Characteristics and Outcomes Among U.S. Commercially Insured Transgender Adults with Cirrhosis: A National Cohort Study.

OBJECTIVE: The National Institute on Minority Health and Health Disparities has noted that transgender individuals experience unique health disparities. We sought to describe the landscape of transgender patients with cirrhosis. METHODS: We identified all trans- and cis-gender adults in Optum's de-identified Clinformatics® Data Mart Database between 2007-2022 using validated billing codes, calculating age-standardized prevalence of cirrhosis among cis- vs. transgender adults. Among those with incident cirrhosis diagnoses, we calculated age-standardized incidence densities of liver-related outcomes (decompensation, transplantation, hepatocellular carcinoma), and all-cause mortality. We examined 5-year survival using inverse probability treatment weighting (IPTW) to balance trans- and cis-gender populations on demographic and clinical characteristics. RESULTS: Among 64,615,316 adults, 42,471 (0.07%) were transgender. Among 329,251 adults with cirrhosis, 293 (0.09%) were transgender. Trans- (vs cis-)genders had higher prevalence of cirrhosis (1,285[95%CI 1,136-1,449] per 100,000 vs 561[559-563] per 100,000). Among adults with cirrhosis, trans- (vs cis-)genders had higher proportions of anxiety (70.7%[56.9-86.9] vs 43.2%[42.7-43.8]), depression (66.4%[53.3-81.7] vs 38.4%[37.9-38.9]), HIV/AIDS (8.5%[3.9-16.1] vs 1.6%[1.5-1.7]), and alcohol (57.5%[46.0-71.1] vs 51.0%[50.5-51.6]) and viral (30.5%[22.8-39.8] vs 24.2%[23.9-24.5]) etiologies, although etiologies had overlapping confidence intervals. Trans- (vs cis-)genders had similar incidence densities of death (12.0[95%CI 8.8-15.3] vs 14.0[13.9-14.2] per 100 person-years), decompensation (15.7[10.9-20.5] vs 14.1[14.0-14.3]), and liver transplantation (0.3[0.0-0.8] vs 0.3[0.3-0.4]). In IPTW survival analysis, trans- and cis-gender individuals had similar 5-year survival probabilities (63.4%[56.6-71.1] vs 59.1%[58.7-59.4]). CONCLUSIONS: Trans- (vs cis-)gender adults have double the prevalence of cirrhosis and the majority have a diagnosis of anxiety and/or depression. These results are informative for researchers, policymakers, and clinicians to advance equitable care for transgender individuals.

Addressing sex-based disparities in liver transplantation.

PURPOSE OF REVIEW: Disparities in access to liver transplantation by sex have been well described, disadvantaging women. Understanding the multifactorial causes of these disparities as well as the variety of proposed solutions is critical to improving access to this life-saving intervention for women. This review aims to summarize the current body of evidence on observed sex disparities in liver transplantation and highlight actionable, evidence-based mechanisms by which these disparities can be addressed. RECENT FINDINGS: Strategies for addressing sex disparities in liver transplantation include increasing organ utilization, changing allocation policy, and leveraging public policies to reduce the incidence of end-stage liver disease. Several other promising interventions are currently being explored. SUMMARY: In the United States, women face additional barriers to liver transplantation on the basis of sex. Immediate action is necessary to systematically address these inequities.

We Are Not Immune: Racial and Ethnic Disparities in Autoimmune Liver Diseases.

Autoimmune liver diseases are attributed to a complex interplay of biologic, acquired, and environmental factors. Increased prevalence, later stage at presentation, worse response to standard therapy, and transplant-related disparities have all been reported in racial and ethnic minorities such as Black and Latinx patients with autoimmune liver diseases. While biology and inherited genetic predispositions may partly explain these disparities, definitive and universal genetic variations underlying these differences in outcomes have not been defined. Nonetheless, socioeconomic status, access to health care, environmental and societal factors, and implicit provider bias can all contribute to poor patient outcomes. There remains an unmet need to understand and mitigate the factors contributing to health inequity in autoimmune liver diseases. In this review, we summarize the data on racial and ethnic disparities in presentation, treatment response, and outcomes pertaining to autoimmune liver diseases in minority populations, on the premise that understanding disparities is the first step toward reaching health equity.

