NASH Cirrhosis Research Articles

Therapeutic Role of Bone Marrow Mesenchymal Stem Cells (BMSCs) in Nonalcoholic Steatohepatitis (NASH) Cirrhosis

Abstract: NASH cirrhosis is a late-stage nonalcoholic fatty liver disease (NAFLD) characterized by high morbidity, high relapse rate, and high mortality, which is clinical to treat. Presently, liver transplantation is the most effective radical treatment, but it is difficult to be widely carried out due to the problems of large surgical trauma, lack of liver donors, and strong immunological rejection. Bone marrow mesenchymal stem cells (BMSCs) are a type of stem cell with characteristics of self-replication, multidirectional differentiation, and easy accessibility. The use of BMSCs for cell transplantation therapy has the advantages of fewer complications and significant efficacy, and it has become an important option for cell transplantation therapy, especially for liver diseases. In this paper, we will review the studies related to the use of BMSCs for the treatment of NASH cirrhosis in recent years.

Evaluation of Patients with Hepatic Cirrhosis due to Etiology for the Complication

Objectives: Hepatic cirrhosis is a disease with high mortality. The leading causes of morbidity and mortality in patients with hepatic cirrhosis are disease-associated complications. We aimed to describe the association between the difference in laboratory parameters, complications, and commonly known causes of cirrhosis, such as hepatitis B, hepatitis C, alcoholic liver disease (NASH), and autoimmune hepatitis. Methods: We investigated 541 patients with different etiologies of cirrhosis who applied to a gastroenterology clinic from 2009 to 2018 in Florance Nightingale Hospital. All patients were divided into five groups according to the etiology of cirrhosis, such as hepatitis B, hepatitis C, alcoholic liver disease (ALD), NASH, and autoimmune hepatitis. Biochemical and metabolic parameters were evaluated between five groups. Results: 83 patients with alcoholic liver disease, 242 patients with hepatitis B-associated cirrhosis, 112 patients with hepatitis C-associated cirrhosis, 77 patients with NASH, and 27 patients with autoimmune hepatitis were enrolled. Laboratory parameters due to the etiology of hepatic cirrhosis are shown in Table 2. Ascites and hepatic encephalopathy were statistically higher in alcoholic liver disease, hepatitis B, and NASH cirrhosis, while esophageal variceal bleeding was higher in NASH and autoimmune hepatitis. Spontaneous bacterial peritonitis was statistically higher only in cirrhosis due to autoimmune hepatitis. Conclusion: It is very important to assign complications that may develop in liver cirrhosis and manage them by etiology.

Single cell RNA sequencing and spatial transcriptomic to profile Kupffer cells during NASH and liver cirrhosis

Single cell RNA sequencing and spatial transcriptomic to profile Kupffer cells during NASH and liver cirrhosis

H2FPEF Scores Are Increased in Patients with NASH Cirrhosis and Are Associated with Post-liver Transplant Heart Failure

IntroductionPatients with cirrhosis are at risk for cardiac complications such as heart failure, particularly heart failure with preserved ejection fraction (HFpEF) due to left ventricular diastolic dysfunction (LVDD). The H2FPEF score is a predictive model used to identify patients with HFpEF. Our primary aim was to assess the H2FPEF score in patients with cirrhosis and determine its potential to identify patients at risk for heart failure after liver transplant.MethodsThis was a cohort study of patients undergoing liver transplant for cirrhosis from January 2010 and October 2018 who had a pre-transplant transthoracic echocardiogram.Results166 cirrhosis subjects were included in the study. The majority were men (65%) and Caucasian (85%); NASH was the most common cause of cirrhosis (41%) followed by alcohol (34%). The median H2FPEF score was 2.0 (1.0–4.0). Patients with NASH cirrhosis had higher H2FPEF scores (3.22, 2.79–3.64) than those with alcohol induced cirrhosis (1.89, 1.5–2.29, p < 0.001) and other causes of cirrhosis (1.73, 1.28–2.18, p < 0.001). All subjects with a H2FPEF score > 6 had NASH cirrhosis. There was no association between the H2FPEF scores and measures of severity of liver disease (bilirubin, INR, or MELD score). Patients with heart failure after liver transplant had higher H2FPEF scores than those without heart failure (4.0, 3.1–4.9 vs. 2.3, 2.1–2.6, respectively; p = 0.015), but the score did not predict post-transplant mortality.ConclusionH2FPEF scores are higher in cirrhosis patients with NASH and appear to be associated with post-transplant heart failure, but not death.

