Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD

Hagström, Hannes; Nasr, Patrik; Ekstedt, Mattias; Hammar, Ulf; Stål, Per; Hultcrantz, Rolf; Kechagias, Stergios

doi:10.1016/j.jhep.2017.07.027

Cited by 777 publications

(747 citation statements)

References 24 publications

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“…This is supported by a recent study of 646 patients with biopsy‐proven NAFLD and a mean follow‐up of 20 years 34. In that study, the mean time for development of end‐stage liver disease in 90% of patients per stage of fibrosis was 33.4 years for F0 (95% confidence interval [CI], 24.2, 42.6), 34.1 years for F1 (95% CI, 25.1, 43.2), 22.7 years for F2 (95% CI, 13.7, 31.7), 11.8 years for F3 (95% CI, 4.3, 19.4), and 5.6 years for F4 (95% CI, 0.9, 10.3).…”

Section: Discussionsupporting

confidence: 56%

Natural history of nonalcoholic fatty liver disease: A prospective follow‐up study with serial biopsies

Nasr

Ignatova

Kechagias

et al. 2017

Hepatology Communications

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112

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Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high‐quality follow‐up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow‐up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow‐up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end‐stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty‐six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy‐proven fibrosis stage F3‐F4 and 2 patients with end‐stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end‐stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end‐stage liver disease. (Hepatology Communications 2018;2:199–210)

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Section: Discussionsupporting

confidence: 56%

Natural history of nonalcoholic fatty liver disease: A prospective follow‐up study with serial biopsies

Nasr

Ignatova

Kechagias

et al. 2017

Hepatology Communications

Self Cite

112

104

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“…Remarkably, measurements of liver MALAT1 abundance showed a dramatic 8‐fold increase in a patient who progressed from NAFL to NASH fibrosis and a 29‐fold increase in a NASH patient who progressed from fibrosis 0 to fibrosis 3. This observation is particularly significant as fibrosis stage is known to be associated with long‐term outcomes in patients with NAFLD 33, 34. Certainly, a more comprehensive study is needed but will require time and an adequate sample size.…”

Section: Discussionmentioning

confidence: 99%

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Sookoian

Flichman

Garaycoechea

et al. 2018

Hepatology Communications

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Long noncoding RNAs (lncRNAs) are functional molecules that orchestrate gene expression. To identify lncRNAs involved in nonalcoholic fatty liver disease (NAFLD) severity, we performed a multiscale study that included: (a) systems biology modeling that indicated metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) as a candidate lncRNA for exploring disease‐related associations, (b) translational exploration in the clinical setting, and (c) mechanistic modeling. MALAT1 liver profiling was performed in three consecutive phases, including an exploratory stage (liver samples from patients with NAFLD who were morbidly obese [n = 47] and from 13 individuals with normal liver histology); a replication stage (patients with NAFLD and metabolic syndrome [n =49]); and a hypothesis‐driven stage (patients with chronic hepatitis C and autoimmune liver diseases, [n = 65]). Liver abundance of MALAT1 was associated with NAFLD severity (P = 1 × 10–6); MALAT1 expression levels were up‐regulated 1.75‐fold (P = 0.029) and 3.6‐fold (P = 0.012) in patients with nonalcoholic steatohepatitis compared to those diagnosed with simple steatosis (discovery and replication set, respectively; analysis of covariance adjusted by age, homeostasis model assessment, and body mass index). Quantification of liver vascular endothelial growth factor A messenger RNA, a target of MALAT1, revealed a significant correlation between the two RNAs (R, 0.58; P = 5 × 10–8). Increased levels of MALAT1 were also associated with autoimmune liver diseases. Interactome assessment uncovered significant biological pathways, including Janus kinase‐signal transducers and activators of transcription and response to interferon‐γ. Conclusion: Deregulated expression of MALAT1 stratifies patients into the histologic phenotypes associated with NAFLD severity. MALAT1 up‐regulation seems to be a common molecular mechanism in immune‐mediated chronic inflammatory liver damage. This suggests that convergent pathophenotypes (inflammation and fibrosis) share similar molecular mediators. (Hepatology Communications 2018;2:654‐665)

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“…Some recent studies have clearly shown that fibrosis stage, without other histological characteristics of steatohepatitis, predicts all‐cause and liver‐related mortality in patients with NAFLD . Hagström et al .…”

Section: Introductionmentioning

confidence: 99%

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

Fujii

Imajo

Yoneda

et al. 2019

J of Gastro and Hepatol

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Background and Aim Although non‐alcoholic fatty liver disease (NAFLD) is common in the general population, identifying patients with advanced fibrosis remains a challenge. We investigated whether the homeostasis model assessment parameter of insulin resistance (HOMA‐IR), an index of IR and one of the most important metabolic factors, is an independent predictive factor for advanced fibrosis in nondiabetic patients with NAFLD. Methods This was a retrospective, cross‐sectional multicenter study. We included 361 patients with biopsy‐proven NAFLD who had not been diagnosed with type 2 diabetes mellitus: 175 (48%) were women and 48 (13%) had advanced fibrosis. We used simple random sampling; the sampling ratio of the estimation and validation groups was 7:3. A logistic model was constructed for both the estimation and validation groups. The explanatory variables were age ≥ 49 years, sex (women), body mass index ≥ 26.7 kg/m2, the presence of hypertension, presence of dyslipidemia, fasting plasma glucose level ≥ 98 mg/dL, fasting immune reactive insulin level ≥ 12.0 μU/mL, and HOMA‐IR ≥ 2.90. The median HOMA‐IR of the patients was 2.88 (interquartile range: 2.1–4.8). Results In the estimation group, univariate and multivariate analyses showed that age, dyslipidemia, and HOMA‐IR were independent predictors of advanced fibrosis. In the validation group, only age and HOMA‐IR were found to be independent predictors of advanced fibrosis. Conclusions Homeostasis model assessment parameter of insulin resistance was an independent predictor of advanced liver fibrosis in nondiabetic patients with NAFLD. Given that most patients with NAFLD are nondiabetic, it is important to set goals with respect to improving IR to subsequently reduce liver fibrosis.

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Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD

Cited by 777 publications

References 24 publications

Natural history of nonalcoholic fatty liver disease: A prospective follow‐up study with serial biopsies

Natural history of nonalcoholic fatty liver disease: A prospective follow‐up study with serial biopsies

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

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