Development and validation of the Gender-Equity Model for Liver Allocation (GEMA) to prioritise candidates for liver transplantation: a cohort study.

BACKGROUND: The Model for End-stage Liver Disease (MELD) and its sodium-corrected variant (MELD-Na) have created gender disparities in accessing liver transplantation. We aimed to derive and validate the Gender-Equity Model for liver Allocation (GEMA) and its sodium-corrected variant (GEMA-Na) to amend such inequities. METHODS: In this cohort study, the GEMA models were derived by replacing creatinine with the Royal Free Hospital glomerular filtration rate (RFH-GFR) within the MELD and MELD-Na formulas, with re-fitting and re-weighting of each component. The new models were trained and internally validated in adults listed for liver transplantation in the UK (2010-20; UK Transplant Registry) using generalised additive multivariable Cox regression, and externally validated in an Australian cohort (1998-2020; Royal Prince Alfred Hospital [Australian National Liver Transplant Unit] and Austin Hospital [Victorian Liver Transplant Unit]). The study comprised 9320 patients: 5762 patients for model training, 1920 patients for internal validation, and 1638 patients for external validation. The primary outcome was mortality or delisting due to clinical deterioration within the first 90 days from listing. Discrimination was assessed by Harrell's concordance statistic. FINDINGS: 449 (5·8%) of 7682 patients in the UK cohort and 87 (5·3%) of 1638 patients in the Australian cohort died or were delisted because of clinical deterioration within 90 days. GEMA showed improved discrimination in predicting mortality or delisting due to clinical deterioration within the first 90 days after waiting list inclusion compared with MELD (Harrell's concordance statistic 0·752 [95% CI 0·700-0·804] vs 0·712 [0·656-0·769]; p=0·001 in the internal validation group and 0·761 [0·703-0·819] vs 0·739 [0·682-0·796]; p=0·036 in the external validation group), and GEMA-Na showed improved discrimination compared with MELD-Na (0·766 [0·715-0·818] vs 0·742 [0·686-0·797]; p=0·0058 in the internal validation group and 0·774 [0·720-0·827] vs 0·745 [0·690-0·800]; p=0·014 in the external validation group). The discrimination capacity of GEMA-Na was higher in women than in the overall population, both in the internal (0·802 [0·716-0·888]) and external validation cohorts (0·796 [0·698-0·895]). In the pooled validation cohorts, GEMA resulted in a score change of at least 2 points compared with MELD in 1878 (52·8%) of 3558 patients (25·0% upgraded and 27·8% downgraded). GEMA-Na resulted in a score change of at least 2 points compared with MELD-Na in 1836 (51·6%) of 3558 patients (32·3% upgraded and 19·3% downgraded). In the whole cohort, 3725 patients received a transplant within 90 days of being listed. Of these patients, 586 (15·7%) would have been differently prioritised by GEMA compared with MELD; 468 (12·6%) patients would have been differently prioritised by GEMA-Na compared with MELD-Na. One in 15 deaths could potentially be avoided by using GEMA instead of MELD and one in 21 deaths could potentially be avoided by using GEMA-Na instead of MELD-Na. INTERPRETATION: GEMA and GEMA-Na showed improved discrimination and a significant re-classification benefit compared with existing scores, with consistent results in an external validation cohort. Their implementation could save a clinically meaningful number of lives, particularly among women, and could amend current gender inequities in accessing liver transplantation. FUNDING: Junta de Andalucía and EDRF.

Malnutrition and low muscle strength are independent predictors of clinical outcomes and healthcare costs after liver transplant.

