Reversing malnutrition and low muscle strength with targeted enteral feeding in patients awaiting liver transplant: A randomized controlled trial.

BACKGROUND AND AIMS: Most patients with decompensated cirrhosis fail to meet their nutrition targets. The impact of nasogastric feeding (NGF) on malnutrition in cirrhosis remains unknown. This study aims to assess the impact of pretransplant NGF on pre-liver transplant and post-liver transplant outcomes. APPROACH AND RESULTS: This single-center, prospective randomized controlled trial of 55 patients with severe malnutrition and low handgrip strength (HGS) compared a standard high-energy high-protein diet to diet plus supplemental nocturnal NGF while awaiting transplant. The primary outcome was a change in HGS. The median age was 58.5 years (IQR: 51.1-64), median MELD was 24 (20-28.5), and 32 (58%) patients were male. The median duration of NGF was 63.0 days (34.5-127), following which time the median between-group difference in HGS was 3.6 kg (95% CI: 1.7-5.2, p <0.001), an increase of 20% from baseline. Mid-upper-arm circumference, triceps skinfold, and immune function all increased significantly with NGF. Muscle and nutritional parameters continued to improve with increasing duration of feeding. NGF significantly increased daily energy intake between groups by 1285 kcal (95% CI: 860-1677) and protein intake by 51 g (95% CI: 32-71) (both p <0.001). All NGF patients met >100% of their measured nutritional requirements. Posttransplant clinical outcomes were similar between groups. CONCLUSIONS: Targeted enteral feeding before liver transplant improves HGS, anthropometry, and immune function in severely malnourished patients with cirrhosis. These findings provide a strong rationale for early consideration of NGF to reverse malnutrition and improve muscle strength. Appropriately powered studies should explore whether NGF can also impact clinically relevant outcomes including pretransplant and posttransplant mortality.

Branched-chain amino acid supplementation does not improve measures of sarcopenia in cirrhosis: results of a randomised controlled trial.

BACKGROUND: Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. AIMS: We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. METHODS: We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures. RESULTS: A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045). CONCLUSION: BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202.

Transjugular intrahepatic portosystemic shunt insertion improves muscle mass but not muscle function or frailty measures.

INTRODUCTION: Sarcopenia in cirrhosis is associated with poor outcomes. While transjugular intrahepatic portosystemic shunt (TIPS) insertion improves radiological measures of muscle mass, its impact on muscle function, performance and frailty has not been evaluated. METHODS: Patients with cirrhosis referred for TIPS were prospectively recruited and followed for 6 months. L3 CT scans were used to calculate skeletal muscle and adipose tissue parameters. Handgrip strength, Liver Frailty Index and short physical performance battery were serially monitored. Dietary intake, insulin resistance, insulin-like growth factor (IGF)-1, and immune function using QuantiFERON Monitor (QFM) were measured. RESULTS: Twelve patients completed the study with a mean age of 58 ±â€…9 years and model for end-stage liver disease score of 16 ±â€…5. At 6 months post-TIPS, skeletal muscle area increased from 139.33 cm 2  ±â€…22.72 to 154.64 ±â€…27.42 ( P  = 0.012). Significant increases were observed in the subcutaneous fat area ( P  = 0.0076) and intermuscular adipose tissue ( P  = 0.041), but not muscle attenuation or visceral fat. Despite marked changes in muscle mass, no improvements were observed in handgrip strength, frailty, or physical performance. At 6 months post-TIPS, IGF-1 ( P  = 0.0076) and QFM ( P  = 0.006) increased compared to baseline. Nutritional intake, hepatic encephalopathy measures, insulin resistance and liver biochemistry were not significantly impacted. CONCLUSION: Muscle mass increased following TIPS insertion as did IGF-1, a known driver of muscle anabolism. The lack of improvement in muscle function was unexpected and may relate to impairment in muscle quality and the effects of hyperammonaemia on muscle contractile function. Improvements in QFM, a marker of immune function, may suggest a reduction in infection susceptibility in this at-risk population and requires further evaluation.

Reduced upper limb lean mass on dual energy X-ray absorptiometry predicts adverse outcomes in male liver transplant recipients.

