Factors associated with high costs of patients with metabolic dysfunction-associated steatotic liver disease: an observational study using the French CONSTANCES cohort.

BACKGROUND & AIMS: Despite its high prevalence in the western world metabolic dysfunction-associated steatotic liver disease (MASLD) does not benefit from targeted pharmacological therapy. We measured healthcare utilisation and identified factors associated with high-cost MASLD patients in France. METHODS: The prevalent population with MASLD (including non-alcoholic steatohepatitis) in the CONSTANCES cohort, a nationally representative sample of 200,000 adults aged between 18 and 69, was linked to the French centralised national claims database (SNDS). Study participants were identified by the fatty liver index (FLI) over the period 2015-2019. MASLD individuals were classified according as "high-cost" (above 90th percentile) or "non-high cost" (below 90th percentile). Factors significantly associated with high costs were identified using a multivariate logistic regression model. RESULTS: A total of 14,437 predominantly male (69%) participants with an average age of 53 ± SD 12 years were included. They mainly belonged to socially deprived population groups with co-morbidities such as diabetes, high blood pressure, mental health disorders and cardiovascular complications. The average expenditure was €1860 ± SD 4634 per year. High-cost MASLD cost €10,863 ± SD 10,859 per year. Conditions associated with high-cost were mental health disorders OR 1.79 (1.44-2.22), cardiovascular diseases OR 1.54 (1.21-1.95), metabolic comorbidities OR 1.50 (1.25-1.81), and respiratory disease OR 1.50 (1.11-2.00). The 10% high-cost participants accounted for 58% of the total national health care expenditures for MASLD. CONCLUSION: Our results emphasize the need for comprehensive management of the comorbid conditions which were the major cost drivers of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in European countries, affecting 4­50% of the European population. Confirmation of diagnosis requires liver biopsy which is an invasive procedure. We studied the healthcare costs of patients with MASLD in order to identify cost predictors and cost drivers. We found that patients cost on average €1860 per year. Conditions associated with high-cost were mental health disorders, cardiovascular diseases, metabolic comorbidities, and respiratory disease.

The NAFLD burden on mortality and morbidities in general population: A community-based longitudinal study (NASH-CO study).

BACKGROUND: The impact of non-alcoholic fatty liver disease (NAFLD) on morbidity and mortality has yet to be documented at the general population level. This study aimed to assess whether NAFLD was associated with morbidities and mortality and to estimate its impact on health status and mortality. METHODS: The study population consisted of 137 206 participants from Constances cohort. Non-invasive diagnosis of NAFLD and advanced fibrosis was performed using the fatty liver index and Forns index, respectively. Constances data were linked to health care and hospitalization data to identify liver-related events, cardiovascular diseases (CVD), extrahepatic cancers (EHC), chronic kidney disease (CKD) and all-cause mortality. RESULTS: The prevalence of NAFLD was 18.3% in subjects without other chronic liver diseases, among whom 2.7% had fibrosis. NAFLD after IPTW-weighted remained associated with an increased risk of death (HR 1.26, 95% CI 1.01-1.57), hepatic-related complications (HR 2.48, 95% CI 1.99-3.29), CVD (HR 1.42, 95% CI 1.30-1.55), EHC (HR 1.11, 95% CI 1.01-1.28) and CKD (HR 1.81, 95% CI 1.53-2.07) compared to those without chronic liver diseases risk factors (Non-NAFLD). In the trend analysis over the study period of inclusion and compared to Non-NAFLD, NAFLD has shown a fastest growing cause of hepatic events (HR 1.38, 95% CI 1.07-1.76 per year), CVD (HR 1.08, 95% CI 1.03-1.12), CKD (HR 1.16, 95% CI 1.07-1.25), and death (HR 1.39, 95% CI 1.39-1.50). CONCLUSION: This large community-based cohort showed that NAFLD was associated with excess morbidity and mortality and demonstrated a fastest-growing trend.

Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study).

