Diagnosis and management of immune mediated liver injury from checkpoint inhibitors.

PURPOSE OF REVIEW: The aim is to summarize the latest data on the incidence, clinical manifestations, and management of immune- mediated liver injury from checkpoint inhibitors (ILICI). RECENT FINDINGS: ILICI develops in 10-15% of oncology patients receiving immunotherapy with most having asymptomatic serum aminotransferase and/or alkaline phosphatase elevations. Most grade 1-2 ILICI patients improve with drug discontinuation and/or short-term oral corticosteroids. In contrast, the 2-3% with grade 3/4 hepatotoxicity frequently require oral or intravenous corticosteroids and some are hospitalized to initiate further immunosuppression with mycophenolate mofetil or azathioprine. Liver biopsy is generally reserved for patients with atypical features or those with severe hepatotoxicity who fail to respond to treatment. Up to 3% of ILICI patients with a cholestatic profile have MRI evidence of intra or extrahepatic cholangitis that responds poorly to immunosuppression. Most ILICI patients improve during follow-up and liver-related death is very uncommon (<1%). Up to 30% of rechallenged ILICI patients develop recurrent hepatotoxicity with a shorter latency. SUMMARY: ILICI is increasingly encountered by gastroenterologists evaluating oncology patients with abnormal liver biochemistries. A stepwise approach to exclude viral hepatitis, alcohol, hepatic metastases, and pancreaticobiliary disease is recommended. The majority of ILICI patients fully recover with ICI discontinuation and short-term corticosteroids or a second line immunosuppressant.

Controversies of Direct-Acting Antivirals in Hepatocellular Carcinoma.

Therapy for chronic hepatitis C virus infection with direct-acting antiviral agents (DAAs) has been highly successful in achieving sustained virological response (SVR) with associated improvements in liver dysfunction, liver-related mortality, and transplant-free survival. There is a high risk of hepatocellular carcinoma (HCC) with an annual incidence of 2% to 4% in patients with cirrhosis. Following DAAs treatment and achievement of SVR, the risk of incident and recurrent HCC drops significantly over time, with risk associated with demographic and liver disease-related factors. Several risk factors have been described including age, male, diabetes comorbidities, alcohol abuse, hepatitis B virus or human immunodeficiency virus-coinfection, and advanced liver disease or increased liver fibrosis. Recurrence risk after DAA therapy has been associated with baseline tumor burden, with increased risk with larger lesion(s), multifocal disease, elevated alpha-fetoprotein level, treatment type (curative vs palliative), and shorter interval between HCC complete response and DAA initiation. Overall, due to the heterogeneity among individual patient data and lack of adequately controlled data, there are no conclusive statements that can be drawn that DAAs exposure is directly associated with HCC occurrence or recurrence. However, the best available data suggest a decreased risk of incident HCC with DAA therapy and no increased risk of recurrence with DAAs after complete tumor response.

Safety and outcomes of hip and knee replacement surgery in liver transplant recipients.

BACKGROUND: Liver transplant (LT) is becoming increasingly common with improved life expectancy. Joint replacement is usually a safe procedure; however, its safety in LT recipients remains understudied. AIM: To evaluate the mortality, outcome, and 90-d readmission rate in LT patients undergoing hip and knee replacement surgery. METHODS: Patients with history of LT who underwent hip and knee replacement surgery between 2016 and 2019 were identified using the National Readmission Database. RESULTS: A total of 5046119 hip and knee replacement surgeries were identified. 3219 patients had prior LT. Mean age of patients with no history of LT was 67.51 [95% confidence interval (CI): 67.44-67.58], while it was 64.05 (95%CI: 63.55-64.54) in patients with LT. Patients with history of LT were more likely to have prolonged length of hospital stay (17.1% vs 8.4%, P < 0.001). The mortality rate for patients with no history of LT was 0.22%, while it was 0.24% for patients with LT (P = 0.792). Patients with history of LT were more likely to have re-admissions within 90 d of initial hospitalization: 11.4% as compared to 6.2% in patients without history of LT (P < 0.001). The mortality rate between both groups during readmission was not statistically different (1.9% vs 2%, P = 0.871) respectively. CONCLUSION: Hip and knee replacements in patients with history of LT are not associated with increased mortality; increased re-admissions were more frequent in this cohort of patients. Chronic kidney disease and congestive heart failure appear to predict higher risk of readmission.

