The impact of macro- and micro-steatosis on the outcomes of patients who undergo liver transplant: Analysis of the UNOS-STAR database.

BACKGROUND AND AIMS: The presence of steatosis in a donor liver and its relation to post-transplantation outcomes are not well defined. This study evaluates the effect of the presence and severity of micro- and macro-steatosis of a donor graft on post-transplantation outcomes. METHODS: The UNOS-STAR registry (2005-2019) was used to select patients who received a liver transplant graft with hepatic steatosis. The study cohort was stratified by the presence of macro- or micro-vesicular steatosis, and further stratified by histologic grade of steatosis. The primary endpoints of all-cause mortality and graft failure were compared using sequential Cox regression analysis. Analysis of specific causes of mortality was further performed. RESULTS: There were 9184 with no macro-steatosis (control), 150 with grade 3 macro-steatosis, 822 with grade 2 macro-steatosis and 12 585 with grade 1 macro-steatosis. There were 10 320 without micro-steatosis (control), 478 with grade 3 micro-steatosis, 1539 with grade 2 micro-steatosis and 10 404 with grade 1 micro-steatosis. There was no significant difference in all-cause mortality or graft failure among recipients who received a donor organ with any evidence of macro- or micro-steatosis, compared to those receiving non-steatotic grafts. There was increased mortality due to cardiac arrest among recipients of a grade 2 macro-steatosis donor organ. CONCLUSION: This study shows no significant difference in all-cause mortality or graft failure among recipients who received a donor liver with any degree of micro- or macro-steatosis. Further analysis identified increased mortality due to specific aetiologies among recipients receiving donor organs with varying grades of macro- and micro-steatosis.

Proton beam stereotactic body radiotherapy and hypofractionated therapy with pencil beam scanning is safe and effective for advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma: A single center experience.

Background: Proton beam therapy (PBT) is a non-surgical treatment that spares adjacent tissues compared to photon radiation and useful for Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). We present a single center experience in HCC and iCCA treated with Pencil Beam Scanning (PBS) PBT. Methods: Forty-four consecutive patients (22 patients in each group) receiving PBT were included and reviewed. PBT was delivered with hypofractionated or stereotactic body radiation therapy (SBRT) using PBS. Tumor size was approximated by clinical target volume (CTV). Outcomes were evaluated with Kaplan-Meier and liver toxicity was determined by MELD-Na and albumin-bilirubin (ALBI) grade. Results: Median follow up was 38.7 months, fourteen (35%) had multifocal disease and median CTV was 232.5cc. Four (9%) and 40 (91%) patients received SBRT and hypofractionated radiation, respectively. Two year overall survival was statistically higher for HCC (entire group: 68.9% months [95% CI: 61.3 - 76.3%]; iCCA: 49.8% [95% CI: 38.5% - 61.1%]; HCC: 89.4% [95% CI: 82.3 - 96.5%]; P <0.005). There was no statistical difference in progression-free survival or freedom from local failure. Biologically Equivalent Dose (BED) was greater than or equal to 80.5Gy in 37 (84%) patients. All iCCA patients had stable or improved ALBI grade following treatment. ALBI grade was stable in 83% of HCC patients and average MELD-Na score remained stable. Tumor size, pretreatment liver function, and total radiation dose were not associated with liver toxicity. Conclusions: PBT for unresectable HCC and iCCA is safe and effective, even for large and multifocal tumors. Liver function was preserved even in those with baseline cirrhosis in this advanced population with large tumors.

Impact of Inflammatory Bowel Disease Subtypes on the Post-liver Transplant Outcomes of Patients with Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: Liver transplant patients with primary sclerosing cholangitis often present with concurrent inflammatory bowel disease. The effect of comorbid conditions on post-transplant prognosis was evaluated. METHODS: The 2005-2019 United Network of Organ Sharing Standard Transplant Analysis and Research database was used to identify patients with primary sclerosing cholangitis. Patients were categorized as having Crohn's Disease, ulcerative colitis, unclassified inflammatory bowel disease, or no inflammatory bowel disease. Baseline characteristics were assessed between cohorts, and outcomes were examined using Cox regression. Outcomes included all-cause mortality, graft failure, infection-induced mortality, and organ system-delineated mortality. Supplementary analyses with unique exclusion and stratification criteria were also performed. RESULTS: Among 2829 patients undergoing transplant, 1360 were considered to have ulcerative colitis, 372 were considered to have Crohn's Disease, and 69 were considered to have an unclassified form of inflammatory bowel disease. Primary sclerosing cholangitis patients with some form of inflammatory bowel disease had no increased risk for any outcomes. However, patients with ulcerative colitis had lower risks of general infectious (aHR 0.65 95%CI 0.44-0.95) and sepsis-induced (aHR 0.56 95%CI 0.35-0.91) mortality, whereas patients with Crohn's Disease had higher risks of sepsis-induced mortality (aHR 2.13 95%CI 1.22-3.70). Supplementary analyses showed effect modification by abdominal surgery history and era. CONCLUSION: The type of inflammatory bowel disease in liver transplant patients with primary sclerosing cholangitis was found to portend risk difference for infection-induced mortality, with ulcerative colitis found to be protective and Crohn's Disease predictive of increased mortality secondary to infectious etiologies. These associations warrant further investigation.

