Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review.

Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs' role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects.

Racial Disparities in Treatment and Outcomes of Patients With Hepatitis C Undergoing Elective Total Joint Arthroplasty.

BACKGROUND: African Americans have the highest prevalence of chronic Hepatitis C virus (HCV) infection. Racial disparities in outcome are observed after elective total hip arthroplasty (THA) and total knee arthroplasty (TKA). This study sought to identify if disparities in treatments and outcomes exist between Black and White patients who have HCV prior to elective THA and TKA. METHODS: Patient demographics, comorbidities, HCV characteristics, perioperative variables, in-hospital outcomes, and postoperative complications at 1-year follow-up were collected and compared between the 2 races. Patients who have preoperative positive viral load (PVL) and undetectable viral load were identified. Chi-square and Fisher's exact tests were used to compare categorical variables, while 2-tailed Student's Kruskal-Wallis t-tests were used for continuous variables. A P value of less than .05 was statistically significant. RESULTS: The liver function parameters, including aspartate aminotransferase and model for end-stage liver disease scores, were all higher preoperatively in Black patients undergoing THA (P = .01; P < .001) and TKA (P = .03; P = .003), respectively. Black patients were more likely to undergo THA (65.8% versus 35.6%; P = .002) and TKA (72.1% versus 37.3%; 0.009) without receiving prior treatment for HCV. Consequently, Black patients had higher rates of preoperative PVL compared to White patients in both THA (66% versus 38%, P = .006) and TKA (72% versus 37%, P < .001) groups. Black patients had a longer length of stay for both THA (3.7 versus 3.3; P = .008) and TKA (4.1 versus 3.0; P = .02). CONCLUSIONS: The HCV treatment prior to THA and TKA with undetectable viral load has been shown to be a key factor in mitigating postoperative complications, including joint infection. We noted that Black patients were more likely to undergo joint arthroplasty who did not receive treatment and with a PVL. While PVL rates decreased over time for both races, a significant gap persists for Black patients.

Beta-blockers and cirrhosis: Striking the right balance.

Decompensated cirrhosis is associated with a significantly increased risk of mortality. Variceal hemorrhage (VH) further increases the risk of mortality, and of future variceal bleed events. Non-selective beta-blockers (NSBBs) are effective therapy for primary and secondary prophylaxis of VH and have become the cornerstone of pharmacologic therapy in cirrhosis. Beta-blockers are associated with reduced overall mortality and GI-bleeding related mortality in patients with decompensated cirrhosis; they may also confer hemodynamically independent beneficial effects. Long-term treatment with beta-blockers may improve decompensation-free survival in compensated cirrhosis with clinically significant portal hypertension (CSPH). Carvedilol more effectively lowers the hepatic vein portal gradient than traditional NSBBs and has been shown to improve survival in compensated cirrhosis. Treatment goals in compensated cirrhosis with CSPH should focus on early utilization of beta-blockers to prevent decompensation and reduce mortality.

Metabolic dysfunction associated steatotic liver disease: Current practice, screening guidelines and management in the primary care setting.

Metabolic dysfunction associated steatotic liver disease, previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease in the United States with rapidly rising prevalence. There have been significant changes recently in the field with screening now recommended for patients at risk for significant liver fibrosis in primary care and endocrine settings, along with clear guidance for management of metabolic comorbidities and changes in nomenclature. This paper serves as a summary of recent guidance for the primary care physician focusing on identifying appropriate patients for screening, selecting suitable screening modalities, and determining when referral to specialty care is necessary. The hope is that providers will shift away from past practices of utilizing liver tests alone as a screening tool and shift towards fibrosis screening in patients at risk for significant fibrosis. This culture change will allow for earlier identification of patients at risk for end stage liver disease and serious liver related complications, and overall improved patient care.

The correlation in echocardiogram to right heart catheterization in identifying pulmonary hypertension as a barrier to liver transplantation.

