄(51±12)岁,平均体质量指数为(27±5)kg/m2,糖尿病患者15(51.7%);病理肝纤维化分级提示显著纤维化S3-S4:6例(20.6%).各诊断模型对肝脏显著纤维化程度都具有一定诊断价值,其中AST/ALT比率表现最佳[其曲线下面积(AUROC)为0.83],其次为BARD评分(AUROC0.77)和APRI指数(AUROC0.67).AST/ALT比率和BARD评分模型的阴性预测值均大于90%(分别为93%和95%).阳性预测值均处于中低等水平.AST/ALT比率和BARD评分模型分别可使68.9%和37.9%的患者避免肝活检.结论:肝纤维化非创伤性诊断模型能较好地区分存在显著肝纤维化的NAFLD患者,其中以AST/ALT比率、BARD评分模型较为有效,可以避免部分患者行肝穿刺检查.     

Noninvasive biomarkers in pediatric nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide among children and adolescents. It encompasses a spectrum of disease, from its mildest form of isolated steatosis, to nonalcoholic steatohepatitis (NASH) to liver fibrosis and cirrhosis, or end-stage liver disease. The early diagnosis of pediatric NAFLD is crucial in preventing disease progression and in improving outcomes. Currently, liver biopsy is the gold standard for diagnosing NAFLD. However, given its invasive nature, there has been significant interest in developing noninvasive methods that can be used as accurate alternatives. Here, we review noninvasive biomarkers in pediatric NAFLD, focusing primarily on the diagnostic accuracy of various biomarkers as measured by their area under the receiver operating characteristic, sensitivity, and specificity. We examine two major approaches to noninvasive biomarkers in children with NAFLD. First, the biological approach that quantifies serological biomarkers. This includes the study of individual circulating molecules as biomarkers as well as the use of composite algorithms derived from combinations of biomarkers. The second is a more physical approach that examines data measured through imaging techniques as noninvasive biomarkers for pediatric NAFLD. Each of these approaches was applied to children with NAFLD, NASH, and NAFLD with fibrosis. Finally, we suggest possible areas for future research based on current gaps in knowledge.     

Fibrosis in nonalcoholic fatty liver disease: Noninvasive assessment using computed tomography volumetry

AIM To evaluate the diagnostic performance of computed tomography(CT) volumetry for discriminating the fibrosis stage in patients with nonalcoholic fatty liver disease(NAFLD).METHODS A total of 38 NAFLD patients were enrolled. On the basis of CT imaging, the volumes of total, left lateral segment(LLS), left medial segment, caudate lobe, and right lobe(RL) of the liver were calculated with a dedicated liver application. The relationship between the volume percentage of each area and fibrosis stage was analyzed using Spearman's rank correlation coefficient. A receiver operating characteristic(ROC) curve analysis was performed to determine the accuracy of CT volumetry for discriminating fibrosis stage.RESULTS The volume percentages of the caudate lobe and the LLS significantly increased with the fibrosis stage(r = 0.815, P 0.001; and r = 0.465, P = 0.003, respectively). Contrarily, the volume percentage of the RL significantly decreased with fibrosis stage(r =-0.563, P 0.001). The volume percentage of the caudate lobe had the best diagnostic accuracy for staging fibrosis, and the area under the ROC curve values for discriminating fibrosis stage were as follows: ≥ F1, 0.896; ≥ F2, 0.929; ≥ F3, 0.955; and ≥ F4, 0.923. The best cut-off for advanced fibrosis(F3-F4) was 4.789%, 85.7% sensitivity and 94.1% specificity.CONCLUSION The volume percentage of the caudate lobe calculated by CT volumetry is a useful diagnostic parameter for staging fibrosis in NAFLD patients.