Selective Androgen Receptor Modulators (SARMs)-Induced Liver Injury: A Case Report and Review of Literature.

Drug-induced liver injury (DILI) is one of the leading causes of death from acute liver failure (ALF) in the United States, accounting for approximately 13% of ALF cases in the United States. Selective androgen receptor modulators (SARMs) were first developed to increase muscle mass while avoiding the side effects of conventional androgenic steroids. Although not Food and Drug Administration (FDA) approved, they are widely available online and are consumed to enhance athletic performance. We report a 22-year-old, previously healthy male, who presented with a two-week history of worsening jaundice, nausea, fatigue, pruritus, dark urine, and light stools. He reported taking the SARM, RAD-140, for 16 weeks. Examination showed scleral icterus. The liver panel showed alkaline phosphatase (ALP) 5.3 µkat/L, alanine transaminase (ALT) 1.66 µkat/L, aspartate transaminase (AST) 1.18 µkat/L, direct bilirubin 294 µmol/L, total bilirubin 427.5 µmol/L, and international normalized ratio (INR) 0.9. Viral hepatitis and autoimmune panel were unremarkable. Alpha-1 antitrypsin and ceruloplasmin levels were within normal limits. Bile sludge was seen on ultrasound. Magnetic resonance cholangiopancreatography (MRCP) abdomen showed segmental narrowing of the intrahepatic ducts. Endoscopic retrograde cholangiopancreatography (ERCP) was unremarkable. Liver biopsy showed mixed portal hepatitis, cholestasis, and biliary reactive changes with ceroid-loaded macrophages; a picture consistent with DILI. The patient was treated supportively and discharged with scheduled hepatology follow-up. At the one-month follow-up, his total bilirubin had fallen from a peak of 530 mol/L to 188 mol/L. The diagnosis of DILI can be made based on the timing of exposure and the exclusion of other etiologies. Liver enzymes normalized three to 12 months after product discontinuation. We hope this report will remind primary care physicians of the potential hepatotoxic side effects of muscle-building compounds and encourage them to report suspected DILI to the FDA using the MedWatch system.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

The association between microscopic colitis and celiac disease: a systematic review and meta-analysis.

Background: Multiple studies suggested that celiac disease (CD) may be associated with microscopic colitis (MC); however, most were limited by a small sample size or the main scope of interest. We aimed to analyze previously published literature on this association to determine its extent and significance. Methods: A systematic review was conducted in PubMed, Embase, PubMed Central, Cochrane, and ScienceDirect databases from inception through January 2022. The PRISMA guideline was followed for data extraction. Effect estimates were extracted and combined using random effect, the generic inverse variance method of DerSimonian and Laird and pooled odds ratio (OR), and event rates (ER) were calculated. The Newcastle-Ottawa scale was used to evaluate the risk of bias. Forest plots were generated and publication bias assessed via conventional techniques. Results: Twenty-six studies with a total of 22,802 patients with MC were included in this analysis. CD was significantly associated with MC (odds ratio [OR] 8.276, 95% confidence interval [CI] 5.888-11.632; P<0.001). The ER for MC in CD patients was 6.2% (95%CI 4.1-9.2%; P<0.001), while the ER for CD in MC patients was 6.1% (95%CI 3.9-9.5%; P<0.001). CD was prevalent in both types of MC: 5.2% (95%CI 2.2-12.1%; P<0.001) in collagenous colitis and 6.3% (95%CI 3.4-11.5%; P<0.001) in lymphocytic colitis. We found no publication bias, according to funnel plots and Egger's regression asymmetry testing. Conclusions: Our meta-analysis confirms a statistically significant association between CD and MC, with a high prevalence of CD in both types of MC. Gastroenterologists should be wary of this association when evaluating patients with either disease, particularly patients with a suboptimal response to first-line therapy.

Granulomatous Hepatitis Secondary to Histoplasmosis in an Immunocompetent Patient.

Histoplasma capsulatum is the most common endemic mycosis in the United States and usually occurs in certain geographic areas, such as the Mississippi or Ohio River valleys. Histoplasmosis usually causes a mild disease in the immunocompetent but can progress to disseminated disease in patients with impaired immunity. Granulomatous hepatitis as a manifestation of disseminated histoplasmosis in immunocompetent patients is extremely rare. We report the case of a 62-year-old immunocompetent gentleman with a history of histoplasmosis who presented with abdominal pain, elevated liver enzymes, who was diagnosed with granulomatous hepatitis secondary to histoplasmosis.

