Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.
In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.
“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.
The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.
A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.
“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.
“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.
Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
Managing asymptomatic patients
Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.
This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.
They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.
The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).
The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
Findings and outcomes
During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.
There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.
Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.
Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.
The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.
Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.
Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”
Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.
The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.