Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis

Serena Pelusi, Annalisa Cespiati, Raffaela Rametta, Grazia Pennisi, Ville Mannisto, Chiara Rosso, Guido Baselli, Paola Dongiovanni, Anna Ludovica Fracanzani, Sara Badiali, Marco Maggioni, Antonio Craxi, Silvia Fargion, Daniele Prati, Valerio Nobili, Elisabetta Bugianesi, Stefano Romeo, Jussi Pihlajamaki, Salvatore Petta, Luca Valenti

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. Methods: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. Results: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). Conclusions: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis.

Original languageEnglish
Pages (from-to)2310-2319.e6
JournalClinical Gastroenterology and Hepatology
Volume17
Issue number11
DOIs
Publication statusPublished - Oct 1 2019

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Fatty Liver
Fibrosis
Hyperglycemia
Inflammation
Fasting
Biopsy
Morbid Obesity
Non-alcoholic Fatty Liver Disease
Italy
Liver
Adiposity
Finland
Tertiary Care Centers
Comorbidity
Hepatocytes

Keywords

  • History
  • Inflammatory Response
  • Progression
  • Risk Factors

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis. / Pelusi, Serena; Cespiati, Annalisa; Rametta, Raffaela; Pennisi, Grazia; Mannisto, Ville; Rosso, Chiara; Baselli, Guido; Dongiovanni, Paola; Fracanzani, Anna Ludovica; Badiali, Sara; Maggioni, Marco; Craxi, Antonio; Fargion, Silvia; Prati, Daniele; Nobili, Valerio; Bugianesi, Elisabetta; Romeo, Stefano; Pihlajamaki, Jussi; Petta, Salvatore; Valenti, Luca.

In: Clinical Gastroenterology and Hepatology, Vol. 17, No. 11, 01.10.2019, p. 2310-2319.e6.

Research output: Contribution to journalArticle

Pelusi, Serena ; Cespiati, Annalisa ; Rametta, Raffaela ; Pennisi, Grazia ; Mannisto, Ville ; Rosso, Chiara ; Baselli, Guido ; Dongiovanni, Paola ; Fracanzani, Anna Ludovica ; Badiali, Sara ; Maggioni, Marco ; Craxi, Antonio ; Fargion, Silvia ; Prati, Daniele ; Nobili, Valerio ; Bugianesi, Elisabetta ; Romeo, Stefano ; Pihlajamaki, Jussi ; Petta, Salvatore ; Valenti, Luca. / Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis. In: Clinical Gastroenterology and Hepatology. 2019 ; Vol. 17, No. 11. pp. 2310-2319.e6.
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title = "Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis",
abstract = "Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. Methods: We analyzed data from 1738 subjects (44.9{\%} with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5{\%} of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. Results: In the cross-sectional cohort, 132 of 389 patients (33.9{\%}) with significant fibrosis had no NASH and 39 patients (10.0{\%}) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0{\%}) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). Conclusions: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis.",
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TY - JOUR

T1 - Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis

AU - Pelusi, Serena

AU - Cespiati, Annalisa

AU - Rametta, Raffaela

AU - Pennisi, Grazia

AU - Mannisto, Ville

AU - Rosso, Chiara

AU - Baselli, Guido

AU - Dongiovanni, Paola

AU - Fracanzani, Anna Ludovica

AU - Badiali, Sara

AU - Maggioni, Marco

AU - Craxi, Antonio

AU - Fargion, Silvia

AU - Prati, Daniele

AU - Nobili, Valerio

AU - Bugianesi, Elisabetta

AU - Romeo, Stefano

AU - Pihlajamaki, Jussi

AU - Petta, Salvatore

AU - Valenti, Luca

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. Methods: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. Results: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). Conclusions: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis.

AB - Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. Methods: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. Results: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). Conclusions: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis.

KW - History

KW - Inflammatory Response

KW - Progression

KW - Risk Factors

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