The Role of the Anaesthesiologist in Liver Transplantation - Preoperative Evaluation

Preoperative evaluation prior to listing for orthotopic liver transplantation (LT) requires a careful multidisciplinary approach with specialized teams including surgeons, hepatologists and anesthesiologists in order to improve short- and long-term clinical outcomes. Due to inadequate supply of donor organs and changing demographics, patients listed for LT have become older, sicker and share more comorbidities. As cardiovascular events are the leading cause for early mortality precise evaluation of risk factors is mandatory. This review focuses on the detection and management of coronary artery disease, cirrhotic cardiomyopathy, portopulmonary hypertension and hepatopulmonary syndrome in patients awaiting LT. Further insights are being given into scoring systems, patients with Acute-on-chronic-liver-failure (ACLF), frailty, NASH cirrhosis and into psychologic evaluation of patients with substance abuse.

Abstract 4683: Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and &amp;gt; in situ

Abstract Introduction: Conophylline is an alkaloid isolated from the leaves of the Thai plant, Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions and an activator of pancreatic β-cell differentiation. It ameliorates various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and conophylline binds to the cytoplasmic portion of ARL6ip1. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. Previously, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and found that either deletion of ARL6ip1 or addition of conophylline inhibited migration, invasion and tumorigenicity in cultured cancer cells. In the present research we have studied the in vivo anticancer effect of conophylline and ARL6ip1 knockout, and the mechanism of anticancer activity in cultured cells. Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cell lines as human colorectal cancer cells. Cellular migration was measured by a wound-healing assay. The activity of Akt was measured by the phospho-Akt antibody. BALB/cSlc-nu/nu mice were used for the animal experiment. Results: Colon adenocarcinoma tissue microarray comparing tumor and adjacent normal tissues revealed that ARL6ip1 expression was significantly higher in cancer than in normal tissues. Intraperitoneal administration of conophylline and knockout of ARL6ip1 both inhibited the growth of HCT116 in mice. Neither influenced the bodyweight of animals. Conophylline and deletion of ARL6ip1 both inhibited the migration. Rescue of ARL6ip1 canceled the effect of ARL6ip1 deletion on migration in HCT116 and DLD1 cells. As the mechanism, either conophylline or ARL6ip1 knockout inhibited the Akt activity, which was canceled by the rescue of ARL6ip1 in both cell lines. Conclusion: ARL6ip1 was found to be highly expressed in the tumor tissue in colorectal cancer. CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline in the animal experiment. It is likely that the anticancer activity of conophylline would be mediated by Akt. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer. Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and &amp;gt; in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4683.

Increasing prevalence of cirrhosis among insured adults in the United States, 2012-2018.

Liver cirrhosis is a chronic disease that is known as a "silent killer" and its true prevalence is difficult to describe. It is imperative to accurately characterize the prevalence of cirrhosis because of its increasing healthcare burden. In this retrospective cohort study, trends in cirrhosis prevalence were evaluated using administrative data from one of the largest national health insurance providers in the US. (2011-2018). Enrolled adult (≥18-years-old) patients with cirrhosis defined by ICD-9 and ICD-10 were included in the study. The primary outcome measured in the study was the prevalence of cirrhosis 2011-2018. Among the 371,482 patients with cirrhosis, the mean age was 62.2 (±13.7) years; 53.3% had commercial insurance and 46.4% had Medicare Advantage. The most frequent cirrhosis etiologies were alcohol-related (26.0%), NASH (20.9%) and HCV (20.0%). Mean time of follow-up was 725 (±732.3) days. The observed cirrhosis prevalence was 0.71% in 2018, a 2-fold increase from 2012 (0.34%). The highest prevalence observed was among patients with Medicare Advantage insurance (1.67%) in 2018. Prevalence increased in each US. state, with Southern states having the most rapid rise (2.3-fold). The most significant increases were observed in patients with NASH (3.9-fold) and alcohol-related (2-fold) cirrhosis. Between 2012-2018, the prevalence of liver cirrhosis doubled among insured patients. Alcohol-related and NASH cirrhosis were the most significant contributors to this increase. Patients living in the South, and those insured by Medicare Advantage also have disproportionately higher prevalence of cirrhosis. Public health interventions are important to mitigate this concerning trajectory of strain to the health system.