BACKGROUND: Pulmonary hypertension (PH) and portopulmonary hypertension (POPH) can be limitations towards listing for liver transplantation (LT). Our study evaluates the correlation of right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) on transthoracic echocardiogram (TTE) compared to mPAP on right heart catheterization (RHC). METHODS: We performed a retrospective review of 723 patients who underwent LT evaluation at our institution between 2012 and 2020. Our cohort consisted of patients with RVSP and mPAP measured on TTE. A Wald t-test and area under the curve analysis were used for statistical analyses. RESULTS: Patients with higher mPAP values on TTE (N=33) did not correlate with mPAP ≥ 35 mmHg on RHC, while patients with higher RVSP values (N=147) on TTE were associated with mPAP ≥ 35 mmHg on RHC. The cutoff value of RVSP ≥ 48 mmHg on TTE was associated with mPAP ≥ 35 mmHg on RHC. CONCLUSIONS: Our data suggest that RVSP compared to mPAP on TTE is a better indicator for mPAP ≥ 35 mmHg on RHC. RVSP can be used as a marker on echocardiography for identifying patients with a higher likelihood of PH being a barrier to LT listing.

Multicentered study of patient outcomes after declined for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Early liver transplantation for alcohol-associated hepatitis is controversial in part because patients may recover, and obviate the need for liver transplantation. METHODS: In this retrospective study among 5 ACCELERATE-AH sites, we randomly sampled patients evaluated and then declined for liver transplantation for alcohol-associated hepatitis. All had Model of End-Stage Liver Disease (MELD) >20 and <6 months of abstinence. Recompensation was defined as MELD <15 without variceal bleeding, ascites, or overt HE requiring treatment. Multilevel mixed effects linear regression was used to calculate probabilities of recompensation; multivariable Cox regression was used for mortality analyses. RESULTS: Among 145 patients [61% men; median abstinence time and MELD-Na was 33 days (interquartile range: 13-70) and 31 (interquartile range: 26-36), respectively], 56% were declined for psychosocial reasons. Probability of 30-day, 90-day, 6-month, and 1-year survival were 76% (95% CI, 68%-82%), 59% (95% CI, 50%-66%), 49% (95% CI, 40%-57%), and 46% (95% CI, 37%-55%), respectively. Probability of 1-year recompensation was low at 10.0% (95% CI, 4.5%-15.4%). Among patients declined because of clinical improvement, 1-year probability of recompensation was 28.0% (95% CI, 5.7%-50.3%). Among survivors, median MELD-Na at 30 days, 90 days, and 1-year were 29 (interquartile range: 22-38), 19 (interquartile range : 14-29), and 11 (interquartile range : 7-17). Increased MELD-Na (adjusted HR: 1.13, p <0.001) and age (adjusted HR: 1.03, p <0.001) were associated with early (≤90 d) death, and only history of failed alcohol rehabilitation (adjusted HR: 1.76, p =0.02) was associated with late death. CONCLUSIONS: Liver recompensation is infrequent among severe alcohol-associated hepatitis patients declined for liver transplantation. Higher MELD-Na and age were associated with short-term mortality, whereas only history of failed alcohol rehabilitation was associated with long-term mortality. The distinction between survival and liver recompensation merits further attention.

Marijuana use and post-transplant complications and non-compliance in liver transplant patients.

BACKGROUND: Liver transplant (LT) is a lifesaving treatment for patients with end stage liver disease. Historically, institutions across the United States have deemed active marijuana use as an exclusion criterion for listing. This study aims to investigate LT outcomes in patients with history of marijuana use prior to LT. METHODS: We performed a retrospective review of 111 patients who tested positive for marijuana on urine drug screen during initial LT evaluation between February 2016 and January 2021. 100 non-marijuana users who underwent LT were cross matched for control. Patient demographics, substance use history, and transplant decisions were recorded. Post-LT variables were also collected up to 1 year post surgery including postoperative infections, issues with non-compliance, and continued substance use. Chi-square analysis was used to assess the association between pre-transplant marijuana use and post-transplant complications. Logistics regression was implemented to measure associations amongst the entire cohort. RESULTS: From 111 marijuana users, 32 (29%) received a transplant. There was no statistical difference in post-LT outcomes between marijuana and non-marijuana users, including incidence of cardiac, respiratory, renal, psychiatric, or neurological complications, as well as readmission rates post-surgery. There were no statistically significant associations between marijuana use with post-transplant bacterial or fungal infections, medication non-compliance, or continued substance use (all p>0.05). Marijuana use was associated with pre-LT tobacco use (p = 0.020). CONCLUSIONS: Our data indicates that marijuana is not associated with increased risk of postoperative noncompliance, other organ complications, infections, or death. As a single factor, marijuana may not need to be a contraindication for LT.

