Continuous home terlipressin infusion increases handgrip strength and reduces ascites-A prospective randomized crossover study.

BACKGROUND AND AIMS: Observational studies suggest a beneficial effect of continuous terlipressin infusion (CTI) on ascites and sarcopenia in decompensated cirrhosis with portal hypertension. APPROACH AND RESULTS: This single-center, prospective, cross-over study randomized 30 patients with cirrhosis, ascites, and sarcopenia to commence on 12 weeks of home CTI or 12 weeks of observation prior to cross-over. The co-primary outcomes were change in handgrip strength and paracentesis volume. Secondary outcomes included quality of life, sarcopenia measures, renal function, safety, and hospitalization. The median age of participants was 62 years (IQR: 57-64), the median Model for End-Stage Liver Disease-Sodium was 16 (12.3-20.8), and 22 (73%) were male. Handgrip strength increased by a mean adjusted difference (MAD) of 3.09 kg (95% CI: 1.11-5.08 kg) between CTI and observation ( p =0.006); an 11.8% increase from baseline. The total volume of ascites drained decreased by a MAD of 11.39L (2.99-19.85, p =0.01), with 1.75 fewer episodes of paracentesis (0.925-2.59, p <0.001) on CTI. Serum creatinine decreased, urinary sodium excretion increased, and quality of life was significantly higher on CTI (all p <0.001), with an increase in Chronic Liver Disease Questionnaire score of 0.41 points (0.23-0.59). There were 7 minor line-related complications but no cardiac events or pulmonary edema. CONCLUSIONS: This novel study demonstrates a significant increase in handgrip strength, reduction in paracentesis volume, and improved quality of life in patients with decompensated cirrhosis treated with continuous terlipressin infusion. These findings provide a strong rationale for the use of ambulatory CTI in appropriately selected patients with cirrhosis.

Atherosclerosis on CT coronary angiography and the risk of long-term cardiovascular events after liver transplantation.

Computed tomography coronary angiography (CTCA) is increasingly utilized for preoperative risk stratification before liver transplantation (LT). We sought to assess the predictors of advanced atherosclerosis on CTCA using the recently developed Coronary Artery Disease-Reporting and Data System (CAD-RADS) score and its impact on the prediction of long-term major adverse cardiovascular events (MACE) following LT. We conducted a retrospective cohort study of consecutive patients who underwent CTCA for LT work-up between 2011 and 2018. Advanced atherosclerosis was defined as coronary artery calcium scores > 400 or CAD-RADS score ≥ 3 (≥50% coronary artery stenosis). MACE was defined as myocardial infarction, heart failure, stroke, or resuscitated cardiac arrest. Overall, 229 patients underwent CTCA (mean age 66 ± 5 y, 82% male). Of these, 157 (68.5%) proceeded with LT. The leading etiology of cirrhosis was hepatitis (47%), and 53% of patients had diabetes before transplant. On adjusted analysis, male sex (OR 4.6, 95% CI 1.5-13.8, p = 0.006), diabetes (OR 2.2, 95% CI 1.2-4.2, p = 0.01) and dyslipidemia (OR 3.1, 95% CI 1.3-6.9, p = 0.005) were predictors of advanced atherosclerosis on CTCA. Thirty-two patients (20%) experienced MACE. At a median follow-up of 4 years, CAD-RADS ≥ 3, but not coronary artery calcium scores, was associated with a heightened risk of MACE (HR 5.8, 95% CI 1.6-20.6, p = 0.006). Based on CTCA results, 71 patients (31%) commenced statin therapy which was associated with a lower risk of all-cause mortality (HR 0.48, 95% CI 0.24-0.97, p = 0.04). The standardized CAD-RADS classification on CTCA predicted the occurrence of cardiovascular outcomes following LT, with a potential to increase the utilization of preventive cardiovascular therapies.

Impact of Share 35 liver transplantation allocation in Australia and New Zealand.