Sarcoidosis Manifesting as Liver Granuloma With Asteroid Bodies.

Sarcoidosis is an autoimmune disease, which most commonly affects the lungs and lymph nodes and is characterized with non-caseating granulomas. Hepatic involvement in sarcoidosis occurs in less than 1% of patients. Most patients with hepatic sarcoidosis remain asymptomatic with only laboratory abnormalities. We present the case of a 59-year-old man with sarcoidosis who was evaluated for an elevation of alkaline phosphatase. Laboratory test results revealed an alkaline phosphatase level of 230 U/L, with normal alanine aminotransferase, aspartate aminotransferase, bilirubin, and albumin. Computed tomography of the abdomen and pelvis with intravenous contrast of the liver showed a mildly enlarged liver. Liver biopsy sections showed steatosis, active steatohepatitis, and focal portal granuloma formation with asteroid body. The patient was scheduled regular liver function tests and clinical monitoring. Most patients with hepatic sarcoidosis remain asymptomatic with only laboratory abnormalities such as elevation of liver enzymes and alkaline phosphatase. Although liver involvement is common in gastrointestinal sarcoidosis, progression to liver cirrhosis is rare in such patients. While symptomatic patients may be managed with systematic prednisone, asymptomatic patients may require only laboratory and clinical monitoring.

Small Bowel Metastasis as a Presentation of Testicular Seminoma.

Testicular germ cell tumors account for 95% of testicular cancers in men with approximately 71,000 patients being diagnosed with testicular cancer every year. The overall survival of testicular germ cell tumors is approximately 95%. However, the prognosis becomes less favorable when distant metastasis is present. Gastrointestinal (GI) tract metastasis occurs in less than 5% of patients with non-seminomatous tumors, and in less than 1% in patients with pure seminomas. GI metastasis usually involves the colon, esophagus, and stomach with the most common symptoms of GI metastasis being diarrhea, nausea, vomiting, and obstruction. We discuss the case of a 42-year-old male patient with GI manifestations as the first presentation of testicular seminoma with metastasis to the small bowel. Computed tomography of the abdomen and pelvis revealed a small bowel mass, and the diagnosis was confirmed with histopathologic examination of endoscopic biopsy samples. The patient subsequently underwent chemotherapy treatment with close surveillance. Clinicians should maintain a high index of suspicion in the differential diagnosis of abdominal pain in young male patients, especially when associated with symptoms like unexplained weight loss, constitutional symptoms, and testicular pain or swelling. Metastasis to the GI tract from the testis should be promptly diagnosed and managed, as the overall survival rates can significantly decrease with the delay of diagnosis.

Marijuana use among adult liver transplant candidates and recipients.

BACKGROUND: Data regarding marijuana (MJ) use among liver transplant (LT) candidates are limited. We set out to determine the incidence and pre- and post-LT outcomes of adult LT candidates with a self-reported history of MJ use. METHODS: Baseline clinical characteristics, waitlist, and post-LT outcomes of adult LT candidates from January 2010 to March 2017 were compared. RESULTS: Among 2690 LT candidates, 630(23%) and 298(11%) reported a history of MJ use and use within the past 12 months, respectively. Although the proportion of MJ users increased over time(ß = .76, p = .03), the proportion listed and transplanted did not change. Listing for LT increased with male (OR 1.24, 95% CI 11.01-1.52), MELD score (OR 1.08, 95% CI 1.01-1.15), HCC (OR 1.83, 95% CI 1.39-2.41) but decreased among MJ users (OR 0.67, 95% CI 0.50-0.91, p = .01). The median time to listing was longer among MJ users compared to non-users (115 vs. 87 days, p < .0005). Post-LT survival was similar in 83 MJ users and 306 non-users. CONCLUSION: The proportion of MJ users among LT candidates is increasing. MJ users have a greater burden of psychosocial issues which may contribute to longer evaluations and lower rate of LT listing. Post-LT survival was not impacted by self-reported MJ use history.

Economic Implications of Hepatocellular Carcinoma Surveillance and Treatment: A Guide for Clinicians.