BACKGROUND & AIMS: Malnutrition and sarcopenia are associated with increased morbidity and mortality in cirrhosis but conflicting data are reported after liver transplantation (LT), with little known about the economic burden of malnutrition at LT. This study aims to investigate the impact of pre-transplant malnutrition and muscle strength on post-transplant clinical outcomes and healthcare costs. METHODS: Pre-transplant nutritional status (via subjective global assessment, SGA) and handgrip strength (HGS) were assessed in patients transplanted from 2009-2017. Descriptive statistics and regression analysis were used to analyse the association between nutrition and muscle function with post-LT clinical outcomes and hospital costs. RESULTS: 373 patients (70% male, median age 55 [IQR: 47, 60]) were transplanted, with 79% malnourished and mean HGS 31.4 ± 9.35 kg for males and 17.6 ± 5.78 kg for females. Malnutrition and reduced HGS independently predicted adverse post-transplant outcomes. ICU length of stay (LOS) was associated with severe malnutrition (HR (time to discharge (TTD)) 0.706, p = 0.014) and low HGS (HR (TTD) 0.692, p = 0.003); hospital LOS with severe malnutrition (HR (TTD) 0.759, p = 0.049) and low HGS (HR (TTD) 0.730, p = 0.011), and post-transplant infection with severe malnutrition (OR 1.76, p = 0.042) and low HGS (OR 1.83, p = 0.015). Accordingly, hospital costs were 30% higher in severely malnourished compared to well-nourished recipients (p = 0.012). Neither malnutrition or impaired HGS were associated with post-transplant mortality. CONCLUSIONS: This large cohort study demonstrates malnutrition and muscle weakness are independently associated with early post-transplant morbidity, namely infection and ICU and hospital LOS; with significantly increased hospital costs. Strategies to combat malnutrition and deconditioning pre-transplant may improve patient and health system outcomes after LT.

Cardiac Risk Stratification in Liver Transplantation: Results of a Tiered Assessment Protocol Based on Traditional Cardiovascular Risk Factors.

Coronary artery disease (CAD) confers increased perioperative risk in patients undergoing liver transplantation (LT). Although routine screening for CAD is recommended, there are limited data on the effectiveness of screening strategies. We evaluated the safety and efficacy of a 3-tiered cardiac risk-assessment protocol that stratifies patients based on age and traditional cardiac risk factors. We peformed a single-center, prospective, observational study of consecutive adult patients undergoing LT assessment (2010-2017). Patients were stratified into low-risk (LR), intermediate-risk (IR), or high-risk (HR) cardiac groups and received standardized investigations with selective use of transthoracic echocardiography (TTE), dobutamine stress echocardiography (DSE), computed tomography coronary angiography (CTCA), and coronary angiography (CA). Primary outcomes were cardiac events (CEs) and cardiovascular death up to 30 days after LT. Overall, 569 patients were included, with 76 patients identified as LR, 256 as IR, and 237 as HR. Cardiac risk factors included diabetes mellitus (26.0%), smoking history (47.3%), hypertension (17.8%), hypercholesterolemia (7.2%), family (17.0%) or prior history of heart disease (6.0%), and obesity (27.6%). Of the patients, 42.0% had ≥2 risk factors. Overall compliance with the protocol was 90.3%. Abnormal findings on TTE, DSE, and CTCA were documented in 3, 23, and 44 patients, respectively, and 12 patients were not listed for transplantation following cardiac assessment (1 LR, 2 IR, and 9 HR). Moderate or severe CAD was identified in 25.4% of HR patients on CTCA following a normal DSE. CEs were recorded in 7 patients (1.2%), with 2 cardiovascular deaths (0.4%). Cardiac risk stratification based on traditional cardiac risk factors with the selective use of DSE, CTCA, and CA is a safe and feasible approach that results in a low perioperative cardiac event rate.

Estimates of the global reduction in liver disease-related mortality with increased coffee consumption: an analysis of the Global Burden of Disease Dataset.

BACKGROUND: Epidemiological data suggest that coffee has a dose-dependent protective effect on liver-related mortality. AIM: To estimate the potential impact of increased per capita coffee consumption on global liver-related mortality. METHODS: Using the Global Burden of Disease 2016 dataset (adults > 15 years), we modelled the impact of increased per capita coffee consumption on liver-related mortality in 2016 for 194 countries using published risk ratios for >2 cups coffee/ day (RR 0.54, 95% CI 0.42-0.69) and ≥4 cups/ day (RR 0.29, 95% CI 0.17-0.50), adjusted for confounders and tested model assumptions using sensitivity analyses. RESULTS: Worldwide, there were an estimated 1,240,201 (95% CI 118 4300-1 354 410) adult liver-related deaths in 2016. Median global liver mortality rate in 2016 was 15 deaths/ 100 000 population/ year (all ages, both genders; IQR 11-21 deaths per 100 000). If all countries with per capita coffee intake ≤2 cups/ day increased to >2 cups/ day, the predicted total number of liver-related deaths would have been 630 947 in 2016 (95% CI 629 693-631 861) with 452 861 (95% CI 451 948-454 116) deaths averted (PPR 7.8 liver-related deaths/ 100 000/ year). If per capita consumption was ≥ 4 cups/ day, the predicted number of liver-related deaths in 2016 would have been 360 523 (95% CI 359 825-361 992) with 723 287 (95% CI 721 817-723 984) deaths averted (PPR 12.1 liver-related deaths/100 000/year). CONCLUSION: Increasing per capita coffee consumption to > 2 cups per day on a population level has the potential to avert hundreds of thousands of liver-related deaths annually if the impact of coffee on liver-related mortality is confirmed in clinical trials.

