Marie Sinclair

Review article: sarcopenia in cirrhosis--aetiology, implications and potential therapeutic interventions.

Sarcopenia (loss of muscle mass) is common in cirrhosis and is associated with poor outcomes. Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting.

Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial

BACKGROUND & AIMS Low testosterone and sarcopenia are common in men with cirrhosis and both are associated with increased mortality. Whether testosterone therapy in cirrhosis improves muscle mass and other outcomes is unknown. METHODS We conducted a 12-month, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in 101 men with established cirrhosis and low serum testosterone (total testosterone <12nmol/L or free testosterone <230pmol/L) in a single tertiary centre. Body composition was assessed using dual-energy X-ray absorptiometry at baseline, 6 and 12months. RESULTS At study completion, appendicular lean mass was significant higher in testosterone-treated subjects, with a mean adjusted difference (MAD) of +1.69kg, (CI +0.40; +2.97kg, p=0.021). Secondary outcomes included a substantially higher total lean mass in the active group (MAD +4.74kg, CI +1.75; +7.74kg, p=0.008), matched by reduced fat mass (MAD -4.34kg, CI -6.65; -2.04, p<0.001). Total bone mass increased (MAD +0.08kg, CI +0.01; +0.15kg, p=0.009) as did bone mineral density at the femoral neck (MAD +0.287points, CI +0.140; +0.434, p<0.001). Haemoglobin was higher with testosterone therapy (MAD +10.2g/L, CI +1.50; +18.9g/L, p=0.041) and percentage glycosylated haemoglobin (HbA1c) lower (MAD -0.35%, CI -0.05; -0.54, p=0.028). Mortality was non-significantly lower in testosterone-treated patients (16% vs. 25.5%, p=0.352). There was no increase in adverse events in testosterone-treated subjects. CONCLUSION Testosterone therapy in men with cirrhosis and low serum testosterone safely increases muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is the first evidence-based therapy for sarcopenia in cirrhosis and thus requires larger-scale investigation into its potential impact on mortality. LAY SUMMARY Both low testosterone and muscle wasting are associated with increased risk of death in men with severe liver disease. Administering testosterone to men with liver disease who have low testosterone levels significantly increases their muscle mass. In addition, testosterone has non-muscle beneficial effects which may be able to increase survival in this population. CLINICAL TRIAL NUMBER Australian New Zealand Clinical Trials Registry trial number ACTRN 12614000526673.

Testosterone in men with advanced liver disease: Abnormalities and implications

Serum testosterone is reduced in up to 90% of men with cirrhosis, with levels falling as liver disease advances. Testosterone is an important anabolic hormone, with effects on muscle, bone, and hematopoiesis. Many of the features of advanced liver disease are similar to those seen in hypogonadal men, including sarcopenia, osteoporosis, gynecomastia, and low libido. However, the relative contribution of testosterone deficiency to the symptomatology of advanced liver disease has not been well established. More recently, it has been demonstrated that low testosterone in men with cirrhosis is associated with increased mortality, independent of the classically recognized prognostic factors, such as the Model for End‐Stage Liver Disease score. Only several small clinical trials have examined the role of testosterone therapy in men with cirrhosis, none of which have resolved the issue of whether or not testosterone is beneficial. However, in men with organic hypogonadism due to structural hypothalamic–pituitary–testicular axis disease, testosterone therapy has been shown to improve muscle mass and bone mineral density, increase hemoglobin, and reduce insulin resistance. Despite initial concerns linking testosterone with hepatocellular carcinoma, more recent data suggest that this risk has been overstated. There is, therefore, now a strong rationale to assess the efficacy and safety of testosterone therapy in cirrhosis in well‐designed randomized controlled trials.

Additive impact of pre-liver transplant metabolic factors on survival post-liver transplant.

Diabetes at time of liver transplantation is associated with reduced post‐transplant survival. We aimed to assess whether additional metabolic conditions such as obesity or hypertension had additive prognostic impact on post‐transplantation survival.

Acute hepatic decompensation precipitated by pregnancy-related catabolic stress: a rare mimic of acute liver failure.

BACKGROUND: Abnormal liver function tests are common in pregnancy; however, liver failure is rare. Pregnancy is a catabolic state that can precipitate illness in patients with underlying metabolic disorders. CASE: A 19-year-old woman presented at 14 weeks of gestation with an alanine transaminase of 2,252 international units/L (less than 30), an international normalized ratio of 6.9 (0.9–1.2), and an ammonia of 58 micromole/L (11–51 micromole/L). No cause was identified on routine investigations including liver biopsy. Biochemical and clinical deterioration prompted investigation for a metabolic disorder. Urinary orotic acid was elevated, consistent with the urea cycle disorder type 1 citrullinemia. Appropriate management (arginine supplementation and dietary protein restriction) led to rapid improvement and later delivery of a healthy neonate. CONCLUSION: This is an unusual presentation that reminds us of the importance of considering metabolic disorders during the catabolic stress of pregnancy.

Something fishy: an unusual Erysipelothrix rhusiopathiae infection in an immunocompromised individual.

A 39-year-old man with a history of Crohns disease presented to the emergency department with a 12-h history of worsening febrile illness. He deteriorated rapidly with progression to sepsis and was admitted to the intensive care unit. Initial treatment comprised broad spectrum antibiotics and inotropic support resulting in rapid improvement. With the immunocompromised state of the patient, and multiple blood cultures revealing Erysipelothrix rhusiopathiae, a detailed history disclosed a recent injury sustained from a fishing wire as the probable source of an infection. Treatment was narrowed to target the identified pathogen, the patient made a full recovery, and was counselled to be more cautious in future fishing activities.

Regression of hepatocellular adenomas and systemic inflammatory syndrome after cessation of estrogen therapy

We report a case of dramatic systemic inflammatory symptoms and biochemical signs of inflammation related to multiple hepatic adenomas that completely resolved after cessation of the oral contraceptive pill (OCP) and associated adenoma regression. This represents a case of dramatic symptoms that resolved after estrogen withdrawal alone. (Hepatology 2017;66:989–991).

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

Both sarcopenia and low serum testosterone have been associated with increased mortality in men with cirrhosis. It is not known how these variables interact.

In reference to higher serum testosterone is associated with increased risk of advanced hepatitis c‐related liver disease in males

VINCENZO CARDINALE, M.D. GUIDO CARPINO, M.D., PH.D. ALFREDO CANTAFORA, PH.D. LOLA M. REID, PH.D. EUGENIO GAUDIO, M.D., PH.D. DOMENICO ALVARO, M.D. Department of Medico-Surgical Sciences and Biotechnologies Polo Pontino, Sapienza University of Rome, Rome, Italy Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy Department of Health Sciences, University of Rome ‘‘Foro Italico’’ Rome, Italy Department of Cell and Molecular Physiology Program in Molecular Biology and Biotechnology UNC School of Medicine, Chapel Hill, NC Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy References

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.