Medicine (Austin & Northern Health) - Research Publications
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ItemStopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels(WILEY, 2022-07)BACKGROUND AND AIMS: Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS: We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION: Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.
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ItemNo Preview AvailableHepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways(OXFORD UNIV PRESS INC, 2022-12-28)BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.
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ItemClinical outcomes of patients with two small hepatocellular carcinomas(BAISHIDENG PUBLISHING GROUP INC, 2021-10-27)BACKGROUND: Management of single small hepatocellular carcinoma (HCC) is straightforward with curative outcomes achieved by locoregional therapy or resection. Liver transplantation is often considered for multiple small or single large HCC. Management of two small HCC whether presenting synchronously or sequentially is less clear. AIM: To define the outcomes of patients presenting with two small HCC. METHODS: Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC ≤ 3 cm between January 2000 and March 2018. Primary outcomes were overall survival (OS) and transplant-free survival (TFS). RESULTS: 104 patients were identified (male n = 89). Median age was 63 years (interquartile range 58-67.75) and the most common aetiology of liver disease was hepatitis C (40.4%). 59 (56.7%) had synchronous HCC and 45 (43.3%) had sequential. 36 patients died (34.6%) and 25 were transplanted (24.0%). 1, 3 and 5-year OS was 93.0%, 66.1% and 62.3% and 5-year post-transplant survival was 95.8%. 1, 3 and 5-year TFS was 82.1%, 45.85% and 37.8%. When synchronous and sequential groups were compared, OS (1,3 and 5 year synchronous 91.3%, 63.8%, 61.1%, sequential 95.3%, 69.5%, 64.6%, P = 0.41) was similar but TFS was higher in the sequential group (1,3 and 5 year synchronous 68.5%, 37.3% and 29.7%, sequential 93.2%, 56.6%, 48.5%, P = 0.02) though this difference did not remain during multivariate analysis. CONCLUSION: TFS in patients presenting with two HCC ≤ 3 cm is poor regardless of the timing of the second tumor. All patients presenting with two small HCC should be considered for transplantation.
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ItemRegression of Hepatocellular Adenomas and Systemic Inflammatory Syndrome After Cessation of Estrogen Therapy(WILEY, 2017-09)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).
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ItemAdditive impact of pre-liver transplant metabolic factors on survival post-liver transplant(WILEY-BLACKWELL, 2016-05)BACKGROUND AND AIM: 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. METHODS: A multi-center cohort study of 617 adult subjects undergoing liver transplantation between 2003 and 2009 has been used. Dry body mass index was calculated following adjustment for ascites. RESULTS: After a median follow-up of 5.8 years (range 0-10.5), 112 (18.2%) patients died. Diabetes was associated with reduced post-transplant survival (hazard ratio 1.89, 95% confidence interval [CI] 1.25-2.86, P = 0.003), whereas obesity, hypertension, dyslipidemia, and the metabolic syndrome itself were not (P > 0.3 for all). Patients with concomitant diabetes and obesity had lower survival (adjusted Hazard Ratio [aHR] 2.40, 95%CI 1.32-4.38, P = 0.004), whereas obese non-diabetic patients or diabetic non-obese patients had similar survival compared with non-diabetic, non-obese individuals. The presence of hypertension or dyslipidemia did not impact on survival in patients with diabetes (P > 0.1 for both). Obese diabetic patients had longer intensive care and hospital stays than non-obese diabetic or obese, non-diabetic patients (P < 0.05). The impact of concomitant obesity and diabetes on survival was greater in subjects aged 50+ years (52.6% 5-year survival, aHR 3.04, 95% CI 1.54-5.98) or those transplanted with hepatocellular carcinoma (34.1% 5-year survival, aHR 3.35, 95% CI 1.31-5.57). Diabetes without obesity was not associated with an increased mortality rate in these sub-groups. CONCLUSIONS: Concomitant diabetes and obesity but not each condition in the absence of the other is associated with reduced post-liver transplant survival. The impact of diabetes and obesity is greater in older patients and those with hepatocellular carcinoma.