BACKGROUND AND AIMS: The severity of liver injury and clinical outcomes in lean individuals with NAFLD is a subject of debate and very few studies have been performed in the general population. The aim of this study was to compare subject characteristics and mortality between lean and nonlean NAFLD in a community setting. APPROACH AND RESULTS: The study population included 169,303 participants from the nationwide Constances cohort. Subjects with excessive alcohol consumption, viral hepatitis, or other liver diseases were excluded and 137,206 subjects were analyzed. The diagnosis of NAFLD and fibrosis was performed using the Fatty Liver Index and the Forns Index. The median follow-up was 3.58 years. The prevalence of NAFLD was 5.3% (95% CI: 5.2-5.4) in lean subjects, while 16.3% (95% CI: 15.7-16.8) of NAFLD subjects were lean. Despite their better metabolic profile, the prevalence of advanced fibrosis was significantly higher in lean than in nonlean NAFLD (3.7% vs. 1.7%, respectively, p < 0.01). Among NAFLD subjects and after adjustment for demographics, metabolic risk factors and lifestyle, lean status was associated with advanced fibrosis (OR=1.26, 95% CI: 1.20-1.65, p = 0.005), an increased risk of liver-related events (adjusted HR=5.84, 95% CI: 4.03-8.46), chronic kidney disease (adjusted HR=2.49, 95% CI: 1.49-4.16), and overall mortality (adjusted HR=3.01, 95% CI: 2.21-4.11). Liver-related events and overall mortality were related to the severity of fibrosis, both in lean and nonlean NAFLD subjects, whatever the usual risk factors. CONCLUSION: This study in a large community-based cohort confirms that NAFLD in lean subjects is more severe for fibrosis, the progression of liver disease, chronic kidney disease, and overall mortality.

Screening HIV Patients at Risk for NAFLD Using MRI-PDFF and Transient Elastography: A European Multicenter Prospective Study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a growing concern in the aging population with human immunodeficiency virus (HIV). Screening for NAFLD is recommended in patients with metabolic risk factors or unexplained transaminitis. This study aimed to prospectively assess the prevalence and associated factors of liver steatosis and advanced fibrosis (AF) in HIV-monoinfected patients at risk of NAFLD. METHODS: We conducted a multicenter study in HIV-monoinfected patients, nonexcessive drinkers with metabolic syndrome, and/or persistently elevated liver enzymes, and/or clinical lipodystrophy. All participants had magnetic resonance imaging proton density fat fraction (MRI-PDFF), Fibroscan/controlled attenuation parameter (CAP), and cytokine and genetic analysis. RESULTS: From March 2014 to November 2015, we enrolled 442 participants and analyzed 402: male (85%); median age, 55 years (interquartile range [IQR], 50-61 years); body mass index, 27.0 kg/m2 (IQR, 23.6-28.7 kg/m2); metabolic syndrome (67%); and CD4 cell count, 630/mm3 (IQR, 510-832/mm3). Overall 257 of 402 (64%) had NAFLD (MRI-PDFF ≥5%). Among them, 11.3% had a liver stiffness ≥9.6 kPa, suggestive of AF. Multivariable analysis identified 7 factors of steatosis: high CD4-cell count (odds ratio [OR], 4.04; 95% confidence interval [CI], 1.92-8.51), high leptin level (OR, 2.12; 95% CI, 1.14-3.93), non-CC PNPLA3s738409 genetic polymorphism (OR, 1.92; 95% CI, 1.11-3.33), low high-density lipoprotein (OR, 1.83; 95% CI, 1.03-3.27), high triglycerides (OR, 1.48; 95% CI, 1.18-1.84), elevated alanine transaminase (OR, 1.23; 95% CI, 1.16-1.31), and hyper ferritinemia (OR, 1.05; 95% CI, 1.03-1.07). Two factors were associated with AF: high body mass index (OR, 1.23 ; 95% CI, 1.07-1.42 ; P = .005, and elevated aspartate aminotransferase (OR, 1.03; 95% CI, 1.01-1.05; P = .001). Using MRI-PDFF as a reference, CAP (best cutoff, 280 dB/m) had good accuracy (area under the receiver operating characteristic curve = 0.86; 95% CI, 0.82-0.90) for the diagnosis of moderate to severe steatosis. CONCLUSIONS: In a large cohort of HIV-moninfected patients at risk of NAFLD, steatosis is present in two-thirds of cases, and around 10% have AF. The CAP technique is accurate for screening steatosis in this population.

Association between birth weight, preterm birth, and nonalcoholic fatty liver disease in a community-based cohort.

