Continuing Medical Education Questions: August 2023.

Article Title: Impact of Cold Snare v Cold Forceps Resection of Diminutive Adenomas on Segmental Incomplete Resection Rate.

Use of Lactulose to Treat Hyperammonemia in ICU Patients Without Chronic Liver Disease or Significant Hepatocellular Injury.

OBJECTIVES: To review ICU patients with elevated ammonia without a clear hepatic etiology, to compare outcomes between those who received lactulose and those who did not. DESIGN: Retrospective observational study. SETTING: Medical, surgical, and subspecialty intensive care units at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina between December 2012 and August 2016. PATIENTS: Adults with ammonia levels above 50 µmol/L, excluding those with known chronic liver disease, inborn error of metabolism, active use of valproic acid, total bilirubin ≥ 2 µmol/L, or alanine aminotransferase ≥ 100 units/L. INTERVENTIONS: Comparison in ICU length of stay (LOS), hospital LOS, in-hospital mortality, and mortality at 30 and 90 days. MEASUREMENTS AND MAIN RESULTS: Criteria for inclusion were met in 103 cases. Mean ammonia level was 75 µmol/L, with undetermined etiology in the majority of subjects. Lactulose was given in 48 cases (46.6%), with a median of 9.5 doses given. There were no significant differences in outcomes between the lactulose and non-lactulose groups. Among subjects with multiple data points, lactulose did not have a dose-dependent effect on ammonia level, and was not associated with faster ammonia normalization compared to non-lactulose. When analyzed separately, patients with moderate hyperammonemia (60-99 µmol/L) who received lactulose had longer hospital and ICU length of stay compared to non-lactulose (417.8 hours vs. 208.4 hours, P = 0.003, and 229.2 hours vs. 104.7 hours, P = 0.025; respectively), though confounders were present. CONCLUSIONS: Routine use of lactulose to treat mild to moderate hyperammonemia in this patient population was not associated with improved outcomes.

Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

BACKGROUND & AIMS: Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). METHODS: We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. RESULTS: Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. CONCLUSIONS: The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.

Continuing Medical Education Questions: June 2021.

Article Title: Exploratory comparative effectiveness trial of green kiwifruit, psyllium, or prunes in US patients with chronic constipation.

Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplantation (LT) recipients with COVID-19 are open for study. APPROACH AND RESULTS: We conducted a multicenter study in the United States of 112 adult LT recipients with COVID-19. Median age was 61 years (interquartile range, 20), 54.5% (n = 61) were male, and 39.3% (n = 44) Hispanic. Mortality rate was 22.3% (n = 25); 72.3% (n = 81) were hospitalized and 26.8% (n = 30) admitted to the intensive care unit (ICU). Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5× upper limit of normal [ULN]) in 22.2% (n = 18) and severe liver injury (ALT > 5× ULN) in 12.3% (n = 10). Compared to age- and sex-matched nontransplant patients with chronic liver disease and COVID-19 (n = 375), incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; P = 0.037). Variables associated with liver injury in LT recipients were younger age (P = 0.009; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), Hispanic ethnicity (P = 0.011; OR, 6.01; 95% CI, 1.51-23.9), metabolic syndrome (P = 0.016; OR, 5.87; 95% CI, 1.38-24.99), vasopressor use (P = 0.018; OR, 7.34; 95% CI, 1.39-38.52), and antibiotic use (P = 0.046; OR, 6.93; 95% CI, 1.04-46.26). Reduction in immunosuppression (49.4%) was not associated with liver injury (P = 0.156) or mortality (P = 0.084). Liver injury during COVID-19 was significantly associated with mortality (P = 0.007; OR, 6.91; 95% CI, 1.68-28.48) and ICU admission (P = 0.007; OR, 7.93; 95% CI, 1.75-35.69) in LT recipients. CONCLUSIONS: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

Management of Patients With Pancreatic Cysts: Analysis of Possible False-Negative Cases of Malignancy.

