Management of long-term complications from immunosuppression.

This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well.

Noninvasive prognostic models, imaging, and elastography to predict clinical events in primary sclerosing cholangitis: A review.

Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.

Prognostic modeling in biliary diseases.

PURPOSE OF REVIEW: To discuss the prognostic models for the cholestatic diseases focusing on primary sclerosing cholangitis and primary biliary cholangitis. RECENT FINDINGS: Noninvasive prognostic models that outperform alkaline phosphatase and Mayo Risk Score have been developed to predict clinically significant events, such as transplant free survival or hepatic decompensation. Models for primary sclerosing cholangitis (PSC) include UK-PSC, Primary Sclerosing Cholangitis Risk Estimate Tool, and Amsterdam Oxford models. Models for primary biliary cirrhosis (PBC) include UK-PBC, Global primary biliary cholangitis group score (GLOBE) and Paris II scores. Other models have incorporated elastography with or without findings on magnetic resonance imaging. SUMMARY: Noninvasive prognostic models can inform patients about their risk for clinical outcomes and serve as surrogate intermediate outcomes to determine efficacy of novel agents in clinical trials.

Primary Care Evaluation of a Hepatitis C Virus (HCV) Screening Education Intervention.

INTRODUCTION: Increased screening efforts and the development of effective antiviral treatments have led to marked improvement in Hepatitis C (HCV) patient outcomes. However, many people in the US are believed to have undiagnosed HCV. Successful screening strategies and access to a coordinated system of care are critical for HCV affected adults. The objective of this study was to evaluate a primary care HCV screening education intervention that took place 2018 to 2019 to improve primary care training and management of patients after the implementation of the electronic medical record (EMR) screening alert. METHODS: Using 15 primary care practices located in vicinity of neighborhoods at-risk for higher rates of HCV infections, a stepped wedge randomized control study design was utilized to deliver an educational screening intervention. The education intervention was implemented sequentially with 5 practices being presented to every 3 months. Number of patients within the Baby Boomer cohort (birth years 1945-1965) were collected 3 months before the first practice receiving the intervention to 3 months after the last practice receiving the education intervention. The main outcome collected was the HCV screening. Generalized linear mixed models were used to test the hypothesis of improved screening rates after intervention implementation. RESULTS: There were a total of 85,697 patients within the Baby Boomer cohort seen at the 15 practices. Practices receiving the intervention had patients who were more likely to be screened for HCV (ß = 0.259, P < .001; Odds Ratio [OR] [95%CI] 1.296 [1.098-1.529]).In terms of demographics, results showed that females are less likely to be screened than males (ß = -0.141, P < .001; OR [95%CI] 0.868[0.813 to 0.927]), Baby Boomer patients aged less than 65 were more likely to be screened than Baby Boomer patients aged 65 and older (ß = 0.293, P < .001; OR [95%CI] 1.340[1.251 to 1.436]). DISCUSSION: This study looked at screening rates before and after an educational intervention which happened subsequent to the activation of an EMR alert. Whereas HCV EMR alerts showed an increase in HCV screenings before the education intervention, the addition of the education showed a modest increase in HCV screening rates for Baby Boomer patients.

Pros and Cons of the Safety Net Rule for Prioritization of Liver Transplant Recipients Who Receive Liver Alone Transplant but Develop End-Stage Renal Disease.

The number of patients presenting with cirrhosis with kidney injury and the potential need for SLKT is increasing. In 2017, standardized criteria were implemented to identify candidates for SLKT as well as criteria for prioritizing LTA recipients for kidney transplant if they developed kidney failure, which is referred to as the 'safety net rule.' Goal of the safety net rule is to provide a pathway that provides increased priority to LTA recipients with renal failure who may have previously undergone SLKT. This article reviews the pros and cons of the safety net rule for liver transplant recipients who develop ESRD.

Impact of the Corona Virus Disease 2019 Pandemic on Hepatology Practice and Provider Burnout.

