Nonalcoholic Steatohepatitis Cirrhosis Research Articles

Impact of living donor liver transplantation on long-term cardiometabolic and graft outcomes in cirrhosis due to nonalcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a leading indication for liver transplantation (LT). This study aimed to determine whether living donor LT (LDLT) recipients experienced less recurrent NASH, cirrhosis, and cardiometabolic complications compared to deceased donor LT (DDLT). Patients with LDLT and DDLT for NASH between February 2002 and May 2018 at University Health Network (UHN) were compared. Cox Proportional Hazard model was used to analyze overall survival (OS), Fine and Gray's Competing Risk models were conducted to analyze cumulative incidence of post LT outcomes. One hundred and ninety-nine DDLTs and 66 LDLTs were performed for NASH cirrhosis. Time and rate of recurrence of NAFLD and NASH were comparable in both groups. Graft cirrhosis was more common in DDLT recipients (n=14) versus LDLT (n=0) (p<.0001). Significant fibrosis (Fibrosis≥F2) developed in 50 recipients (12 LDLT and 38 DDLT) post LT (DDLT vs. LDLT: HR=1.00, 95% CI=(.52-1.93), p=.91) and there was no difference in time to significant fibrosis (p=.57). There was no difference in development of post-transplant diabetes, dyslipidemia, metabolic syndrome, cardiovascular disease, and cancers. LDLT group had better renal function at 10years (MDRD eGFR of 57.0mL/min vs. 48.5mL/min, p=.047). Both groups had a comparable OS (HR=1.83 (95% CI=.92-3.62), p=.08). Overall, LDLT recipients had significantly better renal function by virtue of having early transplantation in their disease course. LDLT was also associated with significantly less graft cirrhosis, although OS and cardiometabolic outcomes were comparable between LDLT and DDLT.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Discovery of Core-Fucosylated Glycopeptides as Diagnostic Biomarkers for Early HCC in Patients with NASH Cirrhosis Using LC-HCD-PRM-MS/MS.

Aberrant changes in site-specific core fucosylation (CF) of serum proteins contribute to cancer development and progression, which enables them as potential diagnostic markers of tumors. An optimized data-dependent acquisition (DDA) workflow involving isobaric tags for relative and absolute quantitation-labeling and enrichment of CF peptides by lens culinaris lectin was applied to identify CF of serum proteins in a test set of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis (N = 16) and hepatocellular carcinoma (HCC, N = 17), respectively. A total of 624 CF peptides from 343 proteins, with 683 CF sites, were identified in our DDA-mass spectrometry (MS) analysis. Subsequently, 19 candidate CF peptide markers were evaluated by a target parallel reaction-monitoring-MS workflow in a validation set of 58 patients, including NASH-related cirrhosis (N = 29), early-stage HCC (N = 21), and late-stage HCC (N = 8). Significant changes (p < 0.01) were observed in four CF peptides between cirrhosis and HCC, where peptide LGSFEGLVn160LTFIHLQHNR from LUM in combination with AFP showed the best diagnostic performance in discriminating HCC from cirrhosis, with an area under curve (AUC) of 0.855 compared to AFP only (AUC = 0.717). This peptide in combination with AFP also significantly improved diagnostic performance in distinguishing early HCC from cirrhosis, with an AUC of 0.839 compared to AFP only (AUC = 0.689). Validation of this novel promising biomarker panel in larger cohorts should be performed.

Predicting the outcome of liver transplantation in patients with non-alcoholic steatohepatitis cirrhosis: The NASH LT risk-benefit calculator.

Non-alcoholic Steatohepatitis (NASH) cirrhosis is the second most common indication for liver transplantation (LT) in the US and often is associated with significant co-morbidities. We validated a model and risk prediction score that reflects the benefit derived from LT for NASH cirrhosis by predicting 5-year survival post-LT. We developed a prediction score utilizing 6515 NASH deceased donor LT (DDLT) recipients from 2002 to 2019 from the Scientific Registry of Transplant Recipients (SRTR) database to identify a parsimonious set of independent predictors of survival. Coefficients of relevant recipient factors were converted to weighted points to construct a risk scoring system that was then externally validated. The final risk score includes the following independent recipient predictors and corresponding points: recipient age (5 points for age ≥70 years), functional status (3 points for total assistance), presence of TIPSS (2 points), hepatic encephalopathy (1 point), serum creatinine (5 points if>1.45mg/dl), need for mechanical ventilation (3 points), and dialysis within 1 week prior to LT (7 points). Diabetes is a stratifying variable for baseline risk. Scores range from 0 to 20 with scores above 13 having an overall survival of<65% at 5 years post-LT. Internal and external validation indicated good predictive ability. Our practically useable and validated risk score helps to identify and stratify candidates who will derive the most long-term benefit from LT for NASH cirrhosis.