GOALS: To examine the utility of integrated molecular pathology (IMP) in managing surveillance of pancreatic cysts based on outcomes and analysis of false negatives (FNs) from a previously published cohort (n=492). BACKGROUND: In endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of cyst fluid lacking malignant cytology, IMP demonstrated better risk stratification for malignancy at approximately 3 years' follow-up than International Consensus Guideline (Fukuoka) 2012 management recommendations in such cases. STUDY: Patient outcomes and clinical features of Fukuoka and IMP FN cases were reviewed. Practical guidance for appropriate surveillance intervals and surgery decisions using IMP were derived from follow-up data, considering EUS-FNA sampling limitations and high-risk clinical circumstances observed. Surveillance intervals for patients based on IMP predictive value were compared with those of Fukuoka. RESULTS: Outcomes at follow-up for IMP low-risk diagnoses supported surveillance every 2 to 3 years, independent of cyst size, when EUS-FNA sampling limitations or high-risk clinical circumstances were absent. In 10 of 11 patients with FN IMP diagnoses (2% of cohort), EUS-FNA sampling limitations existed; Fukuoka identified high risk in 9 of 11 cases. In 4 of 6 FN cases by Fukuoka (1% of cohort), IMP identified high risk. Overall, 55% of cases had possible sampling limitations and 37% had high-risk clinical circumstances. Outcomes support more cautious management in such cases when using IMP. CONCLUSIONS: Adjunct use of IMP can provide evidence for relaxed surveillance of patients with benign cysts that meet Fukuoka criteria for closer observation or surgery. Although infrequent, FN results with IMP can be associated with EUS-FNA sampling limitations or high-risk clinical circumstances.

Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts.

BACKGROUND AND STUDY AIMS: Current diagnostic testing is inadequate to determine the malignant potential of pancreatic cysts, resulting in overcautious patient management. Integrated molecular pathology (IMP) testing combines molecular analysis with first-line test results (cytology, imaging, and fluid chemistry) to assess the malignant potential of pancreatic cysts. This multicenter study aimed to determine the diagnostic accuracy of IMP for pancreatic adenocarcinoma, and the utility of IMP testing under current guideline recommendations for managing pancreatic cysts. PATIENTS AND METHODS: Patients who had undergone previous IMP testing as prescribed by their physician and for whom clinical outcomes were available from retrospective record review were included (n = 492). Performance was determined by correlation between clinical outcome and previous IMP diagnosis ("benign"/"statistically indolent" vs. "statistically higher risk [SHR]"/ "aggressive") or an International Consensus Guideline (Sendai 2012) criteria model for "surveillance" vs. "surgery." The Cox proportional hazards model determined hazard ratios for malignancy. RESULTS: Benign and statistically indolent IMP diagnoses had a 97 % probability of benign follow-up for up to 7 years and 8 months from initial IMP testing. SHR and aggressive diagnoses had relative hazard ratios for malignancy of 30.8 and 76.3, respectively (both P < 0.0001). Sendai surveillance criteria had a 97 % probability of benign follow-up for up to 7 years and 8 months, but for surgical criteria the hazard ratio was only 9.0 (P < 0.0001). In patients who met Sendai surgical criteria, benign and statistically indolent IMP diagnoses had a > 93 % probability of benign follow-up, with relative hazard ratios for SHR and aggressive IMP diagnoses of 16.1 and 50.2, respectively (both P < 0.0001). CONCLUSION: IMP more accurately determined the malignant potential of pancreatic cysts than a Sendai 2012 guideline management criteria model. IMP may improve patient management by justifying more relaxed observation in patients meeting Sendai surveillance criteria. IMP can more accurately differentiate between the need for surveillance or surgery in patients meeting Sendai surgical criteria.

Chlamydial Proctitis Mimicking Inflammatory Bowel Disease in a Young Active Duty Sailor With Undiagnosed Human Immunodeficiency Virus Infection: A Case Report.

Proctitis is an inflammation of the lining of the rectum that can be either acute or chronic in presentation. Symptoms include rectal bleeding, constipation, rectal discharge, rectal pain, and tenesmus. It is commonly associated with inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease. However, it is important to consider the infectious causes of proctitis such as the sexually transmitted infections (STIs), especially Chlamydia trachomatis and Neisseria gonorrhoeae, as these can mimic the symptoms and pathology of IBD. We present the case of a young male sailor with subacute rectal bleeding who was hospitalized with initial concern for an index presentation of IBD. Endoscopic evaluation revealed proctitis although findings were atypical for inflammation related to IBD. Acquisition of additional history revealed that he had both receptive and insertive anal intercourse with both male and female partners. A full STI screening, including HIV was performed. Results were positive for both rectal C. trachomatis and HIV antigen and antibody serology, which were confirmed as HIV-1 on confirmatory testing. He was treated with doxycycline for his chlamydial proctitis with symptom resolution and was also initiated on antiretroviral therapy for his HIV infection. This case highlights the importance of obtaining a sexual history and considering STIs as a cause of proctitis, as this will ensure proper screenings and prompt subsequent treatment and potentially avoid unnecessary endoscopic and medical evaluation, which could potentially worsen the underlying process.