The corona virus disease 2019 (COVID-19) pandemic has had a wide-ranging impact on the clinical practice of medicine and emotional well-being of providers. Our aim was to determine the impact of the COVID-19 pandemic on practice and burnout among hepatology providers. From February to March 2021, we conducted an electronic survey of American Association for the Study of Liver Diseases (AASLD) members who were hepatologists, gastroenterologists, and advanced practice providers (APPs). The survey included 26 questions on clinical practice and emotional well-being derived from validated instruments. A total of 230 eligible members completed the survey as follows: 107 (47%) were adult transplant hepatologists, 43 (19%) were adult general hepatologists, 14 (6%) were adult gastroenterologists, 11 (5%) were pediatric hepatologists, 45 (19%) were APPs, and 9 (4%) were other providers. We found that 69 (30%) experienced a reduction in compensation, 92 (40%) experienced a reduction in staff, and 9 (4%) closed their practice; 100 (43%) respondents reported experiencing burnout. In univariate analysis, burnout was more frequently reported in those ≤55 years old (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.2), women (OR, 2.2; 95% CI, 1.3-3.7), nontransplant hepatology (OR, 2.0; 95% CI, 1.1-3.3), APPs (OR, 2.7; 95% CI, 1.4-5.1), and those less than 10 years in practice (OR, 1.9; 95% CI, 1.1-3.3). In multivariable analysis, only age ≤55 years was associated with burnout (OR, 2.3; 95% CI, 1.1-4.8). The most common ways the respondents suggested the AASLD could help was through virtual platforms for networking, mentoring, and coping with the changes in practice due to the COVID-19 pandemic. Conclusion: The COVID-19 pandemic has had a substantial impact on the clinical practice of hepatology as well as burnout and emotional well-being. Women, APPs, and early and mid-career clinicians more frequently reported burnout. Identified strategies to cope with burnout include virtual platforms to facilitate networking and mentoring.

Systematic Review of Prognostic Models Compared to the Mayo Risk Score for Primary Sclerosing Cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a variable clinical course that can ultimately lead to end-stage liver disease, cholangiocarcinoma, and the need for liver transplantation. Several prognostic models have been developed to predict clinical outcomes and have been compared to the revised Mayo Risk Score (rMRS). AIM: To conduct a systematic review comparing the rMRS to other non-invasive prognostic tests for PSC. METHODS: A systematic review of studies from 2000 to 2020 was performed that compared non-invasive biochemical prognostic models to the rMRS in predicting outcomes in patients with PSC. RESULTS: Thirty-seven studies were identified, of which five studies that collectively included 3230 patients were reviewed. Outcomes included transplant-free survival or composite clinical outcomes. The rMRS was better than the Amsterdam-Oxford model for predicting 1-year transplant-free survival, c-statistics 0.75 and 0.70, respectively. The UK-PSC score outperformed the rMRS for 10-year transplant-free survival, c-statistics 0.85 and 0.69, respectively. An enhanced liver fibrosis score was independently associated with transplant-free survival after adjusting for rMRS. PREsTo predicts 5-year hepatic decompensation with a c-statistic modestly higher than rMRS; 0.90 and 0.85, respectively. CONCLUSION: Newer prognostic models, including the UK-PSC score and PREsTo, are more accurate at predicting clinical endpoints in PSC compared to the rMRS. Time frames and clinical endpoints are not standard among studies.

Current state of endohepatology: Diagnosis and treatment of portal hypertension and its complications with endoscopic ultrasound.

