Background: Patient survival after liver transplantation is lower in donor-recipient race mismatched patients for indications other than primary sclerosing cholangitis. Objectives: To determine if survival is lower after liver transplantation in donor-recipient race mismatched recipients with primary sclerosing cholangitis. Methods: The Organ Procurement and Transplantation Network database was analyzed for deceased donor adult liver transplant recipients with primary sclerosing cholangitis. Graft and patient survival by donor-recipient race were estimated using Kaplan-Meier survival method and compared using the log-rank test. Multivariable analysis was performed using Cox regression. Results: From 2002 to 2018, 5-year patient survival in White (n = 2223) and Black recipients (n = 491), was 89.8% and 87.1%, respectively. Five-year patient survival for the donor-recipient pairs, White-White (n = 1622), Black-Black (n = 110), Black-White (n = 335), and White-Black (n = 314) was 90.8%, 91.1%, 87.1%, and 86.0%, respectively, p = 0.026. In multivariable analysis, 5-year patient mortality was higher in Black recipients of White donors [HR 1.69, 95% CI 1.16, 2.45], compared to White recipients of White donors. Conclusions: Five-year patient mortality after deceased donor liver transplantation for primary sclerosing cholangitis is higher in Black recipients who received livers from White donors compared to matched White donors and recipients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is quickly emerging as a global public health concern, primarily fueled by the rising consumption of processed and ultraprocessed foods. This global health issue, showing a 50% increase in prevalence over two decades to 38% of the global population, is now the second most common cause of end-stage liver disease and liver transplants in Europe and the United States and an emerging driver of hepatocellular carcinoma, particularly in Hispanic and non-Hispanic White populations. Its prevalence, driven by increasing consumption of ultraprocessed foods, obesity, and sedentary lifestyles, disproportionately impacts racial and ethnic minorities, exacerbating health disparities. Genetic polymorphisms contribute to interindividual and interethnic variations in disease susceptibility. However, genetics alone cannot explain the disparities; social determinants, food insecurity, and limited access to healthcare also play pivotal roles. MASLD prevalence is rising fastest among older adults and Hispanic women, particularly in low-income and rural communities. Despite advances in pharmacologic therapies, access remains inequitable. Lifestyle interventions remain essential. Integrating genetic and epigenetic insights into risk stratification and treatment can support precision medicine approaches. A comprehensive MASLD management framework must include policy reforms to address food deserts, healthcare access, and socioeconomic inequities. Culturally tailored public health programs and personalized care models are crucial for enhancing outcomes in vulnerable populations. In this narrative review, we examine the multifaceted contributors to MASLD pathogenesis and disparities, with a focus on genetic risk, social determinants, dietary patterns, and cancer risk and policy-level interventions to inform more equitable liver health strategies.

BACKGROUND Obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC) and may influence its outcomes. However, after diagnosis of HCC, like other malignancies, the obesity paradox may exist where higher body mass index (BMI) may in fact confer a survival benefit. This is frequently observed in patients with advanced HCC and cirrhosis, who often present late with advanced tumor features and cancer related weight loss. AIM To explore the relationship between BMI and survival in patients with cirrhosis and HCC. METHODS This is a retrospective cohort study of over 2500 patients diagnosed with HCC between 2009-2019 at two United States academic medical centers. Patient and tumor characteristics were extracted manually from medical records of each institutions' cancer registries. Patients were stratified according to BMI classes: < 25 kg/m2 (lean), 25-29.9 kg/m2 (overweight), and > 30 kg/m2 (obese). Patient and tumor characteristics were compared according to BMI classification. We performed an overall survival analysis using Kaplan Meier by the three BMI classes and after adjusting for Milan criteria. A multivariable Cox regression model was then used to assess known risk factors for survival in patients with cirrhosis and HCC. RESULTS A total of 2548 patients with HCC were included in the analysis of which 11.2% (n = 286) were classified as non-cirrhotic. The three main BMI categories: Lean (n = 754), overweight (n = 861), and obese (n = 933) represented 29.6%, 33.8%, and 36.6% of the total population overall. Within each BMI class, the non-cirrhotic patients accounted for 15% (n = 100), 12% (n = 94), and 11% (n = 92), respectively. Underweight patients with a BMI < 18.5 kg/m2 (n = 52) were included in the lean cohort. Of the obese cohort, 42% (n = 396) had a BMI ≥ 35 kg/m2. Out of 2262 patients with cirrhosis and HCC, 654 (29%) were lean, 767 (34%) were overweight, and 841 (37%) were obese. The three BMI classes did not differ by age, MELD, or Child-Pugh class. Chronic hepatitis C was the dominant etiology in lean compared to the overweight and obese patients (71%, 62%, 49%, P < 0.001). Lean patients had significantly larger tumors compared to the other two BMI classes (5.1 vs 4.2 vs 4.2 cm, P < 0.001), were more likely outside Milan (56% vs 48% vs 47%, P < 0.001), and less likely to undergo transplantation (9% vs 18% vs 18%, P < 0.001). While both tumor size (P < 0.0001) and elevated alpha fetoprotein (P < 0.0001) were associated with worse survival by regression analysis, lean BMI was not (P = 0.36). CONCLUSION Lean patients with cirrhosis and HCC present with larger tumors and are more often outside Milan criteria, reflecting cancer related cachexia from delayed diagnosis. Access to care for hepatitis C virus therapy and liver transplantation confer a survival benefit, but not overweight or obese BMI classifications.