The impact of recipient and donor gender-match and mismatch on the post-liver transplant outcomes of patients with primary biliary cholangitis.

BACKGROUND & AIMS: In this study, we evaluate the effects of donor gender on post-liver transplant (LT) prognosis. We specifically consider patients with primary biliary cholangitis (PBC). METHODS: The 2005 to 2019 UNOS transplant registry was used to select patients with PBC. The study cohort was stratified by donor gender. All-cause mortality and graft failure hazards were compared using iterative Cox regression analysis. Subanalyses were performed to evaluate gender mismatch on post-LT prognosis. RESULTS: There were 1885 patients with PBC. Of these cases, 965 entries had male donors and 920 had female donors. Median follow-up was 4.82 (25-75% IQR 1.83-8.93) years. Having a male donor was associated with higher all-cause mortality (aHR 1.28 95%CI 1.03-1.58) and graft failure (aHR 1.70 95%CI 1.02-2.82). Corresponding incidence rates were also relatively increased. In the sub-analysis of female recipients (n = 1581), those with gender-mismatch (male donors, n = 769) were associated with higher all-cause mortality (aHR 1.41 95%CI 1.11-1.78) but not graft failure. In the male recipient subanalysis (n = 304), no associations were found between gender-mismatch (female donors, n = 108) and all-cause mortality or graft failure. CONCLUSION: This study shows that recipients who have male donors experienced higher rates of all-cause mortality following LT. This finding was consistent in the female recipient-male donor mismatch cohort.

The prognostic relationship between donor age and infectious risk in liver transplant patients with nonalcoholic steatohepatitis: Analysis of UNOS database.

BACKGROUND & AIMS: We investigate the effects of advancing donor age on the prognostic outcomes of patients with NASH who undergo liver transplant (LT), with a specialized attention toward infectious outcomes post-LT. METHODS: The UNOS-STAR registry was used to select 2005 to 2019 LT recipients with NASH, who were stratified by donor age into the following categories: recipients with younger donors (less than 50 years of age-reference), quinquagenarian donors, sexagenarian donors, septuagenarian donors, and octogenarian donors. Cox regression analyses were conducted for all-cause mortality, graft failure, infectious causes of death. RESULTS: From a total of 8888 recipients, the quinquagenarian, septuagenarian, and octogenarian donor cohorts showed greater risk of all-cause mortality (quinquagenarian: aHR 1.16 95%CI 1.03-1.30; septuagenarian: aHR 1.20 95%CI 1.00-1.44; octogenarian: aHR 2.01 95%CI 1.40-2.88). With advancing donor age, there was an increased risk of death from sepsis (quinquagenarian: aHR 1.71 95% CI 1.24-2.36; sexagenarian: aHR 1.73 95% CI 1.21-2.48; septuagenarian: aHR 1.76 95% CI 1.07-2.90; octogenarian: aHR 3.58 95% CI 1.42-9.06) and infectious causes (quinquagenarian: aHR 1.46 95% CI 1.12-1.90; sexagenarian: aHR 1.58 95% CI 1.18-2.11; septuagenarian: aHR 1.73 95% CI 1.15-2.61; octogenarian: aHR 3.70 95% CI 1.78-7.69). CONCLUSION: NASH patients who receive grafts from elderly donors exhibit higher risk of post-LT mortality, especially due to infection.