The diagnosis and management of cirrhosis and portal hypertension (PH) with its complications including variceal hemorrhage, ascites, and hepatic encephalopathy continues to evolve. Although there are established "standards of care" in liver biopsy and measurement of PH, gastric varices remain an area without a universally accepted therapeutic approach. The concept of "Endo Hepatology" has been used to describe of the applications of endoscopic ultrasound (EUS) to these challenges. EUS-liver biopsy (EUS-LB) offers an alternative to percutaneous and transjuglar liver biopsy without compromising safety or efficacy, and with added advantages including the potential to reduce sampling error by allowing biopsies in both hepatic lobes. Furthermore, EUS-LB can be performed during the same procedure as EUS-guided portal pressure gradient (PPG) measurements, allowing for the collection of valuable diagnostic and prognostic data. EUS-guided PPG measurements provide an appealing alternative to the transjugular approach, with proposed advantages including the ability to directly measure portal vein pressure. In addition, EUS-guided treatment of gastric varices (GV) offers several possible advantages to current therapies. EUS-guided treatment of GV allows detailed assessment of the vascular anatomy, similar efficacy and safety to current therapies, and allows the evaluation of treatment effect through doppler ultrasound visualization. The appropriate selection of patients for these procedures is paramount to ensuring generation of useful clinical data and patient safety.

A Case Series of Extrapulmonary Mycobacterium in Liver Transplant Recipients.

Liver transplant recipients are at increased risk of infection because of the immunosuppression required after transplantation. Infection by Mycobacterium species increases the morbidity and mortality of liver transplant recipients. The prompt recognition and diagnosis of opportunistic infection is necessary for good outcomes, particularly during periods of increased immunosuppression. The balance of immunosuppressive therapies during prolonged treatment with hepatotoxic medications has not been well studied and should be tailored for the unique clinical setting of each patient. The goal of treatment in these patients is to eradicate the disease and preserve allograft function.

Is There a Futility Discriminant Function Score for Alcoholic Hepatitis?

The treatment for patients with alcoholic hepatitis (AH) who have a discriminant function (DF) score greater than 32 has been steroids. A prior study reported that mortality approaches 100% when the DF score is greater than 54, despite the use of prednisolone. Our aim was to determine if a DF score greater than 54 is associated with high mortality despite steroids. We conducted a retrospective study of 531 first-time inpatient encounters of AH. We compared 30-day mortality between patients with DF 54 or less to those greater than 54 treated with steroids, as well as a matched group not treated with steroids. A total of 531 inpatients diagnosed with AH were identified, of which 124 had a DF greater than 32 and 52 were treated with steroids. Among patients treated with steroids, 30-day mortality for patients with DF greater than 54 (n = 27) and 54 or below (n = 25) was 22% and 12%, respectively (p = 0.47). Among patients with DF greater than 54, the 30-day mortality for those who did (n = 27) and did not (n = 29) receive steroids was 22% and 24%, respectively (p = 0.87). In our study population, steroids were not futile in patients with a DF score of greater than 54.

ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are the most common classes of agents to cause DILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presenting with suspected DILI. DILI carries a mortality rate up to 10% when hepatocellular jaundice is present. Patients with DILI who develop progressive jaundice with or without coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features.

Systematic review: non-invasive prognostic tests for primary sclerosing cholangitis.

BACKGROUND: Several prognostic tests for primary sclerosing cholangitis (PSC) have been developed, including biochemical models, elastography and magnetic resonance imaging scores. AIM: To conduct a systematic review of non-invasive prognostic tests for PSC. METHODS: A systematic review was conducted from 1987 to 2020 of blood tests, biochemical models, elastography and imaging scores associated with outcomes in PSC. RESULTS: Forty studies of prognostic tests that collectively included 16 094 subjects with PSC were reviewed, of which 26 studies of non-invasive tests including 13 759 subjects with PSC were included. Normalisation or reduction of alkaline phosphatase with or without therapy was associated with transplant-free survival and reduced risk of hepatobiliary cancers but cut-off values for alkaline phosphatase were not consistent among studies. The most studied prognostic biochemical model was the Mayo Risk Score (MRS) evaluated in 18 studies with a c-statistic from 0.63 to 0.85 for clinical outcomes. One study demonstrated that the UK-PSC score outperforms MRS for predicting clinical outcomes with a c-statistics of 0.81and 0.75 respectively. A transient elastography score greater than 11.1 kPa is associated with survival and liver-related complications. The Anali score, derived from specific MRI and MRCP features, is associated with the development of cholangiocarcinoma and decompensated cirrhosis. Promising prognostic models include the enhanced liver fibrosis (ELF) score, ELF test and PREsTo scores. CONCLUSION: MRS is the most studied prognostic score for clinical outcomes in PSC but the UK-PSC score and PREsTo have better test performance. Further studies comparing MRS to UK-PSC score, PREsTo or ELF with elastography or imaging-based scores are warranted.