BACKGROUND & AIMS:Hospitalized patients with cirrhosis frequently undergo multiple procedures. The risk of procedural-related bleeding remains unclear, and management is not standardized. We conducted an international, prospective, multicenter study of hospitalized patients with cirrhosis undergoing nonsurgical procedures to establish the incidence of procedural-related bleeding and to identify bleeding risk factors. METHODS:Hospitalized patients were prospectively enrolled and monitored until surgery, transplantation, death, or 28 days from admission. The study enrolled 1187 patients undergoing 3006 nonsurgical procedures from 20 centers. RESULTS:A total of 93 procedural-related bleeding events were identified. Bleeding was reported in 6.9% of patient admissions and in 3.0% of the procedures. Major bleeding was reported in 2.3% of patient admissions and in 0.9% of the procedures. Patients with bleeding were more likely to have nonalcoholic steatohepatitis (43.9% vs 30%) and higher body mass index (BMI; 31.2 vs 29.5). Patients with bleeding had a higher Model for End-Stage Liver Disease score at admission (24.5 vs 18.5). A multivariable analysis controlling for center variation found that high-risk procedures (odds ratio [OR], 4.64; 95% confidence interval [CI], 2.44-8.84), Model for End-Stage Liver Disease score (OR, 2.37; 95% CI, 1.46-3.86), and higher BMI (OR, 1.40; 95% CI, 1.10-1.80) independently predicted bleeding. Preprocedure international normalized ratio, platelet level, and antithrombotic use were not predictive of bleeding. Bleeding prophylaxis was used more routinely in patients with bleeding (19.4% vs 7.4%). Patients with bleeding had a significantly higher 28-day risk of death (hazard ratio, 6.91; 95% CI, 4.22-11.31). CONCLUSIONS:Procedural-related bleeding occurs rarely in hospitalized patients with cirrhosis. Patients with elevated BMI and decompensated liver disease who undergo high-risk procedures may be at risk to bleed. Bleeding is not associated with conventional hemostasis tests, preprocedure prophylaxis, or recent antithrombotic therapy.

Cardiac diseases are one of the most common causes of morbidity and mortality following liver transplantation (LT). Prior studies have shown that cardiac diseases affect close to one-third of liver transplant recipients (LTRs) long term and that their incidence has been on the rise. This rise is expected to continue as more patients with advanced age and/or non-alcoholic steatohepatitis undergo LT. In view of the increasing disease burden, a multidisciplinary initiative was developed to critically review the existing literature (between January 1, 1990 and March 17, 2021) surrounding epidemiology, risk assessment, and risk mitigation of coronary heart disease, arrhythmia, heart failure, and valvular heart disease and formulate practice-based recommendations accordingly. In this review, the expert panel emphasizes the importance of optimizing management of metabolic syndrome and its components in LTRs and highlights the cardioprotective potential for the newer diabetes medications (e.g., sodium glucose transporter-2 inhibitors) in this high-risk population. Tailoring the multidisciplinary management of cardiac diseases in LTRs to the cardiometabolic risk profile of the individual patient is critical. The review also outlines numerous knowledge gaps to pave the road for future research in this sphere with the ultimate goal of improving clinical outcomes.

INTRODUCTION: The impact of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) on burden of cirrhotic and noncirrhotic hepatocellular carcinoma (HCC) has not been examined. We assessed recent trends in liver disease etiologies of HCC and proportion of noncirrhotic HCC since DAAs introduction. METHODS: Clinical characteristics including presence or absence of underlying cirrhosis were collected from 2,623 patients diagnosed with HCC between 2009 and 2019 at 2 large US centers. Logistic regression was performed to investigate the annual trends of HCC due to different liver diseases and proportions of noncirrhotic cases. RESULTS: In the DAA era (2014–2019), annual decline in HCV-HCC (odds ratio [OR] = 0.93, 95% confidence interval [CI] 0.88–0.99, P = 0.019), without change in trends of other liver diseases–related HCC, was observed. Annual increase in noncirrhotic HCC (OR 1.13, 95% CI 1.03–1.23, P = 0.009) and decline in cirrhotic HCC (OR 0.89, 95% CI 0.81–0.97, P = 0.009) along with similar trends for HCV-HCC—increase in noncirrhotic cases (OR 1.35, 95% CI 1.08–1.69, P = 0.009) and decrease in cirrhotic cases (OR 0.92, 95% CI 0.86–0.98, P = 0.012)—were observed during the DAA era. Compared with the pre-DAA era, HCC resection rate increased (10.7% vs 14.0%, P = 0.013) whereas liver transplantation rate decreased (15.1% vs 12.0%, P = 0.023) in the DAA era. DISCUSSION: Since introduction of DAAs, proportions of cirrhotic HCC have decreased, whereas proportions of noncirrhotic HCC have increased. These new trends were associated with change in utilization of liver resection and transplantation for HCC. The impact of changing patterns of DAA use on these trends will require further study.