The nationwide trends in hospital admissions, deaths, and costs related to hepatitis C stratified by psychiatric disorders and substance use: an analysis of US hospitals between 2016 and 2019.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) is a prominent liver disease that often presents with mental illness. We stratify the HCV population and review its healthcare burden on the US hospital system. METHODS: The US National Inpatient Sample was used to select admissions related to HCV between 2016 and 2019. Weights were assigned to discharges, and trend analyses were performed. Strata were formed across demographics, comorbidities, psychiatric and substance use conditions, and other variables. Outcomes of interest included hospitalization incidences, mortality rates, total costs, and mean per-hospitalization costs. RESULTS: From 2016 to 2019, there were improvements in mortality and hospitalization incidence for HCV, as well as a decline in aggregate costs across the majority of strata. Exceptions that showed cost growth included admissions with multiple psychiatric, stimulant use, or poly-substance use disorders, and a history of homelessness. Admissions with no psychiatric comorbidities, admissions with no substance use comorbidities, and admissions with housing and without HIV comorbidity showed decreasing total costs. Along with per-capita mean costs, admissions with comorbid opioid use, bipolar, or anxiety disorder showed significant increases. No significant trends in per-capita costs were found in admissions without mental illness diagnoses. CONCLUSIONS: Most strata demonstrated decreases in hospitalization incidences and total costs surrounding HCV; however, HCV cases with mental illness diagnoses saw expenditure growth. Cost-saving mechanisms for these subgroups are warranted.

Clinical implications of gender and race in patients admitted with autoimmune hepatitis: updated analysis of US hospitals.

Background: Autoimmune hepatitis (AIH) can result in end-stage liver disease that requires inpatient treatment of the hepatic complications. Given this phenomenon, it is important to analyse the impact of gender and race on the outcomes of patients who are admitted with AIH using a national hospital registry. Methods: The 2012-2017 National Inpatient Sample database was used to select patients with AIH, who were stratified using gender and race (Hispanics and blacks as cases and whites as reference). Propensity score matching was employed to match the controls with cases and compare mortality, length of stay and hepatic complications. Results: After matching, there were 4609 females and 4609 males, as well as 3688 blacks and 3173 Hispanics with equal numbers of whites, respectively. In multivariate analysis, females were less likely to develop complications, with lower rates of cirrhosis, ascites, variceal bleeding, hepatorenal syndrome, encephalopathy and acute liver failure (ALF); they also exhibited lower length of stay (adjusted OR, aOR 0.96 95% CI 0.94 to 0.97). When comparing races, blacks (compared with whites) had higher rates of ALF and hepatorenal syndrome related to ALF, but had lower rates of cirrhosis-related encephalopathy; in multivariate analysis, blacks had longer length of stay (aOR 1.071, 95% CI 1.050 to 1.092). Hispanics also exhibited higher rates of hepatic complications, including ascites, varices, variceal bleeding, spontaneous bacterial peritonitis and encephalopathy. Conclusion: Males and minorities are at a greater risk of developing hepatic complications and having increased hospital costs when admitted with AIH.

A Systematic Review of Crohn's Disease Case Definitions in Administrative or Claims Databases.

BACKGROUND: We sought to review Crohn's disease (CD) case definitions that use diagnosis, procedure, and medication claims. METHODS: We searched PubMed and Embase from inception through January 31, 2022, using terms related to CD, inflammatory bowel disease, administrative claims, or validity. Each article was scrutinized by 2 authors independently screening and abstracting data. Collected data included participant characteristics, case definition characteristics, and case definition validity. When diagnostic accuracy was provided for multiple case definitions, we extracted the case definition selected by the authors. All diagnostic accuracy characteristics were captured. RESULTS: We identified 30 studies that evaluated a case definition using claims data to identify CD patients. The most common case definition included counts of diagnosis codes (57%) followed by a combination of diagnosis codes and medications (20%). All but 1 study validated the case definition with a medical chart review. In 2 studies, the patient's primary care provider completed a survey to confirm disease status. The positive predictive value of the case definitions ranged from 18% (≥1 code at a single U.S. health plan) to 100% (≥1 code plus a relevant prescription at a U.S. hospital). More complex case definitions (eg, ≥1 code + prescription or ≥2 codes) had lower variability in positive predictive value (≥80%) and specificity (≥85%) than the ≥1 code requirement. CONCLUSIONS: Health services researchers should validate case definitions in their research cohorts. When such validation cannot be performed, we recommend using a more complex case definition. Studies without a validated CD case definition should use sensitivity analyses to confirm the robustness of their results.

This systematic review of Crohn's disease (CD) case definitions identified that complex case definitions such as ≥1 diagnosis code + ≥1 prescription had desirable diagnostic accuracy properties.

The differences in post-liver transplant outcomes of patients with autoimmune hepatitis who present with overlapping autoimmune liver diseases.

