Bhanji, Rahima A.

Abstract Liver transplantation (LT) is the definitive treatment for end‐stage liver disease. Unfortunately, women are disadvantaged at every stage of the LT process. We conducted a literature review to increase the understanding of this disparity. Hormonal differences, psychological factors, and Model for End‐Stage Liver Disease (MELD) score inequalities are some pretransplantation factors that contribute to this disparity. In the posttransplantation setting, women have differing risk than men in most major outcomes (perioperative complications, rejection, long‐term renal dysfunction, and malignancy) and assessing the two groups together is disadvantageous. Herein, we propose interventions including standardized criteria for LT referral, using an alternate MELD, education for support of women, and motivating women to seek living donors. Understanding sex‐based differences will allow us to improve access, tailor management, and improve overall outcomes for all patients, particularly women.

Physiologic reserve is an important prognostic indicator. Because of its complexity, no single test can measure an individual’s physiologic reserve. Frailty is the phenotypic expression of decreased reserve and portends poor prognosis. Both subjective and objective tools have been used to measure one or more components of physiologic reserve. Most of these tools appear to predict pretransplant mortality, but only some predict posttransplant survival. Incorporation of these measures of physiologic reserve in the clinical and research settings including prediction models are reviewed, and the applicability to patient‐related outcomes are discussed. Commonly used tools, in patients with cirrhosis, that have been associated with clinical outcomes were reviewed. The strength of subjective tools lies in low‐cost, wide availability, and quick assessments at the bedside. A disadvantage of these tools is the manipulative capacity, restricting their value in allocation processes. The strength of objective tests lies in objective measurements and the ability to measure change. The disadvantages include complexity, increased cost, and limited accessibility. Heterogeneity in the definitions and tools used has prevented further advancement or a clear role in transplant assessment. Consistent use of objective tools, including the 6‐minute walk test, gait speed, Liver Frailty Index, or Short Physical Performance Battery, are recommended in clinical and research settings.

Sarcopenia is a common complication of cirrhosis and is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. Sarcopenia is associated with poor prognosis and increased mortality. How sarcopenia and muscle wasting relate to such poor outcomes requires looking beyond the overt muscle loss and at this entity as a systemic disease that affects muscles of vital organs including cardiac and respiratory muscles. This review explores the pathophysiological pathways and mechanisms that culminate in poor outcomes associated with sarcopenia. This provides a launching pad to identify potential targets for therapeutic intervention and optimization to improve patient outcomes.

Summary Background Sarcopenia is associated with both increased wait‐list mortality and mortality following liver transplantation. Aims To determine the course of sarcopenia from transplant evaluation until 1 year post‐transplant, and its implications on hospitalisation and mortality following liver transplantation. Methods Two hundred and ninety‐three transplant recipients from 2002 to 2006 had pre‐transplant CT scans analysed at the third lumbar region for sarcopenia, myosteatosis and abdominal visceral fat content. Half the recipients had post‐transplant CT scan for interpretation (161/293). Results Sarcopenia was present in 146/293 (50%) of the patients pre‐transplant. There was a significant decrease in muscle mass (loss 2.0 ± 4.9 cm 2 /m 2 ; P < 0.001), and an increase in myosteatosis while awaiting liver transplantation. There was no significant change in abdominal visceral fat. For every 1 cm 2 /m 2 decrease in muscle mass there was an increase in post‐transplant length of stay by 0.36 days ( P = 0.005). Post‐transplant, 98/161 (61%) of patients with CT imaging had sarcopenia (25 de novo and 73 persistent), with continued increase in myosteatosis, lower Hounsfield units (−5.0 [IQR −8.6 to 0.1]; P < 0.001) and an increase in abdominal visceral fat (4.9 [IQR −4.4 to 15.6] cm 2 /m 2 ; P < 0.001). There was no statistically significant difference in 1‐year mortality in patients with de novo sarcopenia compared to patients with sarcopenia both pre‐ and post‐transplant (HR 1.88; P = 0.088). Conclusions Sarcopenia progresses up to 1 year following liver transplantation and is associated with an increase in post‐transplant length of stay.

