Considerations in gender-affirming hormone therapy in transgender and gender diverse patients undergoing liver transplantation.

Liver transplantation is lifesaving for patients with end-stage liver disease. Similar to the role of transplantation for patients with end-stage liver disease, gender-affirming hormone therapy (GAHT) can be lifesaving for transgender and gender diverse (TGGD) patients who experience gender dysphoria. However, management of such hormone therapy during the perioperative period is unknown and without clear guidelines. Profound strides can be made in improving care for TGGD patients through gender-affirming care and appropriate management of GAHT in liver transplantation. In this article, we call for the transplant community to acknowledge the integral role of GAHT in the care of TGGD liver transplant candidates and recipients. We review the current literature and describe how the transplant community is ethically obligated to address this health care gap. We suggest tangible steps that clinicians may take to improve health outcomes for this minoritized patient population.

Hepatitis C Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection.

The Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have collaboratively developed evidence-based guidance regarding the diagnosis, management, and treatment of hepatitis C virus (HCV) infection since 2013. A panel of clinicians and investigators with extensive infectious diseases or hepatology expertise specific to HCV infection periodically review evidence from the field and update existing recommendations or introduce new recommendations as evidence warrants. This update focuses on changes to the guidance since the previous 2020 published update, including ongoing emphasis on recommended universal screening; management recommendations for incomplete treatment adherence; expanded eligibility for simplified chronic HCV infection treatment in adults with minimal monitoring; updated treatment and retreatment recommendations for children as young as 3 years old; management and treatment recommendations in the transplantation setting; and screening, treatment, and management recommendations for unique and key populations.

You Can't Have One Without the Other: Innovation and Ethical Dilemmas in Gastroenterology and Hepatology.

Medical innovation and ethical dilemmas are intertwined in gastroenterology and hepatology. This narrative review explores direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) as a touchstone example of how medical innovation breeds ethical dilemmas. A few quandaries-informed consent as well as informed deferral during the first wave of DAA approvals, sobriety restrictions from payors, and high DAA costs for patients-are addressed through the lens of the foundational principles of clinical medical ethics: autonomy, beneficence, non-maleficence, justice, and utility. By placing these issues within a medical ethics framework, we hope not only to focus on the solutions that the gastroenterology and hepatology community developed in the advent of DAA therapy, but to highlight an ethical paradigm that can be applied to similar dilemmas that will be faced as new therapies for other gastrointestinal diseases are approved.

Case Management and Capacity Building to Enhance Hepatitis C Treatment Uptake at Community Health Centers in a Large Urban Setting.

An estimated 4.1 million people in the United States are infected with hepatitis C virus (HCV). In 2014, the Hepatitis C Community Alliance to Test and Treat (HepCCATT) collaborative was formed to address hepatitis C in Chicago. From 2014 to 2017, the HepCCATT Case Management Program case managed 181 HCV-infected people and performed on-site capacity building at a 6-site community health center (CHC) that produced codified protocols, which were translated into a telehealth program to build capacity within CHCs to deliver hepatitis C care. HepCCATT's innovative approach to addressing multilevel barriers is a potential model for increasing access to hepatitis C care and treatment.

Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure on the Waitlist for Liver Transplantation.

