Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation.

Objective: This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types. Methods: This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy. Results: A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia. Conclusion: Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.

Spotlight on Impactful Research: Relationship Between Relative Skeletal Muscle Mass and Nonalcoholic Fatty Liver Disease: A 7-Year Longitudinal Study.

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A North American Expert Opinion Statement on Sarcopenia in Liver Transplantation.

Loss of muscle mass and function, or sarcopenia, is a common feature of cirrhosis and contributes significantly to morbidity and mortality in this population. Sarcopenia is a main indicator of adverse outcomes in this population, including poor quality of life, hepatic decompensation, mortality in patients with cirrhosis evaluated for liver transplantation (LT), longer hospital and intensive care unit stay, higher incidence of infection following LT, and higher overall health care cost. Although it is clear that muscle mass is an important predictor of LT outcomes, many questions remain, including the best modality for assessing muscle mass, the optimal cut-off values for sarcopenia, the ideal timing and frequency of muscle mass assessment, and how to best incorporate the concept of sarcopenia into clinical decision making. For these reasons, we assembled a group of experts to form the North American Working Group on Sarcopenia in Liver Transplantation to use evidence from the medical literature to address these outstanding questions regarding sarcopenia in LT. We believe sarcopenia assessment should be considered in all patients with cirrhosis evaluated for liver transplantation. Skeletal muscle index (SMI) assessed by computed tomography constitutes the best-studied technique for assessing sarcopenia in patients with cirrhosis. Cut-off values for sarcopenia, defined as SMI < 50 cm2 /m2 in male and < 39 cm2 /m2 in female patients, constitute the validated definition for sarcopenia in patients with cirrhosis. Conclusion: The management of sarcopenia requires a multipronged approach including nutrition, exercise, and additional pharmacological therapy as deemed necessary. Future studies should evaluate whether recovery of sarcopenia with nutritional management in combination with an exercise program is sustainable as well as how improvement in muscle mass might be associated with improvement in clinical outcomes.

American Ancestry Is a Risk Factor for Suspected Nonalcoholic Fatty Liver Disease in Hispanic/Latino Adults.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) disproportionally affects Hispanic/Latino populations. However, the magnitude varies among Hispanic/Latino ethnic groups. We investigated the mechanisms of these disparities. METHODS: We examined associations of NAFLD-associated genetic variants and continental ancestry with suspected NAFLD, levels of alanine aminotransferase (ALT), and liver fibrosis using data from the Hispanic Community Health Study/Study of Latinos-a population-based study of Hispanic/Latino adults in the United States. We evaluated data from 16,415 Hispanic/Latino adults in 4 cities from 2008 through 2011. Subjects suspected of having NAFLD or liver fibrosis were identified based on unexplained increases in levels of aminotransferases and FIB-4 score, respectively. RESULTS: Among the 9342 participants with available genetic and aminotransferase data, the PNPLA3 G allele (odds ratio [OR], 1.53; 95% CI, 1.41-1.66), TM6SF2 T allele (OR, 1.41; 95% CI, 1.20-1.67), and PPP1R3B G allele (OR, 1.16; 95% CI, 1.06-1.28) were associated with suspected NAFLD. PNPLA3 G was also associated with increased levels of ALT, except in participants with Dominican and South American backgrounds, and with liver fibrosis. The frequency of PNPLA3 G was high (41%) and TM6SF2 T (5%) was low in Hispanic/Latinos. PNPLA3 G frequency differed among Hispanic background groups with the highest proportion in Mexicans (52%) and the lowest proportion in Dominicans (23%). After adjustment for demographic, clinical, and behavioral factors, as well as PNPLA3 G, TM6SF2 T, and PPP1R3B G, American ancestry had a positive association with level of ALT (r = 6.61%; P < .001), whereas African (r = -3.84%; P < .001) and European (r = -4.31%; P < .001) ancestry were inversely associated with level of ALT. CONCLUSIONS: American ancestry and PNPLA3 G are independent predictors of ALT levels in US Hispanic/Latinos and may in part explain NAFLD disparities in US Hispanic/Latinos.

Case Series of 10 Patients with Cirrhosis Undergoing Emergent Repair of Ruptured Umbilical Hernias: Natural History and Predictors of Outcomes.