Severe Drug-Induced Liver Injury in the Military: A Retrospective Review.

OBJECTIVES: Drug-induced liver injury (DILI) is a significant cause of morbidity and mortality. Establishing a diagnosis is challenging due to the broad differential diagnosis of liver injury. We retrospectively reviewed patients with severe idiosyncratic DILI at Walter Reed National Military Medical Center in order to define the scope and patterns of injury in the military population. METHODS: Using the military health database, we identified a total of 110 patients who had an International Classification of Disease (ICD)-10 code for toxic liver injury in the electronic medical record at Walter Reed National Military Medical Center between 2016 and 2019. Each patient record was reviewed, and all pertinent data for included patients were recorded into a database for analysis. RESULTS: Twenty-seven out of 110 patients with a diagnostic code for toxic liver injury met inclusion criteria for severe idiosyncratic DILI. Nine cases were caused by supplements, including 5 active duty service members using synthetic anabolic steroids or preworkout supplements. The majority of patients were men and one-third were serving on active duty. The ranges of liver enzyme elevation and patterns of liver injury widely varied. CONCLUSION: Military service members are at particularly high risk for DILI given the frequent use of over-the-counter and other unregulated strength- and performance-enhancing supplements. These injuries not only have significant medical consequences but can profoundly impact military readiness and mission capability. Diagnosis of DILI among active duty service members requires a strong index of suspicion, and inquiry regarding all ingestions is crucial. Educating physicians, providers, and policy makers on the risks of supplement-induced liver injury among service members is crucial. These data will facilitate additional studies exploring susceptibility to severe idiosyncratic DILI among the military population.

A Case of Refractory Eosinophilic Gastrointestinal Disease Successfully Treated With Dupilumab.

Eosinophilic infiltration of the gastrointestinal (GI) tract beyond the esophagus is a rare condition in adults with limited data on treatment. Current treatments with steroids and diet modifications have shown benefit, but when these treatments fall short, there is little research-driven guidance for further recommendations. We present a case of eosinophilic GI disease with extensive involvement of the GI tract successfully treated with dupilumab after failure of traditional treatment occurred.

Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users.

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.

Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

Care of the Hepatology Patient in the COVID-19 Era.

Background and Purpose of Review: The COVID-19 pandemic has resulted in over 800,000 deaths worldwide and resulted in fundamental changes in practice in nearly every aspect of medicine. The majority of symptomatic patients experience liver-associated enzyme (LAE) elevations which appear to be correlated to disease severity. Furthermore, there are unique considerations of COVID-19 on chronic liver disease. Background, including epidemiology, pathophysiologic mechanisms and therapeutics, as well as the impact of COVID-19 on specific chronic liver disease, is discussed. Findings: Studies suggest that degree of LAE elevation correlates with illness severity, although it is unclear whether this represents true liver injury. Numerous proposed treatments for COVID-19 have been linked with drug induced liver injury and may have clinically significant drug-drug interactions. Others may have unintended consequences on chronic liver disease treatment including reactivation of hepatitis B. The risk of severe COVID-19 in patients with chronic liver disease is largely unknown; metabolic dysfunction-associated fatty liver disease may be linked to higher risk for severe illness. Implications for cirrhosis of other etiologies, autoimmune hepatitis, and viral hepatitis are less well defined. The treatment of chronic liver disease has been severely impacted by the pandemic. The societal factors created by the pandemic have led to decreased in person visits, evolving access to invasive screening modalities, food and financial insecurity, and likely increased alcohol use. Conclusions: The impacts of COVID-19 on the liver range from a potential increased risk of severe infection in chronic liver disease patients, to hepatotoxic effects of proposed treatments, to second and third order impacts on the care of patients with chronic liver disease.