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.

Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis.

In cirrhotic nonalcoholic steatohepatitis (NASH) clinical trials, primary efficacy endpoints have been hepatic venous pressure gradient (HVPG), liver histology and clinical liver outcomes. Important histologic features, such as septa thickness, nodules features and fibrosis area have not been included in the histologic assessment and may have important clinical relevance. We assessed these features with a machine learning (ML) model. NASH patients with compensated cirrhosis and HVPG ≥6 mm Hg (n=143) from the Belapectin phase 2b trial were studied. Liver biopsies, HVPG measurements and upper endoscopies were performed at baseline and at end of treatment (EOT). A second harmonic generation/two-photon excitation fluorescence provided an automated quantitative assessment of septa, nodules and fibrosis (SNOF). We created ML scores and tested their association with HVPG, clinically significant HVPG (≥10 mm Hg) and the presence of varices (SNOF-V). We derived 448 histologic variables (243 related to septa, 21 related to nodules and 184 related to fibrosis). The SNOF score (≥11.78) reliably distinguished CSPH at baseline and in the validation cohort (baseline + EOT) [AUC=0.85 and 0.74, respectively]. The SNOF-V score (≥0.57) distinguished the presence of varices at baseline and in the same validation cohort [AUC=0.86 and 0.73, respectively]. Finally, the SNOF-C score differentiated those who had >20% change in HVPG against those who did not, with an AUROC of 0.89. The ML algorithm accurately predicted HVPG, CSPH, the development of varices and HVPG changes in patients with NASH cirrhosis. The use of ML histology model in NASH cirrhosis trials may improve the assessment of key outcome changes.

Expression of Integrin β1, Focal Adhesion Kinase, and PDZ-Binding Motif in Human Liver Cirrhosis and Simple Steatosis

Background: Integrins are transmembrane mechanosensitive proteins that negatively contribute to the pathogenesis of different types of chronic liver disease and can activate focal adhesion kinase (FAK). Objectives: This study aimed to determine the hepatic integrin β1 and FAK mRNA as well as the transcriptional coactivator with PDZ-binding motif (TAZ) protein expressions in cirrhotic patients and simple steatosis. Methods: In this case–control study, liver tissues were collected from 30 cirrhotic patients with various etiologies (i.e., nonalcoholic steatohepatitis-, primary sclerosing cholangitis-, alcoholic-, autoimmune hepatitis [AIH]- and hepatitis B virus [HBV]/hepatitis C virus [HCV]-related cirrhosis [six per group]), liver samples with simple steatosis (n=6), and control liver tissues (n=9). Results: Integrin β1 gene expression was significantly up-regulated in all cirrhotic groups compared to control group (P&lt;0.05), with the exception of AIH cirrhosis. However, hepatic FAK gene expression and TAZ protein level in the cirrhotic groups were not significantly different than those in the control group. Furthermore, hepatic integrin β1 and FAK gene expressions as well as TAZ protein level in simple steatosis were significantly lower than those in nonalcoholic steatohepatitis (NASH) cirrhosis and control (P&lt;0.05). Conclusion: Integrin β1 was up-regulated in cirrhotic liver tissues. In addition, FAK, integrin β1, and TAZ were concordantly down-regulated in simple steatosis, and may have been involve in the steatosis development.

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.

Does Non-Alcoholic Steatohepatitis Independently Increase the Risk of Venous Thromboembolism?