Role of Spleen Stiffness Measurement in the Evaluation of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Spleen stiffness measurement (SSM) correlates with the severity of portal hypertension. We investigated the utility of SSM in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) for detecting cirrhosis, esophageal varices (EV), and high-risk EV. 154 study participants with MASLD underwent simultaneous liver stiffness measurement (LSM) and SSM. 96 (62%) participants had an upper endoscopy (73 participants, i.e., 47% undergoing within a year). The diagnostic performance of SSM, as well as the BAVENO VII proposed SSM cutoffs (≥ 21kPa, > 40kPa, and > 50kPa), was examined. The failure rate for SSM was 19% compared to 5% for LSM. An invalid SSM was statistically significantly associated with a higher body mass index, a larger waist circumference, and a lower fibrosis stage. The area under the receiver operating characteristics for SSM to diagnose cirrhosis, EV, and high-risk EV was 0.78 (95% CI 0.70-0.85), 0.74 (95% CI 0.61-0.84), and 0.82 (95% CI 0.75-0.98), respectively. SSM ≥ 21kPa cutoff had a sensitivity > 96% for all three outcomes, with a positive predictive value (PPV) of 88% for cirrhosis. In contrast, SSM > 40kPa and SSM > 50kPa cutoffs had better diagnostic abilities for identifying EV, particularly high-risk EV (sensitivity of 100% and 93% with NPV of 100% and 96%, respectively). SSM has a higher failure rate in individuals who are non-cirrhotic or have a higher BMI, or larger waist circumference. Although useful for diagnosing NASH cirrhosis, SSM is most reliable in excluding EV and high-risk EV.

COVID-19 and acute pancreatitis clinical outcomes among hospitalized patients in the United States: A propensity matched analysis of national inpatient sample

BackgroundPancreatitis is one of the leading causes of gastrointestinal-related hospitalization, with significant morbidity and mortality. SARS-COV-2 virus can access the pancreas via angiotensin-converting enzymes and can cause direct and indirect injury to the pancreatic parenchyma. The objective of this study to understand clinical outcomes of hospitalized patients with COVID-19 with and without pancreatitis utilizing National Inpatient Sample database. MethodsWe utilized the United States National Inpatient Sample database to study clinical outcomes in hospitalized patients with COVID-19 infection (a total of 1,659,040 hospitalized patients with 10,075 (0.6 %) with pancreatitis) between January 1 to December 31, 2020, along with propensity matching. ResultsWhile after propensity matching, we did not find a statistical difference in in-hospital mortality amongst COVID-19 patients with pancreatitis compared to COVID-19 patients without pancreatitis (13.2 % vs 10.3 %, adjusted odds ratio: 0.7 [95 % CI 0.5–1], p = 0.11). Patients with COVID-19 and pancreatitis had more episodes of septic shock, higher incidence of acute kidney injury and acute kidney injury requiring hemodialysis. We also found an increased prevalence of NASH cirrhosis, alcohol liver cirrhosis, and a lesser incidence of pulmonary embolisms in the COVID-19 with pancreatitis cohort. ConclusionWorse in-hospital outcomes, including increased incidence of septic shock, acute kidney injury, and acute kidney injury requiring hemodialysis in hospitalized patients with COVID-19 infection and pancreatitis, emphasize the need for more research to understand the effect of COVID-19 disease in hospitalized patients with pancreatitis and in the role of vaccination to improve long term outcome in this patient population.