BACKGROUND: Pre-transplant muscle wasting measured by computed tomography has been associated with adverse clinical outcomes after liver transplantation including increased rates of sepsis and hospitalisation days. Upper limb lean mass (LM) measured by dual-energy X-ray absorptiometry (DEXA) was recently identified as a novel predictor of sarcopenia-associated mortality in men waitlisted for transplantation. AIM: To investigate the use of DEXA LM in predicting gender-stratified early post-transplant outcomes. METHODS: Liver transplant recipients who underwent pre-transplant DEXA body composition imaging between 2002 and 2017 were included. Endpoints included post-transplant mortality and graft failure, bacterial infections, acute cellular rejection (ACR) and intensive care and total hospital length of stay. RESULTS: Four hundred and sixty-nine patients met inclusion criteria of which 338 were male (72%). Median age was 55.0 years (interquartile range 47.4, 59.7) and model for end-stage liver disease (MELD) score 16. Median time from assessment to transplantation was 7 mo (3.5, 12). Upper limb LM was inversely associated with bacterial infections at 180 d post-transplant (hazard ratio = 0.42; 95% confidence interval: 0.20-0.89; P = 0.024) in males only. There was a negative correlation between upper limb LM and intensive care (τb = -0.090, P = 0.015) and total hospital length of stay (τb = -0.10, P = 0.0078) in men. In women, neither MELD nor body composition parameters were associated with post-transplant adverse outcomes or increased length of stay. Body composition parameters, MELD and age were not associated with 90-d mortality or graft failure in either gender. There were no significant predictors of early ACR. CONCLUSION: Sarcopenia is an independent and potentially modifiable predictor of increased post-transplant bacterial infections and hospital length of stay in men with cirrhosis. DEXA upper limb LM provides a novel measure of muscle wasting that has prognostic value in this cohort. The lack of association in women requires further investigation.

The sex-specific prognostic utility of sarcopenia in cirrhosis.

Sarcopenia is an increasingly recognized complication of cirrhosis that is associated with morbidity and mortality. Differences in the prevalence and prognosis of sarcopenia between men and women have been reported in other patient groups, but there is insufficient understanding of how sex impacts the prognostic value of sarcopenia in cirrhosis. A search of MEDLINE and Embase was conducted from earliest entries to April 2021. Studies were included if they examined sex-stratified mortality impact of reduced muscle function or mass in outpatient populations with cirrhosis. We identified 700 studies of which 6 were deemed relevant for inclusion in this narrative review. Studies of interest were heterogeneous, precluding pooling of data and making interpretation of the literature challenging. Muscle mass was assessed in five studies (n = 2566, 1730 men, 836 women) and was reduced in 36-50% of men and 24-43% of women. All five studies found that reduced muscle mass determined by computed tomography, dual-energy X-ray absorptiometry, and bioelectrical impedance analysis was associated with increased mortality in men. Of these, two studies identified a corresponding relationship in women; reduced muscle mass defined by computed tomography was associated with increased mortality [hazard ratio (HR) 2.82, P = 0.001], while increasing muscle mass by bioelectrical impedance analysis likewise conferred a survival benefit (HR 0.45, P = 0.0016). Only one study assessed the relationship of muscle function with sex-stratified mortality (n = 1405, 827 men, 578 women), concluding that reduced muscle function predicted mortality in both men and women (HR 1.65, P < 0.001 and HR 1.54, P < 0.001, respectively). Reduced muscle mass in cirrhosis is consistently associated with mortality in men, but lack of sex-stratification of mortality analyses limits the ability to make strong conclusions about the impact of sarcopenia specifically in women, with even fewer data available for analysing muscle function. Improved understanding of the sex-specific impacts of sarcopenia may help address patient deterioration and mortality while awaiting liver transplantation and allow for early intervention to mitigate mortality risk. Large, multicentre studies with adequate female participation and sex-stratified mortality analyses are warranted.

Nutraceuticals for the treatment of sarcopenia in chronic liver disease.

BACKGROUND AND AIMS: Sarcopenia, defined as loss of muscle mass, strength and function, is associated with adverse clinical outcomes in patients with cirrhosis. Despite improved understanding of the multifaceted pathogenesis, there are few established therapies to treat or prevent muscle loss in this population. This narrative review examines the available literature investigating the role of nutraceuticals for the prevention or treatment of muscle wasting in chronic liver disease. METHODS: A comprehensive search or Medline and PubMED databases was conducted. Reference lists were screened to identify additional articles. RESULTS: A number of nutritional supplements and vitamins target the specific metabolic derangements that contribute to sarcopenia in cirrhosis including altered amino acid metabolism, hyperammonaemia and inflammation. Branched chain amino acid (BCAA) supplementation has proposed anabolic effects through dual pathways of enhanced ammonia clearance and stimulation of muscle protein synthesis. l-carnitine also has multimodal effects on muscle and shows promise as a therapy for muscle loss through anti-inflammatory, antioxidant and ammonia lowering properties. Other nutraceuticals including l-ornithine l-aspartate, omega-3 polyunsaturated fatty acids and zinc and vitamin D supplementation, may similarly have positive effects on muscle homeostasis, however further evidence to support their use in cirrhotic populations is required. CONCLUSION: Nutraceuticals offer a promising and likely safe adjunct to standard care for sarcopenia in cirrhosis. While there is most evidence to support the use of BCAA and l-carnitine supplementation, further well-designed clinical trials are needed to elucidate their efficacy as a therapy for muscle loss in this population.

