Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease

Abstract

Background & Aim Histologic analysis of liver biopsies allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. Methods We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3–12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HR). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. Results Over a median follow-up of 12.6 years (range 0.3–35.1), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% CI, 1.28, 2.77), stage 2 (HR, 2.89; 95% CI, 1.93, 4.33), stage 3 (HR, 3.76; 95% CI, 2.40, 5.89), and stage 4 (HR, 10.9; 95% CI, 6.06, 19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05, 1.08), diabetes (HR, 1.61; 95% CI, 1.13, 2.30), current smoking (HR, 2.62; 95% CI, 1.67, 4.10) and statin use (HR, 0.32; 95% CI, 0.14, 0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR 14.2 [95% CI 3.38, 59.68]) and stage 4 (HR 51.5 [95% CI 9.87, 269.2]) compared to stage 0, were significantly associated with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis. Conclusions In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were independently associated with long-term overall mortality, liver transplantation, and liver-related events.

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

“…Our findings showed more patients developed end‐stage liver disease compared to what has been reported (1.2%‐5.4%) 7, 8, 13, 33. Angulo et al13 showed 4.2% of all patients developed end‐stage liver disease.…”

“…Angulo et al13 showed 4.2% of all patients developed end‐stage liver disease. Theirs was a retrospective study with 619 patients and with a high loss to follow‐up (15.7%).…”

“…However, recent longitudinal studies have shown that only fibrosis and no other histologic features predicts mortality in patients with NAFLD 12, 13…”

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

“…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.…”

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

“…Data published in the past few years suggest that risk of liver related mortality in NAFLD grows exponentially as the stage of fibrosis increases 38,91,92 . Furthermore, evidence from familial aggregation and twin studies have shown a herit able component to NAFLD 93,94 .…”