New Insights Into Liver Disease and Transplantation

Editor's Note:
Several important advances emerged from abstracts presented at the Liver Meeting®, the 2016 Annual Meeting of the American Association for the Study of Liver Diseases. Topics covered included the assessment of frailty to enhance the care of patients awaiting liver transplantation; long-term outcomes after liver transplantation, including the potential for withdrawal of immunosuppression; new therapeutic options for patients with primary biliary cholangitis and primary sclerosing cholangitis; the risk for hepatocellular carcinoma in patients with chronic hepatitis B despite optimal antiviral therapy; and the potential to cure, rather than merely control, chronic hepatitis B virus infection.

Liver Transplantation

Prediction of Waitlist Mortality

Patients with end-stage liver disease are subject to muscle wasting, malnutrition, and functional decline. These extrahepatic manifestations, which contribute to excess waiting list and post-transplant mortality, are not quantified by the Model for End-Stage Liver Disease (MELD) score. However, these features have recently been captured as proposed frailty measures. For example, one study suggested that a 5-item frailty index (FI) could predict mortality, independent of the MELD score, in adults with liver disease who were listed for liver transplantation.^[1]

Because there is no consensus as to which specific measures best represent frailty and predict mortality in patients with cirrhosis, Lai and colleagues^[2] assessed several candidate measures of physical frailty in consecutive outpatients listed for liver transplant. These measures, which included gait speed, chair stands, 30-second balance, grip strength, instrumental activities of daily living, weight loss, exhaustion, and physical activity, were used to construct a final FI.

The ability of this FI and the MELDNa to correctly rank patients according to their 3-month waitlist mortality risk was 0.75 to 0.79, and 0.82 for MELDNa and the FI combined. Compared with MELDNa alone, MELDNa plus the FI correctly reclassified 13% of deaths/delistings and 8% of non-deaths/delistings. Compared with patients with robust FI scores (≥ 75th percentile), patients with cirrhosis who had poor FI scores (≤ 25th percentile) were more impaired by gait speed, exhaustion, and low physical activity, as well as according to the subjective clinician assessment.

A useful, independent predictor of outcomes after liver transplantation in children and adolescents (a pediatric version of the FI) was reported by Lurz and colleagues^[3] at the 2016 World Congress of Pediatric Gastroenterology, Hepatology and Nutrition in October. Pediatric-oriented measures for each of the five items (the Pediatric Quality of Life Inventory, 6-minute walk test, grip strength, triceps skinfold thickness, and an age-appropriate physical activity questionnaire) were validated in children with compensated and end-stage liver disease. The frailty scores did not correlate with MELDNa scores, indicating that this frailty evaluation captures additional components of ill health that are not assessed by standard laboratory assessments.

Although the general applicability of age-specific FIs should be validated in further studies, these two observations strongly support the value of routine assessment of frailty to enhance the care of patients of all ages awaiting liver transplantation. In addition, the elements that contribute to the FI should be the targets of pretransplant interventions.

Immunosuppression Withdrawal After Liver Transplant

In a study published in 2012, Feng and colleagues^[4] reported that 12 of 20 liver transplant recipients who underwent withdrawal of immunosuppressive drugs became immune-tolerant. They now report on the durable impact of immunosuppression withdrawal in a long-term follow-up (> 8 years) of 11 of these 12 tolerant participants.^[5]

The investigators confirmed that a percentage of liver allografts can durably remain histologically quiescent without immunosuppression. Although several participants exhibited modestly increased inflammation or fibrosis over 8 years, accelerated or progressive changes were not observed. Class II donor-specific antibodies, even of high mean fluorescence intensity, were neither prohibitive of tolerance nor associated with histologic deterioration. The investigators suggest that further studies should assess the mechanisms that render the liver, compared with other organs, relatively resistant to alloimmune attack.

Levitsky and colleagues^[6] determined whether operational immune tolerance could be achieved if treatment with the mammalian target of rapamycin (mTOR) inhibitor sirolimus was withdrawn in stable liver transplant recipients, and whether immunophenotypic regulatory cells correlated with successful withdrawal. They based this study on the hypothesis that conversion from a calcineurin inhibitor to sirolimus increases cellular/genomic regulatory signatures in liver transplant recipients; therefore, mTOR inhibitor withdrawal may be more successful than calcineurin inhibitor withdrawal.

In carefully selected recipients receiving sirolimus monotherapy (> 3 years after transplant), patients were weaned from the drug over approximately 6 months and biopsies were performed. The investigators documented that 53% of patients achieved operational tolerance. There was no difference in age, duration of sirolimus monotherapy, or time from liver transplant to weaning between the tolerant and nontolerant patients. At baseline and end of study, the tolerant patients had a higher percentage of tolerogenic dendritic cell than the nontolerant patients. The investigators therefore concluded that the percentage of regulatory dendritic cell might be useful to predict the success of mTOR inhibitor withdrawal or to monitor this approach.

Graft Fibrosis After Liver Transplantation

Histologic abnormalities, including graft fibrosis, are recognized in protocol biopsies in liver transplantation recipients, even those with normal findings on liver tests. The long-term histologic outcome of idiopathic graft fibrosis in asymptomatic liver allograft recipients is unclear.

Rajanayagam and colleagues^[7] described the 20-year outcomes for asymptomatic persons (alanine aminotransferase [ALT] level < 50 IU/L) with liver allograft fibrosis, determined via a protocol biopsy performed during the 10th year after transplant. Normal or near-normal histology was reported in 23% of patients; however, periportal or central fibrosis without bridging was noted in 47%, 20% had bridging fibrosis, and 10% had cirrhosis.

Significant, potentially modifiable factors that were predictive of graft fibrosis included the recipient being negative for cytomegalovirus at time of transplant; prior episodes of biopsy-proven rejection; positive serum autoantibodies (odds ratio, 2.97); and a maintenance immunosuppression regimen that included steroids. Fibrosis was not found to be significantly associated with transplant-related factors, such as cold ischemia time or type of graft. The investigators found that liver allograft fibrosis detected on the 10th-year protocol biopsy predicted cirrhosis and liver failure with graft loss or mortality by the second decade after liver transplantation.

Of 108 patients studied, six underwent a repeat transplant (five had unexplained cirrhosis). The estimated death-censored retransplantation rate was 3%. Of patients retransplanted for unexplained cirrhosis, all had either bridging fibrosis or cirrhosis at the 10-year biopsy. Ten patients had died by last follow-up, including one after retransplantation. Of the five patients who died of liver failure due to cirrhosis, all had variable degrees of fibrosis at the 10th-year biopsy.

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