BACKGROUND: Patients with autoimmune hepatitis (AIH) may co-present with features of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). Using a national transplant registry, the outcomes of patients with these autoimmune liver conditions were compared. METHODS: The UNOS-STAR registry was used to select a study population of AIH, PSC, and PBC liver transplant (LT) patients. Living and multi-organ transplant cases were excluded. Using the UNOS-registered diagnoses, the study population was subdivided into those with nonoverlapping autoimmune liver diseases and those with overlapping forms (e.g., AIH-PBC). Outcomes were compared, using endpoints such as all-cause mortality, graft failure, and organ-system specific causes of death. RESULTS: The main analysis featured 2048 entries, with 1927 entries having nonoverlapping AIH, 52 entries having PSC overlap, and 69 entries having PBC overlap. Patients with PBC overlap were more likely to have graft failure (adjusted hazard ratio [aHR] 3.46 95% CI 1.70-7.05), mortality secondary to respiratory causes (aHR 3.57 95% CI 1.23-10.43), and mortality secondary to recurrent disease (aHR 9.53 95% CI 1.85-49.09). Case incidence rates reflected these findings, expressed in events per 1000 person-years. For patients with PBC overlap and nonoverlapping AIH cases, respectively. Graft failure: 28.87 events vs. 9.42 events, mortality secondary to respiratory causes: 12.83 deaths vs. 3.77 deaths, mortality secondary to recurrent disease: 6.42 deaths vs. 1.26 deaths. Those with AIH-PSC overlap experienced a higher risk of death from graft infection (aHR 10.43 95% CI 1.08-100.37; case-incidence rate: 3.89 vs. 0.31 mortalities per 1000 person-years). Supplementary analysis showed similar findings, in which overlapping autoimmune conditions were associated with higher adverse outcome rates. CONCLUSION: Patients with AIH-PBC overlap have higher risk of mortality due to recurrent liver disease and respiratory causes, and patients with AIH-PSC overlap have higher risk of mortality due to graft infection. While further prospective studies are needed to clarify the underlying mechanisms related to these findings, our study characterizes the prognostic implications of AIH overlap on post-LT mortality and graft failure risks.

The clinical implications of pre-liver transplant diabetes on post-liver transplant outcomes in patients with NASH: analysis of the UNOS database.

BACKGROUND AND AIMS: The presence of perioperative diabetes may lead to increased mortality risks following liver transplant (LT) in patients with non-alcoholic steatohepatitis (NASH). This risk factor was evaluated using a UNOS-STAR national database. METHODS: The UNOS-STAR liver transplant registry 2005-2019 was used to select patients with NASH (including cryptogenic liver disease). The following populations were excluded: those younger than 18 years old and those with living donors/dual transplants. Selected patients were stratified into those with and without pre-LT diabetes and compared to the individual mortality endpoints using iterative Cox analyses. RESULTS: 6324 recipients with and 8251 without diabetes were selected. The median follow-up time was 3.07 years. Those with diabetes were older (58.50 vs. 54.50 years, p < 0.001), were more likely to be Hispanic or Asian, and had higher BMI than the non-diabetics (31.10 vs. 29.70 kg/m2 p < 0.001); however, there was no difference in gender (female 41.9 vs. 43.1% p = 0.170). Compared to non-diabetics, recipients with diabetes had a higher rate of all-cause mortality (61.68 vs. 47.80 per 1000 person-years). In multivariate iterations, pre-LT diabetes was associated with all-cause mortality (aHR 1.19 95% CI 1.11-1.27) as well as deaths due to cardiac (p = 0.014 aHR 1.24 95% CI 1.04-1.46) and renal causes (p = 0.039 aHR 1.38 95% CI 1.02-1.87). CONCLUSION: The presence of pre-LT diabetes is associated with all-cause mortality and deaths due to cardiac and renal causes following LT. The findings warrant an early preoperative screening procedure to ensure that patients with diabetes have their metabolic risk factors optimized prior to LT.

The clinical implication of psychiatric illnesses in patients with alcoholic liver disease: an analysis of US hospitals.