S3483 A Curious Case of Happy Hypoxia in NASH Cirrhosis

S3483 A Curious Case of Happy Hypoxia in NASH Cirrhosis

How the Underlying Etiology of Cirrhosis Impacts Response to SBRT

In the US, incidence rates of hepatocellular carcinoma (HCC) have more than tripled and death rates have doubled since 1980. In 2022, it is expected for 41,260 new cases to be diagnosed with 30,520 deaths. Many etiologies contribute to the development of HCC including alcoholic cirrhosis, cryptogenic cirrhosis, HCV, HBV, NASH, and genetic disorders like hereditary hemochromatosis. An increasing number of patients are not candidates for curative options such as resection or transplant and the role of alternative liver directed as therapies has increased. SBRT has emerged as a safe and effective option, but there is little known about the outcomes related to the etiology of the HCC. The purpose of this study is to characterize the rates of toxicity and efficacy between different HCC etiologies in patients who were treated with SBRT. A single institutional database was compiled of all patients with HCC who were treated with SBRT. Patients with HCC etiologies of HCV, alcoholic cirrhosis, or NASH cirrhosis who received SBRT and monitored with liver function tests and imaging (MRI or CT) and were not transplanted were included Demographic information, disease etiology, all treatment courses, lab values, radiologic response, and follow-up were collected on all patients. SPSS was used to analyze the data. Consecutive patients (n = 37, 43 courses of radiation) who received SBRT between 2013- January 2022 were included. Most patients were male (n = 32, 86.5%) and average age was 64.73 ± 7.42 years (range: 50-82 years). A majority of patients had either HCV or HCV and alcoholic cirrhosis (n = 28, 75.7%) and there were no baseline difference in child Pugh score, tumor size, or number of prior treatments. Most patients were treated with 50Gy/5 fx (n = 26, 70.3%) with 5 others being treated with 45Gy/5fx to meet mean liver constraints. Most patients had a decrease in ALT (n = 22, 59.5%) while almost half of patients had a decrease in AFP (n = 14, 48.3%) at average follow-up of 11.84 ± 5.35 months. There was a significant correlation between HCC etiology and change in bilirubin with patients with HCV being more likely to have increases in total bilirubin (χ2 (6) = 17.5, p < 0.01). Patients with HCV induced cirrhosis may be more fragile and have a significant increased risk of toxicity after SBRT based on total bilirubin changes. Most patients did have a decrease in ALT showing potential for some improvement in liver function with SBRT. However, almost half of patients have some biologic efficacy with SBRT independent of HCC etiology. Further studies should include looking at the biologic differences in the etiologies and what treatment liver-directed therapies may be best for each population.

SAT-444 - Imaging and biomarker thresholds to accurately diagnose NASH cirrhosis in a 180 patient biopsy confirmed cohort

SAT-444 - Imaging and biomarker thresholds to accurately diagnose NASH cirrhosis in a 180 patient biopsy confirmed cohort

An integrated analysis of fecal microbiome and metabolomic features distinguish non-cirrhotic NASH from healthy control populations.

There is great interest in identifying microbiome features as reliable noninvasive diagnostic and/or prognostic biomarkers for non-cirrhotic NASH fibrosis. Several cross-sectional studies have reported gut microbiome features associated with advanced NASH fibrosis and cirrhosis, where the most prominent features are associated with cirrhosis. However, no large, prospectively collected data exist establishing microbiome features that discern non-cirrhotic NASH fibrosis, integrate the fecal metabolome as disease biomarkers, and are unconfounded by BMI and age. Results from shotgun metagenomic sequencing performed on fecal samples prospectively collected from 279 US patients with biopsy-proven NASH (F1-F3 fibrosis) enrolled in the REGENERATE I303 study were compared to those from 3 healthy control cohorts and integrated with the absolute quantification of fecal bile acids. Microbiota beta-diversity was different, and BMI- and age-adjusted logistic regression identified 12 NASH-associated species. Random forest prediction models resulted in an AUC of 0.75-0.81 in a receiver operator characteristic analysis. In addition, specific fecal bile acids were significantly lower in NASH and correlated with plasma C4 levels. Microbial gene abundance analysis revealed 127 genes increased in controls, many involving protein synthesis, whereas 362 genes were increased in NASH many involving bacterial environmental responses (false discovery rate < 0.01). Finally, we provide evidence that fecal bile acid levels may be a better discriminator of non-cirrhotic NASH versus health than either plasma bile acids or gut microbiome features. These results may have value as a set of baseline characteristics of non-cirrhotic NASH against which therapeutic interventions to prevent cirrhosis can be compared and microbiome-based diagnostic biomarkers identified.

Ethnic disparities in waitlist outcomes of patients with nonalcoholic steatohepatitis listed for liver transplantation in the US.

