Pre-diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population-based cohort studies from the United States and the United Kingdom.

Previous studies suggest a role for inflammation in hepatocarcinogenesis. However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case-control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p < .05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (pFDR < .05). Two proteins (stem cell factor, OR per SD = 0.31, 95% CI = 0.16-0.58; tumor necrosis factor superfamily member 12, OR per SD = 0.51, 95% CI = 0.31-0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs per SD ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.

A Meta-Analysis of Cumulative Incidence of Hepatocellular Carcinoma After the Fontan Operation.

BACKGROUND: Hepatic complications are increasingly recognized after the Fontan operation. The development of hepatocellular carcinoma (HCC) is associated with high mortality when diagnosed, but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the cumulative incidence of HCC after Fontan and associated risk factors. METHODS: We searched PubMed, CINAHL, and MEDLINE databases for articles reporting the cumulative incidence of HCC after Fontan operation on March 21, 2023. A single-arm random effects meta-analysis was conducted to assess cumulative incidence at 10, 20, and 30 years after Fontan. Meta-analysis of the difference of the medians was used to assess the influence of risk factors on the development of HCC. RESULTS: Four studies including a total of 1320 patients reported cumulative incidence. The cumulative incidence of HCC at 10, 20, and 30 years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01-0.06), and 7% (0.03-0.17) respectively. Seven studies including 6,250 patients reported overall incidence of HCC and associated risk factors. At a median 18.4 (IQR 11.9-24.9) years of follow-up, incidence of HCC was 2% (0.01-0.04). Only use of anticoagulation was associated with a lower risk of HCC (RR 0.3, 95% CI 0.1-0.88). DISCUSSION: By 30 years after Fontan, cumulative incidence of HCC is high (7%). Risk of HCC development prior to 10 years post-Fontan is low (0%), though the decision to defer HCC surveillance in this period may require future investigation based on larger studies. Screening with ultrasound every 6 months starting 20 years post-Fontan is reasonable, however, further research regarding timing, cost-effectiveness, additional risk factors associated with HCC risk, and different screening modalities is required.

Development of an Algorithm to Identify Cases of Nonalcoholic Steatohepatitis Cirrhosis in the Electronic Health Record.

BACKGROUND AND AIMS: Current genetic research of nonalcoholic steatohepatitis (NASH) cirrhosis is limited by our ability to accurately identify cases on a large scale. Our objective was to develop and validate an electronic health record (EHR) algorithm to accurately identify cases of NASH cirrhosis in the EHR. METHODS: We used Clinical Query 2, a search tool at Beth Israel Deaconess Medical Center, to create a pool of potential NASH cirrhosis cases (n = 5415). We created a training set of 300 randomly selected patients for chart review to confirm cases of NASH cirrhosis. Test characteristics of different algorithms, consisting of diagnosis codes, laboratory values, anthropomorphic measurements, and medication records, were calculated. The algorithms with the highest positive predictive value (PPV) and the highest F score with a PPV ≥ 80% were selected for internal validation using a separate random set of 100 patients from the potential NASH cirrhosis pool. These were then externally validated in another random set of 100 individuals using the research patient data registry tool at Massachusetts General Hospital. RESULTS: The algorithm with the highest PPV of 100% on internal validation and 92% on external validation consisted of ≥ 3 counts of "cirrhosis, no mention of alcohol" (571.5, K74.6) and ≥ 3 counts of "nonalcoholic fatty liver" (571.8-571.9, K75.81, K76.0) codes in the absence of any diagnosis codes for other common causes of chronic liver disease. CONCLUSIONS: We developed and validated an EHR algorithm using diagnosis codes that accurately identifies patients with NASH cirrhosis.

Waitlist mortality and transplant free survival in Hispanic patients listed for liver transplant using the UNOS database.