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, with significant morbidity and associated costs. Treatment allocation depends on the stage of diagnosis; however, resource utilization can be significant across all stages. We aimed to summarize the available data on the cost effectiveness of surveillance of and treatments for HCC in the context of current treatment guidelines. We performed a focused review of studies investigating the economic burden and cost effectiveness of HCC surveillance treatment modalities published between January 2000 and January 2019. The overall economic burden of HCC is increasing in the USA and in several countries worldwide due to its rising incidence and the proliferation of therapies. Liver transplantation is a cost-effective strategy for early-stage HCC treatment in selected patients. In settings where liver transplantation is not available or in patients awaiting transplant, ablative or locoregional therapies are cost effective with increases in quality-adjusted life-years. First-line therapy with sorafenib for advanced stage HCC is cost effective in the treatment of compensated cirrhosis. The cost effectiveness of recently approved systemic therapies for advanced HCC require further investigation. Existing studies have shown that guideline-recommended surveillance techniques and several available therapies for the treatment of HCC are cost effective; however, there are limitations in the literature, including reliance on suboptimal modeling with incomplete/simplified model structure or inadequate inputs. With increasing therapeutic options in patients with HCC, understanding their relative value is critical in designing HCC treatment algorithms.

Gender Disparities in Patients With Alcoholic Liver Disease Evaluated for Liver Transplantation.

BACKGROUND: The morbidity and mortality from alcohol-related liver disease (ALD) is increasing in the United States. However, little is known about gender differences in evaluation and listing for liver transplantation (LT) in patients with ALD. METHODS: This is a retrospective review of adult patients with ALD evaluated for LT at a single transplant center from January 1, 2010, to March 1, 2017. Univariate, multivariate, and time-series analyses were performed. RESULTS: Among the 949 patients with ALD evaluated, mean age was 53 years, 84% were Caucasian, and 33% were women. The median model for end-stage liver disease score was similar between the genders. Women were less likely to be listed for LT (10% versus 19%; P < 0.05). The proportion of women not listed due to active substance use was significantly higher versus men (42% versus 35%; P < 0.05), while the frequency of medical contraindications was comparable between the genders. During a median follow-up of 416 days (range: 0-2784), listed women with ALD were less likely to undergo transplantation (42% versus 47%; P < 0.05). CONCLUSIONS: Men with ALD were 95% more likely to be listed and 105% more likely to be transplanted compared to women with ALD. While men had more lifetime substance use and related consequences, women had more psychiatric comorbidities and were less likely to be listed due to active alcohol and opioid use. Early detection and effective treatment of psychiatric and substance use disorders in women with ALD may improve their transplant eligibility.

High prevalence of non-alcoholic fatty liver disease in patients with inflammatory bowel disease receiving anti-tumor necrosis factor therapy.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common in patients with inflammatory bowel disease (IBD). This study evaluated the prevalence of NAFLD and the associated risk factors among IBD patients who received anti-tumor necrosis factor (TNF) therapy. METHODS: Adult IBD patients receiving anti-TNF therapy (infliximab, adalimumab, certolizumab, golimumab) were enrolled. Hepatic steatosis was assessed by abdominal ultrasound. Patients with a history of excessive alcohol or recent steroid use were excluded. Univariate and multivariate analysis were performed. RESULTS: Eighty patients, 55% male, mean age 42±15 years, were enrolled. The sonographic prevalence of NAFLD was 54% (43/80), significantly higher than the general prevalence in the US adult population (30%) (P<0.0001). NAFLD patients had a significantly higher proportion of males, as well as greater body weight and body mass index, compared to non-NAFLD. The Crohns disease activity index (CDAI) was significantly higher among patients with NAFLD. Multivariate analysis demonstrated that a higher CDAI was independently associated with NAFLD, with an odds ratio of 1.6 (95% confidence interval 1.05-2.44; P=0.03). CONCLUSIONS: The presence of IBD is strongly associated with NAFLD. We identified a high prevalence of NAFLD among IBD patients receiving anti-TNF. CDAI was independently associated with hepatic steatosis. Further studies are still needed to evaluate the pathophysiology of NAFLD development and disease progression among IBD populations.

Understanding the Natural History of Hepatitis B Virus Infection and the New Definitions of Cure and the Endpoints of Clinical Trials.