NASH is the fastest-growing cause of liver cirrhosis and is the leading indication for liver transplantation (LT). However, significant racial and ethnic disparities in waitlist outcomes and LT allocation may unfairly disadvantage minorities. Our aim was to characterize racial and ethnic disparities in waitlist mortality and transplantation probability among patients with NASH. This is a retrospective analysis of the United Network for Organ Sharing registry data of LT candidates from January 1, 2000 to December 31, 2021. Outcomes analysis was performed using competing risk analysis with the Fine and Gray model. The multivariable adjustment was conducted, and mixed-effect regression was used to compare the model for end-stage liver disease scores at listing and removal. Of 18,562 patients with NASH cirrhosis, there were 14,834 non-Hispanic Whites, 349 African Americans, 2798 Hispanics, 312 Asians, and 269 of other races/ethnicities; African American (effect size: 2.307, 95% CI: 1.561-3.053, and p < 0.001) and Hispanic (effect size: 0.332, 95% CI: 0.028-0.637, p = 0.032) patients were found to have a significantly higher model for end-stage liver disease scores at the time of listing than non-Hispanic Whites. African Americans had a higher probability of receiving LT relative to non-Hispanic Whites (subdistribution HR: 1.211, 95% CI: 1.051-1.396, and p = 0.008). However, Hispanic race/ethnicity was associated with a lower transplantation probability (subdistribution HR: 0.793, 95% CI: 0.747-0.842, and p < 0.001) and increased waitlist mortality (subdistribution HR: 1.173, CI: 1.052-1.308, and p = 0.004) compared with non-Hispanic Whites. There are significant racial and ethnic disparities in waitlist outcomes of patients with NASH in the US. Hispanic patients are less likely to receive LT and more likely to die while on the waitlist compared with non-Hispanic Whites despite being listed with a lower model for end-stage liver disease scores.

Abstract 3968: Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells

Abstract Introduction: Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions. It is known to ameliorate various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and the conophylline-binding domain was determined by deletion mutation analysis. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. However, whether ARL6ip1 is involved in the mechanisms of various biological activities of conophylline has not been proven, since knockdown of ARL6ip1 has often failed to change the cellular phenotypes. Therefore, in the present research, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and studied the involvement and mechanism of ARL6ip1 in the anticancer activity of conophylline. Ran activity was measured by a pull-down assay with Ran-GTP antibody. Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cells as human colorectal cancer cells. Tumorigenicity was measured by soft agar colony formation. Cellular migration was measured by a wound healing assay and cell tracking analysis. Cellular invasion was measured by a Matrigel chamber assay. Results: Conophylline inhibited soft agar colony formation in HCT116 and DLD1 cells. It inhibited migration and invasion in HCT116 and DLD1 cells at nontoxic concentrations. Knockout of ARL6ip1 also decreased tumorigenicity, migration, and invasion in HCT116 and DLD1 cells. The mechanistic study was carried out with HCT116 cells. ARL6 and Ran are both G-proteins and are reported to interact with ARL6ip1. Although knockdown of ARL6 did not change the cell migratory activity, knockdown of Ran inhibited the migration. Conophylline inhibited the interaction of ARL6ip1 to Ran in the proximity ligation assay. Moreover, conophylline inhibited the Ran activity. Conclusion: CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline. It is likely that the anticancer activity of conophylline would be mediated by the ARL6ip1-Ran system. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer. Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3968.

Therapeutic Physical Exercise Programs in the Context of NASH Cirrhosis and Liver Transplantation: A Systematic Review.

In recent years, various physical exercise interventions have been developed with a view to reducing comorbidity and morbidity rates among patients with chronic diseases. Regular physical exercise has been shown to reduce hypertension and mortality in patients with type 2 diabetes. Diabetes and obesity are often associated with the development of nonalcoholic fatty liver disease, which can lead to liver fibrosis and then (in some cases) nonalcoholic steatohepatitis cirrhosis. We searched the literature for publications on personalized physical exercise programs in cirrhotic patients before and after liver transplantation. Eleven studies in cirrhotic patients and one study in liver transplant recipients were included in the systematic review, the results of which were reported in compliance with the preferred reporting items for systematic reviews and meta-analyses guidelines. The personalized physical exercise programs lasted for 6 to 16 weeks. Our review evidenced improvements in peak oxygen consumption and six-minute walk test performance and a reduction in the hepatic venous pressure gradient. In cirrhotic patients, personalized physical exercise programs improve quality of life, are not associated with adverse effects, and (for transplant recipients) might reduce the 90-day hospital readmission rate. However, none of the literature data evidenced reductions in the mortality rates before and after transplantation. Further prospective studies are needed to evaluate the benefit of long-term physical exercise programs in cirrhotic patients before and after liver transplantation.

635. Is Azole Prophylaxis in Liver Transplant Recipients Effective in Preventing Invasive Candidiasis in the Era of Emerging Resistance?