BACKGROUND AND AIMS: The association between birth weight (BW) and metabolic outcomes has been described since the 1980s but NAFLD has been rarely studied. This study aimed to investigate the association between BW and NAFLD occurrence in adult subjects. APPROACH AND RESULTS: The study population consisted of participants from the French nationwide Constances cohort from 2012 to 2019. Participants with a history of chronic viral hepatitis or excessive alcohol consumption were excluded. Noninvasive diagnosis of NAFLD and fibrosis was performed using a combination of the Fatty Liver Index (FLI) and the Forns Index. The relationship between BW and NAFLD was analyzed with a sex-stratified logistic regression model adjusted for sociodemographic parameters, lifestyle, and birth term, whereas liver fibrosis was analyzed with a sex-stratified linear regression model. In total, 55,034 individuals with reliable BW were included (43% men, mean age: 38 years). NAFLD (FLI ≥ 60) was present in 5530 individuals (10%). Multivariate logistic regression showed a significant U-shaped relationship between BW and NAFLD, with no significant interaction with sex. A significant and slightly decreasing association was found between BW and Forns Index (ß = -0.05; p = 0.04). Premature birth (OR, 1.23; 95% CI, 1.03-1.48 for birth between 33 and 37 weeks versus ≥ 37 weeks) was associated with NAFLD, with a significant direct effect of premature birth, and without an indirect effect of low BW in mediation analysis. Forns Index was not significantly higher in participants with preterm birth compared to full-term birth. CONCLUSIONS: This large prospective adult-based cohort confirms the relationship between BW and NAFLD occurrence.

The burden of NAFLD in type 2 diabetic subjects from the general population: A Nationwide population-based follow-up study (NASHCO).

BACKGROUND: The epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD) in diabetes have been mainly investigated in the hospital setting. The goal of this study was to evaluate the characteristics of NAFLD and its impact on morbidity and mortality in type 2 diabetic subjects in a community setting. METHOD: This study included 199 341 participants in the nationwide Constances cohort. After patients with excessive alcohol consumption, viral hepatitis or other causes of liver disease were excluded, 164 285 were analysed and 8386 (5.3%) were considered to have type 2 diabetes. The non-invasive diagnosis of NAFLD and advanced fibrosis was made using a combination of the fatty liver index and Forns index. Median follow-up was 2.5 years. RESULTS: Diabetes increased the risk of NAFLD by sixfold (adjusted OR 6.05, 95% CI 5.68-6.45) and the risk of advanced fibrosis by 3.76-fold (aOR 3.76, 95% CI 2.87-4.91) in NAFLD subjects. After controlling for confounders, the presence of NAFLD in diabetic subjects was associated with an increased risk of severe liver-related events (aHR 2.53, 95% CI 1.36-4.69), cardiovascular disease (CVD, aHR 2.71, 95% CI 1.72-4.26) and overall mortality (aHR 2.91, 95% CI 1.53-5.53). The risk of hepatic and extrahepatic complications in diabetic subjects with NAFLD significantly increased with the severity of fibrosis (P < .05). CONCLUSION: This prospective, longitudinal study in a large community-based cohort provides real-world evidence of the risk for NAFLD and advanced fibrosis in diabetes, and its impact on liver disease progression, diabetes-related complications such as CVD, and overall mortality. These data could be used to estimate real clinical and economic burden of NAFLD in diabetic subjects.

Immunosuppression in patients with grade 3 acute-on-chronic liver failure at transplantation: A practice analysis study.

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV < 40% (P = .019), absence of early tacrolimus overdose (P = .033), use of anti-IL2-receptor antibodies (P = .034), and early mycophenolic acid introduction (P = .038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P = .001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation.

ABO blood group does not influence Child-Pugh A cirrhosis outcome: An observational study from CIRRAL and ANRS CO12 CIRVIR cohorts.

BACKGROUND AND AIMS: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients. METHODS: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 µmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation¼ or « the occurrence of one or more parameters ¼ among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival. RESULTS: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1). CONCLUSION: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170.

Comorbidities Are Associated with Fibrosis in NAFLD Subjects: A Nationwide Study (NASH-CO Study).

