Robert S. Rahimi M.D.

Tapper, E. B. and R. S. Rahimi (2019). “Low-Value Levels: Ammonia Testing Does Not Improve the Outcomes of Overt Hepatic Encephalopathy.” Am J Gastroenterol Nov 8. [Epub ahead of print].

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Hepatic encephalopathy is a clinical diagnosis. However, many clinicians measure ammonia levels in hospitalized patients presenting with hepatic encephalopathy. In this editorial, we review the results of an important study by Haj and Rockey (see Haj M and Rockey DC. Ammonia levels do not guide clinical management of patients with hepatic encephalopathy caused by cirrhosis. Am J Gastroenterol [Epub ahead of print October 14, 2019.]). The authors examined the management decisions effected affected by and outcomes associated with (i) ordering an ammonia level and (ii) knowing the ammonia level. They find found that ammonia level determination did not impact affect clinical decision-making or patient outcomes. These persuasive data demonstrate the limited clinical utility of ammonia levels and highlight the need for testing stewardship to dissuade unnecessary use through educational efforts and decision supports.

Sundaram, V., S. Kogachi, R. J. Wong, C. J. Karvellas, B. E. Fortune, N. Mahmud, J. Levitsky, R. S. Rahimi and R. Jalan (2019). “Effect of the clinical course of acute on chronic liver failure prior to liver transplantation on post-transplant survival.” J Hepatol Oct 25. [Epub ahead of print].

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BACKGROUND AND AIMS: We evaluated whether the clinical course of acute on chronic liver failure (ACLF) between time of listing and liver transplantation (LT) affects one-year post-transplant survival. METHODS: We identified patients from the UNOS database who were transplanted within 28 days of listing, and categorized them by ACLF grade at waitlist registration and LT, per the EASL-CLIF definition. RESULTS: 3,636 patients listed with ACLF-3 underwent LT within 28-days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 versus 88.2% among those improving to ACLF 0-2 (p<0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n=2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n=17,631) at the time of LT (83.8% vs 90.2%, p<0.001). Cox modeling demonstrated that recovery of ACLF-3 to ACLF 0-2 at LT was associated with reduced one-year mortality after transplantation (HR=0.65, 95% CI 0.53-0.78). Improvement in circulatory (HR=0.57, 95% CI 0.43-0.75) and brain failure (HR=0.76, 95% CI 0.60-0.97) and stopping mechanical ventilation (HR=0.55, 95% CI 0.42-0.71) were also associated with reduced post-LT mortality. Age above 60 years was a risk factor for post-transplant mortality (HR=1.68, 95% CI 1.31-2.18), but one-year survival increased from 74.9% to 82.7% among those older than 60 years who improved from ACLF-3 to ACLF 0-2 (p<0.001). CONCLUSIONS: Improvement of ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in recipients who are older than age 60, who were removed from the mechanical ventilator, or who recovered from circulatory or brain failure. LAY SUMMARY: Liver transplantation (LT) for patients with acute on chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients above 60 years. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation has the strongest impact on post-transplant survival.

Haugen, C. E., M. McAdams-DeMarco, E. C. Verna, R. Rahimi, M. R. Kappus, M. A. Dunn, M. L. Volk, A. Gurakar, A. Duarte-Rojo, D. R. Ganger, J. G. O’Leary, D. Ladner, J. Garonzik-Wang, D. L. Segev and J. C. Lai (2019). “Association Between Liver Transplant Wait-list Mortality and Frailty Based on Body Mass Index.” JAMA Surgery 2019 Sep 11. [Epub ahead of print].