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Studies have shown a strong association between NASH (non-alcoholic steatohepatitis) cirrhosis and portal vein thrombosis (PVT). Data is scarce on the association of NASH and venous thromboembolism (VTE), with one such study predicting a 2.5-fold increased risk for VTE in comparison to other liver diseases in hospitalized patients. The mechanism is believed to be hepatocellular injury causing a chronic inflammatory state leading to unregulated activation of procoagulant factors. There is no prior analysis of the degree of steatosis and fibrosis (measured on transient elastography, commonly known as Fibroscan®) in NASH patients and its association with VTE. We performed an analysis to study the risk of unexplained VTE in patients with NASH. Methods: In our case-control study, we included patients with a documented diagnosis of NASH and excluded patients with inherited thrombophilia, hemoglobinopathy, malignancy, alcohol use disorder, autoimmune hepatitis, and primary biliary cirrhosis. Collected data included age, tobacco use, recreational drug use, medical history, and vibration-controlled transient elastography (VCTE) scores. Venous thromboembolism specific data included location, type of anticoagulant, need for hospital stay, and history of VTE recurrence. Steatosis was categorized as S0-S1 (mild) and S2-S3 (moderate to severe) based on the controlled attenuation parameter (CAP) score. Fibrosis was classified based on the kilopascal(KPA) score and graded as F0-F1 (metavir stage), F2, F3, and F4(cirrhosis). Chi-square and Mann-Whitney U tests were used for qualitative and quantitative variable analysis, respectively. Furthermore, we computed logistic regression using VTE as a dependent variable. Results: A total of 415 patients were analyzed, and 386 met the inclusion criteria (Figure 1). Fifty-one patients were in the VTE group and 335 in the non-VTE group. Patients with VTE had a mean age of 60.63 years compared to 55.22 years in the non-VTE group (p=0.014). Patients with VTE had a higher body mass index (31.14 kg/m² vs. 29.30 kg/m²) and a higher prevalence of diabetes mellitus (29.4% vs. 13.1%, p=0.002). The history of NASH was significantly higher in the VTE group (45.1% vs. 30.4%, p=0.037). Further, moderate to severe steatosis was significantly higher in the VTE group (66.7% vs. 47.2%, p=0.009). Similarly, the F2-F4 fibrosis grade had a higher prevalence of 58.8 % in the VTE group compared to 38.5% in the non-VTE group (p=0.006) (Table 1). On logistic regression, using VTE as a dependent variable, diabetes mellitus type II had an OR =1.702 (p = 0.015) and F2-F4 fibrosis grade had an OR = 2.5 (p=0.033). In the VTE group, 58.8% had deep vein thrombosis (DVT), 17.6 % had superficial venous thrombosis (SVT), 13.7 % had pulmonary embolism (PE), 5.9% had portal vein thrombosis, and embolic stroke (3.9%). The most common location of VTE was the lower extremity (56.9%), followed by the upper extremity (19.6%). Right-sided VTE (66.7%) was more common and a majority of patients (74.5%) required hospital admission with 2% requiring ICU admission. Concerning anticoagulation 64.71% of patients were on direct oral anticoagulants (DOAC), 25.5% were on warfarin, and 84.3% of patients continued indefinite anticoagulation. Discussion: Our analysis shows that NASH is an independent risk factor for VTE, especially DVT. Demographics including gender, tobacco use, alcohol consumption, and ethnicity, were equally distributed between the two groups. There is a statistically significant association between the incidence of VTE and moderate to severe steatosis and fibrosis. The current management strategy for NASH includes abstinence from alcohol and intense lifestyle modification to lose weight. Newer medications like glucagon-like peptides (semaglutide) and bariatric surgery are other recommended modalities for weight loss. All hospitalized patients should be considered for medical thromboprophylaxis, particularly in those with NASH, where a high index of suspicion for VTE should be maintained even in the presence of thromboprophylaxis. Additional studies are needed to analyze the risk of bleeding in this patient population who continue indefinite anticoagulation. Another area of interest would be to determine the reversibility of VTE risk with appropriate management of NAFLD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ODP047 Intramuscular ACTH stimulation test in a patient with liver disease

Abstract Introduction High dose (250 mcg) ACTH stimulation test is the gold standard dynamic testing to diagnose primary adrenal insufficiency (PAI). While the current guidelines do not elaborate on the preferable route of administration of corticotropin (intravenous or intramuscular), most published studies have been conducted on healthy people using the intravenous route. We present a patient with non-alcoholic steatohepatitis cirrhosis and hypotension who was thought to have suboptimal response with intramuscular ACTH stimulation test. Case 62-year-old male with cirrhosis, presented with dizziness, and was found to be hypotensive. Lab tests showed normal cell counts, electrolytes, renal function and lactic acid. His albumin was 2.6 g/dL. His blood pressure did not improve with intravenous fluids. Workup initiated for adrenal insufficiency showed 8 am cortisol level of 7. 0 mcg/dL, and ACTH level of 26 pg/mL. He underwent ACTH stimulation test with 250 mcg intramuscular cosyntropin, after which the 30-minute cortisol level was 13.7 mcg/dL and the 60-minute level was 15.1 mcg/dL (level immediately before the test 7.2 mcg/dL). Due to the patient not having signs of adrenal insufficiency and low albumin level due to liver disease, the cortisol response was considered adequate. Discussion Per the current Endocrine Society Clinical Practice Guidelines, the standard method of performing the ACTH stimulation test involves measuring baseline cortisol level, administration of 250 mcg of cosyntropin, and then measuring cortisol level 30 and 60 minutes post administration. Traditionally, an appropriate response is characterized by peak cortisol level above 18 mcg/dL, with lower values indicative of AI. While the responses can vary due to multitude of factors including time of testing etc., the individual response to the intravenous versus intramuscular injections is similar. However, the cut-off points between the two administration methods may differ. In a study on 64 healthy adult men who were administered 250 mcg cosyntropin intramuscularly, Longui et al. demonstrated lower cut-off values of 12.6 mcg/dL and 16.3 mcg/dL at 30 and 60 minutes respectively. In addition, with the introduction of newer monoclonal antibody and LC-MS/MS assays having greater specificity for cortisol, a study by Jarvosky et. al. recommends a new lower cut-off of 14-15 mcg/dL. Furthermore, several studies have shown higher prevalence of low total cortisol levels in cirrhosis and other liver disease leading to overdiagnosis of PAI, due to deficiency of cortisol binding globulin and albumin. In our patient, we hypothesize that the combination of all these factors could have caused a falsely low cortisol peak level without any underlying PAI. Our case highlights the need for additional studies on patients with underlying liver disease and hypoalbuminemia who undergo testing with intramuscular cosyntropin administration, and analysis with the new assays available. Presentation: No date and time listed