Abstract Background Antifungal prophylaxis (px) in liver transplant (LT) recipients reduces invasive candidiasis (IC) and its associated mortality. Studies from our institution (UPMC) and others have shown that targeted px was as effective as universal px. Antifungal resistance has emerged among Candida spp., with ∼7% of the bloodstream isolates tested at CDC resistant to fluconazole. We sought to determine if our targeted antifungal px in LT recipients remained effective in the era of rising azole resistance. Methods We performed a retrospective study of patients undergoing LT at UPMC between 11/2010 and 06/2021. IC episodes were included if they occurred within 6 months of transplant. IC was defined using EORTC/MSGERC criteria, 2020. CLSI’s M60 2nd edition was used for antifungal susceptibility interpretation. Px was with fluconazole or voriconazole, based on risk factors for yeast or mold infection, respectively (Fig. 1). Results 1065 patients (pts) underwent LT over the study period. The most common indications for LT were HCC and NASH cirrhosis. Thirty-four pts (3%) developed IC within six months. 74% and 65% of these pts had risk factors for yeast or mold infection at some point, respectively (Table 1). Twenty-five of 34 (73.5%) pts received antifungal px, with voriconazole most commonly. Sixteen pts with IC (47%) had living donor transplant, and 11 (32%) had Roux-en-Y anastomosis. Types of IC were intra-abdominal candidiasis in 19 (56%), fungemia in 11 (32%), and intra-abdominal IC with secondary fungemia in 4 (12%). Seventeen (50%) episodes were breakthrough (BT) IC (most BT occurred in the voriconazole group), eight (24%) developed after stopping px, and nine (26%) occurred in those without px (Table 2). C. albicans and C. glabrata were the most common species (Fig. 2). Sixteen isolates underwent susceptibility testing: 12% and 44% were resistant and S-DD to fluconazole (Fig. 2); none were resistant to voriconazole. Attributable mortality of IC was 8%. Conclusion Targeted antifungal px in LT recipients with fluconazole or voriconazole effectively prevented IC, even in the era of rising azole resistance among Candida spp. We recommend antifungal susceptibility testing for Candida spp. obtained from infected sites to guide antifungal therapy. Disclosures Fernanda P. Silveira, MD, Ansun: Grant/Research Support|Janssen: Honoraria|Merck: Grant/Research Support|Novartis: Grant/Research Support|Regeneron: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Grant/Research Support.

COVID-19 Alcoholic Cirrhosis and Non-Alcoholic Steatohepatitis Cirrhosis Outcomes among Hospitalized Patients in the United States: Insight from National Inpatient Sample Database.

Patients with co-morbidities like cirrhosis are at risk of worse outcome from COVID-19 infection. Given limited prior studies, we evaluated outcomes associated with COVID-19 infection in alcoholic and non-alcoholic steatohepatitis cirrhotic (CC+) versus cirrhotic without COVID-19 (CC−). We performed retrospective analysis of 822,604 patients including 28,610 COVID-19 patients from the National Inpatient Sample database with alcoholic and NASH cirrhosis enrolled between 1 January 2020 to 31 December 2020, with univariate and multivariate regression analyses. Primary outcome was mortality and secondary outcomes was mechanical ventilation, vasopressor use, length of stay, hospitalization expense and predictors of mortality. In-hospital mortality was three time higher in the CC+ group compared to those in the CC− group(18.6% vs. 5.96%, p < 0.001, adjusted odds ratio (OR)3.39 (95% 3.08−3.74 CI). Hospitalization was more likely for underrepresented racial and ethnic groups with COVID-19 and cirrhosis. CC+ group had over twice the rates of mechanical ventilation (19.92% vs. 9.07%, adjusted OR 2.71 2.71 (95% 2.51−2.93 CI)),1.7 times likelihood of receiving vasopressors (4.12% vs. 2.45%, p < 0.001, adjusted OR 1.71 (95% CI 1.46−2.01). COVID-19 is associated with increased mortality in patients with alcoholic and NASH cirrhosis, and patients with alcoholic cirrhosis and COVID-19 have a slightly higher mortality compared to NASH cirrhosis.