Excess liver transplant waitlist mortality for patients with primary biliary cholangitis under MELD-Na allocation.

BACKGROUND: Historically, patients with primary biliary cholangitis (PBC) experience waitlist mortality and low rates of liver transplant (LT). Herein, the impact of MELD-Na based allocation on PBC waitlist mortality was examined. METHODS: Adult patients with PBC were compared to those with alcohol-related liver disease (ALD) or non-alcoholic steatohepatitis (NASH) listed for LT from 2013 to 2019 in OPTN. Competing risk regression evaluated waitlist mortality in the MELD and MELD-Na eras using propensity score weights. RESULTS: Overall, 1508 patients with PBC, 13581 with ALD, and 10455 with NASH were examined. In the MELD-Na era, 24-month cumulative incidence of waitlist mortality for PBC was 23.0% (95%CI 19.7-26.5%), ALD 13.9% (95%CI 13.1-14.8%), and NASH 20.0% (95%CI 18.9-21.2%). Using propensity score weights, adjusted risk of waitlist mortality was higher for PBC versus ALD (HR = 1.45, 95%CI 1.22-1.71) and NASH (HR = 1.32, 95%CI 1.14-1.55). Furthermore, among PBC, waitlist mortality risk per five-point elevation in MELD-Na (HR = 1.22, 95%CI 1.11-1.35) and Karnofsky score ≤30% (HR = 2.02, 95%CI 1.39-2.92) was significantly higher than among ALD (HR = 1.08, 95%CI 1.04-1.13; HR = 1.28, 95%CI 1.10-1.49) and NASH (HR = 1.05, 95%CI 1.00-1.09; HR = 1.16, 95%CI .99-1.37; all P-interactions < .05). CONCLUSIONS: The MELD-Na score continues to underestimate risk of waitlist death for patients with PBC relative to ALD and NASH and highlights need for additional score modifications or exceptions.

Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis.

Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of plasma cell hepatitis (PCH). As these histologically and serologically indistinguishable diagnoses are differentiated by clinical context, it remains uncertain whether they represent distinct immunologic phenomena. Improved understanding of immunoglobulin subclass 4-producing plasma cells (IgG4-PC) has brought attention to IgG4 as an immunophenotypic biomarker. To date, degree and clinical significance of IgG4-PC infiltration in PCH remain elusive. This retrospective, single-center study assessed IgG4-PC infiltration in AIH, rAIH, and PCR via standardized immunohistochemistry analysis. Identified cases from 2005 to 2020 (n = 47) included AIH (treatment-naïve AIH (tnAIH): n = 15 and AIH-flare on treatment (fAIH); n = 10), rAIH (n = 8), and PCR (n = 14) were analyzed and correlated with clinical characteristics. IgG4-Positivity (# IgG4-PC/# pan-IgG-expressing cells) distribution was heterogenous and overlapping [tnAIH: 0.060 (IQR 0.040-0.079), fAIH: 0.000 (0.000-0.033), rAIH: 0.000 (0.000-0.035), PCR: 0.228 (0.039-0.558)]. IgG4-Positivity was inversely correlated with corticosteroid use (p < 0.001). IgG4-Positivity ≥0.500 was associated with rapid AST improvement (p = 0.03). The variable IgG4-Positivity of AIH, rAIH and PCR suggests diverse and overlapping immunopathologic mechanisms and that current diagnostic schemes inadequately capture PCH immunopathology. We propose incorporation of IgG4-Positivity to refine current PCH classification and treatment strategies.

Treatment and outcomes of hepatocellular carcinoma in patients with Sickle cell disease: a population-based study in the U.S.