BACKGROUND: The relationship between the severity of NAFLD and extra-hepatic events such as cardiovascular disease (CVD), extra-hepatic cancer (EHC) or chronic kidney diseases (CKD) has not been clearly investigated in the general population. AIMS: The aim of this study was to assess whether the severity of fibrosis in NAFLD subjects was associated with extra-hepatic diseases based on noninvasive markers in a large population-based cohort. METHODS: The study population included a cohort of 118,664 participants from the nationwide CONSTANCES cohort. After excluding individuals with excessive alcohol consumption and other causes of liver disease, 102,344 were included. The noninvasive diagnosis of NAFLD and fibrosis was performed using a combination of the Fatty Liver Index (FLI) and the Forns Index. The history of CVD or EHC was recorded by a physician, and CKD was defined by a glomerular filtration rate < 60 ml/mn. RESULTS: The prevalence of NAFLD (FLI > 60) was 18.2%, 10% with mild fibrosis (Forns Index < 4.2), 7.7% with intermediate fibrosis (Forns Index 4.2-6.9), and 0.4% with advanced fibrosis (Forns Index > 6.9). The prevalence of CVD, EHC, or CKD increased significantly with the severity of fibrosis (p < 0.0001). When adjusted for demographic, metabolic risk factors, and smoking, NAFLD with intermediate or advanced fibrosis remained associated with CVD (OR 1.36, p < 0.0001 and OR 3.07, p < 0.0001, respectively), EHC (OR 1.24, p = 0.001 and OR 1.64, p = 0.004, respectively), and CKD (OR 1.18, p = 0.03 and OR 2.09, p < 0.0001, respectively). CONCLUSIONS: In a large adult population-based cohort, there is a dose-dependent relationship between the severity of fibrosis and CVD, EHC, or CKD in NAFLD subjects.

Cannabis Use Is Inversely Associated with Overweight and Obesity in Hepatitis B Virus-Infected Patients (ANRS CO22 Hepather Cohort).

Background: Chronic hepatitis B virus (HBV) infection may evolve into cirrhosis and hepatocellular carcinoma, and this progression may be accelerated by specific risk factors, including overweight and obesity. Although evidence for a protective effect of cannabis use on elevated body weight has been found for other populations, no data are available for HBV-infected patients. Aims: We aimed to identify risk factors (including cannabis use) for overweight and obesity in patients with HBV chronic infection. Methods: Using baseline data from the French ANRS CO22 Hepather cohort, we performed two separate analyses, one using "central obesity" (based on waist circumference) and the other "overweight" and "obesity" (based on body mass index) as outcomes. Logistic and multinomial regressions were used to model central obesity and overweight/obesity, respectively. Results: Among the 3706 patients in the study population, 50.8% had central obesity, 34.7% overweight, and 14.4% obesity. After multivariable adjustment, current cannabis use was associated with a 59% lower risk of central obesity compared with no lifetime use (adjusted odds ratio [95% CI]: 0.41 [0.24 to 0.70]). It was also associated with a 54% and 84% lower risk of overweight (adjusted relative risk ratio [95% CI]: 0.46 [0.27 to 0.76]) and obesity (0.16 [0.04 to 0.67]), respectively. Conclusions: Cannabis use was associated with lower risks of overweight and obesity in patients with HBV chronic infection. Future studies should test whether these potential benefits of cannabis and cannabinoid use translate into reduced liver disease progression in this high-risk population.

Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement.

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction.

Predicting the available space for liver transplantation in cirrhotic patients: a computed tomography-based volumetric study.

BACKGROUND: Anthropometric parameters (weight, height) are usually used for quick matching between two individuals (donor and recipient) in liver transplantation (LT). This study aimed to evaluate clinical factors influencing the overall available space for implanting a liver graft in cirrhotic patients. METHODS: In a cohort of 275 cirrhotic patients undergoing LT, we calculated the liver volume (LV), cavity volume (CV), which is considered the additional space between the liver and the right hypocondrium, and the overall volume (OV = LV + CV) using a computed tomography (CT)-based volumetric system. We then chose the formula based on anthropometric parameters that showed the best predictive value for LV. This formula was used to predict the OV in the same population. Factors influencing OV variations were identified by multivariable logistic analysis. RESULTS: The Hashimoto formula (961.3 × BSA_D-404.8) yielded the lowest median absolute percentage error (21.7%) in predicting the LV. The median LV was 1531 ml. One-hundred eighty-five patients (67.2%) had a median CV of 1156 ml (range: 70-7006), and the median OV was 2240 ml (range: 592-8537). Forty-nine patients (17%) had an OV lower than that predicted by the Hashimoto formula. Independent factors influencing the OV included the number of portosystemic shunts, right anteroposterior abdominal diameter, model for end-stage liver disease (MELD) score > 25, high albumin value, and BMI > 30. CONCLUSIONS: Additional anthropometric characteristics (right anteroposterior diameter, body mass index) clinical (number of portosystemic shunts), and biological (MELD, albumin) factors might influence the overall volume available for liver graft implantation. Knowledge of these factors might be helpful during the donor-recipient matching.

