History of depression is associated with higher prevalence of hepatic encephalopathy in patients with advanced liver disease.

INTRODUCTION: Depression and hepatic encephalopathy are common in patients with advanced liver disease. Although these are distinct entities, they share several clinical features. In this analysis, we evaluated whether having a history of depression was associated with developing hepatic encephalopathy in patients with advanced liver disease METHODS: : We performed a retrospective cohort study of patients with cirrhosis referred for liver transplant. Patients were categorized into one of two groups: "history of depression" or "no history of depression." Multivariable logistic regression was used to evaluate history of depression as a potential independent predictor of hepatic encephalopathy RESULTS: : A total of 447 patients were included, of which 158 (35%) had a history of depression and 233 (52%) had experienced hepatic encephalopathy. Hepatic encephalopathy was more common in patients with a history of depression (63% vs. 46%, p<0.01). On multivariate analyses, depression history was independently associated with hepatic encephalopathy (aOR 2.3, 95% CI 1.4-3.6), along with alcohol associated cirrhosis (aOR 2.0, 95% CI 1.3-3.2), history of ascites (aOR 3.5, 95% CI 2.1-5.9) and presence of a trans-jugular intra-hepatic shunt (aOR 9.2, 95% CI 2.6-32.6). The relationship between history of depression and hepatic encephalopathy remained significant in a subgroup of patients with alcohol associated liver disease (p=0.04). Among those with a history of depression, SNRI prescription was more common in the hepatic encephalopathy group (14% vs. 3%), and SNRI prescription was as an independent predictor of hepatic encephalopathy in the multivariable model (OR 4.8, 95% CI 1.0, 24.6) CONCLUSION: : Patients with a history of depression were significantly more likely to experience hepatic encephalopathy. Patients with cirrhosis who have a history of depression should be closely monitored for the development of hepatic encephalopathy. Further research is needed to understand the nuances of this relationship and whether the use of certain psychiatric medications may modify the relationship between depression and hepatic encephalopathy.

Alcohol associated liver disease and bariatric surgery: Current perspectives and future directions.

Bariatric surgery is a routinely performed procedure and is associated with a reduction in all-cause mortality in patients with obesity. However, bariatric surgery has also been linked to increased alcohol use with up to 30% of these patients developing alcohol use disorder (AUD). The mechanism of AUD after bariatric surgery is multifactorial and includes anatomic, metabolic, and neurohumoral changes associated with post-surgical anatomy. These patients are at increased risk of alcohol associated liver disease and, in some cases, require liver transplantation. In this article, we provide a scoping review of epidemiology, pathophysiology, and clinical outcomes of alcohol-related health conditions after bariatric surgery.

Management of alcohol-associated liver disease and alcohol use disorder in liver transplant candidates and recipients: Challenges and opportunities.

Alcohol-associated liver disease poses a significant global health burden, with rising alcohol consumption and prevalence of alcohol use disorder (AUD) contributing to increased morbidity and mortality. This review examines the challenges and opportunities in the care of candidates and recipients of liver transplant (LT) with AUD. Despite advancements in posttransplant patient survival, the risk of disease recurrence and alcohol relapse remains substantial. Several challenges have been identified, including (1) rising disease burden of alcohol-associated liver disease, variable transplant practices, and systemic barriers; (2) disparities in mental health therapy access and the impact on transplant; (3) variable definitions, underdiagnosis, and stigma affecting access to care; and (4) post-LT relapse, its risk factors, and consequential harm. The review focuses on the opportunities to improve AUD care for candidates and recipients of LT through effective biochemical monitoring, behavioral and pharmacologic approaches, creating Centers of Excellence for post-LT AUD care, advocating for policy reforms, and ensuring insurance coverage for necessary services as essential steps toward improving patient outcomes. The review also highlights unmet needs, such as the scarcity of addiction specialists, and calls for further research on personalized behavioral treatments, digital health, and value-based care models to optimize AUD care in the LT setting.

Sex differences in chronic liver disease and benign liver lesions.

The epidemiology, natural history, and therapeutic responses of chronic liver diseases and liver lesions often vary by sex. In this review, we summarize available clinical and translational data on these aspects of the most common liver conditions encountered in clinical practice, including the potential contributions of sex hormones to the underlying pathophysiology of observed differences. We also highlight areas of notable knowledge gaps and discuss sex disparities in access to liver transplant and potential strategies to address these barriers. Given established sex differences in immune response, drug metabolism, and response to liver-related therapies, emerging clinical trials and epidemiological studies should prioritize dedicated analyses by sex to inform sex-specific approaches to liver-related care.