S1336 Role of FIB-4 Score in Predicting Risk of Hepatocellular Carcinoma in Patients With Cirrhosis due to Nonalcoholic Steatohepatitis

Introduction: Hepatocellular carcinoma (HCC) represents the main cause of death in patients with nonalcoholic steatohepatitis (NASH) cirrhosis and is a leading indication for liver transplantation. Identification of high-risk patients for HCC is essential for long term monitoring of disease progression, early detection, and effective intervention. Fibrosis-4 (FIB-4) is a noninvasive index of readily available laboratory measurements and is widely validated for predicting cirrhosis and HCC. We sought to determine if FIB-4 score is associated with high risk of HCC among patients with NASH cirrhosis. Methods: We conducted a retrospective cohort study of adult patients with NASH cirrhosis (n=1,441) who were evaluated at our medical center between 2005 and 2015. Those who developed HCC were identified via ICD codes until the end of September 2021. At day of index NASH cirrhosis diagnosis, clinical and biochemical measurements were recorded on each patient. Descriptive statistics were calculated for all factors. Kaplan-Meier analysis was performed to evaluate time to HCC event. Cox regression models were used to evaluate associations between HCC and factors of interest. Models were adjusted for age, sex, number of comorbidities, and laboratory values. Results: During a median follow-up time of 8.3 years, 218 (15%) patients with NASH cirrhosis developed HCC. At index visit, the study population had a median age 57 years, 44% males, 78.6% White, median BMI 31.5 kg/m2, 26.7% had diabetes mellitus, 10.4% current smokers, mean FIB-4 score 4.2, and mean MELD score 8.1. Multivariable Cox regression models revealed that age, sex, race/ethnicity, BMI and FIB-4 were independent factors associated with development of HCC in patients with NASH cirrhosis (Table). Compared to patients with FIB-4 < 1.45, patients with FIB-4 between 1.45-3.25 had a similar risk of HCC (95% CI: 0.61-1.86, p=0.82). Patients with FIB-4 > 3.25 had a 2.51 (95% CI: 1.53-4.12, p< 0.001) increased hazard of HCC (Figure). Conclusion: Age, sex, race/ethnicity, BMI and FIB-4 were independently associated with HCC in NASH cirrhosis. We found that FIB-4 > 3.25 was an independent predictor of HCC risk. Providers should pay attention to FIB-4 for long term monitoring of disease progression. An inexpensive, available, validated marker like FIB-4 is a promising tool for identification of high-risk patients and may be used in routine clinical practice as a simple screening strategy for HCC risk in patients with NASH cirrhosis.Figure 1.: Kaplan-Meier estimates of developing HCC in patients with NASH cirrhosis by FIB-4 score within 5 years of follow up Table 1. - Factors Associated with HCC in NASH Cirrhosis: Univariate and Multivariable Analyses Univariate Multivariable Factors Unadjusted Hazard Ratio (95% Confidence Interval) p-value Adjusted Hazard Ratio (95% Confidence Interval) p-value Age group, yrs <49 1 [reference] 1 [reference] >49-59 1.40 (0.96-2.04) 0.08 1.22 (0.74-2.04) 0.43 >59-69 2.13 (1.47-3.11) 0.000 1.72 (1.02-2.90) 0.04 >69 4.26 (2.66-6.80) 0.000 3.03 (1.57-5.88) 0.001 Sex Female 1 [reference] 1 [reference] Male 2.13 (1.62-2.8) 0.000 2.00 (1.37-2.91) 0.000 Race and ethnicity Hispanic 0.72 (0.29-1.7) 0.46 0.42 (0.10-1.74) 0.23 Non-Hispanic White 1 [reference] 1 [reference] Black 0.62 (0.42-0.91) 0.01 0.70 (0.43-1.13) 0.15 Other* 0.59 (0.19-1.8) 0.36 0.50 (0.12-2.06) 0.34 BMI, Kg/m2 0.989 (0.97-1.01) 0.24 BMI category, Kg/m2 < 18.5 0.95 (0.22-4.16) 0.95 1.52 (0.34-6.85) 0.59 18.5–24.9 1 [reference] 1 [reference] 25.0–29.9 1.73 (0.96-3.11) 0.07 1.69 (0.89-3.20) 0.11 30.0–34.9 1.49 (0.81-2.7) 0.20 1.46 (0.76-2.81) 0.26 35.0–39.9 1.59 (0.83-3.02) 0.16 1.63 (0.82-3.26) 0.16 >40 0.95 (0.47-1.91) 0.89 1.16 (0.53-2.50) 0.71 Diabetes 0.76 (0.55-1.06) 0.11 Total cholesterol, mg/dL 125-200 1 [reference] >200 0.78 (0.39-1.6) 0.50 LDL, mg/dL < 130 1 [reference] >130 0.42 (0.17-1.01) 0.05 MELD score <20 1 [reference] >20 1.14 (0.60-2.16) 0.68 FIB-4 score < 1.45 1 [reference] 1 [reference] 1.45-3.25 1.22 (0.79-1.9) 0.37 1.07 (0.61-1.86) 0.82 > 3.25 2.74 (1.89-3.97) 0.000 2.51 (1.53-4.12) 0.000 Albumin, g/dL 0.685 (0.566-0.828) 0.000 INR 1.52 (1.19-1.95) 0.001 Creatinine, mg/dL 0.91 (0.77-1.07) 0.26 Total Bilirubin, mg/dL 1.04 (1.01-1.07) 0.01 Platelet count, ×109/L 0.997 (0.996-0.999) 0.001 *Other category included Asian, American Indian-Alaskan or other.