Intramural Hematoma and Retroperitoneal Hematoma Following a Routine Colonoscopy: An Uncommon Complication of a Common Procedure.

Colonoscopy is used worldwide for screening colon cancer. Routine colonoscopy is considered a safe procedure with relatively fewer adverse events. We present a case of intracolonic and retroperitoneal hematoma following a routine colonoscopy. This case highlights an uncommon life-threatening complication of a common procedure. A 50-year-old female presented with abdominal pain and syncopal episode following an uneventful screening colonoscopy. CT abdomen revealed intracolonic and retroperitoneal hematoma. This eventually led to exploratory laparotomy and right hemicolectomy after failure of conservative management. Clinicians need to be aware of the potentially life-threatening complications associated with colonoscopy for overall safety of colonoscopy.

The misclassification of gastric antral vascular ectasia.

Background: Gastric antral vascular ectasia (GAVE) is characterized by angiodysplastic lesions and is a rare form of gastrointestinal bleeding. Given the multiple patterns, GAVE can be misclassified. Aim: We analyzed the misclassification of GAVE among patients undergoing esophagogastroduodenoscopy (EGD). Methods: We performed a retrospective review of 941 EGDs between 2017 and 2019. Inclusion criteria included findings of GAVE on EGD±biopsy. Correct classification was based on visual EGD findings. Outcome variables included misclassification rate, endoscopist's background, and concordance between EGD and pathology. Cohen's Kappa test was used for concordance analysis. Results: A total of 110 patients had EGD findings of GAVE with a corresponding 184 EGDs. The misclassification rate among EGDs was 74/184 (40%). Furthermore, 81/110 patients were correctly classified with their first workup, whereas 29/110 patients needed repeat testing. In cases of misclassification, GAVE was mostly referred to as erythema (43%), with ulceration, gastritis, or polyps. Sixty-six (60%) patients had biopsies with a concordance of 76% between EGD and biopsy (κ=0.35). Conclusions: Our findings indicate GAVE was misclassified up to 40% on EGDs with hepatologists and gastroenterologists having similar misclassification rates. Proper identification is crucial given susceptibility to upper gastrointestinal bleeding. Relevance for Patients: This study emphasizes the importance of accurate classification of GAVE to ensure proper treatment of these lesions which can improve clinical outcomes.

Early Liver Transplantation for Severe Alcohol-Associated Hepatitis and a History of Prior Liver Decompensation.

INTRODUCTION: In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is unknown. METHODS: Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use. RESULTS: A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval [CI] 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94). DISCUSSION: Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.

Nutritional Deficiencies and Clinical Practices in Decompensated Cirrhotics With Hepatic Encephalopathy.

Background Hepatic encephalopathy (HE), a major complication of end-stage cirrhosis, is often associated with nutritional deficiencies. We aimed to assess the frequency in which vitamins and zinc were tested for and deficient in our cirrhotic population with HE. Methods We performed a retrospective chart review of 143 patients with decompensated cirrhosis that were seen in a hepatology clinic from January 2020 to May 2021. Patient demographics and decompensations were recorded. Vitamins and minerals that were evaluated included zinc, vitamin B12, folate, vitamin D, and thiamine. Continuous variables were reported as mean ± standard deviation and categorical variables were calculated as frequency percentages. Results Out of 143 patients, 73 were found to have HE. Out of 73, 33 were male, and the average MELD was 15.5 ± 6.3. 44% of patients had NASH cirrhosis, and 30% had alcoholic cirrhosis. Of the minority of patients that had their nutrient levels checked, 17/23 (74%) were deficient in zinc (<60 mcg/dL). 75% of patients were deficient in thiamine. 2/34 (6%) were deficient in folate (<5.9 ng/mL), 2/10 (20%) in vitamin D (<20 ng/mL), and 2/47 (4%) in B12 (<300 pg/mL). Conclusion Nutritional deficiencies are common in cirrhotics with HE. Further studies are needed to determine if routine testing and treatment for vitamin and Zinc deficiencies would have a positive impact on the clinical trajectory of HE.