BACKGROUND: In this study, we evaluate the clinical impact of psychiatric illnesses (PI) on the hospital outcomes of patients admitted with alcoholic liver disease (ALD). METHODS: From the National Inpatient Sample from 2012-2017, patients with alcoholic cirrhosis or alcoholic hepatitis were selected and stratified using the presence/absence of PI (which was a composite of psychiatric conditions). The cases were propensity score-matched to PI-absent controls and were compared to the following endpoints: mortality, death due to suicide, length of stay (LOS), hospitalization charges, and hepatic complications. RESULTS: After matching, there were 122,907 PI with and 122,907 without PI. Those with PI were younger (51.8 vs. 51.9 years p = 0.02) and more likely to be female (39.2 vs. 38.7% p = 0.01); however, there was no difference in race. Patients with PI had lower rates of alcoholic cirrhosis but higher rates of alcoholic hepatitis/alcoholic hepatic steatosis. In multivariate, patients with PI had lower rates of all-cause mortality (aOR 0.51 95%CI 0.49-0.54); however, they experienced higher rates of deaths due to suicide (aOR 3.00 95%CI 1.56-5.78) and had longer LOS (aOR 1.02 95%CI 1.01-1.02). CONCLUSION: Presence of PI in ALD patients is associated with prolonged hospital stay and higher rates deaths due to suicide.

Clinical Practice Issues for Liver Transplantation in COVID-19 Recovered Recipients.

The ongoing burden of COVID-19 in persons with end stage liver failure necessitates the development of sound and rational policies for organ transplantation in this population. Following our initial experience with two COVID-19 recovered recipients who died shortly after transplant, we adjusted our center policies, re-evaluated outcomes, and retrospectively analyzed the clinical course of the subsequent seven COVID-19 recovered recipients. There were two early deaths and 5 successful outcomes. Both deceased patients shared common characteristics in that they had positive SARS-CoV2 PCR tests proximal to transplant (7-17 days), had acute on chronic liver failure, and suffered thromboembolic phenomena. After a careful review of clinical and virological outcome predictors, we instituted policy changes to avoid transplantation in these circumstances. We believe that our series offers useful insights into the unique challenges that confront transplant centers in the COVID-19 era and could guide future discussions regarding this important area.

Hepatitis C-positive donor liver transplantation for hepatitis C seronegative recipients.

BACKGROUND: The opioid crisis has led to an increase in hepatitis C virus-positive donors in the past decade. Whereas historically hepatitis C seropositive organs were routinely discarded, the advent of direct-acting antiviral agents has notably expanded the utilization of organs from donors with hepatitis C. There has been growing experience with liver transplantation (LT) from hepatitis C seropositive donors to hepatitis C seropositive recipients. However, data remain limited on LT from hepatitis C seropositive or hepatitis C ribonucleic acid positive donors to hepatitis C seronegative recipients. METHODS: We performed a retrospective study of 26 hepatitis C seronegative recipients who received hepatitis C seropositive donor livers followed by preemptive antiviral therapy with direct-acting antiviral treatment at the Johns Hopkins Hospital Comprehensive Transplant Center from January 1, 2017, to August 31, 2019. RESULTS: Twenty-five of the 26 recipients are alive with proper graft function; 20 of them received livers from hepatitis C nucleic acid testing positive donors. All 12 recipients who completed their direct-acting antiviral courses and have reached sufficient follow-up for sustained virologic response have achieved sustained virologic response. Nine of our recipients have either completed direct-acting antiviral treatment without sufficient follow-up time for sustained virologic response or are undergoing direct-acting antiviral treatment. One patient is awaiting antiviral treatment initiation pending insurance approval. Of note, 11 of 12 patients with sustained virologic response received a hepatitis C nucleic acid testing positive donor liver. CONCLUSION: Hepatitis C seronegative patients who receive a hepatitis C seropositive or hepatitis C nucleic acid testing positive liver allograft can enjoy good short-term outcomes with hepatitis C cure following direct-acting antiviral treatment.

Pseudomembranous colitis: Not always Clostridium difficile.

Although Clostridium difficile infection is the cause of most cases of pseudomembranous colitis, clinicians should consider less common causes, especially if pseudomembranes are seen on endoscopy but testing remains negative for C difficile or if presumed C difficile infection does not respond to treatment. Histologic review of colonic mucosal biopsy specimens can provide clues to the underlying cause.

Data regarding M1 muscarinic receptor-mediated modulation of hepatic catalase activity in response to oxidative stress.

We recently demonstrated the role of M1 muscarinic receptors (M1R) in modulating oxidative stress in liver and hepatocytes (Urrunaga et al., 2015) [1]. Here we provide data regarding the effect of a novel M1R agonist, VU0357017 (Lebois et al., 2010) [2], on H2O2-mediated hepatocyte injury, the effect of an M1R antagonist VU0255035 (Sheffler et al., 2009) [3] on catalase and super oxide dismutase (SOD) activities in H2O2-treated hepatocytes in vitro, and finally, the effect of M1R ablation on hepatic catalase activity in acetaminophen (APAP)-treated mice.