S3302 Acute Esophageal Obstruction: An Uncommon Complication of Variceal Ligation Treated With Band Removal and Stenting

Introduction: Esophageal varices (EV) are a complication of portal hypertension. Over time, EV enlarge and may spontaneously rupture, leading to bleeding and possibly death with a high mortality rate of up to 20%. Esophageal variceal ligation (EVL) is used for prophylaxis, as well as treatment of acute variceal bleeding with the goal of eradicating varices. EVL is an effective therapy with rare but serious complications including bleeding, ulcers, strictures, and rarely acute obstruction. Amongst the few reported cases of esophageal obstruction, treatment has varied but mostly involved conservative management or band removal. We present a case of post EVL acute esophageal obstruction that was uniquely treated with band removal and esophageal stenting. Case Description/Methods: A 79yo female with nonalcoholic steatohepatitis cirrhosis and a MELD-Na of 12, complicated by portal hypertension and EV status post previous banding one year prior came to the emergency room two days after esophagogastroduodenoscopy (EGD) for routine EV surveillance with placement of two bands resulting in complete eradication. She presented with one episode of hematemesis and dysphagia to liquids, and regurgitation; denied odynophagia and chest pain. Hematologic parameters were at baseline. EGD revealed near-complete occlusion of the esophagus from banding at 40cm from the incisors (fig1). One band was dislodged with the gastroscope, which permitted the obstructed area to be traversed after downsizing the gastroscope. No active bleeding was evident. To prevent recurrent bleeding given hematemesis at presentation, the area of obstruction was stented with a 16mm x 100mm fully covered stent (fig2), proximal and distal margins at 30cm and 40cm respectively. She was discharged home after 24 hours able to tolerate soft foods. The stent was kept for seven days. At follow-up EGD for stent removal, there was slight luminal narrowing treated with graded balloon dilation from 18mm to 20mm. She continued to do well and nine months later had EGD surveillance with banding of grade II varices only. Discussion: Acute esophageal obstruction, though rare, is a complication of variceal banding that should be considered in patients with dysphagia after banding. This is a case that required innovative thinking and priority to treatment options that provide hemostasis while relieving obstruction in a cirrhotic patient with a high risk of bleeding.Figure 1.: 1. Near complete occlusion of esophagus Fig 2. After placement of esophageal stent.