The increasing burden of potentially preventable liver disease among adult liver transplant recipients: A comparative analysis of liver transplant indication by era in Australia and New Zealand.

BACKGROUND: Hepatitis C (HCV), hepatitis B (HBV), alcohol-related liver disease (ALD), and non-alcohol-related fatty liver disease (NAFLD) are leading indications for adult liver transplantation in Australia and New Zealand. However, these diseases are potentially preventable through effective primary and/or secondary prevention strategies. This study evaluates the relative contribution of potentially preventable liver diseases to liver transplant numbers in Australia and New Zealand over time. METHODS: Prospectively recorded clinical, demographic, and outcome data were collected from the Australian and New Zealand Liver Transplant Registry for all primary adult liver transplants performed in Australia and New Zealand from 1 January 1985 until 31 December 2012. Potentially preventable liver disease was defined as HBV, HCV, NAFLD, ALD, and HCC. The etiology of liver disease leading to liver transplantation and the proportion of preventable liver disease-related liver transplantation was compared between Era 1 (1985-1993), Era 2 (1994-2003), and Era 3 (2004-2012). RESULTS: Overall, 1252 of 3266 adult primary liver transplants (38.3%) were performed for potentially preventable liver disease. There was a significant increase in the proportion of liver transplants because of preventable liver disease from 21.2% (93 of 439) in Era 1, to 49.8% (623 of 1252) in Era 2 and 63.5% (1000 of 1575) in Era 3 (P < 0.0001). Over time, there was a significant increase in HCV (P < 0.0001), ALD (P = 0.002), and NAFLD (P < 0.0001) as a primary indication for adult liver transplant, whereas HBV has significantly decreased from Era 1 to Era 3 as an indication for transplant (P < 0.0001). The number of transplants performed for HCC also increased across Eras (P < 0.0001), with 84% due to underlying potentially preventable liver disease. CONCLUSION: Since 2004, the majority of primary adult liver transplants within Australia and New Zealand have been because of potentially preventable liver diseases and the prevalence of these diseases has increased over time. This finding represents an opportunity for clinicians to make a significant impact on the overall burden of advanced liver disease in Australia and New Zealand by improving primary and secondary prevention measures.

Paracetamol overdose in Victoria remains a significant health-care burden.

BACKGROUND AND AIM: Paracetamol is the most frequently used analgesic in Australia and can be purchased without a prescription. We aimed to investigate the epidemiology and outcome of paracetamol overdoses occurring in Victoria, Australia. METHODS: The Victorian admitted episode dataset was examined for all patients who had a diagnosis of paracetamol poisoning (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification [ICD-10-AM]: T39.1) or paracetamol adverse effect in therapeutic use (Y45.5) from July 1, 2000 to June 30, 2007. Data extracted included all ICD-10 codes related to their admissions, gender, age range, date of admission, and cause of death (if applicable). RESULTS: Over 7 years, there was a total of 14,662 hospital admissions for paracetamol overdose with a mean of 2095 cases per year. Accidental overdoses comprised 15% (n = 2149) of cases. The overdose rate fell from 46 cases per 100,000 in 2001 to 39 cases per 100,000 in 2006 (P < 0.001). Most overdoses occurred in women (71%), and patients between 15 and 50 years old comprised 78% of all cases. Complications and mortality were relatively uncommon, with only 26 deaths directly attributable to paracetamol overdose over the 7 years. No child under 15 years old died from their overdose. CONCLUSION: Admission to Victorian hospitals with paracetamol overdose presents an enormous and in many cases preventable health-care burden. Fortunately, there has been a gradual fall in admissions, and most cases appear relatively benign. Further reductions in overdose could be achieved with increased awareness by physicians and the general public regarding the potential for accidental overdose, and increasing funding for mental health initiatives.

