Hepatologists

This study included patients enrolled in the Functional Assessment in Liver Transplantation (FrAILT) Study from March 2012 until February 2016. The FrAILT Study, initiated in July 2012, is an ongoing study of adults (≥18 years) with cirrhosis who are listed for liver transplantation at the University of California, San Francisco (UCSF) and are seen in the outpatient UCSF Transplant Hepatology clinic. To ensure an adequate number of events during follow-up, we prioritized consecutive recruitment of all patients with a laboratory MELD score ≥12. In September 2013, we relaxed our recruitment criteria to include all patients 60 years and older, regardless of laboratory MELD score, given the conceptual association between frailty and advancing age. Patients were excluded if they were listed with MELD exception points, as these patients have a trajectory to liver transplantation that is independent of hepatic decompensation. While national liver allocation changed in January 2016 to be based on MELDNa rather than MELD, we maintained study inclusion criteria as MELD for consistency. Also excluded were those with severe hepatic encephalopathy (n=8), as defined by the time to complete a Numbers Connection Test^{6 (link)} of >120 seconds, as this may impair the patient’s ability to provide informed consent and complete tests of physical function. Of those who met inclusion criteria, 97% enrolled in the FrAILT Study.^{2 (link),5 (link)} Four subjects who refused to complete all study procedures (i.e., assessments of frailty) were excluded from the analyses.
At enrollment, all patients underwent the tests of physical frailty that have been commonly utilized in the geriatric literature (Table 1). These measures included four performance-based tests (gait speed, grip strength, chair stands, and balance) and five self-reported tests (unintentional weight loss, exhaustion, physical activity, activities of daily living (ADL), and instrumental ADLs. All assessments were performed by one of two study personnel specifically trained at administering these study procedures in the same order and same manner for each study subject. On the same day as the clinic visit, the patient’s hepatologist was asked to subjectively rate his or her patient’s health using the following question:

“We are interested in your general impression about your patient’s overall health, as compared to other patients with underlying liver disease. How would you rate this patient’s overall health today? Excellent (0), very good (1), good (2), fair (3), poor (4), or very poor (5)”.

This rating was collected solely for the purposes of providing information regarding construct validity of the frailty measures. We have previously demonstrated that this subjective clinician assessment can identify liver transplant candidates at high risk for waitlist mortality.^{7 (link)}At the time of enrollment, demographic data were extracted from the clinic visit note from the same day as the physical frailty testing. Patients were classified as having hypertension or diabetes if listed in the past medical history or taking a medication to manage hypertension or diabetes. Ascites was ascertained from the physical examination or mention of ascites in the management plan. Laboratory data within 3 months of the frailty assessment were collected from the electronic health record. Candidate prognostic indicators were recorded in blind with respect to the primary endpoint. All patients were followed prospectively until their terminal waitlist event (e.g., death/delisting, liver transplantation) or, for those who had not experienced a terminal waitlist event, until February 2016. “Delisting for being too sick for liver transplant” was decided by consensus among the liver transplant team members if there was concern that an individual would not achieve acceptable outcomes after liver transplantation due to medical co-morbidities or current medical acuity. This decision was made independently of the frailty assessments performed for the study, as the results from the study assessments were not made available to the clinical care team. Outcomes (e.g., death, delisting, transplant) were ascertained quarterly from UNet℠, the official online database for the United Network for Organ Sharing (UNOS). Per UNOS requirements, outcomes must be recorded into UNet℠ within 24 hours of the outcome and therefore, is a reliable source of information about the patients’ current waitlist status.

The main outcome of this study was clinically confirmed ESLD (also referred to as decompensated liver disease). ESLD was defined by the presence of a definitive diagnosis of cirrhosis and a definitive diagnosis of a hepatic decompensation event (ascites, hepatorenal syndrome [HRS], spontaneous bacterial peritonitis [SBP], hepatic encephalopathy [HE), or gastric/esophageal variceal bleeding) in the medical record.
Cirrhosis was confirmed if a patient had a: a) liver biopsy demonstrating cirrhosis, b) radiographic imaging study (abdominal ultrasound, CT scan, or MRI) reporting cirrhosis, or c) physician’s note documenting cirrhosis based on one of the two prior criteria.(5 (link))
Definitions for hepatic decompensation events were based on guidelines published by the American Association for the Study of Liver Diseases (AASLD).(6 (link)) Confirmation of an event required physical exam (ascites, encephalopathy), imaging (ascites), or endoscopic (variceal bleeding) findings confirming a decompensation event, or documentation of an event by a treating physician within the medical record. Patients were required to have had a decompensation event within 365 days of receiving an ICD-9-CM code for that event.
Medical records were reviewed by a hepatologist (D.G.) to confirm outcomes. Chart review also determined if patients would be potential liver transplant candidates based on AASLD criteria.(7 (link))