Gastroenterology

Gastroenterology

Volume 149, Issue 2, August 2015, Pages 389-397.e10
Gastroenterology

Original Research
Full Report: Clinical—Liver
Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease

https://doi.org/10.1053/j.gastro.2015.04.043Get rights and content

Background & Aims

Histologic analysis of liver biopsy specimens 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 (HRs). 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 period of 12.6 years (range, 0.3–35.1 y), 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% confidence interval [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 with stage 0, were associated significantly 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 associated independently with long-term overall mortality, liver transplantation, and liver-related events.

Section snippets

Patients and Methods

This was a longitudinal, international, multicenter cohort study. Patients were identified retrospectively by reviewing the pathology database at each participating center of subjects with the pathology diagnosis of steatosis, steatohepatitis, or fatty liver. After an extensive review of the patients’ medical records including all notes from clinic visits, laboratory and imaging data, and liver biopsy reports, only patients with the diagnosis of NAFLD were included in the analysis, as described

Baseline Characteristics

Of the 859 patients, 240 were excluded (Supplementary Figure 1), leaving 619 patients for analysis. Supplementary Figure 2 illustrates the number of liver biopsies performed by calendar year period. Table 1 describes the baseline clinical and laboratory characteristics of the 619 patients. The median age was 49 years (IQR, 38–60), and the median BMI was 30.7 kg/m2 (IQR, 26.4–36.5 kg/m2). There was a predominance of white race, approximately two thirds were women, and approximately a third of

Discussion

Our study showed, first, fibrosis stage independently, and regardless of the presence or severity of other histologic features, is the most relevant liver biopsy feature associated with overall- and liver-related mortality/liver transplantation or liver-related events. This effect was seen even with the earliest stages of fibrosis detectable by microscopic examination, and even when individuals with advanced (fibrosis stages 3–4) disease were excluded. Second, the presence of fibrosis rather

Acknowledgment

The authors thank Dr Oscar Arauz (School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia) and Dr Ananya Pongpaibul (Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand) for their invaluable help in collecting the data for this study. Drs Arauz and Pongpaibul did not receive compensation in association with their contributions to this article.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by a National Institute of Health R01 DK82426 grant. This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The sponsor played no role in the study design or the collection, analysis, and interpretation of data.

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