Serum markers detect the presence of liver fibrosis: a cohort study

BACKGROUND & AIMS: Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis. METHODS: In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples. RESULTS: The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P < .0001; 95% confidence interval, .758-.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists' agreement over histologic scores ranged from very good to moderate (kappa = .97-.46). CONCLUSIONS: Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.     

Liver steatosis assessment: Correlations among pathology,radiology, clinical data and automated image analysis software

Quantitating hepatic steatosis is important in many liver diseases and liver transplantation. Since steatosis estimation by pathologists has inherent intra- and inter-observer variability, we compared and contrasted computerized techniques with magnetic resonance imaging measurements, pathologist visual scoring, and clinical parameters. Computerized methods applied to whole slide images included a commercial positive pixel count algorithm and a custom algorithm programmed at our institution. For all liver samples (n = 59), including pediatric, adult, frozen section, and permanent specimens, statistically significant correlations were observed between pathology, radiology, and each image analysis modality (r = 0.75–0.97, p < 0.0001), with the strongest correlations in the pediatric cohort. Statistically significant relationships were observed between each method and with body mass index (r = 0.37–0.56, p from <0.0001 to <0.05) and with albumin (r = 0.55–0.64, p < 0.05) but not with alanine aminotransferase or aspartate aminotransferase. Although pathologist assessments correlated (r = 0.64–0.86, 0.92–0.97, and 0.78–0.91 for microvesicular, macrovesicular, and overall steatosis, respectively), the absolute values of hepatic steatosis visual assessment were susceptible to intra- and inter-observer variability, particularly for microvesicular steatosis. Image analysis, pathologist assessments, radiology measurements, and several clinical parameters all showed correlations in this study, providing evidence for the utility of each method in different clinical and research settings.     

The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options

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Effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (NAFLD)

A number of epidemiologic studies show a protective effect of light to moderate daily alcohol consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis (NASH) should not use ethanol chronically since the data available at present do not support a beneficial effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with underlying NASH should abstain from alcohol at any amounts.     

Differing clinical phenotype for higher alanine-aminotransferase (ALT) compared with high-risk NAFLD fibrosis score in type 2 diabetes mellitus

Aims

The impact of non-alcoholic fatty liver disease (NAFLD) presence and severity on the diabetes phenotype remains unclear. Our study aimed to explore and contrast the phenotypes associated with higher ALT and high-risk NAFLD fibrosis score (NFS) in type 2 diabetes.

Peripheral Artery Disease and Risk of Fibrosis Deterioration in Nonalcoholic Fatty Liver Disease: A Prospective Investigation

Objective Liver fibrosis is an important predictor of mortality in nonalcoholic fatty liver disease(NAFLD). Peripheral artery disease(PAD) and liver fibrosis share many common metabolic dysfunctions.We aimed to explore the association between PAD and risk of fibrosis deterioration in NAFLD patients.Methods The study recruited 1,610 NAFLD patients aged ≥ 40 years from a well-defined community at baseline in 2010 and followed up between August 2014 and May 2015. Fibrosis deterioration was defined as the NAFLD fibrosis score(NFS) status increased to a higher category at the follow-up visit.PAD was defined as an ankle-brachial index of 0.90 or 1.40.Results During an average of 4.3 years' follow-up, 618 patients progressed to a higher NFS category.PAD was associated with 92% increased risk of fibrosis deterioration [multivariable-adjusted odds ratio(OR): 1.92, 95% confidence interval(CI): 1.24, 2.98]. When stratified by baseline NFS status, the OR for progression from low to intermediate or high NFS was 1.74(95% CI: 1.02, 3.00), and progression from intermediate to high NFS was 2.24(95% CI: 1.05, 4.80). There was a significant interaction between PAD and insulin resistance(IR) on fibrosis deterioration(P for interaction = 0.03). As compared with non-PAD and non-IR, the coexistence of PAD and IR was associated with a 3.85-fold(95% CI: 2.06, 7.18) increased risk of fibrosis deterioration.Conclusion PAD is associated with an increased risk of fibrosis deterioration in NAFLD patients,especially in those with IR. The coexistence of PAD and IR may impose an interactive effect on the risk of fibrosis deterioration.     