BACKGROUND & AIMS: Concurrent to development of more effective drugs for treatment of hepatitis C virus (HCV) infection, there has been an increase in the incidence of nonalcoholic fatty liver disease. Data indicate that liver transplantation prolongs survival times of patient with acute hepatitis associated with alcoholic liver disease (ALD). We compared data on disease prevalence in the population with data from liver transplantation waitlists to evaluate changes in the burden of liver disease in the United States. METHODS: We collected data on the prevalence of HCV from the 2010 and 2013-2014 cycles of the National Health and Nutrition Examination Survey. We also collected data from the HealthCore Integrated Research Database on patients with cirrhosis and chronic liver failure (CLF) from 2006 through 2014, and data on patients who received transplants from the United Network for Organ Sharing from 2003 through 2015. We determined percentages of new waitlist members and transplant recipients with HCV infection, stratified by indication for transplantation, modeling each calendar year as a continuous variable using the Spearman rank correlation, nonparametric test of trends, and linear regression models. RESULTS: In an analysis of data from the National Health and Nutrition Examination Survey (2013-2014), we found that the proportion of patients with a positive HCV antibody who had a positive HCV RNA was 0.5 (95% confidence interval, 0.42-0.55); this value was significantly lower than in 2010 (0.64; 95% confidence interval, 0.59-0.73) (P = .03). Data from the HealthCore database revealed significant changes (P < .05 for all) over time in percentages of patients with compensated cirrhosis (decreases in percentages of patients with cirrhosis from HCV or ALD, but increase in percentages of patients with cirrhosis from nonalcoholic steatohepatitis [NASH]), CLF (decreases in percentages of patients with CLF from HCV or ALD, with an almost 3-fold increase in percentage of patients with CLF from NASH), and hepatocellular carcinoma (HCC) (decreases in percentages of patients with HCC from HCV or ALD and a small increase in HCC among persons with NASH). Data from the United Network for Organ Sharing revealed that among patients new to the liver transplant waitlist, or undergoing liver transplantation, for CLF, there was a significant decrease in the percentage with HCV infection and increases in percentages of patients with nonalcoholic fatty liver disease or ALD. Among patients new to the liver transplant waitlist or undergoing liver transplantation for HCC, proportions of those with HCV infection, nonalcoholic fatty liver disease, or ALD did not change between 2003 and 2015. CONCLUSIONS: In an analysis of 3 different databases (National Health and Nutrition Examination Survey, HealthCore, and United Network for Organ Sharing), we found the proportion of patients on the liver transplant waitlist or undergoing liver transplantation for chronic HCV infection to be decreasing and fewer patients to have cirrhosis or CLF. However, the percentages of patients on the waitlist or receiving liver transplants for NASH or ALD are increasing, despite different relative burdens of disease among the entire population of patients with cirrhosis.

Calciphylaxis in end-stage liver and renal disease patients before and after transplant.

Calciphylaxis is a rare vascular disorder characterized by calcification of arterioles which causes tissue inflammation and necrosis. It is associated with the metabolic disturbances seen in end-stage renal disease (ESRD) and has also been described in patients with cirrhosis with preserved kidney function. Characteristic calciphylaxis lesions are black eschars surrounded by retiform purpura, and the gold standard for diagnosis is skin biopsy. Reported 1-year mortality rates range between 45% and 80%. No treatment modality has been evaluated in a prospective randomized trial, and reports of treatment efficacy vary. Kidney transplant has been reported as a successful therapy for calciphylaxis; however, cases exist of the initial onset of calciphylaxis following kidney transplant as well as simultaneous liver-kidney (SLK) transplant. The decision to maintain a patient with end-stage renal and liver disease on the waiting list for SLK transplant following the onset of calciphylaxis must consider the high 1-year mortality associated with this condition. More research is necessary to understand how to allocate donor allografts to manage patients with calciphylaxis and ESRD and/or cirrhosis effectively.

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection.

Hepatitis C virus (HCV) and human pegivirus (HPgV), formerly GBV-C, are the only known human viruses in the Hepacivirus and Pegivirus genera, respectively, of the family Flaviviridae. We present the discovery of a second pegivirus, provisionally designated human pegivirus 2 (HPgV-2), by next-generation sequencing of plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology. HPgV-2 is highly divergent, situated on a deep phylogenetic branch in a clade that includes rodent and bat pegiviruses, with which it shares <32% amino acid identity. Molecular and serological tools were developed and validated for high-throughput screening of plasma samples, and a panel of 3 independent serological markers strongly correlated antibody responses with viral RNA positivity (99.9% negative predictive value). Discovery of 11 additional RNA-positive samples from a total of 2440 screened (0.45%) revealed 93-94% nucleotide identity between HPgV-2 strains. All 12 HPgV-2 RNA-positive cases were identified in individuals also testing positive for HCV RNA (12 of 983; 1.22%), including 2 samples co-infected with HIV, but HPgV-2 RNA was not detected in non-HCV-infected individuals (p<0.0001), including those singly infected by HIV (p = 0.0075) or HBV (p = 0.0077), nor in volunteer blood donors (p = 0.0082). Nine of the 12 (75%) HPgV-2 RNA positive samples were reactive for antibodies to viral serologic markers, whereas only 28 of 2,429 (1.15%) HPgV-2 RNA negative samples were seropositive. Longitudinal sampling in two individuals revealed that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies. One individual harboring both HPgV-2 and HCV RNA was found to be seronegative for both viruses, suggesting a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event. Taken together, our results indicate that HPgV-2 is a novel bloodborne infectious virus of humans and likely transmitted via the parenteral route.