Hepatitis B virus (HBV) infection is the most common chronic viral infection worldwide and remains a significant global health problem. Chronic HBV infection can progress to cirrhosis, liver failure, and hepatocellular carcinoma. Outcome of chronic HBV infections depends on the host, virus, and environmental factors. Although effective prophylactic vaccines and antiviral therapies exist, curative treatment is not yet available. Intense research into a cure for HBV is ongoing and proposed definitions of cure and endpoints for clinical trials evaluating "curative" therapy are discussed.

Impact of a Prohibitive Versus Restrictive Tobacco Policy on Liver Transplant Candidate Outcomes.

Tobacco use has been associated with poorer outcomes after liver transplantation (LT). Our study examined the effect on LT listing outcomes of a newly implemented policy prohibiting the use of all tobacco products compared with a prior restrictive policy. Medical records of consecutive adult patients evaluated for LT from January 2010 to July 2013 (era 1, n = 1344) and August 2013 to March 2017 (era 2, n = 1350) were reviewed. The proportion of LT candidates listed was the primary outcome. The mean age of the 2694 LT candidates was 54 ± 11 years, 60% were male, and the mean Model for End-Stage Liver Disease (MELD) score was 15 ± 7. Although the proportion of LT candidates who were smokers was significantly higher in era 2 (33% versus 23%; P < 0.005), the proportion of smokers listed for LT remained stable (13% versus 17%; P = 0.25). However, there were more smokers excluded for ongoing tobacco use in era 2 compared with era 1 (9.6% versus 4.4%; P = 0.001). Factors independently associated with LT listing included a diagnosis of hepatocellular carcinoma, being married, private insurance, absence of psychiatry comorbidity, and absence of tobacco, marijuana, or opiate use but evaluation during era 2 was not associated with LT listing. However, the median time to listing significantly increased over time, especially in smokers (from 65 to 122 days; P = 0.001), and this trend was independently associated with evaluation during era 2, a lower MELD score, not having children, and a lower level of education (P < 0.05). In conclusion, despite an increasing incidence of active smokers being referred for LT evaluation, the proportion of smoker candidates listed for LT was unchanged after instituting our prohibitive tobacco use policy. However, the time to get on the waiting list for smokers who were eventually listed was significantly longer due to the need to achieve complete tobacco cessation.

Prevalence of non-alcoholic fatty liver disease on computed tomography in patients with inflammatory bowel disease visiting an emergency department.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common in patients with inflammatory bowel disease (IBD). The purpose of this study was to further examine the prevalence of NAFLD in IBD patients. METHODS: We retrospectively reviewed the medical records of IBD patients who visited the emergency department because of abdominal pain between January 2009 and December 2014. These were compared with a group of 70 controls without IBD, matched for age and body mass index (BMI). Computed tomography data were analyzed for the presence or absence of hepatic steatosis. Patient with recent steroid or excessive alcohol use were excluded. Univariate and multivariate analyses were performed. RESULTS: NAFLD prevalence was 44% (31/70) in the IBD group vs. 16% (11/70) in controls (P<0.001). There was no significant difference between the 2 groups in age, sex distribution, BMI, presence of diabetes, or levels of serum transaminases, serum albumin or platelets. In multivariate analysis, the presence of IBD was independently associated with NAFLD (odds ratio 4.53, 95% confidence interval 2.00-10.26; P=0.002). CONCLUSIONS: The presence of IBD is strongly and independently associated with NAFLD. Systemic inflammation and alteration of the intestinal microbiome have been proposed as mechanisms, but further studies are needed to better elucidate the pathophysiology.

Colovesical Fistula: An Unusual Complication of Cytomegalovirus Colitis.

Cytomegalovirus (CMV) is a double-stranded DNA virus that is associated with clinically significant disease in patients with advanced immunosuppression, particularly those with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). End-organ disease with CMV is classically associated with a CD4 cell count less than 50 cells/microliter. CMV colitis is the second most common manifestation of end-organ disease in this patient population. CMV-associated enteric fistula is a rare complication that has been described in only a few case reports in the literature. These cases describe gastrocolic, enterocutaneous, enterocolic, rectovaginal, and colocutaneous fistulae. However, colovesical fistula has not been described previously. Here, we report the first case of CMV-associated colovesical fistula in a patient with HIV infection and AIDS.