Efficacy and cost of a hepatocellular carcinoma screening program at an Australian teaching hospital.

BACKGROUND AND AIM: Western countries are seeing an increasing prevalence of chronic viral hepatitis and a subsequent rise in the incidence of hepatocellular carcinoma (HCC). Screening patients at high risk of HCC has become standard practice. The aim of this study was to assess the efficacy and cost of screening high-risk individuals for HCC in an Australian tertiary hospital. METHODS: A retrospective review was performed of all patients who underwent HCC screening at the Austin Hospital in Melbourne between 1 October 1998 and 31 August 2004. HCC screening was carried out in all cirrhotic patients and male non-cirrhotic patients with chronic hepatitis B virus. Screening consisted of 6-monthly alpha fetoprotein (AFP) measurements and ultrasounds (US). Outcomes of those who had HCC detected were followed up until 15 February 2007. Patients who had HCC satisfying the Milan criteria for liver transplantation were considered to have potentially curable tumor. Costs for the diagnostic tests were obtained from the 2004 Australian Medicare Benefits Schedule. RESULTS: A total of 268 patient records were reviewed as part of the study. Chronic viral hepatitis accounted for 63% of the patients (n = 167). US screening was carried out at a median of 6.5 months and AFP measurements at a median of 4.0 months. HCC was detected in 22 patients (8.2%) at an incidence of 2.7% per year. These patients had a mean follow up of approximately 5.0 years after tumor detection. At the time of diagnosis, 17 patients had potentially curable tumor and 10 were alive at the conclusion of follow up. Of these 10 patients, six were successfully transplanted, three were successfully treated with radiological therapies and one was awaiting transplantation. The total cost of the screening program over the study period, including secondary investigations, was $A300,568. The cost per HCC detected was $13,662 and cost per potentially curable HCC was $17,680. CONCLUSION: An effective HCC screening program can be provided through a multi-disciplinary outpatient facility in an Australian teaching hospital. Further stratification of the high risk patient cohort may improve the cost effectiveness of this screening program.

The direct cost of managing patients with chronic hepatitis B infection in Australia.

GOALS: To estimate the average annual cost of managing a patient with chronic hepatitis B (CHB) disease in Australia. BACKGROUND: Little is known about the prevalence or economic burden of hepatitis B viral (HBV) infection in Australia, despite it being recognized as a significant cause of morbidity and mortality. STUDY: A retrospective analysis of 149 patients with CHB disease in six disease states (noncirrhotic CHB, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplantation in year 1, and liver transplantation in subsequent posttransplantation years) was conducted. The cost of palliative care for 53 patients with chronic hepatitis and hepatocellular carcinoma was also estimated, based on data from a palliative care unit. RESULTS: The average annual costs (year-2001 AUS$) for each disease state per patient were: noncirrhotic CHB, 1233 dollars (95% CI 939 dollars-1544 dollars); compensated cirrhosis, 1394 dollars (95% CI 975 dollars-1797 dollars); decompensated cirrhosis, 11,961 dollars (95% CI 6993 dollars-18,503 dollars); liver transplantation in year 1, 144,392 dollars (SD, 115,374 dollars); liver transplantation in year 2+, 23,160 dollars (SD, 19,289 dollars); and hepatocellular carcinoma, 11,753 dollars (95% CI 7385 dollars-17,159 dollars). Within the noncirrhotic CHB group, the cost of managing active disease was 1778 dollars (95% CI 1212 dollars-2374 dollars) compared with 758 dollars (95% CI 519 dollars-1045 dollars) for inactive disease. The average cost of palliative care for patients with chronic hepatitis and hepatocellular carcinoma was 6307 dollars (95% CI 4848 dollars-8187 dollars). Multivariate statistical analysis indicated that age, sex, marital status, country of birth, and duration of follow-up were not statistically significant in explaining variation in costs. CONCLUSIONS: The cost of managing patients with CHB disease varies significantly between the noncirrhotic CHB/compensated cirrhosis states and the other four disease states. Within the noncirrhotic CHB state, there is also a significant difference between the cost of managing active and inactive disease. These results will be useful in future cost-effectiveness analyses of prevention and treatment options.