BACKGROUND: Sickle cell disease (SCD) is a rare hemoglobinopathy which can result in chronic liver disease and cirrhosis. Patients with SCD have an increased risk of hematologic malignancy, but the prevalence of hepatocellular carcinoma (HCC) in this population is unknown. Herein, the association of SCD with HCC was examined using registry data. METHODS: The SEER-Medicare database was queried to identify patients diagnosed with HCC between 2000 and 2015, and further stratified by SCD status. Propensity matching was performed to examine cancer-related survival and treatment outcomes. RESULTS: Overall 56,934 patients with HCC were identified, including 81 patients with SCD. Patients with SCD more frequently had cirrhosis [48.1% (39/81) vs 23.5% (13,377/56,853), p < 0.01] yet presented with smaller tumors [<5 cm: 51.9% (42/81) vs 38.5% (21,898/56,853), p = 0.01]. After propensity matching, SCD was not associated with attenuated survival (aHR 0.73 95%CI 0.52-1.01). When stratified by treatment, patients with SCD had equivalent outcomes to chemotherapy (p = 0.65), TACE/TARE (p = 0.35), resection (p = 0.15) and transplantation (p = 0.67) when compared to non-SCD patients. CONCLUSION: This study confirms that a subset of patients with SCD will develop HCC. Importantly, therapeutic options for HCC should not be limited by pre-existing SCD, and similar survival should be expected when compared to non-SCD patients.

Treatment and Outcomes of Early Stage Breast Cancer in Patients with Hepatic Dysfunction.

BACKGROUND: There exists a dogma of surgical nihilism for patients with cirrhosis and breast cancer causing de-escalation of surgery and impacting survival. We hypothesized that breast cancer surgery would not result in a significant change in the Model for End-Stage Liver Disease-Sodium (MELD-Na) scores before and after surgery. METHODS: We performed a single institutional retrospective review of medical records between January 2013 and July 2019 of patients with concurrent cirrhosis and breast cancer. We used the nonparametric Friedman test to compare differences in MELD-Na scores. RESULTS: Eight patients with both cirrhosis and breast cancer were identified. Median follow-up was 30.5 mo. Half of the patients had Child-Pugh class A cirrhosis and half had Child-Pugh class B cirrhosis. Six (75%) patients underwent lumpectomy and two (25%) underwent mastectomy. There was no statistically significant difference (P = 0.66) in median MELD-Na score before surgery (16) and after surgery (18). Two (25%) patients experienced postoperative complications. Three patients were listed for liver transplantation. Of three listed patients, two (25%) patients underwent successful liver transplantation after breast surgery. One (12.5%) patient died without transplant. Three (37.5%) patients were alive for more than 5 y after breast cancer diagnosis without evidence of cancer recurrence. The eighth patient has remained breast cancer free for more than 6 mo since her surgery. CONCLUSIONS: Surgery for patients with Child-Pugh class A and B cirrhosis and early stage breast cancer did not result in a significant change in MELD-Na score before and after surgery, suggesting that selected patients may benefit from breast cancer surgery with curative intent.

The use of organs from hepatitis C virus-viremic donors into uninfected recipients.

PURPOSE OF REVIEW: There has been an ongoing disparity between the number of organs available for solid organ transplantation (SOT) relative to the need. This has resulted in significant waitlist mortality, may affect transplant outcomes due to transplants being performed on sicker patients and may even increase healthcare costs due to extended hospital stays. Transplanting organs from hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-) is now a reality, due to the advent of highly affective direct-acting antivirals (DAAs) which not only have very high efficacy, but also a favorable side effect and drug-drug interaction profile. RECENT FINDINGS: Data from multiple centers reporting outcomes of kidney, liver, heart, lung and liver-kidney transplant during the past few years reveal that SOT from HCV-infected donors into noninfected recipients is safe, efficacious and can result in excellent recipient outcomes, with an opportunity to decrease the time on the waitlist, waitlist mortality and to improve outcomes after transplant due to less morbidity at the time of surgery. When livers are the transplanted organ, 8-12 weeks of DAA treatment will be required. For other organs, 2-4 weeks is likely sufficient. The available DAAs have profiles such that patients with all genotypes, with or without renal insufficiency an on renal replacement therapy and those who fail treatment may be successfully treated, with a sustained virologic response rate of more than 95%. Based upon the available data, starting DAAs shortly after transplant will likely limit posttransplant complications. that This will require cooperation between the transplant team, transplant hospital and insurer providing medication coverage. SUMMARY: SOT from HCV infected recipients is safe, is associated with excellent outcomes and should be considered for recipients who would benefit from receiving an organ earlier than they would if they waited for an organ from an uninfected donor.