S1243 Epidemiology of Hepatocellular Carcinoma (HCC) in a Canadian University Centre

Introduction: Nearly 85% of HCC cases are reported in Asia and Saharan Africa. This explains why data on risk factors often concerns Asian populations. In fact, hepatitis B and C are among the major risk factors leading to HCC in current literature. We believe our predominant Caucasian population might not be the same given the different incidence of Non-Alcoholic Steatohepatitis (NASH) or alcoholic cirrhosis compared to these countries. In this study, we evaluated the prevalence of risk factors of HCC in our Canadian population in order to prevent and identify the best treatments for our population. Since the cause leading to HCC might modify management in the future, it becomes interesting to describe the epidemiology of our population. Methods: We retrospectively reviewed 196 files of patients 18 years of age and older diagnosed with HCC by radiological or pathological criteria between 2010 and 2020 from two of our university databases (Registre Local du Cancer and Ned-Écho). The prevalence of cirrhosis, hepatitis B, hepatitis C, alcoholic cirrhosis and NASH were presented using proportion with the Wilson method using 95% confidence interval. Z tests were used to compare the prevalence of our population’s HCC risk factors with the literature values. Finally, a Cox model was used to assess the risks factors contributing most to mortality. Results: 178 patients were included in our study. 94.9% of our population was Caucasian. 83.1% were male.19.6% did not have an underlying cirrhosis. Only 59.6% had a CHILD A cirrhosis limiting accessibility to treatment. Furthermore, the prevalence of hepatitis B was 4.7% compared to 33% in current literature (p< 0.001), hepatitis C was 25.1% compared to 21% (p =0.183), alcoholism was 45.0% compared to 30% (p< 0.001), NASH was 37.8% compared to less than 16% (p=0.002). There was no statistical difference in mortality by cancer risk factor. Conclusion: New evidence suggest that HCC related to NASH may be a favourable prognostic factor in patients treated with lenvatinib. Hence, the choice of a tyrosine kinase treatment might be better for the management of a Caucasian population. Promoting good lifestyle habits might also reduce the incidence of HCC in our Canadian population given the high prevalence of HCC related to NASH and alcoholic cirrhosis. Finally, approximatively half of our population had a CHILD A cirrhosis which emphasizes how crucial it is to adequately screen for HCC before cirrhosis progression as this will have an effect on management and prognostic.

S1253 Dual Therapy With Metformin and Sodium Glucose Co-Transporter-2 Inhibitors (SGLT2-i) Improves Mortality in Cirrhotic Patients

Introduction: Diabetes mellitus (DM) is a common comorbidity of cirrhosis, but there is limited research on the impact of dual diabetes therapy on mortality and hepatic decompensation in cirrhosis, particularly in non-alcoholic fatty liver disease (NAFLD). Methods: We did propensity score-matched analyses of DM patients with cirrhosis comparing those on metformin with those on both metformin and an GLP1-RA. We queried for people with both Type 2 DM (DM2) and cirrhosis using ICD-10 codes on the TriNetX network. We collected patient demographics—age, sex, race, among others—and our primary outcome was mortality in three years. Our secondary outcome was a composite of hepatic decompensation events over three years. Results: We identified 841 patients with cirrhosis and DM2 who were on both metformin and an SGLT2-i. This cohort included 547 Whites (65.0%), 373 women (44.4%), had a mean age of 63.8 years, and was matched with a baseline group of patients who were on metformin alone (Table). The monotherapy group had a greater mortality risk (RR 2.0, 95%CI 1.4-2.8, p< 0.0001) with survival probability 82.6% at 3 years compared to the dual therapy group (91.1%, p< 0.0001). We also identified a subset of 116 patients within the dual therapy group that was confirmed to have cirrhosis from non-alcoholic steatohepatitis (NASH) and that included 85 Whites (73.7%), 63 women (54.2%), and had a mean age of 60.8 years. When comparing the NASH cohorts, they had equivalent mortality risk (RR 1.0, 95%CI 0.4-2.3, p=1), though survival at 3 years was shorter for the monotherapy group (90.9% vs. 97.1%, p=0.04). The composite risk for hepatic decompensation was equivalent between both therapy groups (Figure). Conclusion: We found a potential mortality benefit in cirrhosis patients on dual DM2 therapy with metformin and SGLT2-i compared to metformin alone that was durable over a 3-years and within a subset of NASH patients. This finding was consistent for men, women, White, and non-White patients in our matched cohort analyses. There was no clear effect on the composite risk for hepatic decompensation, so improved mortality maybe be due to beneficial effects on the patients’ comorbidities rather than on their liver issues. There may be underreporting of NASH patients in the database since our analysis relied in part on patients’ having ICD-10 codes (K76.0, K75.8). Further prospective studies in patients with biopsy-confirmed NASH and from underrepresented populations are needed to investigate our outcomes. Table 1. - Baseline Cohort Demographics after Propensity Score Matching (All Cirrhosis and NASH Cirrhosis Patients) Demographics (All Cirrhosis Patients) Metformin Only (n=841) Metformin + SGLT2-i (n=841) Mean Age (Years) 63.5 63.8 Men (n, %) 457 (54.3) 468 (55.6) Women (n, %) 384 (45.7) 373 (44.4) White (n, %) 553 (65.8) 547 (65.0) Black/LatinX/Other (n, %) 288 (34.2) 294 (35.0) Demographics (NASH Cirrhosis Patients) Metformin Only (n=116) Metformin + SGLT2-i (n= 116) Mean Age (Years) 60.3 60.8 Men (n, %) 46 (37.2) 53 (45.8) Women (n, %) 70 (62.8) 63 (54.2) White (n, %) 86 (76.1) 85 (73.7) Black/LatinX/Other (n, %) 22 (14.9) 24 (20.3) SGLT2-i=Sodium-Glucose Co-Transporter-2 Inhibitor; NASH=Non-Alcoholic Steatohepatitis. Figure 1.: 3 Year Cumulative Incidence; Purple=Patients treated with metformin; Green=Patients treated with metformin and an SGLT2-i; A - 3 Year All-Cause Mortality in DM Cirrhosis Patients; B - 3 Year All-Cause Mortality in DM Cirrhosis Patients; C - 3 Year All-Cause Mortality in DM NASH Cirrhosis Patients