Systems-based Strategies Improve Positive Screening Fecal Immunochemical Testing Follow-up and Reduce Time to Diagnostic Colonoscopy.

INTRODUCTION: Fecal immunochemical testing (FIT) is the most commonly used colorectal cancer (CRC) screening tool worldwide and accounts for 10% of all CRC screening in the United States. Potential vulnerabilities for patients enrolled to facilities within the military health system have recently come to light requiring reassessment of best practices. We studied the impact of a process improvement initiative designed to improve the safety and quality of care for patients after a positive screening FIT given previously published reports of poor organization performance. METHODS: During a time of increased utilization of nonendoscopic means of screening, we assessed rates of colonoscopy completion and time to colonoscopy after positive FIT after a multi-faceted process improvement initiative was implemented, compared against an institutional control period. The interventions included mandatory indication labeling at the time of order entry, as well as utilization of subspecialty nurse navigators to facilitate rapid follow-up even the absence of a referral from primary care. RESULTS: Preintervention, 34.8% of patients did not have appropriate follow-up of a positive FIT. Those that did had a variable and prolonged wait time of 140.1 ± 115.9 days. Postintervention, a standardized order mandating test indication labeling allowed for proactive gastroenterology involvement. Colonoscopy follow-up rate increased to 91.9% with an average interval of 21.9 ± 12.3 days. CONCLUSION: The addition of indication labels and patient navigation after positive screening FIT was associated with 57.1% absolute increase in timely diagnostic colonoscopy. Similar highly reliable systems-based solutions should be adopted for CRC screening, and further implementation for other preventative screening interventions should be pursued.

PRO: Cardiac Catheterization Is the Optimal Strategy for Cardiovascular Risk Stratification in This Patient.

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Infliximab-induced autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an inflammatory disorder of the liver with a wide spectrum of disease presentation, from asymptomatic elevations in liver-associated enzymes to acute liver failure. AIH is classically associated with elevated immunoglobulins and autoantibodies, although approximately 20% of patients with features of AIH lack circulating antibodies. Recently, tumour necrosis factor alpha inhibitors have been implicated in several cases of drug-induced AIH which impact treatment regimens for patients with inflammatory bowel disease (IBD). We present a case of infliximab-induced seronegative AIH responding to budesonide therapy with successful alteration of IBD treatment regimen to vedolizumab.

Perforated Hemocholecyst: An Unintended Consequence of Endoscopic Variceal Ligation?

Ectopic varices are a rare sequelae of portal hypertension and present in unique ways, which may not always prompt consideration. Furthermore, endoscopic interventions on venous collaterals in the setting of portal hypertension affect the portal system hemodynamics, which may further complicate the clinical picture. We report a man with decompensated hepatitis C cirrhosis who developed hemocholecyst complicated by perforation with hemoperitoneum soon after endoscopic variceal ligation of the esophageal varices in the setting of retrospectively discovered gallbladder varices.

Jaundice in a Service member Returning From Taiwan; Diagnostic Challenges in a Case of Acute Hepatitis E.

When the evaluation of newly elevated liver enzymes is unrevealing, a common diagnosis of exclusion is drug-induced liver injury. A 39-year-old active duty service member who presented with jaundice after returning from a mission in Thailand was found to have an acute hepatitis and developing acute liver failure. He was ultimately diagnosed with acute hepatitis E, but his diagnosis was initially confounded by multiple exposures to supplements known to cause drug-induced liver injury. This case illustrates the importance of broadened serologic testing in patients with acute liver injury returning from countries endemic with hepatitis E and also highlights the challenges in diagnosis of acute hepatitis E with currently available testing.

Memantine-Induced Liver Injury With Probable Causality as Assessed Using the Roussel Uclaf Causality Assessment Method (RUCAM).

Presentations of drug-induced liver injury (DILI) are highly variable. Although biochemical evidence of cholestasis is common, the extent of aminotransferase elevations and patterns of liver injury vary. Patients may be asymptomatic, and many cases may never be diagnosed. We describe a case of memantine-induced hepatotoxicity in an elderly patient with Alzheimer's dementia, with probable causality for drug-induced liver injury, as assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) score.