The progression of hepatorenal syndrome-acute kidney injury in acute alcohol-associated hepatitis: renal outcomes after liver transplant.

Background: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a complication of advanced liver disease in patients with ascites and circulatory dysfunction. Little data remain on the relationship between HRS-AKI outcomes and different etiologies of liver disease post-liver transplant (LT). Objectives: The primary aim was to evaluate the effect of HRS-AKI on renal outcomes in patients with acute alcohol-associated hepatitis (AAH) compared to chronic liver disease (CLD) after LT. The secondary aim was to evaluate the impact of acuity and chronicity of alcohol-associated liver disease in patients with HRS-AKI post-LT renal outcomes. Design: A retrospective observational study of patients undergoing urgent inpatient liver transplant evaluation (LTE) for cirrhosis and AAH at single academic LT center between October 2017 and July 2021 was conducted. Methods: Patients with HRS-AKI were selected based on indication for LTE: acute AAHHRS or CLDHRS. CLDHRS was categorized by disease etiology: cirrhosis due to alcohol (A-CLDHRS) versus cirrhosis from other causes (O-CLDHRS). CLD patients without HRS-AKI were labeled CLDno HRS. Results: A total of 210 subjects underwent LTE; 25% were evaluated for AAH and 75% were evaluated for CLD. Hepatorenal syndrome was more common in subjects evaluated for AAH (37/47) than CLD (104/163) (78.7 versus 63.8%, p = 0.04). For the primary outcome, AAHHRS subjects required ⩾30 days post-LT renal replacement therapy (RRT) more often than subjects with CLDHRS (p = 0.02) and CLDno HRS (p < 0.01). There was no significant difference in other forms of long-term renal outcomes including kidney transplant referral and kidney transplant among cohorts. In subgroup analysis, 30-days post-LT RRT was more common in AAHHRS than in A-CLDHRS (p = 0.08). Logistic regression showed that AAHHRS conferred a 20× and 3.3× odds of requiring ⩾30 days post-LT RRT compared to CLDno HRS and CLDHRS, respectively. Postoperative complications were similar across cohorts, but had a significant effect on 30-day renal outcome post-LT. Conclusions: Patients with AAH were more likely to develop HRS and require RRT pre- and post-LT at our center. The etiology of hepatic decompensation and postoperative complications affect renal recovery post-LT. The systemic inflammation of AAH in addition to conditions favoring renal hypoperfusion may contribute to the unfavorable outcomes of HRS-AKI after LT in this patient population.

Delayed referral for liver transplant evaluation worsens outcomes in chronic liver disease patients requiring inpatient transplant evaluation.

BACKGROUND: Indications to refer patients with cirrhosis for liver transplant evaluation (LTE) include hepatic decompensation or a model for end stage liver disease (MELD-Na) score ≥ 15. Few studies have evaluated how delaying referral beyond these criteria affects patient outcomes. AIM: To evaluate clinical characteristics of patients undergoing inpatient LTE and to assess the effects of delayed LTE on patient outcomes (death, transplantation). METHODS: This is a single center retrospective cohort study assessing all patients undergoing inpatient LTE (n = 159) at a large quaternary care and liver transplant center between 10/23/2017-7/31/2021. Delayed referral was defined as having prior indication (decompensation, MELD-Na ≥ 15) for LTE without referral. Early referral was defined as referrals made within 3 mo of having an indication based on practice guidelines. Logistic regression and Cox Hazard Regression were used to evaluate the relationship between delayed referral and patient outcomes. RESULTS: Many patients who require expedited inpatient LTE had delayed referrals. Misconceptions regarding transplant candidacy were a leading cause of delayed referral. Ultimately, delayed referrals negatively affected overall patient outcome and an independent predictor of both death and not receiving a transplant. Delayed referral was associated with a 2.5 hazard risk of death. CONCLUSION: Beyond initial access to an liver transplant (LT) center, delaying LTE increases risk of death and reduces risk of LT in patients with chronic liver disease. There is substantial opportunity to increase the percentage of patients undergoing LTE when first clinically indicated. It is crucial for providers to remain informed about the latest guidelines on liver transplant candidacy and the transplant referral process.

Kidney disease in patients with chronic liver disease: Does sex matter?

Kidney disease in patients with liver disease is serious and increases mortality. Up to 50% of patients hospitalized experience an episode of acute kidney injury. In general, men with liver disease are thought to be at increased risk of kidney disease. However, this association should be considered with caution because most studies use creatinine-based inclusion criteria, which is negatively biased against women. In this review, we synthesize data on sex differences in kidney disease in patients with chronic liver disease in the clinical setting and discuss potential physiologic underpinnings.