INTRODUCTION AND OBJECTIVES: After the implementation of "Share 35", several concerns arose such as the potential to increase travel distance, costs, and decreased liver availability. These elements could have a negative impact on waitlist outcomes among ethnic minorities. We aimed to determine waitlist survival after the implementation of the Share 35 policy in non-Hispanic white and Hispanic patients. MATERIALS AND METHODS: We identified non-Hispanic whites and Hispanics who were listed for liver transplantation from June 18th, 2013 to June 18, 2018. We excluded pediatric patients, patients with acute hepatic necrosis, re-transplants, multiorgan transplant, living donor, and exception cases. The primary outcome was death or removal from the waitlist due to clinical deterioration. We used competing risk analysis to compare waitlist survival between the two groups. RESULTS: There were 23,340 non-Hispanic whites and 4938 Hispanics listed for transplant. On competing risk analysis, Hispanic patients had a higher risk of being removed from the waitlist for death or clinical deterioration compared to their counterpart (SHR 1.23, 95% CI 1.13-1.34; P < 0.001). CONCLUSION: After the implementation of Share 35, disparities are still present and continue to negatively impact outcomes in minority populations especially Hispanic patients.

Hepatitis C-positive liver transplantation: outcomes and current practice.

PURPOSE OF REVIEW: The coincidence of the opioid epidemic and the approval of direct-acting antivirals for the treatment of hepatitis C virus (HCV) has resulted in an imbalance in HCV viraemic donors relative to HCV viraemic patients awaiting liver transplantation. Although ethical concerns exist about knowingly infecting patients with HCV in the absence of prospective, protocolized studies, transplantation of HCV-positive liver allografts into HCV-negative recipients has increased exponentially in recent years. For this reason, we sought to review outcomes, cost-effectiveness and ethical concerns associated with this practice. RECENT FINDINGS: Short-term outcomes in terms of patient and graft survival are equivalent to those who received HCV-negative allografts without an increase in acute rejection, biliary or vascular complications. Few cases of treatment failure have been reported and complications related to the virus itself such as fibrosing cholestatic hepatitis and membranous glomerulonephritis are rare and reversible with prompt direct-acting antiretroviral treatment. The practice appears cost-effective and modelling suggests a survival benefit for patients willing to accept HCV-positive organs compared with those who do not. SUMMARY: In light of the preponderance of current data, one could argue it is unethical to withhold HCV-positive grafts from HCV-negative recipients who have undergone thorough informed consent.

Increased Posttransplant Mortality for Autoimmune Hepatitis Compared With Other Autoimmune Liver Diseases.

GOALS: We sought to compare posttransplant outcomes between autoimmune liver disease. BACKGROUND: Autoimmune liver diseases, namely primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) generally have favorable posttransplant outcomes. PSC is known to require more retransplantation compared with PBC, however, comparisons to AIH are lacking. We sought to compare graft survival and the need for retransplant in AIH compared with other autoimmune liver disease. STUDY: We compared posttransplant graft survival among the 3 entities using Cox regression and competing for risk analyses using the United Network for Organ Sharing (UNOS) database. RESULTS: We found AIH is associated with significantly decreased graft survival compared with PBC [hazard ratio: 0.86; 95% confidence interval (CI): 0.77-0.96] and PSC (hazard ratio: 0.89; 95% CI: 0.8-0.99) after controlling for potential confounders. This is mainly driven by posttransplant death. On competing for risk analysis, AIH was associated with higher risk of death compared with PBC [subdistribution hazard ratio (SHR): 0.79; 95% CI: 0.7-0.89] and PSC (SHR: 0.72; 95% CI: 0.64-0.82) and lower risk of retransplant compared with PSC (SHR: 1.48; 95% CI: 1.19-1.8). CONCLUSION: As prior studies have shown the similar risk of disease recurrence in AIH and PSC, our study indicates at least part of the increased posttransplant mortality in AIH may be due lower retransplantation rate in this population.

Bone Health in Patients With Liver Diseases.

Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.