Epidemiology and outcomes of acute liver failure in Australia.

BACKGROUND: Acute liver failure (ALF) is a life-threatening syndrome with varying aetiologies requiring complex care and multidisciplinary management. Its changing incidence, aetiology and outcomes over the last 16 years in the Australian context remain uncertain. AIM: To describe the changing incidence, aetiology and outcomes of ALF in South Eastern Australia. METHODS: The database of the Victorian Liver Transplant Unit was interrogated to identify all cases of ALF in adults (> 16 years) in adults hospitalised between January 2002 and December 2017. Overall, 169 patients meeting criteria for ALF were identified. Demographics, aetiology of ALF, rates of transplantation and outcomes were collected for all patients. Transplant free survival and overall survival (OS) were assessed based on survival to discharge from hospital. Results were compared to data from a historical cohort from the same unit from 1988-2001. RESULTS: Paracetamol was the most common aetiology of acute liver failure, accounting for 50% of cases, with an increased incidence compared with the historical cohort (P = 0.046). Viral hepatitis and non-paracetamol drug or toxin induced liver injury accounted for 15% and 10% of cases respectively. Transplant free survival (TFS) improved significantly compared to the historical cohort (52% vs 38%, P = 0.032). TFS was highest in paracetamol toxicity with spontaneous recovery in 72% of cases compared to 31% of non-paracetamol ALF (P < 0.001). Fifty-nine patients were waitlisted for emergency liver transplantation. Nine of these died while waiting for an organ to become available. Forty-two patients (25%) underwent emergency liver transplantation with a 1, 3 and 5 year survival of 81%, 78% and 72% respectively. CONCLUSION: Paracetamol toxicity is the most common aetiology of ALF in South-Eastern Australia with a rising incidence over 30 years. TFS has improved, however it remains low in non-paracetamol ALF.

Use of Dual X-ray Absorptiometry in men with advanced cirrhosis to predict sarcopenia-associated mortality risk.

INTRODUCTION: Reduced muscle area on CT scan is an independent predictor of mortality in cirrhosis. We examine for the first time the relationship between dual energy x-ray absorptiometry (DEXA) lean mass parameters on outcomes in cirrhotic men awaiting liver transplantation. MATERIALS AND METHODS: We retrospectively reviewed DEXA scans performed during transplant assessment between 2001 and 2016. Baseline data including the presence of ascites and MELD score were recorded. DEXA lean mass measures were adjusted for height. The primary outcome was 12-month wait-list mortality. RESULTS: Four hundred twenty men with median age 55.4 years [interquartile range 49.2; 59.4] and MELD 16 [12; 20] were studied. Median follow-up was 58.5 [28.8; 109] months. 12-month wait-list mortality was 12.4%. Appendicular lean mass was inversely associated with mortality (HR 0.78 [0.62; 0.98], P = 0.03). Lean mass of arms (HR 0.37 [0.16; 0.83], P  = 0.02) rather than legs (HR 0.77 [0.58; 1.03], P  = 0.08) was responsible for this association. Upper limb lean mass showed a significant interaction with MELD score in predicting wait-list mortality, particularly within 4 months. Total lean mass was not associated with mortality but increased in conjunction with increasing ascites (OR for ascites 1.20 [1.15; 1.25], P < 0.001 for each unit increase in MELD). CONCLUSION: Upper limb lean mass by DEXA is strongly associated with mortality in men awaiting liver transplantation. The superiority of upper limb lean mass probably relates to confounding of lower limb measures by fluid retention. This DEXA parameter represents a novel and reproducible measure of sarcopenia in cirrhosis.

Progressive multifocal leukoencephalopathy secondary to hepatitis C virus infection-related T-cell lymphopenia.

Progressive multifocal leukoencephalopathy (PML) is an uncommon neurological condition known to occur in the setting of T-cell immune suppression. We report a case of hepatitis C virus (HCV) infection-related T-cell lymphopenia manifesting as PML. HCV treatment and transient viral suppression resulted in immunological recovery with clinical stabilisation.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation.

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease.