Palliative Care and Advanced Directive Practices at Liver Transplant Centers in the United States.

Introduction: Patients with cirrhosis have a decreased quality of life due to decompensations of their underlying disease. While liver transplantation (LT) has improved outcomes and quality of life for patients with cirrhosis, many patients die or are delisted before transplant. Despite high morbidity and mortality, palliative care (PC) services are underutilized for patients with cirrhosis. Methods: To evaluate current PC and advance care practices at LT centers, a survey was designed and sent to 115 U.S. LT centers. Results: Forty-two surveys were completed (37% response rate) with representation from all United Network for Organ Sharing regions. Nineteen institutions (46.3%) reported 100 or fewer waitlisted patients, while 22 (53.6%) reported more than 100. Twenty-five institutions (59.5%) reported 100 or fewer transplants performed in the last year and 17 (40.5%) reported more than 100. Nineteen transplant centers (45.2%) require patients to discuss advance directives as part of the LT evaluation, while 23 (54.8%) do not. Only 5 centers (12.2%) reported having a dedicated PC provider as part of their transplant team and only 2 reported requiring patients to meet with a PC provider as part of the LT evaluation process. Discussion: This study shows many LT centers do not engage their patients in advance directive discussions and highlights the underutilization of PC services in the LT evaluation process. Our results also show minimal advancement in the collaboration between PC and transplant hepatology over the last decade. Encouraging or requiring LT centers to hold advance directive discussions and incorporate PC providers into the transplant team is a recommended area for improvement.

COVID-19 associated liver injury: A general review with special consideration of pregnancy and obstetric outcomes.

Liver injury is an increasingly recognized extra-pulmonary manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Coronavirus disease 2019 (COVID-19) associated liver injury (COVALI) is a clinical syndrome encompassing all patients with biochemical liver injury identified in the setting of SARS-CoV-2 infection. Despite profound clinical implications, its pathophysiology is poorly understood. Unfortunately, most information on COVALI is derived from the general population and may not be applicable to individuals under-represented in research, including pregnant individuals. This manuscript reviews: Clinical features of COVALI, leading theories of COVALI, and existing literature on COVALI during pregnancy, a topic not widely explored in the literature. Ultimately, we synthesized data from the general and perinatal populations that demonstrates COVALI to be a hepatocellular transaminitis that is likely induced by systemic inflammation and that is strongly associated with disease severity and poorer clinical outcome, and offered perspective on approaching transaminitis in the potentially COVID-19 positive patient in the obstetric setting.

Alcohol Consumption: Medical Implications, the Liver and Beyond.

Alcohol consumption represents a major factor of morbidity and mortality, with a wide range of adverse medical implications that practically affect every organ system. It is the fifth major cause of deaths in men and women and causes up to 139 million disability-adjusted life years. Solid evidence places the risk as undoubtedly correlated to the length of time and amount of alcohol consumption. While alcohol-related liver disease represents one of the most studied and well-known consequences of alcohol use, the term itself embodies a wide spectrum of progressive disease stages that are responsible for almost half of the liver-related mortality worldwide. We discuss the staged alcohol-related fatty liver, alcohol-related steatohepatitis and, finally, fibrosis and cirrhosis, which ultimately may end up in a hepatocellular carcinoma. Other comorbidities such as acute and chronic pancreatitis; central nervous system; cardiovascular, respiratory and endocrine system; renal disease; urological pathologies; type 2 diabetes mellitus and even infectious diseases are reviewed in their relation to alcohol consumption. This article reviews the impact of alcohol use on different systems and organs, summarizing available evidence regarding its medical implications. It examines current basic and clinical data regarding mechanisms to highlight factors and processes that may be targetable to improve patient outcomes. Although alcohol use is a part of many cultural and social practices, as healthcare providers we must identify populations at high risk of alcohol abuse, educate patients about the potential alcohol-related harm and provide appropriate treatment.

Treatment of Acute Graft-versus-Host Disease in Liver Transplant Recipients.

Acute graft-versus-host disease (aGvHD) is a rare complication of liver transplantation associated with high morbidity and mortality. Death typically occurs due to complications related to severe infection, shock, and multiorgan failure. The clinical presentation involves dysfunction of multiple organ systems with overlapping symptoms that often results in a diagnostic delay. As there are a limited number of cases reported in the literature, there are no clear guidelines for treatment. Many different therapeutic measures have been utilized that target various immune system pathways, but steroids remain the first line of therapy. We report on two patients who developed aGvHD after liver transplantation who were treated with ruxolitinib, a novel Janus kinase 1/2 (JAK) inhibitor that has been shown to improve outcomes in steroid refractory cases of aGvHD after allogenic hematopoietic stem cell transplantation. We reviewed the literature to discuss various therapeutic options currently available for aGvHD after liver transplantation.