Perioperative Transjugular Intrahepatic Portosystemic Shunt Is Associated With Decreased Postoperative Complications in Decompensated Cirrhotics Undergoing Abdominal Surgery.

BACKGROUND: Operative risk in patients with cirrhosis is related to the severity of liver disease and nature of procedure. Pre and postoperative portal decompression via transjugular intrahepatic portosystemic shunt (TIPS) are logical approaches to facilitate surgery and improve postoperative outcomes. We compared postoperative outcomes of decompensated cirrhotics undergoing abdominal surgery either with or without perioperative TIPS placement. METHODS: We performed a retrospective review of 41 decompensated cirrhotic patients who had abdominal surgery from 2010-2019 at the University of Alabama at Birmingham. Patients were stratified based on having received either perioperative TIPS or no TIPS. Demographics, laboratory data, perioperative TIPS status and postoperative complications were compared between the 2 groups using Fisher exact test and Student 2 sample t-test. RESULTS: Group 1 consisted of 28 patients who had TIPS procedure, with 21 being preoperative and 7 being postoperative. Group 2 had 13 patients who had abdominal surgery without TIPS. When compared to those with perioperative TIPS, patients without TIPS had a significantly increased incidence of postoperative ascites (33% vs 77%, P = .0026), infection (18% vs 54%, P = .028), and acute kidney injury (AKI) (14% vs 46%, P = .0485). Additionally, postoperative Model of End Stage Liver Disease Sodium score was significantly higher in patients without TIPS (22 ± 4.74) when compared to those who had TIPS (17.14 ± 5.48) (P = .009). DISCUSSION: Perioperative TIPS placement in decompensated cirrhotics was associated with decreased postoperative ascites, infection, and AKI when compared to those without TIPS. Further studies are needed to validate our findings.

Prevalence of metabolic syndrome in cirrhotics with gastric antral vascular ectasia.

BACKGROUND AND AIMS: Gastric antral vascular ectasia (GAVE) is characterized by angliodysplastic lesions that can cause upper gastrointestinal bleeding (UGIB). The mechanism behind GAVE and its association with other diseases remains unknown. We investigated the association of metabolic syndrome in cirrhotic GAVE patients when compared to esophageal variceal hemorrhage (EVH) patients. METHODS: We performed a retrospective review of 941 consecutive esophagogastroduodenoscopies (EGDs) for UGIB at a medical center between 2017 and 2019. The GAVE group consisted of EGD or biopsy diagnosed cirrhotic GAVE patients, and the EVH group consisted of EVH patients with active bleeding or stigmata of recent hemorrhage on EGD. Baseline variables including co-morbidities and cirrhotic etiology were recorded. Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi-square or Fisher's exact test. Multiple logistic regression analysis evaluated the association between GAVE and covariates. RESULTS: The final cohort had 96 GAVE and 104 EVH patients. Mean BMI was significantly higher in the GAVE cohort (32.6 vs 27.9, p < 0.0001) in addition to diabetes, hypertension, and hyperlipidemia (53.1% vs 37.5%; 76% vs 47.1%; 38.5% vs 14.4%; respectively, all p < 0.05). Non-alcoholic steatohepatitis (NASH) cirrhosis was more prevalent in GAVE than EVH patients (50% vs 24%, p = 0.0001). Multiple logistics regression revealed female sex, increased BMI, hypertension, and hyperlipidemia all having significantly higher risk of GAVE (all p < 0.05). CONCLUSION: Our data indicates that when compared to cirrhotics patients with EVH, cirrhotics with GAVE have increased risk of metabolic syndrome. This may play a role in the underlying pathophysiology of GAVE.

Liver Transplantation in Hepatitis B Reactivation in a Patient With Active HIV Viremia.

Acute hepatitis B virus infection is a common contraindication to liver transplantation surgery in the setting of active HIV viremia. This is a case report of a patient with decompensated cirrhosis and acute renal failure in the setting of hepatitis B virus reactivation and active HIV viremia who underwent liver transplantation with sustained graft survival.

An Unexpected Association: Might GAVE Pave the Way to How the Metabolic Syndrome Behaves.

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Gastrointestinal Stromal Tumor: GIST Another Duodenal Ulcer.