Patients with high model for end-stage liver disease (MELD) scores waiting for liver transplantation in Australia and New Zealand (ANZ) have had limited access to deceased donor livers and therefore binational sharing of livers, for patients with a MELD score ≥35 was introduced in February 2016. Waiting list mortality, post-transplant outcomes and intention-to-treat survival were compared between patients whose MELD score reached 35 on the waiting list between October 2013 and April 2015 (Pre-Share 35 group, n = 23) and patients who were Share 35 listed between February 2016 and May 2022 (Share 35 group, n = 112). There was significantly reduced waiting list mortality in share 35 listed patients in comparison to the pre-Share 35 group (11.7% vs. 52.2%, OR .120 95% CI .044-.328, P < .001). Post-transplant patient and graft survival were not significantly different between the groups (5-year patient survival 82% vs. 84%, P = .991, 5-year graft survival 82% vs. 76%, P = .543). Intention-to-treat survival was superior in the Share 35 group (HR .302, 95% CI .149-.614, P < .001). Introduction of Share 35 in ANZ resulted in a 78% risk reduction in waiting list mortality, equivalent post-transplant survival and an improvement in intention-to-treat survival.

Safety and efficacy of outpatient continuous terlipressin infusion for the treatment of portal hypertensive complications in cirrhosis.

BACKGROUND/AIM: Therapeutic options are limited for patients with hepatorenal syndrome (HRS), diuretic refractory ascites and hepatic hydrothorax who are awaiting liver transplant. We assessed the safety and efficacy of continuous terlipressin infusion (CTI) for treating these conditions in an outpatient setting. METHOD: All patients treated with CTI from May 2013 through March 2018 at our institution were initiated in-hospital on bolus dose terlipressin therapy for 24-72 h prior to commencing CTI for home therapy. Daily home visits for clinical assessment and medication administration were provided. Adverse events, effects of treatment on renal function, model for end-stage liver disease (MELD) score, and paracentesis/thoracentesis requirements were assessed. RESULTS: Twenty-three patients were included (HRS = 17; refractory ascites = 4; refractory hepatic hydrothorax = 2). Median (range) duration of outpatient CTI was 50 (1-437) days with a total of 2482 patient days of treatment. Fourteen patients (60.9%) received a liver transplant; of whom 13 (92.9%) were alive at the end of the study period. There were no cardiac or ischemic complications and no serious adverse events reported. In patients with HRS, median serum creatinine significantly decreased from 202.0 µmol/L at baseline to 125.5 µmol/L at day 14 of CTI (P = 0.0003) and remained stable thereafter. Median MELD score decreased from 22.5 to 19.0 at end of CTI (P = 0.008). Median frequency of paracentesis/thoracentesis was 4 per month prior to CTI versus 1.52 during treatment. CONCLUSION: Transplant-eligible and otherwise stable patients can be managed with CTI at home for an extended duration under supervision without adverse consequences.

Clinical outcomes of patients with two small hepatocellular carcinomas.

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.

Identification of a Latitude Gradient in the Prevalence of Primary Biliary Cholangitis.

INTRODUCTION: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and seems to have a latitudinal gradient with the highest prevalence reported in higher latitudes, as has been observed with other autoimmune diseases. This study aimed to determine whether there is a latitudinal gradient of PBC prevalence in Australia using 2 methods of case ascertainment. METHODS: We investigated the latitudinal variation of PBC prevalence across the states and territories of Australia (latitudinal range 18.0°-42.7°S) using pathology-based (private pathology antimitochondrial antibody results and PBC-specific prescription databases (prescriptions for ursodeoxycholic acid, the only publicly subsidized treatment for this disease). RESULTS: PBC prevalence was significantly positively associated with latitude, and the postcodes in the highest quintile of latitude (encompassing the south coastal areas of the Australian mainland and Tasmania; latitude range -37.75° to -42.72°) had a prevalence estimate that was 1.78 times higher using the pathology-based prevalence estimation than those in the lowest quintile (encompassing tropical and southern Queensland; latitude range -18.02° to -27.59°). Comparing prevalence estimates between states/territories, the result was 2.53 and 2.21 times higher in Tasmania compared with Queensland when using the pathology-based and prescription-based methods, respectively. DISCUSSION: Using 2 different case-ascertainment methods, we have demonstrated that prevalence estimates of PBC vary significantly with latitude in Australia. Further studies are needed to determine whether factors such as variations in ultraviolet radiation exposure and/or vitamin D levels are responsible for this observation and to investigate the latitudinal prevalence of PBC in other populations.