Liver transplant evaluation for fulminant liver failure due to acute hepatitis A infection: Case series and literature review.

Hepatitis A virus can cause liver damage ranging from mild illness to fulminant hepatic failure, constituting 0.35% of all cases of fulminant liver failure. While rates of spontaneous remission are higher for hepatitis A, recent outbreaks attributable to vaccine shortages in highly populated urban cities plagued by insufficient affordable housing and inaccessible sanitation, and changes in the epidemiology of viral strains have resulted in increased hospitalizations and deaths. While the prognosis for patients with FHF has improved since the introduction of transplantation, the decision to transplant is often difficult to reach. We present five patients with HAV and subsequent FHF, one of whom successfully received a liver transplant. We have reviewed all published cases of HAV FHF in the literature and report ten patients, seven of whom received liver transplantation. There are few predictive models that attempt to distinguish between fulminant hepatitis A and spontaneous recovery. Patients found to have positive hepatitis A IgM, encephalopathy, worsening LFT's and coagulation should be monitored closely and referred to transplant centers urgently for management.

Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group.

BACKGROUND & AIMS: While abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease. METHODS: We conducted a survey of primarily (89%) hepatology and gastroenterology providers within (80%) and outside the United States (20%). Surveys were sent to 921 providers with 408 complete responses (44%), of whom 343 (80%) work in a tertiary liver transplant center. RESULTS: While alcohol screening rates in liver disease patients was nearly universal, less than half of providers reported practicing with integrated addiction providers, using alcohol biomarkers and screening tools. Safe alcohol use by liver disease patients was felt to exist by 40% of providers. While 60% of providers reported referring AUD patients for behavioral therapy, 71% never prescribed AUD pharmacotherapy due to low comfort (84%). Most providers (77%) reported low addiction education and 90% desired more during GI/hepatology fellowship training. Amongst prescribers, baclofen was preferred, but with gaps in pharmacotherapy knowledge. Overall, there was low adherence to the 2019 AASLD practice guidance for ALD, although higher in hepatologists and experienced providers. CONCLUSIONS: While our survey of hepatology and gastroenterology providers demonstrated higher rates of alcohol screening and referrals for behavioral therapy, we found low rates of prescribing AUD pharmacotherapy due to knowledge gaps from insufficient education. Further studies are needed to assess interventions to improve provider alignment with best practices for treating patients with AUD and ALD.

Outcomes of Liver Transplantation Among Older Recipients With Nonalcoholic Steatohepatitis in a Large Multicenter US Cohort: the Re-Evaluating Age Limits in Transplantation Consortium.

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65 years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3 years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P < 0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1 year and 82.4% at 3 years compared with 88.9% at 1 year and 80.4% at 3 years for non-NASH patients (log-rank P = 0.58 and P = 0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

Sarcopenia is associated with longer hospital stay and multiorgan dysfunction in alcoholic hepatitis.

INTRODUCTION: Excessive alcohol consumption has steadily risen to become the third leading cause of preventable death in the USA. One consequence of heavy alcohol use recently under considerable investigation is alcoholic hepatitis. Although many risk factors for developing alcoholic hepatitis have been documented, our aim in this study was to examine the potential association between sarcopenia and severity, mortality, 30 days readmission rate, complication, infections and length of hospital stay in alcoholic hepatitis patients. METHODS: A retrospective analysis was performed at a large, academic hospital in 194 alcoholic hepatitis patients aged 18-60 who had cross-sectional computed tomography imaging and met our clinical definition of alcoholic hepatitis. The fifth percentile of the psoas muscle index was used as a cutoff for sarcopenia. RESULTS: One hundred ninety-four patients met the criteria for alcoholic hepatitis and had cross-sectional imaging. Higher Model for End-Stage Liver disease score was found in the sarcopenia group when compared to the non-sarcopenia group (mean Model for End-Stage Liver disease 21.5 and 24.2, respectively, P = 0.03). Sarcopenia also correlated with significantly longer hospital stay; the average length of stay in the sarcopenia group was 17.2 days while the non-sarcopenia patients had an average of 12.4 days. We found higher risk of developing pneumonia, sepsis and hepatic encephalopathy in sarcopenic patients. CONCLUSION: Alcoholic hepatitis patients with sarcopenia have significantly worse outcomes when compared with the patients without sarcopenia, including a severe form of alcoholic hepatitis, longer hospital stays, higher risk of developing pneumonia, sepsis and hepatic encephalopathy.

