Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy‐proven nonalcoholic fatty liver disease subjects

Abstract

Background and Aim Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic‐associated fatty liver disease (MAFLD). Methods Spanish multicenter study including 1893 biopsy‐proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow‐up (4.7 ± 3.8 years). Results Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non‐NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. Conclusions The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.

Digital Pathology Enables Automated and Quantitative Assessment of Inflammatory Activity in Patients with Chronic Liver Disease

“…Finally, I-score and C-score also increased with fibrosis stage (Figure 4). In close agreement with other recent studies, these data support the dynamic of inflammatory cells infiltration in the liver across disease progression of fibrosis to cirrhosis [36,37].…”

“…The C-score performed better than I-score to classify NASH, adding valuable information to previous results that just analyzed inflammatory proportionate areas [ 17 ]. This score based on clusters of stained intensity areas could help to diagnose a NASH given the low inter-observer agreement between pathologists and that non-NASH cases still have some inflammatory degree in the liver [ 2 , 35 , 36 ]. The C-score represents a morphological metric associated with inflammatory changes and key features related to NAFLD: clusters of different cells including lymphocytes, plasma cells, monocytes, polymorphonuclears, eosinophils, and Kupffer cells, all of them positive for CD45 staining [ 28 ].…”

Outcomes and potential surrogate markers for future clinical trials of non‐alcoholic steatohepatitis cirrhosis

“…However, the progression of NASH is associated with a loss of intrahepatic fat and diminished inflammatory activity. 49 Therefore, in the absence of a prior diagnosis of NASH, end-stage liver histology cannot be linked with a specific aetiology, and the term NASH cirrhosis remains hypothetical. In this line, the FDA requires fulfilment of full NASH histological criteria for enrolment in phase 3 trials in the F4 population.…”

Biomarkers of Metabolic (Dysfunction)-associated Fatty Liver Disease: An Update

“…26 On the other hand, another report demonstrated that up to 70% of patients without NASH (NAFLD activity score (NAS) <4) exhibit some inflammatory degree in the liver biopsy. 27 This complexity and the variance with the simple dogmatic steatosis-steatohepatitis-fibrosis chronology emphasizes the importance of the holistic view of liver injury with MAFLD, and we have witnessed some recent efforts at implementing this view in risk assessment. 28 However, some concerns regarding this change have been raised by some other experts; these have included the ambiguity of the term "metabolic", the need for full understanding of the pathogenesis of the disease before moving to this change, the potential consequences on drug development and ongoing clinical trials, and the risk of causing confusion for stakeholders with a subsequent impact on disease awareness among physicians and patients.…”

“… 26 On the other hand, another report demonstrated that up to 70% of patients without NASH (NAFLD activity score (NAS) <4) exhibit some inflammatory degree in the liver biopsy. 27 This complexity and the variance with the simple dogmatic steatosis-steatohepatitis-fibrosis chronology emphasizes the importance of the holistic view of liver injury with MAFLD, and we have witnessed some recent efforts at implementing this view in risk assessment. 28 …”