A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis

Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Patients with NASH and stage 4 fibrosis (n= 30) were randomized 2:1 to receive efruxifermin 50mg (n= 20) or placebo (n= 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n= 7, 23.3%) or grade 2 (n= 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB]-9μg/L efruxifermin vs.-3.4μg/L placebo; p= 0.0130) and ELF score (-0.4 efruxifermin vs.+0.4 placebo; p= 0.0036), with a trend towards reduced liver stiffness (LSMCFB-5.7kPa efruxifermin vs.-1.1kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. NCT03976401.

Treatment of Nonalcoholic Steatohepatitis by Obeticholic Acid: Current Status.

Roy PP, Mahtab MA, Rahim MA, et al. Treatment of Nonalcoholic Steatohepatitis by Obeticholic Acid: Current Status. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S46-S50.

Divergent trajectories of lean vs obese non-alcoholic steatohepatitis patients from listing to post-transplant: A retrospective cohort study.

BACKGROUNDNon-alcoholic steatohepatitis (NASH) cirrhosis is the second most common indication for liver transplantation (LT). The role of body mass index (BMI) on outcomes of NASH cirrhosis has been conflicting.AIMTo compare the longitudinal trajectories of patients with lean vs obese NASH cirrhosis, from listing up to post-transplant, having adjusted their BMI for ascites.METHODSWe retrospectively reviewed all adult NASH patients listed for LT in our program from 2012 to 2019. Fine-Gray Competing Risk analyses and Cox Proportional-Hazard Models were performed to examine the cumulative incidence of transplant and survival outcomes respectively.RESULTSOut of 265 NASH cirrhosis listed patients, 176 were included. Median age was 61.0 years; 46% were females. 111 patients underwent LT. Obese robust patients had better waitlist survival [hazard ratio (HR): 0.12; 95%CI: 0.05–0.29, P < 0.0001] with higher instantaneous rate of transplant (HR: 5.71; 95%CI: 1.26–25.9, P = 0.02). Lean NASH patients had a substantially higher risk of graft loss within 90 d post-LT (1.2% vs 13.8%, P = 0.032) and death post-LT (2.4% vs 17.2%, P = 0.029). 1- 3- and 5-year graft survival was poor for lean NASH (78.6%, 77.3% and 41.7% vs 98.6%, 96% and 85% respectively). Overall patient survival post-LT was significantly worse in lean NASH (HR: 0.17; 95%CI: 0.03–0.86, P = 0.0142) with 83% lower instantaneous rate of death in obese group.CONCLUSIONAlthough lean NASH is considered to be more benign than obese NASH, our study suggests a paradoxical correlation of lean NASH with waitlist outcomes, and graft and patient survival post-LT.

Pre-transplant portal vein thrombosis in non-alcoholic fatty liver disease patients-pathogenesis, risk factors, and implications on management.