BACKGROUND & AIM:Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. METHODS:In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. RESULTS:A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. CONCLUSIONS:Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS. GOV IDENTIFIER:NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

INTRODUCTIONHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further.METHODSPatients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria.RESULTSOf 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031).DISCUSSIONThe frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non‐Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi‐square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two‐tailed P < 0.05 considered statistically significant. Of 5,327 patients, 4,217 met inclusion criteria, of whom 12.3% were Hispanic patients. Compared to their non‐Hispanic White counterparts, Hispanic patients were older at age of diagnosis (mean ± SD, 64.2 ± 10.9 vs. 61.9 ± 10.5 years; P < 0.0001), with higher body mass index (29.6 ± 6.5 vs. 28.8 ± 5.9 kg/m2; P = 0.01), and were more likely to have diabetes and hypertension. Hispanic patients had significantly more nonalcoholic fatty liver disease and alcohol‐related liver disease (both P < 0.0001). Hispanic patients presented with larger tumors, more advanced stage disease, and increased rates of macrovascular invasion and extrahepatic spread. HCCs in Hispanic patients were less likely to be within Milan criteria (26% vs. 38%; P < 0.0001) and were less likely to be treated with resection (9% vs. 13%; P = 0.03) or transplantation (8% vs. 19%; P < 0.0001). Hispanic patients had a median overall survival of 1.4 years (95% confidence interval [CI], 1.22‐1.56), which was similar to that of non‐Hispanic White patients (1.3 years; 95% CI, 1.26‐1.41; P = 0.07). Conclusion: Hispanic patients with HCC were more likely to have metabolic risk factors for chronic liver disease, including obesity. Despite diagnosis at more advanced stages with less curative intervention than non‐Hispanic White patients, median overall survival was similar between groups.

Cytomegalovirus (CMV) is a common opportunistic infection in solid organ transplant (SOT) recipients in the first 6 months after transplant. Late onset CMV infection or disease outside the classical risk period is uncommon and can present with atypical signs and symptoms. Here, we report a case of late onset CMV presenting as a colonic stricture more than 10 years after liver transplantation in the absence of traditional CMV risk factors. We also briefly review CMV colitis presenting as a mass or stricture in SOT recipients.

INTRODUCTION: The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. METHODS: Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. RESULTS: A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P < 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P < 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P < 0.001). DISCUSSION: HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.

INTRODUCTION: Yolk sac tumors (YST) are malignant germ cell tumors commonly arising from the testes or ovaries. Due to their rarity, they are not considered in the differential for hepatic tumors. Diagnosis relies on histology. We report 2 interesting cases of primary hepatic YST. CASE DESCRIPTION/METHODS: Case 1: A 60-year-old African American male presented with right upper quadrant pain for 4 weeks. Evaluation was significant for elevated ALP, AST, and ALT. Acute viral hepatitis panel was negative. CT was significant for multiple infiltrative masses in a non-cirrhotic liver with the largest being 27 cm. AFP was noted to be >13,500 ng/mL. A biopsy revealed primary YST of the liver. He received 4 cycles of VIP with noted improvement in LFTs. Case 2: A 77-year-old female presented with right upper quadrant pain and a 10 lb weight loss over several weeks. Evaluation demonstrated elevated ALP. AFP was noted to be 1.1 million ng/mL. A CT demonstrated multi focal ill-defined hypodense solid hepatic masses, the largest measuring 12.9 cm. A biopsy was consistent with YST. She was started on carboplatin and etoposide, however she rapidly declined after the first cycle of chemotherapy. DISCUSSION: YST is a non-seminomatous germ cell tumor composed of primitive germ cells predominantly arising from the testes or ovaries. However, there have been reports of extragonadal sites such as mediastinum, bladder, and pineal gland. First reported in 1975, YST are more common in young females, Asian ethnicity, and respond well to chemotherapy. In contrast, hepatocellular carcinoma (HCC) occur more commonly in males, >50 years old, and respond poorly to systemic chemotherapy. Both HCC and YST can present in non-cirrhotic livers and with elevated AFP. A biopsy of the liver mass is necessary in non-cirrhotic livers and in those cases in which radiographic features characteristic of HCC are not apparent. On imaging, YSTs will appear as cystic lesions with central necrosis or calcification if associated with teratoma. On histology, YSTs have a characteristic Shiller-Duval body and stain negative for HepPar-1 and Arginase -1 which are positive in HCC. The treatment for YSTs usually involves resection, adjuvant chemotherapy or chemotherapy alone. An ovarian or testicular ultrasound is not necessary prior to initiating treatment. Although rare, primary yolk sac tumor of the liver should be considered as a differential diagnosis in young non-cirrhotic patients with large cystic tumors with necrosis and significantly elevated AFP.Figure 1.: Case 1, Figure 1: Abdominal computed tomography with contrast showing multiple infiltrative liver masses.Figure 2.: Case 2, Figure 2: Axial abdominal computed tomography (CT) showing 6.8 2.9 cm liver mass.Table 1.: Comparison of HCC and YST.