Segmental Distribution of Hepatocellular Carcinoma Correlates with Microvascular Invasion in Liver Explants Undergoing Transplantation.

INTRODUCTION: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients is a poor prognostic factor after liver transplantation and/or resection. Any correlation between MVI and segmental location of HCC has yet to be studied. Our aim is to evaluate the segmental location of HCC and any correlation with the presence of MVI, portal vein thrombosis (PVT) in explanted livers, and the recurrence of HCC after transplantation. Another objective of the study is to assess the treatment history (ablation or transarterial chemoembolization (TACE)) and size of the tumor with respect to the risk of MVI. METHODS: A single center, retrospective chart review, including 98 HCC patients, aged 18 years and older who had liver transplantation in our institute between 2012 and 2017. We reviewed the radiological images of the HCC tumors, the pathological findings of the explanted livers, and the follow-up imaging after transplantation. RESULTS: 98 patients with the diagnosis of HCC underwent liver transplantation between 2012 and 2017. The mean age of the cohort was 63 ± 8.2. Males represented 75% and Caucasian race represented 75% of the cohort. The most common etiology of cirrhosis was chronic hepatitis C virus infection followed by alcohol abuse and nonalcoholic steatohepatitis (NASH) with percentages of 50%, 23%, and 10%, respectively. Microvascular invasion was found in 16% of the patients while PVT and the recurrence of HCC were found in 17% and 6 % of the cohort, respectively. MVI was found in 10 single HCC and 6 multifocal HCC. Right lobe HCC had more MVI when compared to the left and multilobar HCC, with percentages of 11%, 2%, and 3%, respectively. Localization of HCC in segment 8 was associated with the highest percentage of MVI when compared to all other segments. The risk of MVI in segment 8 HCC was 3.5 times higher than the risk from the other segments (p=0.002) while no vascular invasion was found in segments 1, 3, and 5. The risk of vascular invasion in untreated HCC is 3 times the risk in treated HCC (P=0.03). CONCLUSION: Our data indicate that the risk of microvascular invasion is highest in tumors localized to segment 8. The size and number of HCC tumors were not associated with an increased risk of microvascular invasion.

Real World Experience of Drug Induced Liver Injury in Patients Undergoing Chemotherapy.

BACKGROUND & AIM: To better understand the clinical significance of drug induced liver injury (DILI) during chemotherapy, we examined the epidemiology, incidence, and treatment effects of DILI in patients undergoing chemotherapy for genitourinary malignancies over a two-year period. METHODS: We conducted a retrospective review of 284 patients who underwent chemotherapy for prostate, bladder, testicular and renal cell carcinomas over a two year period. Those with abnormal or absent liver test (LT) results prior to chemotherapy initiation were excluded. Post chemotherapy LT results were defined as DILI if ALT>3× ULN and/or total bilirubin (TB)>2× ULN, in the absence of other more likely causes of elevated LT. RESULTS: The cumulative incidence of DILI in the total study population was 6.1% (17/284), and in the population who had appropriate LT performed it increased to 18.9% (17/90). Chemotherapeutic agents were determined to be the cause of DILI in 82% (14/17) of patients, and the treatment plans were changed in 59% (10/17) of patients. CONCLUSION: In this real world study, the cumulative incidence of DILI was higher than commonly reported in clinical trials, and the majority of affected patients had to have their cancer treatment altered or interrupted.

Ectopic pancreas: a rare cause of abdominal pain.

We present a case of recurrent abdominal pain due to an ectopic or heterotopic pancreas. Heterotopic pancreas (HP) is the presence of histologic pancreatic tissue outside its normal location without any anatomic or vascular continuity with the pancreas. The frequency of HP has been estimated as 0.6-13.7%. Most are found in the duodenum, stomach, andjejunum. The exact mechanism remains controversial but it has been theorized that it most likely arises congenitally during embryonic development. The elevations of amylase and lipase levels are modest due to the small volume of pancreatic tissue in the HP. Therefore, diagnostic modalities including barium swallow, upper-gastrointestinal series, CT, EUS, and MRCP can be used when suspecting HP. The need for treatment is based on symptoms and definitive diagnosis, especially when the possibility of malignancy exists. Asymptomatic causes need not require treatment.