Assessment of Fibrosis in Liver Transplant Recipients: Diagnostic Performance of Shear Wave Elastography (SWE) and Correlation of SWE Findings With Biopsy Results.

OBJECTIVE. Liver transplant patients are monitored for rejection and hepatic fibrosis and often undergo liver biopsies. The purpose of the present study is to determine whether noninvasive shear wave elastography (SWE) can quantify fibrosis in liver transplant recipients, with the aim of decreasing and possibly eliminating unnecessary biopsies for patients with suspected or progressive hepatic fibrosis. MATERIALS AND METHODS. Between May 1, 2015, and December 31, 2017, our prospective study evaluated 111 adult liver transplant patients (age range, 23-79 years) who underwent 147 ultrasound (US) SWE examinations of the right hepatic lobe followed by biopsies. SWE values were compared with the histologic fibrosis (Metavir) scores of the biopsy samples. SWE threshold values were determined using classification and regression tree analysis by anchoring to the degree of fibrosis. The sensitivity, specificity, positive predictive value, and negative predictive value (with 95% CIs) were calculated on the basis of the threshold value. Overall prediction accuracy was estimated using the AUC value from the ROC curve. RESULTS. From the 147 US SWE examinations and liver biopsies, consistent threshold values were identified for patients with no or minimal fibrosis (Metavir scores of F0 and F1, respectively) compared with significant fibrosis (Metavir scores of F2, F3, or F4). A median SWE value of 1.76 m/s or less denoted no or minimal fibrosis, whereas a value greater than 1.76 m/s denoted significant fibrosis. The sensitivity of US SWE examinations in classifying fibrosis was 0.77 (95% CI, 0.5-0.93). The specificity, positive predictive value, and negative predictive value were 0.79 (95% CI, 0.71-0.86), 0.33 (95% CI, 0.19-0.49), and 0.96 (95% CI, 0.91-0.99), respectively. CONCLUSION. Liver transplant patients may avoid liver biopsy if US SWE examination shows a median shear wave velocity of 1.76 or less, which corresponds to a Metavir score of F0 or F1, denoting no or minimal fibrosis.

Detection of Occult Hepatitis C Virus Infection in Patients Who Achieved a Sustained Virologic Response to Direct-Acting Antiviral Agents for Recurrent Infection After Liver Transplantation.

Occult infection with hepatitis C virus (HCV) is defined as the presence of the HCV genome in either liver tissue or peripheral blood monocytes, despite constant negative results from tests for HCV RNA in serum. We investigated whether patients who maintained a sustained virologic response 12 weeks after therapy (SVR12) with direct-acting antiviral (DAA) agents for recurrent HCV infection after liver transplantation had occult HCV infections. We performed a prospective study of 134 patients with recurrent HCV infection after liver transplantation who were treated with DAAs, with or without ribavirin, from 2014 through 2016 (129 patients achieved an SVR12). In >10% of the patients who achieved SVR12 (n = 14), serum levels of aminotransferases did not normalize during or after DAA therapy, or they normalized transiently but then increased sharply after DAA therapy. Of these 14 patients, 9 were assessed for occult HCV infection by reverse transcription quantitative polymerase chain reaction. This analysis revealed that 55% of these patients (n = 5) had an occult infection, with the detection of negative strand viral genome, indicating viral replication. These findings indicate the presence of occult HCV infection in some patients with abnormal levels of serum aminotransferases, despite SVR12 to DAAs for HCV infection after liver transplantation.

Imaging appearance in acute liver failure: correlation with clinical and pathology findings.