Novel educational interventions in residency increase knowledge of chronic liver disease and career interest in hepatology.

There is an increasing burden of chronic liver disease (CLD) in the United States but a significant shortage of hepatologists. Thus, it is necessary to develop new recruitment strategies to the field of hepatology as well as ensure that non-gastroenterology-trained physicians are able to capably assist in the care of CLD. We established a novel, nonelective, inpatient hepatology rotation that uses required modules in the American Association for the Study of Liver Diseases Curriculum and Training-First Hepatitis B and C curriculums as well as in LiverLearning. A paper-based anonymous assessment was distributed to the inaugural 25 postgraduate years 2 and 3 internal medicine residents before and after the 2-week rotation over the course of 1 year. Both the prerotation and postrotation assessments included validated multiple-choice questions and Likert-type questions, which evaluated self-perceived knowledge and comfort with managing CLD. The mean comfort level (1 = not at all comfortable/strongly disagree, 5 = very comfortable/strongly agree) of managing several common liver diseases increased significantly after completion of the rotation (i.e., cirrhosis 2.8 versus 3.8, P < 0.001; hepatitis B 2.4 versus 3.4, P = 0.001; hepatitis C 2.6 versus 3.7, P = 0.002; nonalcoholic steatohepatitis 3.0 versus 4.0, P < 0.001; liver transplant care 2.1 versus 3.4, P < 0.001). There was also a significantly increased interest in hepatology as a career (2.6 versus 3.0, P = 0.03). Finally, the mean percentage of multiple-choice questions answered correctly on the pretest was 62% and posttest was 77% (P = 0.02). CONCLUSION: Our novel curriculum and nonelective hepatology rotation has effectively demonstrated improvement in internal medicine residents' comfort with and knowledge of CLD, and increased career interest in hepatology was also observed after completion of the curriculum, which suggests that more exposure to CLD could positively impact recruitment to the workforce; larger, multicenter studies are needed to validate these results. (Hepatology 2016;64:2210-2218).

The benefit of paracentesis on hospitalized adults with cirrhosis and ascites.

BACKGROUND AND AIM: The aim of this study is to assess paracentesis utilization and outcomes in hospitalized adults with cirrhosis and ascites. METHODS: The 2011 Nationwide Inpatient Sample was used to identify adults, non-electively admitted with diagnoses of cirrhosis and ascites. The primary endpoint was in-hospital mortality. Variables included patient and hospital demographics, early (Day 0 or 1) or late (Day 2 or later) paracentesis, hepatic decompensation, and spontaneous bacterial peritonitis. RESULTS: Out of 8 023 590 admissions, 31 614 met inclusion criteria. Among these hospitalizations, approximately 51% (16 133) underwent paracentesis. The overall in-hospital mortality rate was 7.6%. There was a significantly increased mortality among patients who did not undergo paracentesis (8.9% vs 6.3%, P < 0.001). Patients who did not receive paracentesis died 1.83 times more often in the hospital than those patients who did receive paracentesis (95% confidence interval 1.66-2.02). Patients undergoing early paracentesis showed a trend towards reduction in mortality (5.5% vs 7.5%) compared with those undergoing late paracentesis. Patients admitted on a weekend demonstrated less frequent use of early paracentesis (50% weekend vs 62% weekday) and demonstrated increased mortality (adjusted odds ratio 1.12 95% confidence interval 1.01-1.25). Among patients diagnosed with spontaneous bacterial peritonitis, early paracentesis was associated with shorter length of stay (7.55 vs 11.45 days, P < 0.001) and decreased hospitalization cost ($61 624 vs $107 484, P < 0.001). CONCLUSION: Paracentesis is under-utilized among cirrhotic patients presenting with ascites and is associated with decreased in-hospital mortality. These data support the use of paracentesis as a key inpatient quality measure among hospitalized adults with cirrhosis. Future studies are needed to investigate the barriers to paracentesis use on admission.