OBJECTIVES: Ascites represents an important event in the natural history of cirrhosis, portending increased 1-year mortality. Umbilical herniation with rupture is an uncommon complication of large-volume ascites that is associated with significant morbidity and mortality. The aim of this study was to describe predictors of outcomes in patients undergoing emergent repair for spontaneous umbilical hernia rupture. MATERIALS AND METHODS: We report a case series of 10 patients with decompensated cirrhosis (mean age 66 ± 9 years, mean Model for End-Stage Liver Disease score of 21 ± 7) who presented with a ruptured umbilical hernia and had emergent repair. RESULTS: Thirty percent (3/10) of patients died or required liver transplant. Factors associated with death or transplant included the development of bacterial peritonitis (P = .03) and the presurgical 30-day Mayo Clinic Postoperative Mortality Risk in Patient with Cirrhosis Score (P = .03). CONCLUSIONS: Emergent repair after umbilical hernia rupture in patients with decompensated cirrhosis carries a poor prognosis with 30% of patients developing poor postsurgical outcomes.

Sarcopenia and liver transplant: The relevance of too little muscle mass.

Loss of muscle mass and function is a common occurrence in both patients with decompensated cirrhosis and those undergoing liver transplantation. Sarcopenia is associated with morbidity and mortality before and after liver transplantation. The ability of skeletal muscle mass to recover after transplant is questionable, and long term adverse events associated with persistent sarcopenia have not been well studied. Limited data is available examining mechanisms by which decreased muscle mass might develop. It is not clear which interventions might reduce the prevalence of sarcopenia and associated health burdens. However, measures to either decrease portal hypertension or improve nutrition appear to have benefit. Research on sarcopenia in the liver transplant setting is hampered by differing methodology to quantify muscle mass and varied thresholds determining the presence of sarcopenia. One area highlighted in this review is the heterogeneity used when defining sarcopenia. The health consequences, clinical course and potential pathophysiologic mechanisms of sarcopenia in the setting of cirrhosis and liver transplantation are further discussed.

Prevalence of suspected nonalcoholic fatty liver disease in Hispanic/Latino individuals differs by heritage.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) was shown to disproportionally affect Hispanic persons. We examined the prevalence of suspected NAFLD in Hispanic/Latino persons with diverse backgrounds. METHODS: We studied the prevalence of suspected NAFLD among 12,133 persons included in the Hispanic Community Health Study/Study of Latinos. We collected data on levels of aminotransferase, metabolic syndrome (defined by National Cholesterol Education Program-Adult Treatment Panel III guidelines), demographics, and health behaviors. Suspected NAFLD was defined on the basis of increased level of aminotransferase in the absence of serologic evidence for common causes of liver disease or excessive alcohol consumption. In multivariate analyses, data were adjusted for metabolic syndrome, age, acculturation, diet, physical activity, sleep, and levels of education and income. RESULTS: In multivariate analysis, compared with persons of Mexican heritage, persons of Cuban (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.57-0.85), Puerto Rican (OR, 0.67; 95% CI, 0.52-0.87), and Dominican backgrounds (OR, 0.71; 95% CI, 0.54-0.93) had lower rates of suspected NAFLD. Persons of Central American and South American heritage had a similar prevalence of suspected NAFLD compared with persons of Mexican heritage. NAFLD was less common in women than in men (OR, 0.49; 95% CI, 0.40-0.60). Suspected NAFLD associated with metabolic syndrome and all 5 of its components. CONCLUSIONS: On the basis of an analysis of a large database of health in Latino populations, we found the prevalence of suspected NAFLD among Hispanic/Latino individuals to vary by region of heritage.

Imaging surveillance and multidisciplinary review improves curative therapy access and survival in HCC patients.