ODP436 Adrenal Insufficiency After Combined Treatment of Itraconazole and Triamcinolone

Abstract Introduction Adrenal insufficiency (AI) has been reported due to the use of budesonide and itraconazole. We report an unusual presentation of adrenal insufficiency from the use of triamcinolone and itraconazole. Clinical Case 46-year-old man with a history of NASH and alcoholic cirrhosis requiring liver transplant presented to ER with two weeks of progressive lower extremity weakness. He reported difficulty climbing stairs and getting up from a chair. He denied anorexia, nausea, vomiting, abdominal pain, or lightheadedness. He was treated with itraconazole for diffuse histoplasmosis for over one year and received one dose of intra-articular triamcinolone 40mg for shoulder pain 2 weeks prior to the hospital admission. Physical exam was significant for proximal weakness, ecchymoses on upper and lower bilateral extremities, mild truncal obesity, but no violaceous striae, moon facies, dorsocervical fat pad or supraclavicular fullness. Laboratory evaluation was notable for sodium 129 mEq/L (n: 135-145), potassium 5.9 mEq/dl (n: 3.5-5), albumin 2.9 g/dl (n: 3.5-5) and glucose 345 mg/dl (n: 70-140), ACTH of 6 pg/ml (6-20) AM cortisol of &amp;lt;1 ug/dl (n: 4-20), aldosterone &amp;lt;1 ng/dl (n: 3-16), and plasma renin activity (PRA)20.54 ng/mL/h (n: 0.25-5.82). Serum cortisol increased to 3.4 ug/dl at 60 minutes of cosyntropin stimulation test, consistent with adrenal insufficiency. Synthetic glucocorticoid panel detected triamcinolone. Patient was discharged on hydrocortisone and fludrocortisone with marked clinical improvement. Abdominal MRI 3 months after admission did not show any adrenal involvement by histoplasmosis. Fludrocortisone was slowly titrated off and only hydrocortisone continued. Repeat evaluation 6 months after last triamcinolone injection demonstrated recovery of HPA axis with peak cosyntropin stimulation cortisol level 16.3 ug/dL (assay by Abbott Alinity) and recovery of renin/angiotensin/aldosterone axis (AM aldosterone 7 ng/dl, renin 2 ng/ml/h). Repeat synthetic glucocorticoid testing confirmed clearance of triamcinolone. Conclusion Itraconazole is CYP3A inhibitor that has been shown to decrease the metabolism and clearance of different corticosteroids. While our patient's lab results supported a diagnosis of AI, it was unclear if the etiology was primary (PAI) or central AI (CAI). The Na+, K+, aldosterone and PRA levels support a diagnosis of PAI; whereas the suppressed ACTH level supports CAI. We believe that our patient had an atypical presentation of both PAI due to histoplasmosis and CAI due to itraconazole/triamcinolone. This confounding picture can potentially be explained by an underlying PAI that may have been masked and exacerbated by the HPA axis suppression of the itraconazole/triamcinolone combination. Presentation: No date and time listed

Approach to the Patient With Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes (T2D), causing substantial burden from hepatic and extrahepatic complications. However, endocrinologists often follow people who are at the highest risk of its more severe form with nonalcoholic steatohepatitis or NASH (i.e., T2D or obesity with cardiometabolic risk factors). Endocrinologists are in a unique position to prevent cirrhosis in this population with early diagnosis and treatment. This work aims to offer endocrinologists a practical approach for the management of patients with NAFLD, including diagnosis, fibrosis risk stratification, and referral to hepatologists. (1) An asymptomatic patient with obesity and cardiometabolic risk factors, found to have hepatic steatosis; (2) a patient with T2D and NASH with clinically significant liver fibrosis; and (3) a liver transplant recipient with a history of NASH cirrhosis, with significant weight regain and with recurrent NAFLD on the transplanted organ. NASH can be reversed with proper management of obesity and of T2D. While no agents are currently approved for the treatment of NASH, treatment should include lifestyle changes and a broader use of structured weight-loss programs, obesity pharmacotherapy, and bariatric surgery. Diabetes medications such as pioglitazone and some glucagon-like peptide 1 receptor agonists may also improve liver histology and cardiometabolic health. Sodium-glucose cotransporter-2 inhibitors and insulin may ameliorate steatosis, but their effect on steatohepatitis remains unclear. Awareness by endocrinologists about, establishing an early diagnosis of fibrosis (ie, FIB-4, liver elastography) in patients at high-risk of cirrhosis, long-term monitoring, and timely referral to the hepatologist are all critical to curve the looming epidemic of cirrhosis from NAFLD.