Role of CD98 in liver disease

CD98 is a multifunctional glycoprotein that is involved in various biological processes such as amino acid transport, cell adhesion, diffusion, adhesion, and proliferation. The role of CD98 in liver disease has not thoroughly been examined and is limited reports in the literature. Among these reports, direct association for CD98 in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) have been reported. Our lab has reported that targeting CD98 in high fat diet mice reduced steatosis and inflammation in NAFLD. Other reports associate CD98 in HCC due in part to the role of CD98 in activating integrin signaling. Herein, we present CD98 staining on liver biopsies from NAFLD, chronic active hepatitis, cirrhosis, and 3 stages of HCC to demonstrate the upregulation of CD98 expression throughout liver disease progression. In addition, we analyze current literature to elucidate roles and potential roles of CD98 with each stage of liver disease.     

The roles and interaction of FXR and PPARs in the pathogenesis of nonalcoholic fatty liver disease

Background and study aimsTo identify the roles and interaction of farnesoid X receptor (FXR) and peroxisome proliferator activated receptors (PPARs) in Non-alcoholic fatty liver disease (NAFLD) pathogenesis.Material and Methods16 C57/BL male FXR knockout (KO) mice and sex- and age-matched C57/BL wild type mice were received either standard rodent chow or high-fat and sucrose diet (Blank control, NAFLD, FXR KO and FXR KO NAFLD) for 8 weeks. After that, all mice were sacrificed. Liver tissues and blood samples were collected for laboratory and RT-PCR examination.ResultsNAFLD, FXR KO and FXR KO NAFLD mouse models were successful established. Compared with blank control, FXR and PPAR-α mRNA expression decreased significantly (P < 0.05), PPAR-β expression increased slightly (P > 0.05), PPAR-γ expression increased significantly in NAFLD (P < 0.05). Slight increased PPAR-α mRNA expression (P > 0.05) and markedly decreased PPAR-β and PPAR-γ expression (P < 0.05) were found in FXR KO. Compared with FXR KO group, there was a slight increase in PPAR-αand PPAR-βmRNA expression (P > 0.05) and significant increase in PPAR-γ expression (P < 0.05) in FXR KO NAFLD group. Comparison with NAFLD, PPAR-α mRNA expression increased slightly (P > 0.05), PPAR-β and PPAR-γ expression decreased significantly (P < 0.05) in FXR KO NAFLD.ConclusionFXR and PPARs interaction may play important roles in NAFLD pathogenesis.     

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and have been investigated in several clinical trials for their potential in treating non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). PPARγ has specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD. Thus, NAFLD patients receiving treatment with PPARγ agonists might have a liver response apart from the one in adipose tissue. Owing to the different roles of PPARγ, new treatment strategies include development of compounds harnessing the beneficial effects of PPARγ while restricting PPARγ unwanted effects such as adipogenesis resulting in weight gain. Furthermore, dual or pan agonists targeting two or more of the PPARs have shown promising results in pre‐clinical research and some are currently proceeding to clinical trials. This MiniReview explores adipose‐ and liver‐specific actions of PPARγ, and how this knowledge may contribute in the search for new treatment modalities in NAFLD/NASH.     

不同糖调节水平非酒精性脂肪性肝病患者肝脏脂肪含量与胰岛β细胞功能及胰岛素抵抗的关系

目的 观察非酒精性脂肪性肝病（NAFLD）患者肝脏脂肪含量（LF）与IR及胰岛β细胞功能的关系. 方法 将286例NAFLD患者分为正常糖调节（NGR）组和IGR组,以校正CT半定量法测定LF,再根据LF分为6个亚组：NGR-1、2、3亚组及IGR-1、2、3亚组.以OGTT、胰岛素释放试验评估IR及胰岛β细胞功能,分析LF与IR及胰岛β细胞功能的关系. 结果 （1）随LF增加,NGR-2亚组△I30/△G30高于NGR-1亚组（P＜0.05）,NGR-3亚组稍低于NGR-2亚组（P＞0.05）;IGR-3亚组△I30/△G30低于IGR-1亚组（P＜0.05）;（2）随LF增加,NGR-2、3亚组HOMA-β均高于NGR-1亚组（P＜0.05）;IGR-3亚组低于IGR-1、IGR-2亚组（P＜0.05）.（3）多元线性回归分析提示,LF是影响HOMA-IR最强的独立危险因素（P＜0.01）. 结论 在NGR人群中,LF增加至5.1％～9.9％时,IR增加,胰岛β细胞早相和整体分泌代偿性增高;当LF达10.0％～20.0％时,胰岛β细胞早相分泌功能可能出现减退.对IGR人群,LF增加至5.1％～9.9％时,胰岛β细胞早相分泌功能已开始降低;当LF达10.0％～20.0％时,胰岛β细胞整体分泌功能恶化.