Rifaximin Decreases the Incidence and Severity of Acute Kidney Injury and Hepatorenal Syndrome in Cirrhosis.

BACKGROUND: While the effects of rifaximin have been shown to be protective against acute kidney injury (AKI) and hepatorenal syndrome (HRS) in alcohol-induced cirrhosis, its long-term effects on the renal function of other cirrhotic patients are unknown. AIM: To examine the long-term effects of rifaximin on the renal function of patients with cirrhosis from various etiologies. METHODS: In a retrospective study, we examined cirrhotic patients at the University of Chicago Liver Clinic from January 1, 2011, to December 31, 2014. The study enrolled patients on rifaximin for ≥90 days, who were then matched by age, gender, and MELD score to a control group. Patients with malignancy and renal replacement therapy (RRT) at baseline were excluded. Data were censored at the last follow-up, termination of rifaximin therapy, initiation of RRT, death, or liver transplant. RESULTS: Eighty-eight rifaximin cases were identified and matched to 88 control cases. Baseline characteristics were similar, with the exceptions of more prevalent long-term midodrine use (≥90 days) (17.0 vs 4.5 %, p = 0.01) and baseline ascites (37.5 vs 23.8 %, p = 0.05) in the rifaximin group. There was no difference in the frequency of infections, deaths, liver transplants, or hospitalizations. After controlling for cofounders, the incidence rate ratio of AKI (IRR 0.71, p = 0.02) and HRS (IRR 0.21, p = 0.02), as well as the risk of requiring RRT (OR 0.23, p = 0.01), was lower in the rifaximin group. CONCLUSIONS: Long-term use of rifaximin is associated with a decrease incidence of AKI and HRS and a decrease risk of requiring RRT in a general population of cirrhotic patients.

Screening for Zinc Deficiency in Patients with Cirrhosis: When Should We Start?

BACKGROUND: Zinc deficiency has been observed in cirrhosis, but management guidelines do not address screening for zinc deficiency. We aim to determine the prevalence of zinc deficiency in different stages of cirrhosis and to correlate zinc levels with complications of cirrhosis and clinical outcomes. Patients who had a diagnosis of cirrhosis and had serum zinc levels drawn from 2007 to 2011 were identified. Demographics, laboratory data, presence of ascites, encephalopathy, and infection were obtained; Child-Pugh and MELD scores were calculated. Stata software was used for data analysis. A total of 163 patients were included in the study. RESULTS: The median serum zinc level was 0.47 mcg/ml (IQR 0.37-0.63); 83 % of patients were zinc deficient. Zinc deficiency was more prevalent in patients with Child-Pugh score B or C, and with MELD scores ≥15. Zinc levels were lower in alcoholic, hepatitis C, and cholestatic diseases than in other etiologies of liver disease. Zinc levels correlated with INR (r = -0.56, p < 0.001), bilirubin (r = -0.51, p < 0.001), and albumin (r = 0.68, p < 0.001), and were lower in patients with ascites (0.40 vs. 0.57 mcg/ml, p < 0.001), encephalopathy (0.40 vs. 0.53 mcg/ml, p < 0.001), diuretic use (0.45 vs. 0.535 mcg/ml, p = 0.005), and infection (0.32 vs. 0.51 mcg/ml, p < 0.001). Ascites (p = 0.044) and infection (p = 0.009) were independently associated with zinc levels. Zinc-deficient patients had lower transplant-free survival rates than non-deficient patients. CONCLUSION: Zinc deficiency is highly prevalent in cirrhotic patients with Child-Pugh score B or C, and with MELD score ≥15. Zinc deficiency also correlates with disease severity, infection, and a worse transplant-free survival. Screening for zinc deficiency should be considered in this subset of patients.