Along with the worldwide increase in obesity and metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and its more severe subset, non-alcoholic steatohepatitis (NASH), are on path to become the leading cause of liver transplantation in the United States. NAFLD, as well as obesity, create an inflammatory milieu via the release of adipocytokines. In turn, the inflammatory environment can trigger an increase in prothrombotic factors. Independent of inflammation, the severity of NASH is associated with a graded increase in hypercoagulability such as an increase in factor VIII, increase in plasminogen activator inhibitor-1, and decrease in protein C. Ultimately, this environment creates an increase in thrombotic risk, leading to higher rates of pre-transplant portal vein thrombosis (PVT) in patients with NASH cirrhosis vesus other causes of cirrhosis. Many studies have shown worse outcomes in liver transplant recipients with PVT as it complicates anastomotic reconstruction which can negatively affect portal blood supply needed for adequate liver functioning. Management and treatment of PVT is not standardized, but from a pharmacologic standpoint, multiple classes of anticoagulants have shown to be successful in recanalization of the portal vein and preventing recurrence of clot with minimal bleeding complications. The increasing prevalence of NASH cirrhosis and subsequent increase in PVT require further research for improved outcomes.

Intragastric Balloon in Obese Compensated Nonalcoholic Steatohepatitis Cirrhosis Patients Is Safe and Achieves Significant Weight Reduction at 6-Months.

Weight reduction is the mainstay treatment for Nonalcoholic steatohepatitis (NASH). intragastric balloon (IGB) placement has proven benefit in terms of weight reduction. The aim of the present study is to assess the safety and efficacy of IGB placement in compensated NASH cirrhosis. Nonalcoholic steatohepatitis cirrhosis patients with CTP ≤ 7, BMI of > 30, and who were unable to achieve weight reduction with lifestyle modification in past 3months were prospectively enrolled. Spatz3™ adjustable gastric balloon was placed endoscopically. Primary objective was to determine efficacy in weight loss at 6months, with secondary objectives of reduction in hepatic venous pressure gradient (HVPG), liver fat (controlled attenuation parameter, CAP), liver stiffness measurement (LSM) and clinical events as well as the tolerability and adverse events due to IGB placement. Altogether 56 cirrhosis patients, with a baseline BMI of 35.24 ± 3.92 and a CTP score of 6.27 ± 1.28 underwent IGB placement. The absolute weight reduction achieved was 15.88kg (- 16.46%) and reduction in BMI was - 10.1% at 6months. The percentage total body weight loss of ≥ 10% was achieved in 31 (55.35%) patients. The reduction in HVPG at 6-months was 11.12% (n = 16, 14.18 ± 2.12 to 12.60 ± 1.67mmHg). The mean reduction in LSM was 28.6% and in CAP was 10.09%. Three (5.36%) patients required removal of IGB before 6-months due to persisting vomiting. No patient developed new-onset decompensation or any serious adverse event. IGB placement is a safe, well tolerated and effective option for reduction in weight and portal pressure in compensated obese cirrhosis patients. Clinicaltrails.gov identifier no: NCT03753438.

Glycopeptides with Sialyl Lewis Antigen in Serum Haptoglobin as Candidate Biomarkers for Nonalcoholic Steatohepatitis Hepatocellular Carcinoma Using a Higher-Energy Collision-Induced Dissociation Parallel Reaction Monitoring-Mass Spectrometry Method.

Nonalcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC) in the United States. Changes in N-glycosylation on specific glycosites of serum proteins have been investigated as potential markers for the early detection of NASH-related HCC. Herein, we report a glycopeptide with a Sialyl Lewis structure derived from serum haptoglobin (Hp) as a potential marker for NASH related HCCs among 95 patients with NASH, including 46 cirrhosis, 32 early-stage HCC, and 17 late-stage HCC. Hp immuno-isolated from patient serum was analyzed using LC-HCD-PRM-MS/MS followed by data analysis via Skyline software. Two glycopeptides involving site N184 and four glycopeptides involving site N241 were significantly changed in patients with HCC vs NASH cirrhosis (P < 0.05). The two-marker panel using N-glycopeptide N241_A4G4F2S4 showed the best performance for HCC detection when combined with α-fetoprotein (AFP), with an improved estimated area under the curve (AUC) = 0.898 (95% CI: 0.835, 0.951), compared to the AUC of 0.790(95% CI, 0.697 0.872) using AFP alone (P = 0.048). At 90% specificity, the combination of N241_A4G4F2S4 + AFP had an improved sensitivity of 63.3%, compared to the sensitivity of 52.3% using AFP alone. When using three markers, the panel of AFP + N241_A2G2F1S2 + N241_A4G4F2S4 yielded an estimated AUC of 0.928 (95% CI: 0.877, 0.970). Our findings indicated that N241_A4G4F2S4 may play an important role in distinguishing HCC from NASH cirrhosis.