Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease

Kleiner, David E.; Brunt, Elizabeth M.; Wilson, Laura; Behling, Cynthia; Guy, Cynthia D.; Contos, Melissa J.; Cummings, Oscar W.; Yeh, Matthew M.; Gill, Ryan M.; Chalasani, Naga; Neuschwander‐Tetri, Brent A.; Diehl, Anna Mae; Dasarathy, Srinivasan; Terrault, Norah A.; Kowdley, Kris V.; Loomba, Rohit; Belt, Patricia; Tonascia, James; Lavine, Joel E.; Sanyal, Arun J.

doi:10.1001/jamanetworkopen.2019.12565

Cited by 265 publications

(246 citation statements)

References 29 publications

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“…A simple proposal based exclusively on elevated AST in type 2 diabetics would be easy to implement and have acceptable diagnostic properties despite sending “only” 25% to liver specialists. Recent publications have also found AST to be a simple marker for fibrosis 44 and that there is an association with progression of fatty liver disease 45 .…”

Section: Discussionmentioning

confidence: 99%

Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination

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Petroff

Beer

et al. 2020

Sci Rep

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Patients with type 2 diabetes (T2D) are at risk for non-alcoholic fatty liver disease (NAFLD) and associated complications. This study evaluated the performance of international (EASL-EASD-EASO) and national (DGVS) guidelines for NAFLD risk stratification. Patients with T2D prospectively underwent ultrasound, liver stiffness measurement (LSM) and serum-based fibrosis markers. Guideline-based risk classification and referral rates for different screening approaches were compared and the diagnostic properties of simplified algorithms, genetic markers and a new NASH surrogate (FAST score) were evaluated. NAFLD risk was present in 184 of 204 screened patients (age 64.2 ± 10.7 years; BMI 32.6 ± 7.6 kg/m2). EASL-EASD-EASO recommended specialist referral for 60–77% depending on the fibrosis score used, only 6% were classified as low risk. The DGVS algorithm required LSM for 76%; 25% were referred for specialised care. The sensitivities of the diagnostic pathways were 47–96%. A simplified referral strategy revealed a sensitivity/specificity of 46/88% for fibrosis risk. Application of the FAST score reduced the referral rate to 35%. This study (a) underlines the high prevalence of fibrosis risk in T2D, (b) demonstrates very high referral rates for in-depth hepatological work-up, and (c) indicates that simpler referral algorithms may produce comparably good results and could facilitate NAFLD screening.

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Section: Discussionmentioning

confidence: 99%

Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination

Blank

Petroff

Beer

et al. 2020

Sci Rep

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“…NASH can regress without specific pharmacologic intervention; for example, weight loss through lifestyle modification improved NAFLD activity scores [49,50]. On the other hand, chronic inflammation induced by persistent HCV infection drives a maladaptive reparative reaction and over stimulates liver cell death and regeneration, promoting liver fibrosis and carcinogenesis [51].…”

Section: Discussionmentioning

confidence: 99%

Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis

Suwa

Yamaguchi

Yoshida

et al. 2020

Cancers

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Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-β signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-βtype I receptor (TβRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive TβRI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC.

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“…This approach can be combined with serum-based markers of liver scarring to further increase the accuracy in diagnosing liver fibrosis [31]. Indeed, the exact quantification of liver scarring represents the central point in diagnosing patients with NAFLD since numerous studies have shown that fibrosis represents the limiting factor in patient survival [32,33]. Diagnosis of steatohepatitis in patients is based on histopathological evaluation of liver biopsies showing characteristic morphological features: macrovesicular steatosis, ballooned hepatocytes with cytoplasmic inclusions (Mallory-Denk bodies (MDBs)) and lobular inflammation.…”

Section: Diagnosismentioning

confidence: 99%

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD.

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Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease

Cited by 265 publications

References 29 publications

Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination

Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination

Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

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