SummaryBackgroundVitamin D deficiency has been implicated in the outcome of chronic liver disease.AimTo determine the frequency of severe vitamin D deficiency in autoimmune hepatitis (AIH), assess its association with treatment non‐response, and evaluate the relationship between vitamin D status and liver‐related mortality and need for transplantation.MethodsTwo hundred and nine patients were evaluated by liver tissue examination at presentation. Serum vitamin D levels were determined, and serum levels <25 nmol/L (10 ng/mL) were considered severely deficient. Treatment non‐response was defined as non‐normalised aspartate aminotransferase/alanine aminotransferase and immunoglobulin G levels during conventional immunosuppressive therapy. Univariate and multivariate analyses were performed using binary logistic regression and Cox proportional hazards model.ResultsThe mean vitamin D level was 60 ± 38 nmol/L (range, 3‐263 nmol/L), and 42 patients (20%) had severe vitamin D deficiency. Treatment non‐response was more common in patients with severe vitamin D deficiency than in patients without (59% vs 41%, P = 0.04). Severe vitamin D deficiency was also independently associated with a higher risk of developing cirrhosis (HR 3.40; 95% CI 1.30‐8.87, P = 0.01) and liver‐related mortality or requirement for liver transplantation (LT; HR 5.26, 95% CI, 1.54‐18.0, P = 0.008). Patients with persistent severe deficiency following vitamin D supplementation continued to have poor outcomes.ConclusionsSevere vitamin D deficiency is associated with treatment non‐response, progression to cirrhosis, and liver‐related death or need for LT. Severe vitamin D deficiency is a prognostic biomarker in AIH.

Sarcopenia and frailty are commonly encountered in patients with end‐stage liver disease and are associated with adverse clinical outcomes, including decompensation and wait‐list mortality. The impact of these entities in patients with differing disease etiologies has not been elucidated. We aim to ascertain the change in their prevalence over time on the wait list and determine their impact on hospitalization, delisting, and wait‐list survival, specifically for patients with nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD). Adult patients who were evaluated for their first liver transplant from 2014 to 2016 with a primary diagnosis of NASH (n = 136) or ALD (n = 129) were included. Computed tomography scans were used to determine the presence of sarcopenia and myosteatosis. Frailty was diagnosed using the Rockwood frailty index. Patients with NASH had a significantly lower prevalence of sarcopenia (22% versus 47%; P < 0.001) but a significantly higher prevalence of frailty (49% versus 34%; P = 0.03) when compared with patients with ALD at the time of listing. In patients with NASH, sarcopenia was not associated with adverse events, but a higher frailty score was associated with an increased length of hospitalization (P = 0.05) and an increased risk of delisting (P = 0.02). In patients with ALD, univariate analysis showed the presence of sarcopenia was associated with an increased risk of delisting (P = 0.01). In conclusion, sarcopenia and frailty occur with differing prevalence with variable impact on outcomes in wait‐listed patients with NASH and ALD.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Up to one third of individuals with NAFLD will develop nonalcoholic steatohepatitis (NASH), which is associated with progression to cirrhosis and is rapidly becoming the leading indication for liver transplantation. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. It is observed in up to 60% of patients with end‐stage liver disease and portends a poor prognosis. Recent studies have shown that sarcopenia is a novel risk factor for developing NAFLD. Pathophysiological mechanisms relating sarcopenia and NASH may include insulin resistance (IR) and increased inflammation. IR leads to accumulation of triglycerides in both muscle tissue and the liver. It also exacerbates proteolysis and leads to muscle depletion. Chronic inflammation leads to liver injury and progression of fibrosis. The inflammatory milieu also stimulates protein catabolism. Viewing skeletal muscle as an endocrine organ that secretes various salutary myokines may help us understand its role in the development of steatosis. A better understanding of the pathophysiology will aid in developing physical and pharmacological therapeutic interventions. In this review, we will explore the complex inter‐relationships between sarcopenia and NASH. We will discuss the impact of sarcopenia in patients with NASH and therapeutic options for the management of sarcopenia. (Hepatology 2017;66:2055–2065)