Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity.

Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes.

Liver-Resident Bystander CD8+ T Cells Contribute to Liver Disease Pathogenesis in Chronic Hepatitis D Virus Infection.

BACKGROUND & AIMS: The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5 to 10 years. There is no curative treatment, and the mechanisms underlying the accelerated liver disease progression are unknown. METHODS: Innate and adaptive immune responses were studied in blood and liver of 24 patients infected with HDV and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage. RESULTS: The 2 main intrahepatic innate immune-cell populations, mucosal-associated invariant T cells and natural killer (NK) cells, were reduced in the livers of patients infected with HDV compared with those of uninfected controls but were more frequently activated in the liver compared with the blood. Most intrahepatic cluster of differentiation (CD) 8-positive (CD8+) T cells were memory cells or terminal effector memory cells, and most of the activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+C-X-C motif chemokine receptor 6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NK protein 30 (NKp30) and NK group 2D (NKG2D) receptors. The size of this population correlated with liver enzyme activity (r = 1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population, suggesting global bystander activation. This was supported by the correlations between (i) NKG2D expression with degranulation of intrahepatic CD8+ T cells, (ii) frequency of degranulating CD8+ T cells with liver enzyme activity and the aspartate aminotransferase-to-platelet ratio index score, and by the in vitro demonstration of cytokine-induced NKG2D-dependent cytotoxicity. CONCLUSION: Antigen-nonspecific activation of liver-resident CD8+ T cells may contribute to inflammation and disease stage in HDV infection.

Fresh frozen plasma transfusion in acute variceal haemorrhage: Results from a multicentre cohort study.

BACKGROUND: Fresh frozen plasma (FFP) transfusion is often used in the management of acute variceal haemorrhage (AVH) despite best practice advice suggesting otherwise. OBJECTIVE: We investigated if FFP transfusion affects clinical outcomes in AVH. DESIGN, SETTING AND PATIENTS: We performed a retrospective cohort study of 244 consecutive, eligible patients admitted to five tertiary health care centres between 2013 and 2018 with AVH. MAIN OUTCOME MEASUREMENTS: Multivariable regression analyses were used to study the association of FFP transfusion with mortality at 42 days (primary outcome) and failure to control bleeding at 5 days and length of stay (secondary outcomes). RESULTS: Patients who received FFP transfusion (n = 100) had higher mean Model for End Stage Liver Disease (MELD) score and more severe variceal bleeding than those who did not received FFP transfusion (n = 144). Multivariable analysis showed that FFP transfusion was associated with increased odds of mortality at 42 days (odds ratio [OR] 9.41, 95% confidence interval [CI] 3.71-23.90). FFP transfusion was also associated with failure to control bleeding at 5 days (OR 3.87, 95% CI 1.28-11.70) and length of stay >7 days (adjusted OR 1.88, 95% CI 1.03-3.42). The independent association of FFP transfusion with mortality at 42 days persisted when the cohort was restricted to high-risk patients and in patients without active bleeding. LIMITATIONS AND CONCLUSIONS: Fresh frozen plasma transfusion in AVH is independently associated with poor clinical outcomes. As this an observational study, there may be residual bias due to confounding; however, we demonstrate no benefit and potential harm with FFP transfusions in AVH.

Roadmap to resuming care for liver diseases after coronavirus disease-2019.

The global pandemic of coronavirus disease-2019 (COVID-19) has led to significant disruptions in healthcare delivery. Patients with chronic liver diseases require a high level of care and are therefore particularly vulnerable to disruptions in medical services during COVID-19. Recent data have also identified chronic liver disease as an independent risk factor for COVID-19 related hospital mortality. In response to the pandemic, national and international societies have recommended interim changes to the management of patients with liver diseases. These modifications included the implementation of telehealth, postponement or cancelation of elective procedures, and other non-urgent patient care-related activities. There is concern that reduced access to diagnosis and treatment can also lead to increased morbidity in patients with liver diseases and we may witness a delayed surge of hospitalizations related to decompensated liver disease after the COVID-19 pandemic has receded. Therefore, it is paramount that liver practices craft a comprehensive plan for safe resumption of clinical operations while minimizing the risk of exposure to patients and health-care professionals. Here, we provide a broad roadmap for how to safely resume care for patients with chronic liver disease according to various phases of the pandemic with particular emphasis on outpatient care, liver transplantation, liver cancer care, and endoscopy.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSIONS: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

The Spectrum of Hepatic Involvement in Patients With Telomere Disease.

Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity in telomere diseases, but very few studies have characterized the nature and extent of liver involvement in affected patients. We report the prevalence and characteristics of liver involvement in a large cohort of patients with telomere disease evaluated serially at the National Institutes of Health. One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included in the current study. Median follow-up was 2.4 years. Data were collected regarding their demographic information, laboratory analysis, imaging, and histopathology. Forty patients (40% of the cohort) with a median age of 42 years were found to have liver involvement. Liver enzyme elevation was cholestatic in pattern; 8 (21%) had drug-related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% (9) of patients, followed by hepatomegaly in 26% (6). Biopsies were infrequent because of risk associated with thrombocytopenia, but in 6 patients, there were varying findings: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. Almost half the cohort had pulmonary diffusion abnormalities, and 25% died during the follow-up period. Conclusion: In patients with telomere disease, hepatic involvement is common and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities. Liver disease has important implications for morbidity and mortality in patients with telomere disease.

Vibration Controlled Transient Elastography (Fibroscan®) in sickle cell liver disease - could we strike while the liver is hard?

Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.

Comparison of inpatient outcomes in patients with Hepatitis B, Hepatitis C, and Hepatitis B and C co-infection with Cirrhosis.

BACKGROUND: Hepatitis B (HBV) and Hepatitis C (HCV) are among the most common causes of cirrhosis in the USA, with high mortality and morbidity but comparative outcomes were not well studied. METHODS: We retrospectively analyzed cirrhosis patients with HBV, HCV, and HBV/HCV coinfection from 2016 to 2019 in National Inpatient Sample (NIS) database. Our primary outcome was the length of stay (LOS), mean hospital charge and mortality. RESULTS: Our study included 701464 cirrhosis patients with HCV (89.7%), HBV (6.8%), and coinfection (3.5%) (P < 0.001). Male gender and white race were more common in all three cohorts (p < 0.001). The mean age for HBV, HCV, and coinfection was 55.59, 58.69, and 58.27 years. The mean LOS for HBV, HCV, and coinfection were 6.59 ± 0.1, 6.02 ± 0.03, and 6.74 ± 0.12 days respectively. The adjusted length of stay was 0.62 days longer in the HBV cohort and 0.61 days longer in the coinfection cohort, compared to the HCV cohort (P < 0.001). Adjusted hospital charges were $15112 higher in the HBV cohort and $ 6312 higher in the coinfection cohort, compared to the HCV cohort (P < 0.001). Patients with HBV had a higher risk of mortality compared to HCV infection (AOR 1.35, [1.22-1.48], P < 0.001); However, patients with coinfection had no difference in mortality compared to HCV infection. CONCLUSION: Cirrhosis with HBV and coinfection is associated with increased duration of hospital stay and cost when compared to HCV infection. There is a higher risk of mortality in cirrhotic patients with HBV infection compared to HCV; however, no significant difference in mortality for coinfection compared to HCV.

Time to Publication for Randomized Clinical Trials Presented as Abstracts at Three Gastroenterology and Hepatology Conferences in 2017.

Background & Aims: Results of randomized clinical trials are often first presented as conference abstracts, but these abstracts may be difficult to find, and trial results included in the abstract may not be followed by subsequent journal publications. In a review of abstracts submitted to eight major medical and surgical conferences in 2017, we identified 237 abstracts reporting primary results of randomized clinical trials accepted for presentation at three major gastroenterology and hepatology conferences. The aims of this new analysis were to determine the publication rate for these abstracts and the proportion of publications that included trial registration numbers in the publication abstract. Methods: Clinical trial registries, PubMed, Europe PMC, and Google Scholar were searched through November 1, 2021, for publications reporting trial results for the selected abstracts. Publications were reviewed to determine if they included a trial registration number and if the registration number was in the abstract. Results: Publications were found for 157 abstracts (66%) within four years of the conference. Publications were found more frequently for the 194 abstracts reporting results of registered trials (144, 74%) than for the 43 abstracts reporting unregistered trials (13, 30%), but only 67% of these 144 publications included the registration number in the publication abstract. Ten unpublished trials had summary results posted on ClinicalTrials.gov. Conclusions: Clinical trial results could be more accessible if all trials were registered, authors included registration numbers in both conference and journal abstracts, and journal editors required the inclusion of registration numbers in publication abstracts for registered clinical trials.

A retrospective study on use of palliative care for patients with alcohol related end stage liver disease in United States.