Interferon-combination strategies for the treatment of chronic hepatitis C.

Direct acting antiviral agents have revolutionized hepatitis C (HCV) therapy. Many agents that are either currently available or undergoing investigation offer higher rates of sustained virologic response, reduced toxicity and shorter duration of therapy when compared to traditional treatment consisting of pegylated interferon and ribavirin. Although interferon free therapy may be a preferred option, some patients may still require an interferon based regimen to ensure efficacy. In this review, we discuss therapeutic strategies which utilize various combinations of protease inhibitors, NS5A inhibitors, nucleotide polymerase inhibitors and non-nucleoside polymerase inhibitors along with pegylated interferon in the treatment of chronic HCV.

The perils of pathogen discovery: origin of a novel parvovirus-like hybrid genome traced to nucleic acid extraction spin columns.

Next-generation sequencing was used for discovery and de novo assembly of a novel, highly divergent DNA virus at the interface between the Parvoviridae and Circoviridae. The virus, provisionally named parvovirus-like hybrid virus (PHV), is nearly identical by sequence to another DNA virus, NIH-CQV, previously detected in Chinese patients with seronegative (non-A-E) hepatitis. Although we initially detected PHV in a wide range of clinical samples, with all strains sharing ∼99% nucleotide and amino acid identity with each other and with NIH-CQV, the exact origin of the virus was eventually traced to contaminated silica-binding spin columns used for nucleic acid extraction. Definitive confirmation of the origin of PHV, and presumably NIH-CQV, was obtained by in-depth analyses of water eluted through contaminated spin columns. Analysis of environmental metagenome libraries detected PHV sequences in coastal marine waters of North America, suggesting that a potential association between PHV and diatoms (algae) that generate the silica matrix used in the spin columns may have resulted in inadvertent viral contamination during manufacture. The confirmation of PHV/NIH-CQV as laboratory reagent contaminants and not bona fide infectious agents of humans underscores the rigorous approach needed to establish the validity of new viral genomes discovered by next-generation sequencing.

Decision making in liver transplantation--limited application of the liver donor risk index.

The liver donor risk index (LDRI), originally developed in 2006 by Feng et al. and since modified, is a method of evaluating liver grafts from deceased donors through the determination of the relative risk of graft failure after transplantation. Online and paper surveys about attitudes and practices regarding decision making in liver transplantation and the role of the LDRI were sent to liver transplant physicians. One hundred forty-seven of 401 eligible respondents (37%) returned partial or complete surveys. The majority of the respondents were male (116/134 or 87%) and practiced in academic medical centers (128/138 or 93%). Transplant coordinators initially contacted the candidate with an offer in 81% of the programs. Eighty-eight of 143 respondents (62%) reported that they were very familiar with the LDRI, but the vast majority (114/137 or 83%) rarely or never discussed the concept of the LDRI with their patients. A majority of the respondents (96/132 or 73%) believed that the LDRI does not adequately describe a liver's relative risk of graft failure and that there are factors making the LDRI potentially misleading (122/138 or 88%). Nevertheless, 60 of 130 respondents (46%) believed that the LDRI would increase/improve shared decision making. The LDRI has not been widely adopted because of concerns that (1) it does not accurately reflect posttransplant survival, (2) it excludes relevant donor and recipient factors, and (3) it is too complicated for candidates to grasp. There is a need to improve it or to develop other decision-making tools to help promote shared decision making. There is also great diversity in how liver offers are made to ambulatory candidates and in how transplant programs address a candidate's refusal. Research is needed to determine evidence-based best practice.