Exercise physiology in cirrhosis and the potential benefits of exercise interventions: A review.

Reduction in muscle mass is a highly prevalent phenomenon in cirrhosis and is now well-documented to be associated with significant morbidity and mortality. Research into muscle loss in cirrhosis remains limited by an ongoing poor understanding of its relationship with muscle function, physical activity, and aerobic capacity. Alterations in exercise physiology have been documented in studies of individuals with cirrhosis that provide important information on physical function that is not captured by simple quantification of muscle mass. Despite expert consensus recommending regular exercise in end-stage liver disease to maintain muscle mass and function, there is little evidence guiding clinicians as to which form of exercise or delivery mechanism is most effective. It also remains unproven whether any specific intervention can alter clinically relevant outcomes. This review article summarizes the available literature regarding the changes in exercise physiology observed in cirrhosis, the associated impact on physical capacity, and the results of existing trials that examine the potential benefits of exercise delivery in patients with cirrhosis, particularly pertaining to their impact on exercise physiology.

Low participation in preventative health measures in a cohort of liver transplant recipients: A cross-sectional analysis.

BACKGROUND: Despite high rates of infection and malignancy post-solid organ transplant, there are little data on patient participation in preventative health care. METHODS: We conducted a cross-sectional survey of post-liver transplant patients to evaluate insight into transplant-associated infective and neoplastic risks, and receipt of vaccination and cancer surveillance in accordance with Australian and local institution-specific guidelines. Descriptive analyses were used to assess characteristics potentially influencing adherence. RESULTS: Of 219 patients surveyed, adherence to bowel cancer surveillance was significantly reduced in those distant from transplantation compared with those recently transplanted (95.8% if transplanted ≤ 5 years ago vs. 68.3% if transplanted > 5 years ago, P < .001). Skin cancer surveillance participation with annual physician-directed examination was low (42.9%), particularly in younger patients (29.5% in < 50yo vs. 48.1% in ≥ 50yo, P = .01), who were also less adherent to vaccination recommendations (72.1% in < 50yo vs. 87.3% in ≥ 50yo, P = .008). CONCLUSIONS: This is the first analysis of preventative healthcare participation in a cohort of Australian liver transplant recipients, revealing concerning adherence to bowel and skin cancer surveillance recommendations. Major interventions to avoid preventable disease in this high-risk cohort are warranted.

Relationship between QT interval prolongation and structural abnormalities in cirrhotic cardiomyopathy: A change in the current paradigm.

It is postulated that cardiac structural abnormalities observed in cirrhotic cardiomyopathy (CCM) contribute to the electrophysiologic abnormality of QT interval (QTc) prolongation. We sought to evaluate whether QTc prolongation is associated with intrinsic abnormalities in cardiac structure and function that characterize CCM. Consecutive patients undergoing liver transplant work-up between 2010 and 2018 were included. Measures of cardiac function on stress testing including cardiac reserve and chronotropic incompetence were collected prospectively and a corrected QTc ≥ 440 ms was considered prolonged. Overall, 439 patients were included and 65.1% had a prolonged QTc. There were no differences in markers of left ventricular and atrial remodeling, or resting systolic and diastolic function across QTc groups. The proportion of patients that met the criteria for a low cardiac reserve (39.2 vs 36.6%, p = .66) or chronotropic incompetence (18.1 vs 21.3%, p = .52) was not different in those with a QTc ≥ 440 vs <440 ms. Further, there was no association between QTc prolongation and CCM by either the 2005 World College of Gastroenterology or modified 2020 Cirrhotic Cardiomyopathy Consortium criteria. QT interval prolongation was not associated with structural or functional cardiac abnormalities that characterize CCM. These findings suggest that CCM and QT interval prolongation in cirrhosis may be two separate entities with distinct pathophysiological origins.