BACKGROUND: Palliative care (PC) has been shown to be beneficial in end stage liver disease (ESLD), yet the hospitalization data for PC utilization is unknown. AIM: To identify the trend of PC utilization for the special population of alcohol-associated ESLD patients, factors affecting its use and ascertain its impact on healthcare utilization. METHODS: We analyzed around 78 million discharges from the 2007-2014 national inpatient sample and 2010-2014 national readmission database including adult patients admitted for decompensated alcohol-associated cirrhosis. We identified patients with PC consultation as a secondary diagnosis. Odds ratios (OR) and means were adjusted for confounders using multivariate regression analysis models. RESULTS: Out of the total 1421849 hospitalizations for decompensated liver cirrhosis, 62782 (4.4%) hospitalizations had a PC consult, which increased from 0.8% (1258) of all alcohol-associated ESLD hospitalizations in 2007 to 6.6% in 2014 (P < 0.01). Patient and hospital characteristics associated with increased odds of PC utilization were advanced age, lower income, Medicaid coverage, teaching institution, urban location, length of stay > 3 d, prolonged ventilation, and administration of total parenteral nutrition (all P < 0.01). Palliative encounters in alcohol-associated ESLD and acute-on-chronic liver failure (ACLF) score were associated with increased odds of discharge to a rehabilitation facility, but significantly lower odds of 30-d readmissions (aOR: 0.35, 95%CI: 0.31-0.41), lower total hospitalization charges and lower mean hospitalization days (all P < 0.01). CONCLUSION: Inpatient PC is sparingly used for patients with decompensated alcohol related liver disease, however it has increased over the past decade. PC consultation is associated with lower 30-d readmission rates on multivariate analysis, and lower hospitalization cost and length of stay in patients with ACLF score ≥ 2.

COVID-19 Alcoholic Cirrhosis and Non-Alcoholic Steatohepatitis Cirrhosis Outcomes among Hospitalized Patients in the United States: Insight from National Inpatient Sample Database.

Patients with co-morbidities like cirrhosis are at risk of worse outcome from COVID-19 infection. Given limited prior studies, we evaluated outcomes associated with COVID-19 infection in alcoholic and non-alcoholic steatohepatitis cirrhotic (CC+) versus cirrhotic without COVID-19 (CC−). We performed retrospective analysis of 822,604 patients including 28,610 COVID-19 patients from the National Inpatient Sample database with alcoholic and NASH cirrhosis enrolled between 1 January 2020 to 31 December 2020, with univariate and multivariate regression analyses. Primary outcome was mortality and secondary outcomes was mechanical ventilation, vasopressor use, length of stay, hospitalization expense and predictors of mortality. In-hospital mortality was three time higher in the CC+ group compared to those in the CC− group(18.6% vs. 5.96%, p < 0.001, adjusted odds ratio (OR)3.39 (95% 3.08−3.74 CI). Hospitalization was more likely for underrepresented racial and ethnic groups with COVID-19 and cirrhosis. CC+ group had over twice the rates of mechanical ventilation (19.92% vs. 9.07%, adjusted OR 2.71 2.71 (95% 2.51−2.93 CI)),1.7 times likelihood of receiving vasopressors (4.12% vs. 2.45%, p < 0.001, adjusted OR 1.71 (95% CI 1.46−2.01). COVID-19 is associated with increased mortality in patients with alcoholic and NASH cirrhosis, and patients with alcoholic cirrhosis and COVID-19 have a slightly higher mortality compared to NASH cirrhosis.

Abnormal liver tests are not sufficient for diagnosis of hepatic graft-versus-host disease in critically ill patients.

Hepatic graft-versus-host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15-day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = -0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period -30 (days 30 to 16 before death) to period -15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.

Characterization of Hepatic Dysfunction in Subjects Diagnosed With Chronic GVHD by NIH Consensus Criteria.

Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235.

COVID-19 Vaccine Hesitancy and Attitude toward Booster Doses among US Healthcare Workers.

Vaccine reluctance among healthcare workers (HCW) can have widespread negative ramifications, including modeling behavior for the general population and challenges with maintaining a healthy workforce so we can respond to a resurgence of the pandemic. We previously reported that only one-third of HCW were willing to take the vaccine as soon as it became available prior to its Emergency Use Authorization (EUA). Here, we re-examine the attitude toward COVID-19 vaccines among HCW several months after the vaccines have been made widely available. In this study, only 7.9% (n = 107) of respondents were hesitant to take the first or second dose of the vaccine. Younger age (18-40 years) and lower level of education attainment (GED or less) were associated with higher vaccine hesitancy, whereas self-identified Asian racial identity was associated with greater acceptance of COVID-19 vaccination. Among the vaccine-hesitant group, more respondents noted mistrust of regulatory authorities (45.3%), government (48.6%), and pharmaceutical companies (50%) than mistrust of doctors (25.4%). Nearly two-thirds of respondents were concerned that vaccination may be ineffective against new strains and booster doses may be required; however, vaccine-hesitant respondents' acceptance of a hypothetical booster dose was only 14.3%. Overall, vaccine hesitancy was observed to have demographic predictors similar to those previously reported; the hesitancy of some US HCW to receive booster doses may reflect a general hesitancy to receive other forms of vaccination.