Background: Gastrointestinal stromal tumors (GISTs), although exceedingly rare, are the most common mesenchymal tumors in the gastrointestinal (GI) tract. GISTs are often asymptomatic; approximately 10% are found incidentally on imaging or endoscopy for other indications, although GI bleeding, intestinal obstruction, and perforation can occur. We present a case of upper GI bleeding from a duodenal GIST. Proton-pump inhibitor (PPI) therapy resulted in complete endoscopic ulcer healing, yet a discrete mass lesion was identified on endoscopic ultrasound (EUS). Case Report: A 70-year-old female presented with upper GI bleeding, and a duodenal ulcer was identified with esophagogastroduodenoscopy (EGD). Computed tomography (CT) scan of the abdomen and pelvis showed duodenal bulb thickening without clear mass. The ulcer was treated with 1:10,000 concentration epinephrine, injected in 4 quadrants around the ulcer base. The patient's GI bleeding resolved, and she was discharged with a referral for outpatient EUS follow-up. One month later, EUS showed resolution of the ulcer after PPI therapy but also showed a lesion consistent with GIST that was confirmed by cytologic analysis. The patient was started on imatinib therapy and had no further bleeding. Conclusion: Initial EGD and CT findings could have easily been attributed to duodenal peptic ulcer disease for which follow-up endoscopy is not routinely recommended given the low risk of malignancy. However, because of the high index of suspicion on the part of the referring physicians, duodenal GIST was diagnosed. This case extends the spectrum of the presentation, evaluation, and diagnosis of GISTs and stresses the importance of keeping this rare disease on the provider's differential, even after routine workup shows no findings of tumor.

Cholecystectomy does not worsen progression or outcomes in non-alcoholic fatty liver disease.

BACKGROUND: Cholecystectomy is a frequently performed surgical procedure for symptomatic cholelithiasis, which is reported to be more common in patients with non-alcoholic steatohepatitis (NASH), given the common risk factors. However, the data remains unclear on the association of cholecystectomy with NASH. We performed a retrospective study to examine the association of cholecystectomy and NASH. METHODS: Medical charts of patients with steatohepatitis related liver disease at a tertiary care center from 2004 to 2011 were stratified by cholecystectomy and defined by its history and/or absence of gallbladder on ultrasonography. Logistic regression model was built for predictors of cholecystectomy. Patients with NASH were stratified based on timing of cholecystectomy. The diagnosis of NASH and timing of cholecystectomy were compared based on baseline characteristics and outcomes (liver disease complications and survival) on follow up. Kaplan-Meier curves were generated for the two group comparisons. Chi-square and unpaired t-tests were used for comparing outcomes on follow up. P value <0.05 was considered significant. RESULTS: Analysis of 584 patients [379 non-alcoholic fatty liver disease (NAFLD)] showed that patients with cholecystectomy (N=191) were more likely to be female (57% vs. 44%), diabetic (53% vs. 37%), have liver biopsy (43% vs. 25%) and diagnosis of NAFLD (80% vs. 58%) P<0.001 for all. NAFLD diagnosis was associated with 2.79 folds odds of cholecystectomy. Among 379 (192 cholecystectomy) NAFLD patients, cirrhosis and female gender were associated with over 2 and 1.5 folds of cholecystectomy. Of 141 patients with data on timing of cholecystectomy, 55 (39%) with cholecystectomy at or after NAFLD diagnosis vs. 86 with cholecystectomy within median of 6 years prior to NAFLD diagnosis were similar on all characteristics except on model for end-stage liver disease (MELD) score (9.2±8.4 vs. 6.4±7.1, P=0.045). Of 28 with available histology data, there were no differences on histology based on timing of cholecystectomy. On a median follow up of 5 years, timing of cholecystectomy did not impact on development of cirrhosis (74% vs. 67%, P=0.45), ascites (31% vs. 38%, P=0.76), variceal bleeding (11% vs. 16%, P=0.44), hepatic encephalopathy (22% vs. 29%, P=0.74), hepatocellular carcinoma (HCC) (15% vs. 9%, P=0.59), and patient survival (95% vs. 98%, P=0.3). CONCLUSIONS: Cholecystectomy is associated with NAFLD diagnosis. We did not find cause and effect of cholecystectomy in the development of severity of NAFLD. Prospective studies are suggested to examine the role of cholecystectomy and bile acids in the pathogenesis of NAFLD.