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ItemHigh circulating oestrone and low testosterone correlate with adverse clinical outcomes in men with advanced liver disease(WILEY-BLACKWELL, 2016-11)BACKGROUND & AIMS: Circulating testosterone is usually reduced in men with cirrhosis, but there has not been a comprehensive analysis of androgen status or circulating oestrogens. Little is known about associations between circulating sex steroids with aspects of health in this population. METHODS: We report data from men with cirrhosis and low serum testosterone (<12 nmol/L or calculated free testosterone <230 pmol/L). Comprehensive circulating sex steroid profiles were measured by liquid chromatography-mass spectrometry and compared with age-matched controls. Relationships between sex hormone levels, severity of liver disease, biochemistry and clinical outcomes were assessed. RESULTS: Serum oestrone and oestradiol were significantly elevated in men with cirrhosis compared with controls (median, 869.1 pmol/L vs. 133.8 pmol/L and 166.7 pmol/L vs. 84.6 pmol/L respectively). Serum oestrone correlated with MELD score (correlation +0.306, P < 0.001) and inversely correlated with serum sodium (correlation -0.208, P = 0.004) and haemoglobin (correlation -0.177, P = 0.012). No such correlations were observed for oestradiol. Serum testosterone levels inversely correlated with MELD score (correlation -0.294, P < 0.001) and positively with handgrip strength (correlation +0.242, P < 0.001), physical activity (correlation +0.276, P = 0.012), haemoglobin (correlation +0.282, P < 0.001) and serum sodium (+0.344, P < 0.001). Dihydrotestosterone inversely correlated with MELD score (correlation -0.225, P = 0.002) and shared similar significant relationships to testosterone. CONCLUSION: Low serum androgens and elevated serum oestrone (but not oestradiol) are associated with higher MELD and individual adverse health outcomes in cirrhotic cohort of men selected for low testosterone. Serum oestrone may be a novel marker of ill health in this population. Whether low androgens are markers or mediators of ill health requires further investigation.
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ItemLow testosterone as a better predictor of mortality than sarcopenia in men with advanced liver disease(WILEY, 2016-03)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.
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ItemReview article: sarcopenia in cirrhosis - aetiology, implications and potential therapeutic interventions(WILEY, 2016-04)BACKGROUND: 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. AIMS: To summarise existing knowledge regarding the aetiology of sarcopenia in cirrhosis, diagnostic modalities and the clinical significance of this condition. In addition to discuss recent research findings that may allow the development of more effective treatments. METHODS: We conducted a Medline and PubMed search using the search terms 'sarcopenia', 'muscle', 'body composition', 'cirrhosis', 'liver' and 'malnutrition' from inception to October 2015. RESULTS: Cirrhotic patients with sarcopenia have reduced survival, experience increased rates of infection and have worse outcomes following liver transplantation. The aetiology of this condition is more complex than simple protein and calorie malnutrition. Cirrhosis also results in depleted glycogen stores and metabolic alterations that cause excessive protein catabolism, increased activation of the ubiquitin-proteasome pathway and inappropriate muscle autophagy. Satellite cell differentiation and proliferation is also reduced due to a combination of elevated myostatin levels, reduced IGF-1 and hypogonadism. Although there is some evidence supporting the use of late evening snacks, branched chain amino acid supplementation and high protein/high calorie diets, well designed clinical trials addressing the effects of treatment on body composition in cirrhosis are lacking. CONCLUSION: Sarcopenia in cirrhosis has a complex pathogenesis and simple dietary interventions are insufficient. Improved understanding of the multiple mechanisms involved should allow the development of more effective therapies, which target the specific underlying metabolic derangements.
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ItemHandgrip Strength Adds More Prognostic Value to the Model for End-Stage Liver Disease Score Than Imaging-Based Measures of Muscle Mass in Men With Cirrhosis(WILEY, 2019-10)Sarcopenia is associated with mortality in cirrhosis, but there is no gold standard for its diagnosis. The comparative utility of different diagnostic methods is unknown. This single-center observational cohort study followed 145 men referred for liver transplant evaluation between 2005 and 2012. Muscle mass was estimated by handgrip strength, dual energy X-ray absorptiometry (DEXA) lean mass, and single-slice computed tomography (CT) scan at the fourth lumbar vertebra. Recorded outcomes included time to death or liver transplantation. The median (interquartile range [IQR]) age was 54 years (47-59 years), and Model for End-Stage Liver Disease (MELD) score was 17 (14-23). Of 145 men, 56 died with a median (IQR) time to death of 7.44 months (3.48-14.16 months). In total, 79 men underwent transplantation with median (IQR) time to transplant of 7.20 months (3.96-12.84 months). The prevalence of sarcopenia differed between diagnostic modalities with 70.3% using CT muscle mass, 45.9% using handgrip strength, and 38.7% using DEXA. Muscle mass was inversely associated with wait-list mortality for measured CT muscle mass (hazard ratio [HR], 0.94; 95% confidence interval (CI), 0.90-0.98; P = 0.002), DEXA muscle mass (HR, 0.99; 95% CI, 0.99-0.99; P = 0.003), and handgrip strength (HR, 0.94; 95% CI, 0.91-0.98; P = 0.002). These results retained significance independent of the MELD score. In predicting mortality, the MELD-handgrip strength bivariate Cox model was superior to a MELD-CT muscle Cox model (P < 0.001). In conclusion, handgrip strength combined with MELD score was the superior predictive model in this novel study examining 3 commonly employed techniques to diagnose sarcopenia in cirrhosis. Handgrip strength has additional potential clinical benefits because it can be performed serially without the radiation dose, cost, and access issues attributable to CT and DEXA.
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ItemUse of Dual X-ray Absorptiometry in men with advanced cirrhosis to predict sarcopenia-associated mortality risk(WILEY, 2019-06)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.