BACKGROUND AND AIM: Acute liver failure (ALF) is characterized by sudden liver injury without underlying chronic liver disease. Excluding underlying cirrhosis in these patients is often difficult and liver biopsy may be impractical. We review the imaging appearance of acute hepatic failure in patients who underwent transplant and correlate these findings with clinical, laboratory and pathology parameters. METHODS: This is a retrospective review of 47 patients without known chronic liver disease who presented to three institutions between 2002 and 2010 with ALF, 46 of which underwent subsequent orthotopic liver transplantation. Pre-transplant ultrasound, computed tomography and magnetic resonance imaging scans were reviewed for parenchymal homogeneity, surface nodularity and evidence of portal hypertension. Explant histopathology, laboratory values and time intervals between symptom onset to initial imaging and transplant were correlated with imaging findings. RESULTS: The majority of patients with ALF had abnormal radiographic findings. Ascites was seen in 65% of patients. Splenomegaly, collateral vessel formation and hepatofugal flow in the portal vein were present in 28, 15 and 9% of patients, respectively. Nodular liver surface was noted in 23% of patients, more commonly in patients who had been ill for more than 7 days. Liver surface nodularity correlated with massive hepatic necrosis on histology and wrinkled capsule on visual inspection of explanted liver specimen. CONCLUSION: Imaging findings in ALF was variable and can resemble cirrhosis. Assessment for underlying cirrhosis in the setting of liver failure should not be based on imaging findings.

Benign to Malignant Hepatic Lesion Transformation in Abernethy Malformation.

Abernethy malformation or congenital extrahepatic portosystemic shunt is an extremely rare condition whereby the portomesenteric blood drains into a systemic vein and bypasses the liver through a complete or partial shunt. Severe complications include hyperammonemia and encephalopathy, benign and malignant liver tumors, and hepatopulmonary syndrome. We describe a case where a female adult diagnosed with congenital extrahepatic portosystemic shunt subsequently developed focal nodular hyperplasia and then hepatocellular carcinoma.

Factors that determine the development and progression of gastroesophageal varices in patients with chronic hepatitis C.

BACKGROUND & AIMS: We aimed to identify the incidence and predictors of de novo gastroesophageal variceal formation and progression in a large cohort of patients with chronic hepatitis C and advanced fibrosis. METHODS: All participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial were offered an endoscopy before treatment and again after 4 years. Patients with varices at baseline also had an endoscopy at 2 years. Baseline laboratory and clinical parameters were analyzed as predictors of de novo variceal formation and variceal progression. RESULTS: De novo varices developed in 157 of the 598 (26.2%) patients. Most of the new varices were small (76.4%) and only 1% of patients developed variceal hemorrhage. The likelihood of developing varices was associated with subject race (Hispanic > Caucasian > African American; P = .0005), lower baseline levels of albumin (P = .051), and higher levels of hyaluronic acid (P < .001) with an area under the receiver operating characteristic curve = .70. Among 210 patients with existing gastroesophageal varices, 74 (35.2%) had variceal progression or bleeding during follow-up. Patients with higher baseline ratios of serum aspartate/alanine aminotransferase (P = .028) and lower platelet counts (P = .0002) were at greatest risk of variceal progression (area under the receiver operating characteristic = .72). Prolonged, low-dose peginterferon-alpha2a therapy and beta-blockers did not influence the risk of developing new or enlarging varices. CONCLUSION: Development of varices in patients with chronic hepatitis C is associated with patient race/ethnicity and laboratory markers of disease severity. Prolonged low-dose peginterferon-alpha2a therapy and beta-blockers do not reduce the risk of variceal development or progression.

Transfusion-free Retransplantation for Post-liver Transplantation Hepatic Artery Thrombosis: How Much Augmentation Is Too Much?