Cannabis use and reduced risk of elevated fatty liver index in HIV-HCV co-infected patients: a longitudinal analysis (ANRS CO13 HEPAVIH).

Background: Cannabis use and elevated fatty liver index (FLI≥ 60) (a biomarker of hepatic steatosis in the general population) have been identified as predictors of HCV-related and overall mortality, respectively, in HIV-HCV co-infected patients. However, the relationship between cannabis use and the risk of elevated FLI has never been explored.Methods: Using five-year follow-up data from 997 HIV-HCV co-infected patients (ANRS CO13 HEPAVIH cohort), we analyzed the relationship between cannabis use and FLI using mixed-effects multivariable logistic (outcome: elevated FLI yes/no) and linear (outcome: continuous FLI) regression models.Results: At the last follow-up visit, 27.4% of patients reported regular or daily cannabis use and 27.8% had elevated FLI. After multivariable adjustment, regular or daily cannabis use was associated with a 55% lower risk of elevated FLI (adjusted odds ratio [95% confidence interval]: 0.45 [0.22; 0.94]; p = 0.033) and lower FLI values (adjusted model coefficient: -4.24 [-6.57; -1.91], p < 0.0001).Conclusions: Cannabis use is associated with a reduced risk of elevated fatty liver index in HIV-HCV co-infected patients. Further research is needed to confirm whether and how cannabinoids may inhibit the development of hepatic steatosis or other metabolic disorders in high-risk populations.

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: A cost-of-illness analysis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018. METHODS: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups. RESULTS: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%-39.1% for advanced fibrosis (F3-F4 compensated cirrhosis). Total economic costs were €8548-19 546M. Of these, health system costs were €619-1292M. Total wellbeing costs were €41 536-90 379M. The majority of the undiagnosed population (87.3%-88.2% of total prevalence) was found to have early-stage NASH, which, left untreated, may progress to more resource consuming ESLD over time. CONCLUSIONS: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs.

The learning curve for piggyback liver transplantation: identifying factors challenging surgery.

BACKGROUND: This study aimed to quantify the learning curve of piggyback liver transplantation and to identify factors that impact the operative time and blood transfusion during the learning curve. METHODS: A retrospective review was performed on consecutive cases of patients' first piggyback liver transplantations that were performed by a single surgeon. The learning curve for the operative time was evaluated using the cumulative sum method. RESULTS: There were 181, consecutive, first-time piggyback liver transplantations. The median operative time was 345 minutes (range: 180-745 minutes) with a median transfusion rate of 4 packed red blood cell units (range: 0-23 units). The cumulative sum learning curve identified 3 phases: an initial phase (1-70 piggyback liver transplantations), a plateau phase (71-101 piggyback liver transplantations), and a stable phase (102-181 piggyback liver transplantations). Over the 3 phases, there were significant decreases in the median duration of the surgery (388.8 vs 344.8 vs 326.9 minutes; P = .004, P = .0004, P ≤ .0001) and the number of red blood cell units transfused (6.00 vs 3.90 vs 3.71; P = .02, P = .79, P = .0006). Multivariable analysis identified that the following factors impacted the operative time: surgeon experience (P = .00006), previous upper abdominal surgery (P = .01), portocaval shunt fashioning (P = .0003), early portal section (P = .00001), multiple arterial graft reconstruction (P = .03), and the length of the retrohepatic inferior vena covered by segment 1 (P = .0006). Independent risk factors for increased blood loss were surgeon experience (P = .0001), previous upper abdominal surgery (P = .002), the retrohepatic inferior vena cava encirclement by segment 1 (P = .0001), severe portal hypertension (P = .01), early portal section (P = .001), and low prothrombin time (P = .00001). CONCLUSION: Easily identifiable factors related to recipients (segment 1 morphology, previous upper abdominal surgery, severe portal hypertension) and to surgeon (operative experience, portocaval shunt fashioning, early portal section, and multiple arterial reconstructions) impact operative time and blood loss during the learning curve of piggyback liver transplantation. These factors can be used for grading the difficulties of liver transplantation to tailor the surgical strategy.