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Importance: Among liver transplant candidates, obesity and frailty are associated with increased risk of death while they are on the wait-list. However, use of body mass index (BMI) may not detect candidates at a higher risk of death owing to the fact that ascites and muscle wasting are seen across transplant candidates of all BMI measurements. Objective: To evaluate whether the association between wait-list mortality and frailty varied by BMI of liver transplant candidates. Design, Setting, and Participants: A prospective cohort study was conducted at 9 liver transplant centers in the United States from March 1, 2012, to May 1, 2018, among 1108 adult liver transplant candidates without hepatocellular carcinoma. Exposures: At outpatient evaluation, the Liver Frailty Index score was calculated (grip strength, chair stands, and balance), with frailty defined as a Liver Frailty Index score of 4.5 or more. Candidates’ BMI was categorized as nonobese (18.5-29.9), class 1 obesity (30.0-34.9), and class 2 or greater obesity (>/=35.0). Main Outcomes and Measures: The risk of wait-list mortality was quantified using competing risks regression by candidate frailty, adjusting for age, sex, race/ethnicity, Model for End-stage Liver Disease Sodium score, cause of liver disease, and ascites, including an interaction with candidate BMI. Results: Of 1108 liver transplant candidates (474 women and 634 men; mean [SD] age, 55 [10] years), 290 (26.2%) were frail; 170 of 670 nonobese candidates (25.4%), 64 of 246 candidates with class 1 obesity (26.0%), and 56 of 192 candidates with class 2 or greater obesity (29.2%) were frail (P = .57). Frail nonobese candidates and frail candidates with class 1 obesity had a higher risk of wait-list mortality compared with their nonfrail counterparts (nonobese candidates: adjusted subhazard ratio, 1.54; 95% CI, 1.02-2.33; P = .04; and candidates with class 1 obesity: adjusted subhazard ratio, 1.72; 95% CI, 0.99-2.99; P = .06; P = .75 for interaction). However, frail candidates with class 2 or greater obesity had a 3.19-fold higher adjusted risk of wait-list mortality compared with nonfrail candidates with class 2 or greater obesity (95% CI, 1.75-5.82; P < .001; P = .047 for interaction). Conclusions and Relevance: This study's finding suggest that among nonobese liver transplant candidates and candidates with class 1 obesity, frailty was associated with a 2-fold higher risk of wait-list mortality. However, the mortality risk associated with frailty differed for candidates with class 2 or greater obesity, with frail candidates having a more than 3-fold higher risk of wait-list mortality compared with nonfrail patients. Frailty assessments may help to identify vulnerable patients, particularly those with a BMI of 35.0 or more, in whom a clinician's visual evaluation may be less reliable to assess muscle mass and nutritional status.

Lai, J. C., R. S. Rahimi, E. C. Verna, M. R. Kappus, M. A. Dunn, M. McAdams-DeMarco, C. E. Haugen, M. L. Volk, A. Duarte-Rojo, D. R. Ganger, J. G. O’Leary, J. L. Dodge, D. Ladner and D. L. Segev (2019). “Frailty Associated With Waitlist Mortality Independent of Ascites and Hepatic Encephalopathy in a Multicenter Study.” Gastroenterology 156(6): 1675-1682.

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BACKGROUND & AIMS: Frailty is associated with mortality in patients with cirrhosis. We measured frailty using 3 simple tests and calculated Liver Frailty Index (LFI) scores for patients at multiple ambulatory centers. We investigated associations between LFI scores, ascites, and hepatic encephalopathy (HE) and mortality. METHODS: Adults without hepatocellular carcinoma who were on the liver transplantation waitlist at 9 centers in the United States (N = 1044) were evaluated using the LFI; LFI scores of at least 4.5 indicated that patients were frail. We performed logistic regression analyses to assess associations between frailty and ascites or HE and competing risk regression analyses (with liver transplantation as the competing risk) to estimate sub-hazard ratios (sHRs) of waitlist mortality (death or removal from the waitlist). RESULTS: Of study subjects, 36% had ascites, 41% had HE, and 25% were frail. The odds of frailty were higher for patients with ascites (adjusted odd ratio 1.56, 95% confidence interval [CI] 1.15-2.14) or HE (odd ratio 2.45, 95% CI 1.80-3.33) than for those without these features. Larger proportions of frail patients with ascites (29%) or HE (30%) died while on the waitlist compared with patients who were not frail (17% of patients with ascites and 20% with HE). In univariable analysis, ascites (sHR 1.52, 95% CI 1.14-2.05), HE (sHR 1.84, 95% CI 1.38-2.45), and frailty (sHR 2.38, 95% CI 1.77-3.20) were associated with waitlist mortality. In adjusted models, only frailty remained significantly associated with waitlist mortality (sHR 1.82, 95% CI 1.31-2.52); ascites and HE were not. CONCLUSIONS: Frailty is a prevalent complication of cirrhosis that is observed more frequently in patients with ascites or HE and independently associated with waitlist mortality. LFI scores can be used to objectively quantify risk of death related to frailty-in excess of liver disease severity-in patients with cirrhosis.

Alsahhar, J. S. and R. S. Rahimi (2019). “Updates on the pathophysiology and therapeutic targets for hepatic encephalopathy.” Curr Opin Gastroenterol 35(3): 145-154.

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PURPOSE OF REVIEW: Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin). RECENT FINDINGS: Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation). SUMMARY: This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.