Liver transplantation presents unique challenges in patients who do not accept blood transfusions. The difficulty of balancing chemical augmentation and handling the technical difficulty of the surgery make transfusion-free liver transplantation an exception rather than the norm. However, at our center, we have performed 27 successful living donor liver transplants in transfusion-free patients. We describe a case of hepatic artery thrombosis (HAT) after living donor liver transplantation requiring retransplantation. This first report of safe retransplantation without blood products demonstrates that even graft-threatening complications can be safely managed in a transfusion-free setting. However, it remains unclear if the medical augmentation to meet hematologic and coagulation parameters before transfusion-free transplantation may increase the risk of postoperative HAT and other thrombotic complications. Although it is our center's experience that the thrombosis rate is comparable with the published rate in standard transfusion-eligible living donor liver transplantations and this case demonstrates that HAT can be safely managed in this setting, further study on the risks and benefits of hematopoietic stimulants as pretransplant optimization is warranted.

Applying the original model for end-stage liver disease score rather than the model for end-stage liver disease-Na score for risk stratification prior to transjugular intrahepatic portosystemic shunt procedures.

OBJECTIVE: The model for end-stage liver disease (MELD) score can be used to predict survival of patients undergoing transjugular intrahepatic portosystemic shunt procedures (TIPS). The effect of hyponatremia on survival resulted in the development of the MELD-Na score. The aim of this study is to compare the prognostic value of MELD and MELD-Na scores in predicting post-TIPS outcomes. METHODS: A retrospective chart review was performed on consecutive patients with cirrhosis who underwent TIPS placement from 2012 to 2017. Indications for TIPS were either refractory ascites or variceal bleeding. Primary outcomes analyzed were death or liver transplantation. Follow-up data were censored at 1 year. RESULTS: Eighty-three patients underwent TIPS. There was no difference in MELD or MELD-Na score between indication groups. However, the delta MELD (MELD-Na subtracted by MELD score) was higher in those with refractory ascites. There was no difference in outcomes of death or liver transplantation between the MELD and MELD-Na at 1 year. (area under the curve 0.79 vs 0.72, respectively, P = 0.119). In patients with a MELD-Na greater than 18, higher delta MELD was protective (hazard ratio 0.74, P < 0.05). CONCLUSIONS: There was no prognostic difference using either score despite a higher delta MELD in those with refractory ascites. The decision to pursue TIPS should utilize the original MELD score, as the MELD-Na score alone may exclude patients with refractory ascites who may benefit from TIPS.

Diagnosis of Focal Nodular Hyperplasia (FNH) after Liver Transplantation.

Following liver transplantation (LT), recipients can develop benign and malignant hepatic masses just like any other patient. Patients transplanted for hepatocellular carcinoma (HCC) undergo surveillance imaging, and any new mass seen on imaging must be carefully evaluated to rule out recurrent cancer. Focal nodular hyperplasia (FNH) is a benign tumor of the liver that most often occurs in women and is rarely symptomatic. It is important to distinguish FNH from more serious etiologies, such as recurrent HCC and other malignancies, since the treatments differ greatly. To date, there have been very few reports of FNH occurring in a liver allograft. We present a case of a patient with a history of a carcinoid tumor who underwent LT for HCC. Several years posttransplant, the patient was found to have a liver mass with classic features of HCC on imaging. The liver biopsy revealed the unexpected diagnosis of FNH. This finding avoided unnecessary treatment for HCC, which is associated with morbidity, especially in the posttransplant setting. We present our diagnostic approach, discuss the clinicopathologic and imaging findings of FNH, and review the literature on FNH in the posttransplant setting.

Hepatorenal Syndrome.

Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme kidney vasoconstriction leading to decreased GFR. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years. The mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal syndrome need to be clarified. Early diagnosis is central in the management and recent changes in the definition of hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option. Several controlled studies proved that terlipressin is effective at reversing hepatorenal syndrome and may improve short-term survival. Not all patients are responders, and even in responders, early mortality rates are very high in the absence of liver transplantation. Liver transplantation is the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) is often a challenging yet important step because vasoconstrictors are not justified for the treatment of ATN. Hepatorenal syndrome and ATN may be considered as a continuum rather than distinct entities. Emerging biomarkers may help differentiate these two conditions and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the decision for simultaneous liver-kidney transplantation.