INTRODUCTION: Imaging surveillance and multidisciplinary conference (MDC) review can potentially improve survival in patients with hepatocellular carcinoma (HCC) by increasing access to liver transplantation. Geographic disparities in donor organ availability may reduce this benefit. This study evaluated the impact of HCC surveillance on use of curative therapies and survival in a region with long transplant waiting times. MATERIAL AND METHODS: 167 HCC patients were retrospectively studied. Subjects had an established HCC diagnosis or were diagnosed during hepatology follow-up. Collected data included patient demographics, HCC surveillance and MDC review status, portal hypertension complications, laboratory and radiologic parameters, tumor size, therapeutic interventions, tumor progression, and mortality. The primary outcome measures were use of curative treatments and survival. A Cox-regression model was constructed utilizing factors associated with survival in univariate analysis. RESULTS: 58% of subjects underwent surveillance and MDC review of HCC. These patients were more likely to have received treatment with ablation or resection (16 vs. 3%, P = 0.006) and transplantation (23 vs. 4%, P = 0.001), and were less likely to develop tumor progression (45 vs. 68%, P = 0.005) or metastases (0 vs. 19%, P < 0.001). In multivariate analysis, surveillance and MDC review (P = 0.034, HR 0.520, 95% CI 0.284-0.952), tumor meeting Milan criteria (P < 0.001, HR 0.329, 95% CI 0.178-0.607), curative therapy application (P = 0.048, HR 0.130, 95% CI 0.017-0.979), and transplantation (P = 0.004, HR 0.236, 95% CI 0.088-0.632) were associated with survival. CONCLUSION: In conclusion, imaging surveillance and MDC review is associated with detection of early stage HCC, increased access to curative therapies and transplantation, and prolonged survival.

Physical activity and metabolic syndrome in liver transplant recipients.

There is a high prevalence of metabolic syndrome in liver transplant recipients, a population that tends to be physically inactive. The aim of this study was to characterize physical activity and evaluate the relationship between physical activity and metabolic syndrome after liver transplantation. A cross-sectional analysis was performed in patients more than 3 months after transplantation. Metabolic syndrome was classified according to National Cholesterol Education Panel Adult Treatment Panel III guidelines. Physical activity, including duration, frequency, and metabolic equivalents of task (METs), was assessed. The study population consisted of 204 subjects, with 156 more than 1 year after transplantation. The median time after transplantation was 53.5 months (range = 3-299 months). The mean duration of exercise was 90 ± 142 minutes, and the mean MET score was 3.6 ± 1.5. Metabolic syndrome was observed in 58.8% of all subjects and in 63.5% of the subjects more than 1 year after transplantation. In a multivariate analysis involving all subjects, metabolic syndrome was associated with a time after transplantation greater than 1 year [odds ratio (OR) = 2.909, 95% confidence interval (CI) = 1.389-6.092] and older age (OR = 1.036, 95% CI = 1.001-1.072). A second analysis was performed for only patients more than 1 year after transplantation. In a multivariate analysis, metabolic syndrome was associated with lower exercise intensity (OR = 0.690, 95% CI = 0.536-0.887), older age (OR = 1.056, 95% CI = 1.014-1.101), and pretransplant diabetes (OR = 4.246, 95% CI = 1.300-13.864). In conclusion, metabolic syndrome is common after liver transplantation, and the rate is significantly higher in patients more than 1 year after transplantation. The observation that exercise intensity is inversely related to metabolic syndrome after transplantation is novel and suggests that physical activity might provide a means for reducing metabolic syndrome complications in liver transplant recipients.

Prognostic capability of different liver disease scoring systems for prediction of early mortality after transjugular intrahepatic portosystemic shunt creation.

PURPOSE: To compare the performance of various liver disease scoring systems in predicting early mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: In this single-institution retrospective study, eight scoring systems were used to grade liver disease in 211 patients (male-to-female ratio = 131:80; mean age, 54 y) before TIPS creation from 1999-2011. Scoring systems included bilirubin level, Child-Pugh (CP) score, Model for End-Stage Liver Disease (MELD) and Model for End-Stage Liver Disease sodium (MELD-Na) score, Emory score, prognostic index (PI), Acute Physiology and Chronic Health Evaluation (APACHE) 2 score, and Bonn TIPS early mortality (BOTEM) score. Medical record review was used to identify 30-day and 90-day clinical outcomes. The relationship of scoring parameters with mortality outcomes was assessed with multivariate analysis, and the relative ability of systems to predict mortality after TIPS creation was evaluated by comparing area under receiver operating characteristic (AUROC) curves. RESULTS: TIPS were successfully created for variceal hemorrhage (n = 121), ascites (n = 72), hepatic hydrothorax (n = 15), and portal vein thrombosis (n = 3). All scoring systems had a significant association with 30-day and 90-day mortality (P<.050 in each case) on multivariate analysis. Based on 30-day and 90-day AUROC, MELD (0.878, 0.816) and MELD-Na (0.863, 0.823) scores had the best capability to predict early mortality compared with bilirubin (0.786, 0.749), CP (0.822, 0.771), Emory (0.786, 0.681), PI (0.854, 0.760), APACHE 2 (0.836, 0.735), and BOTEM (0.798, 0.698), with statistical superiority over bilirubin, Emory, and BOTEM scores. CONCLUSIONS: Several liver disease scoring systems have prognostic value for early mortality after TIPS creation. MELD and MELD-Na scores most effectively predict survival after TIPS creation.