Postoperative Atrial Fibrillation and Long-Term Risk of Stroke in Patients Undergoing Liver Transplantation.

BACKGROUND AND PURPOSE: Postoperative atrial fibrillation (POAF) is the commonest cardiovascular complication following liver transplantation (LT). This study sought to assess a possible association of POAF with subsequent thromboembolic events in patients undergoing LT. METHODS: A retrospective cohort study of consecutive adults undergoing LT between 2010 and 2018 was undertaken. Patients were classified as POAF if atrial fibrillation (AF) was documented within 30 days of LT without a prior history of AF. Cases of ischemic stroke or systemic embolism were adjudicated by a panel of 2 independent physicians. RESULTS: Among the 461 patients included, POAF occurred in 47 (10.2%) a median of 3 days following transplantation. Independent predictors of POAF included advancing age, postoperative sepsis and left atrial enlargement. Over a median follow-up of 4.9 (interquartile range, 2.9-7.2) years, 21 cases of stroke and systemic embolism occurred. Rates of thromboembolic events were significantly higher in patients with POAF (17.0% versus 3.1%; P<0.001). After adjustment, POAF remained a strong independent predictor of thromboembolic events (hazard ratio, 8.36 [95% CI, 2.34-29.79]). Increasing CHA2DS2VASc score was also an independent predictor of thromboembolic events (hazard ratio, 1.58 [95% CI, 1.02-2.46]). A model using POAF and a CHA2DS2VASc score ≥2 alone yielded a C statistic of 0.77, with appropriate calibration for the prediction of thromboembolic events. However, POAF was not an independent predictor of long-term mortality. CONCLUSIONS: POAF following LT is associated with an 8-fold increased risk of thromboembolic events and the use of the CHA2DS2VASc score may facilitate risk stratification of these patients. Prospective studies are warranted to assess whether the use of oral anticoagulants can reduce the risk of thromboembolism following LT.

Prediction of Perioperative Cardiovascular Events in Liver Transplantation.

BACKGROUND: Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with poor survival in the absence of liver transplantation (LT). HRS represents a state of profound circulatory and cardiac dysfunction. Whether it increases risk of perioperative major adverse cardiovascular events (MACE) following LT remains unclear. METHODS: We performed a retrospective cohort study of 560 consecutive patients undergoing cardiac workup for LT of whom 319 proceeded to LT. All patients underwent standardized assessment including dobutamine stress echocardiography. HRS was defined according to International Club of Ascites criteria. RESULTS: Primary outcome of 30-day MACE occurred in 74 (23.2%) patients. A significantly higher proportion of patients with HRS experienced MACE (31 [41.9%] versus 54 [22.0%]; P = 0.001). After adjusting for age, model for end-stage liver disease score, cardiovascular risk index, history of coronary artery disease, and a positive stress test, HRS remained an independent predictor for MACE (odds ratio [OR], 2.44; 95% confidence interval [CI], 1.13-5.78). Other independent predictors included poor functional status (OR, 3.38; 95% CI, 1.41-8.13), pulmonary hypertension (OR, 3.26; 95% CI, 1.17-5.56), and beta-blocker use (OR, 2.56; 95% CI, 1.10-6.48). Occurrence of perioperative MACE was associated with a trend toward poor age-adjusted survival over 3.6-year follow-up (hazard ratio, 2.0; 95% CI, 0.98-4.10; P = 0.057). CONCLUSIONS: HRS, beta-blocker use, pulmonary hypertension, and poor functional status were all associated with over a 2-fold higher risk of MACE following LT. Whether inclusion of these variables in routine preoperative assessment can facilitate cardiac risk stratification warrants further study.

Effect of QT interval prolongation on cardiac arrest following liver transplantation and derivation of a risk index.