American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.

Modeling the Hepatology Workforce in the United States: A Predicted Critical Shortage.

BACKGROUND AND AIMS: Liver disease is prevalent in the United States, and as the population ages, an increasing number of patients are anticipated to present for care. The state of the current hepatology workforce and future demand for hepatology providers is not known. The aim of this study was to model future projections for hepatology workforce demand. APPROACH AND RESULTS: A workforce study of hepatology providers in the United States was completed using primary and secondary data sources. An integrated workforce framework model was used that combined socioeconomic factors that drive economic demand, epidemiological factors that drive need, and utilization rates of health care services. Supply and demand projections were calculated for adult and pediatric hepatology professionals. Sensitivity analyses were conducted to cover the feasible range of these assumptions. An electronic survey of American Association for the Study of Liver Diseases (AASLD) members whose practice included 50% or more hepatology was conducted. In 2018, the adult and pediatric workforce included 7,296 and 824 hepatology providers, respectively, composed of hepatologists, gastroenterologists, and advanced practice providers whose practice was ≥50% hepatology. The modeling analysis projects that in 2023, 2028, and 2033, there will be shortages of 10%, 23%, and 35% adult hepatology providers, respectively, and 19%, 20%, and 16% pediatric hepatology providers, respectively. In sensitivity analyses, a shortage of hepatology providers is predicted even under optimistic assumptions. Among the respondents to the survey, the median age was higher among gastroenterologists and general hepatologists compared with transplant hepatologists. The most common category treated by transplant hepatologists was general hepatology. CONCLUSIONS: There is an impending critical shortage of adult and pediatric hepatology providers. Strategies are needed to encourage clinicians to pursue hepatology, especially in areas outside of transplant centers.

Novel Models to Identify Census Tracts for Hepatitis C Screening Interventions.

BACKGROUND: Increased screening efforts and the development of effective antiviral treatments have led to marked improvement in hepatitis C (HCV) patient outcomes. However, many people in the United States are still believed to have undiagnosed HCV. Geospatial modeling using variables representing at-risk populations in need of screening for HCV and social determinants of health (SDOH) provide opportunities to identify populations at risk of HCV. METHODS: A literature review was conducted to identify variables associated with patients at risk for HCV infection. Two sets of variables were collected: HCV Transmission Risk and SDOH Level of Need. The variables were combined into indices for each group and then mapped at the census tract level (n = 233). Multiple linear regression analysis and the Pearson correlation coefficient were used to validate the models. RESULTS: A total of 4 HCV Transmission Risk variables and 12 SDOH Level of Need variables were identified. Between the 2 indexes, 21 high-risk census tracts were identified that scored at least 2 standard deviations above the mean. The regression analysis showed a significant relationship with HCV infection rate and prevalence of drug use (B = 0.78, P < .001). A significant relationship also existed with the HCV infection rate for households with no/limited English use (B = -0.24, P = .001), no car use (B = 0.036, P < .001), living below the poverty line (B = 0.014, P = .009), and median household income (B = -0.00, P = .009). CONCLUSIONS: Geospatial models identified high-priority census tracts that can be used to map high-risk HCV populations that may otherwise be unrecognized. This will allow future targeted screening and linkage-to-care interventions for patients at high risk of HCV.