Recurrent hepatitis C virus after transplant and the importance of plasma cells on biopsy.

Hepatitis C virus (HCV) is the leading indication for liver transplantation in the United States. It recurs universally after transplant but the rate of fibrosis and the development of graft failure is variable. Different donor and recipient features have been demonstrated to impact fibrosis. Plasma cell hepatitis, a histologic finding, is one feature associated with poor graft and patient outcomes. The pathogenic mechanism resulting in plasma cell hepatitis is poorly understood, with evidence suggesting a role for both the HCV and the immune system.A recent publication described plasma cell hepatitis in a larger context of immune medicated graft dysfunction in transplant recipients receiving interferon based therapy. This manuscript will highlight the topic of plasma cell hepatitis and provide commentary on the lack of recognition, the data regarding pathophysiologic mechanisms and the potential management options.

Metabolic syndrome after liver transplantation: preventable illness or common consequence?

The metabolic syndrome is common after liver transplant being present in approximately half of recipients. It has been associated with adverse outcomes such as progression of hepatitis C and major vascular events. As the United States population ages and the rate of obesity increases, prevention of the metabolic syndrome in the post-transplant population deserves special consideration. Currently, the metabolic syndrome after transplant appears at least two times more common than observed rates in the general population. Specific guidelines for patients after transplant does not exist, therefore prevention rests upon knowledge of risk factors and the presence of modifiable elements. The current article will focus on risk factors for the development of the metabolic syndrome after transplant, will highlight potentially modifiable factors and propose potential areas for intervention. As in the non-transplant population, behavioral choices might have a major role. Opportunities exist in this regard for health prevention studies incorporating lifestyle changes. Other factors such as the need for immunosuppression, and the changing characteristics of wait listed patients are not modifiable, but are important to know in order to identify persons at higher risk. Although immunosuppression after transplant is unavoidable, the contribution of different agents to the development of components of the metabolic syndrome is also discussed. Ultimately, an increased risk of the metabolic syndrome after transplant is likely unavoidable, however, there are many opportunities to reduce the prevalence.

TIPS for treatment of variceal hemorrhage: clinical outcomes in 128 patients at a single institution over a 12-year period.

PURPOSE: To assess clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) treatment of variceal hemorrhage. MATERIALS AND METHODS: A total of 128 patients (82 men and 46 women; mean age, 52 y) with liver cirrhosis and refractory variceal hemorrhage underwent TIPS creation from 1998 to 2010. Mean Child-Pugh and Model for End-stage Liver Disease (MELD) scores were 9 and 18, respectively. From 1998 to 2004, 12-mm Wallstents (n = 58) were used, whereas from 2004 to 2010, 10-mm VIATORR covered stent-grafts (n = 70) were used. Technical success, hemodynamic success, complications, shunt dysfunction, recurrent bleeding, and overall survival were assessed. RESULTS: Technical and hemodynamic success rates were 100% and 94%, respectively. Mean portosystemic gradient reduction was 13 mm Hg. Complications at 30 days included encephalopathy (14%), renal failure (5.5%), infection (1.6%), and liver failure (0.8%). Shunt patency rates were 93%, 82%, and 60% at 30 days, 1 year, and 2 years, respectively. Dysfunction, or loss of TIPS primary patency, occurred more with Wallstent versus VIATORR TIPSs (29% vs 11%; P = .009). Recurrent bleeding incidences were 9%, 22%, and 29% at 30 days, 1 year, and 2 years, respectively, and were similar between Wallstent and VIATORR TIPSs (19% vs 19%; P = .924). Variceal embolization significantly reduced recurrent bleeding rates (5% vs 25%; P = .013). Overall survival rates were 80%, 69%, and 65% at 30 days, 1 year, and 2 years, respectively, and were similar between Wallstent and VIATORR TIPSs (35% vs 26% mortality rate; P = .312). Advanced MELD score was associated with increased mortality on multivariate analysis. CONCLUSIONS: Wallstent and VIATORR TIPSs effectively treat variceal hemorrhage, particularly when accompanied by variceal embolization. Although TIPS with a VIATORR device showed improved shunt patency, patient survival is similar to that with Wallstent TIPS. These results further validate TIPS creation for refractory variceal bleeding.