Misplacement of transjugular intrahepatic portosystemic shunts: A surgical challenge for liver transplantation?

BACKGROUND: The impact of transjugular intrahepatic portosystemic shunt misplacement on outcomes of liver transplantation remains controversial. We systematically reviewed the literature on the outcomes of liver transplantation with transjugular intrahepatic portosystemic shunt misplacement. METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Cochrane library, PubMed, and Embase were searched (January 1990-April 2020) for studies reporting patients undergoing liver transplantation with transjugular intrahepatic portosystemic shunt misplacement. RESULTS: Thirty-six studies reporting 181 patients who underwent liver transplantation with transjugular intrahepatic portosystemic shunt misplacement were identified. Transjugular intrahepatic portosystemic shunt was misplaced with a variable degree of extension toward the inferior vena cava/right heart in 63 patients (34%), the spleno/portal/superior mesenteric venous confluence in 105 patients (58%), and both in 15 patients (8%). Transjugular intrahepatic portosystemic shunt thrombosis was also present in 21 cases (12%). The median interval between transjugular intrahepatic portosystemic shunt placement and liver transplantation ranged from 1 day to 6 years. Complete transjugular intrahepatic portosystemic shunt removal was successfully performed in all but 12 (7%) patients in whom part of the transjugular intrahepatic portosystemic shunt was left in situ. Cardiac surgery under cardiopulmonary bypass was necessary to remove transjugular intrahepatic portosystemic shunt from the right heart in 4 patients (2%), and a venous graft interposition was necessary for a portal anastomosis in 5 patients (3%). Postoperative mortality (90 days) was 1.1% (2 patients), and portal vein thrombosis developed postoperatively in 4 patients (2%). CONCLUSION: Misplaced transjugular intrahepatic portosystemic shunt removal is possible in most cases during liver transplantation with extremely low mortality and good postoperative outcomes. Preoperative surgical strategy and intraoperative tailored surgical technique reduces the potential consequences of transjugular intrahepatic portosystemic shunt misplacement.

Early Health Technology Assessment during Nonalcoholic Steatohepatitis Drug Development: A Two-Round, Cross-Country, Multicriteria Decision Analysis.

Background. The assessment of value along the clinical development of new biopharmaceutical compounds is a challenging task. Complex and uncertain evidence has to be analyzed, considering a multitude of value preferences from different stakeholders. Objective. To investigate the use of multicriteria decision analysis (MCDA) to support decision making during drug development while considering payer and health technology assessment (HTA) value concerns, by applying the Advance Value Framework in nonalcoholic steatohepatitis (NASH) and testing for the consistency of the results. Design. A multiattribute value theory methodology was applied and 2 rounds of decision conferences (DCs) were organized in 3 countries (England, France, and Germany), with the participation of national key experts and stakeholders using the MACBETH questioning protocol and algorithm. A total of 51 health care professionals, patient advocates, and methodologists, including (ex-) committee members or assessors from national HTA bodies, participated in 6 DCs in the study countries. Target Population. NASH patients in fibrosis stages F2 to 3 were considered. Interventions. The value of a hypothetical product profile was assessed against 3 compounds under development using their phase 2 results. Outcome Measures. DC participants' value preferences were elicited involving criteria selection, options scoring, and criteria weighting. Results. Highly consistent valuation rankings were observed in all DCs, always favoring the same compound. Highly consistent rankings of criteria clusters were observed, favoring therapeutic benefit criteria, followed by safety profile and innovation level criteria. Limitations. There was a lack of comparative treatment effects, early evidence on surrogate endpoints was used, and stakeholder representativeness was limited in some DCs. Conclusions. The use of MCDA is promising in supporting early HTA, illustrating high consistency in results across countries and between study rounds.