Low testosterone as a better predictor of mortality than sarcopenia in men with advanced liver disease.

BACKGROUND AND AIM: Both sarcopenia and low serum testosterone have been associated with increased mortality in men with cirrhosis. It is not known how these variables interact. METHODS: We conducted a retrospective longitudinal cohort study of 145 men referred for liver transplant evaluation between 2005 and 2012. Baseline demographics included hormone profile and model of end-stage liver disease (MELD) score. Baseline computerized tomography was reformatted to calculate skeletal muscle area at L4 using validated, Tomovision software-based methodology. The primary outcome was time to death or liver transplantation. RESULTS: Median testosterone was low at 6.2 nmol/L (ref. 10-27.6 nmol/L) as was muscle mass at 48.0 cm(2)/m(2) (ref. > 52.4 cm(2)/m(2)). Muscle mass correlated with both serum testosterone (tau = 0.132, P = 0.019) and MELD score (tau = -0.155, P = 0.007). In separate multivariable models, both sarcopenia (hazard ratio [HR] 1.05, P = 0.04) and low testosterone (HR 1.08, P = 0.01) were significantly associated with mortality independent of MELD score. When the variables MELD score, muscle area, and testosterone were entered into a single model, low testosterone but not sarcopenia remained significantly predictive of mortality (HR 1.07, P = 0.02, and HR 1.04, P = 0.09, respectively). CONCLUSION: Low testosterone and sarcopenia are both associated with increased mortality in men with advanced liver disease and may identify patients at high risk of mortality that would be missed by the MELD score alone. Low testosterone appears to be a better predictor of mortality than sarcopenia and is a simpler test to improve the prognostic value of the MELD score. Interventional trials are required to determine whether low testosterone and sarcopenia are markers or mediators of mortality in this population.

Risk factors for band-induced ulcer bleeding after prophylactic and therapeutic endoscopic variceal band ligation.

BACKGROUND AND AIMS: Endoscopic variceal band ligation (EVBL) aims to eradicate high-risk oesophageal varices. There is a small risk of precipitating bleeding from EVBL-induced oesophageal ulceration, which is associated with significant mortality. We explore the risk factors and outcome of EVBL-induced ulcer bleeding. METHODS: Retrospective review of our endoscopy database between 2007 and 2012 identified upper endoscopies during which EVBL was performed. Patient demographics, biochemistry and endoscopic findings were recorded as were the complications of EVBL-induced ulcer bleeding and death. RESULTS: A total of 749 episodes of EVBL were performed in 347 patients with a mean Model for End-stage Liver Disease (MELD) score of 15.8. In all, 609 procedures were performed for prophylaxis and 140 for acute haemorrhage. There were 21 episodes (2.8% of procedures) of EVBL-induced ulcer bleeding in 18 patients, five of whom subsequently died (28%). On multivariable analysis, acute variceal haemorrhage was the only significant predictor of EVBL-induced ulcer bleeding [odds ratio (OR) 6.25 (2.57-15.14), P<0.0001]. In 609 procedures performed for prophylaxis, the EVBL-induced ulcer bleeding rate was 1.5%, with 22% mortality. In this group, higher MELD score and reflux oesophagitis were associated significantly with EVBL-induced ulcer bleeding [OR 25.53 (2.14-303.26), P=0.010 and OR 1.07 (1.01-1.13), P=0.019, respectively]. CONCLUSION: Our EVBL-induced ulcer bleeding rate was low, but associated with significant mortality. Highest rates were observed following EVBL for acute variceal haemorrhage, for which EVBL is unavoidable. The incidence was lower following prophylactic EVBL, with the MELD score being the predominant risk factor. Reflux oesophagitis requires further investigation as a potentially modifiable risk factor for EVBL-induced ulcer bleeding.

Cirrhosis, cellulitis and cats: a 'purrfect' combination for life-threatening spontaneous bacterial peritonitis from Pasteurella multocida.

Pasteurella multocida is a Gram-negative coccobacillus that colonises the upper airways of many animals, in particular, dogs and cats. It acts as an opportunistic infection in humans following an animal bite or scratch and is associated with soft tissue infections, septicaemia and pneumonia, particularly in patients with a compromised immune response, such as patients with liver failure. Spontaneous bacterial peritonitis (SBP) is a serious complication of cirrhosis with a death rate of 10-15%. We report a case of a 47-year-old man with cirrhosis who presented with life-threatening P multocida SBP and bacteraemia secondary to a lick from a cat to a cellulitic leg wound. This case highlights the potential severity of an infection from domestic animals and an otherwise innocuous organism in an immunocompromised host.