Rebleeding rates following TIPS for variceal hemorrhage in the Viatorr era: TIPS alone versus TIPS with variceal embolization.

PURPOSE: To compare rebleeding rates following treatment of variceal hemorrhage with TIPS alone versus TIPS with variceal embolization in the covered stent-graft era. METHODS: In this retrospective study, 52 patients (M:F 29:23, median age 52 years) with hepatic cirrhosis and variceal hemorrhage underwent TIPS insertion between 2003 and 2008. Median Child-Pugh and MELD scores were 8.5 and 13.5. Generally, 10-mm diameter TIPS were created using covered stent-grafts (Viatorr; W.L. Gore and Associates, Flagstaff, AZ). A total of 37 patients underwent TIPS alone, while 15 patients underwent TIPS with variceal embolization. The rates of rebleeding and survival were compared. RESULTS: All TIPS were technically successful. Median portosystemic pressure gradient reductions were 13 versus 11 mmHg in the embolization and non-embolization groups. There were no statistically significant differences in Child-Pugh and MELD score, or portosystemic pressure gradients between each group. A trend toward increased rebleeding was present in the non-embolization group, where 8/37 (21.6%) patients rebled while 1/15 (6.7%) patients in the TIPS with embolization group rebled (P = 0.159) during median follow-up periods of 199 and 252 days (P = 0.374). Rebleeding approached statistical significance among patients with acute hemorrhage, where 8/32 (25%) versus 0/14 (0%) rebled in the non-embolization and embolization groups (P = 0.055). A trend toward increased bleeding-related mortality was seen in the non-embolization group (P = 0.120). CONCLUSIONS: TIPS alone showed a high incidence of rebleeding in this series, whereas TIPS with variceal embolization resulted in reduced recurrent hemorrhage. The efficacy of embolization during TIPS performed for variceal hemorrhage versus TIPS alone should be further compared with larger prospective randomized trials.

Ethnicity and body mass index are associated with hepatitis C presentation and progression.

BACKGROUND & AIMS: Ethnicity and the metabolic syndrome are believed to affect progression of hepatitis C virus (HCV) infection, but the interaction between these factors is unknown. We evaluated the association between elements of the metabolic syndrome and ethnicity in the histologic progression of HCV in a large, diverse cohort. METHODS: We retrospectively evaluated clinical data and liver biopsy samples from 812 patients who had no cause of liver disease other than HCV infection. Liver biopsies were scored for steatosis, necroinflammatory activity, and fibrosis. For each patient with a known risk factor for viral acquisition, fibrosis index was calculated as an indicator of disease progression. RESULTS: Hispanics had significantly higher fibrosis index (0.13 +/- 0.09) than non-Hispanic whites (0.11 +/- 0.07) and African Americans (0.10 +/- 0.06; P = .001). Fibrosis index correlated with body mass index (BMI), older age at infection, ethnicity, and degree of steatosis. Cirrhosis was present in 50% of Hispanics, 38% of non-Hispanic whites, and 24% of African Americans (P < .001). The presence of cirrhosis was associated additionally with older age, longer duration of infection, BMI, alcohol consumption, and diabetes. In multivariate analysis, only BMI and ethnicity were associated with both fibrosis index and presentation with cirrhosis. Patients with higher BMIs, diabetes mellitus, and steatosis had higher degrees of necroinflammation. CONCLUSIONS: Ethnicity and BMI each were associated with the progression of fibrosis and the presence of cirrhosis. Hispanics had the highest fibrosis index and prevalence of cirrhosis, whereas African Americans had the lowest. Ethnic differences in fibrosis index and cirrhosis persisted after controlling for elements of metabolic syndrome.