Liver transplantation (LT) has a 4-fold higher risk of periprocedural cardiac arrest and ventricular arrhythmias (CA/VAs) compared with other noncardiac surgeries. Prolongation of the corrected QT interval (QTc) is common in patients with liver cirrhosis. Whether it is associated with an increased risk of CA/VAs following LT is unclear. Rates of 30-day CA/VAs post-LT were assessed in consecutive adults undergoing LT between 2010 and 2017. Pretransplant QTc was measured by a cardiologist blinded to clinical outcomes. Among 408 patients included, CA/VAs occurred in 26 patients (6.4%). QTc was significantly longer in CA/VA patients (475 ± 34 vs 450 ± 34 ms, P < .001). Optimal QTc cut-off for prediction of CA/VAs was ≥480 ms. After adjustment, QTc ≥480 ms remained the strongest predictor for the occurrence of CA/VAs (odds ratio [OR] 5.2, 95% confidence interval [CI] 2.2-12.6). A point-based cardiac arrest risk index (CARI) was derived with the bootstrap method for yielding optimism-corrected coefficients (2 points: QTc ≥480, 1 point: Model for End-Stage Liver Disease [MELD] ≥30, 1 point: age ≥65, and 1 point: male). CARI score ≥3 demonstrated moderate discrimination (c-statistic 0.79, optimism-corrected c-statistic 0.77) with appropriate calibration. QTc ≥480 ms was associated with a 5-fold increase in the risk of CA/VAs. The CARI score may identify patients at higher risk of these events. Whether heightened perioperative cardiac surveillance, avoidance of QT prolonging medications, or beta blockers could mitigate the risk of CA/VAs in this population merits further study.

Sudden cardiac death following liver transplantation: Incidence, trends and risk predictors.

BACKGROUND: Cardiovascular events are a leading cause of mortality following liver transplantation (LT). Although a preponderance of sudden cardiac death (SCD) in this population has been reported, there is a paucity of data evaluating the incidence, timing and predictors of SCD following LT. METHODS: Using the prospectively collected Australian and New Zealand Liver Transplant Registry, a cohort study of all adult LTs from 1985 to 2017 was performed to ascertain the incidence and predictors of SCD. Recipient cause of death was adjudicated by an interdisciplinary panel. RESULTS: 4265 LT patients were followed-up for 37,409 person-years. SCD was the leading mode of cardiovascular death with an incidence rate of 165 per 100,000 person-years. There was a significant increase in the hazard of SCD in the contemporary (1996-2017) vs early era (1985-1995) (hazard ratio [HR] 2.42, 95%CI 1.10-5.40; p = 0.02). On Cox regression after adjusting for significant univariate predictors including age, coronary artery disease and non-alcoholic steatohepatitis, pre-transplant diabetes was the only independent predictor of SCD (HR 2.5 95%CI 1.1-6.0). CONCLUSION: SCD is the leading mode of cardiovascular cause-specific mortality following LT and diabetes was associated with a two-fold higher risk for its occurrence. Given the escalating cardiovascular risk factor profile of LT candidates, targeted therapies especially in patients with diabetes are needed to mitigate risk of post-transplant SCD.

Malnutrition in cirrhosis: More food for thought.

Malnutrition is highly prevalent in liver cirrhosis and its presence carries important prognostic implications. The clinical conditions and pathophysiological mechanisms that cause malnutrition in cirrhosis are multiple and interrelated. Anorexia and liver decompensation symptoms lead to poor dietary intake; metabolic changes characterised by elevated energy expenditure, reduced glycogen storage, an accelerated starvation response and protein catabolism result in muscle and fat wasting; and, malabsorption renders the cirrhotic patient unable to fully absorb or utilise food that has been consumed. Malnutrition is therefore a considerable challenge to manage effectively, particularly as liver disease progresses. A high energy, high protein diet is recognised as standard of care, yet patients struggle to follow this recommendation and there is limited evidence to guide malnutrition interventions in cirrhosis and liver transplantation. In this review, we seek to detail the factors which contribute to poor nutritional status in liver disease, and highlight complexities far greater than "poor appetite" or "reduced oral intake" leading to malnutrition. We also discuss management strategies to optimise nutritional status in this patient group, which target the inter-related mechanisms unique to advanced liver disease. Finally, future research requirements are suggested, to develop effective treatments for one of the most common and debilitating complications afflicting cirrhotic patients.