The Pharmacologic Management of Osteoporosis in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Osteoporosis is a common complication of primary biliary cholangitis (PBC) yet evidence for effective therapy is lacking. We sought to review all randomized controlled trials evaluating pharmacotherapy against placebo or no intervention for treatment of osteoporosis in PBC. METHODOLOGY: A comprehensive database search was conducted from inception through 29 March 2017. The primary outcome was incidence of fractures; secondary outcomes were change in bone mineral density (BMD) and adverse events. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same drug class. RESULTS: We identified 11 randomized controlled trials evaluating bisphosphonates (3), hormone replacement therapy (2), ursodeoxycholic acid (1), obeticholic acid (1), cyclosporin A (1), vitamin K (1), calcitriol (1), and sodium fluoride (1). No intervention significantly reduced fractures compared to control. Although significant improvement in BMD was seen in one study with alendronate, a third-generation bisphosphonate, no significant improvement was seen on pooled analysis of all bisphosphonates including first-generation bisphosphonates (standard mean difference 0.41, p = 0.68). On pooled analysis, hormone replacement therapy modestly improved lumbar BMD (standard mean difference 0.69, p = 0.02), but with significantly increased adverse events (odds ratio 8.82, p = 0.01). CONCLUSIONS: There is a lack of high-quality evidence supporting the efficacy of any treatment of osteoporosis in PBC. This may be explained by lack of power in the included studies. However, our current understanding of PBC-related osteoporosis indicates that it results from decreased bone formation, which may explain the attenuated effect of traditional antiresorptive agents. Future studies should investigate newer anabolic bone agents.

Sclerosing Mesenteritis.

Sclerosing mesenteritis is a rare non-neoplastic disorder characterized by fat necrosis, chronic inflammation, and fibrosis typically of the small bowel mesentery. Our understanding of this disorder is limited by its rarity as well as inconsistent terminology used across the literature. While prior abdominal surgery or trauma, autoimmunity, infection, ischemia, and malignancy have been suggested to be involved in the pathogenesis of the disorder, it remains poorly understood. The clinical course of sclerosing mesenteritis is generally benign with a large proportion of patients diagnosed incidentally on imaging obtained for other indications. In a subset of patients, symptoms may arise from a mass effect on the bowel, lymphatics, or vasculature resulting in bowel obstruction, chylous ascites, or mesenteric ischemia. Symptomatic patients should be treated with a combination of corticosteroid and tamoxifen as first-line therapy based on retrospective case series and experience in other fibrosing disorders. Surgical intervention may be required in those with persistent obstruction despite conservative treatment, though complete resection of the mass is often not feasible given intimate involvement with the mesenteric vasculature. A careful use of terminology and communication between the radiologist, pathologist, and clinicians in the care of these patients will be essential to future efforts at understanding this disease.

Evidence of bias during liver transplant evaluation of non-alcoholic steatohepatitis cirrhosis patients.

BACKGROUND & AIMS: Cardiovascular disease (CVD) is the leading cause of death among non-alcoholic steatohepatitis (NASH) patients and a major source of post-transplant mortality. We sought to examine the effect of comorbidities on listing for orthotopic liver transplant (OLT) in NASH patients. METHODS: In this retrospective cohort study, we included all patients (n = 955) referred to Beth Israel Deaconess Medical Center for OLT between January 2002 and September 2011 and followed their outcomes through March 2018. RESULTS: Compared with non-NASH patients (n = 881), NASH patients (n = 74) were older, more likely female, more overweight, with higher rates of diabetes, hypertension and CVD. NASH patients were less likely to be listed for OLT (55% vs 68.9%, P = 0.01) and were more often declined for 'medical comorbidities' (36.1% vs 15.7%, P < 0.001). However, on multivariate analysis, the only significant predictors of listing were model for end-stage liver disease (MELD) score (OR 1.04, P = 0.01), HCC (OR 2.16, P = 0.01), and diagnosis of non-NASH cirrhosis (OR 2.56, P = 0.003) while controlling for comorbidities. NASH patients declined for OLT died primarily from their liver disease and were not more likely to die from CVD than non-NASH patients. There was no difference in outcomes of NASH vs non-NASH patients on the waitlist and post-transplant. CONCLUSIONS: This study demonstrates potential bias against NASH patients referred for OLT arising from heightened concern for comorbidities. Despite being declined for comorbidities, NASH patients are likely to die of their liver disease.

Treatment of Fatigue in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Fatigue is the most common complication of primary biliary cholangitis (PBC) and can be debilitating. Numerous interventions have been trialed targeting several proposed mechanisms of PBC-associated fatigue. We sought to summarize and perform a meta-analysis to determine the efficacy of these interventions. METHODS: A comprehensive database search was conducted from inception through March 27, 2018. The primary outcome was proportion of fatigued patients or reduction in degree of fatigue. Adverse events were a secondary outcome. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same class. RESULTS: We identified 16 studies evaluating ursodeoxycholic acid (UDCA) (7), liver transplantation (2), serotonin reuptake inhibitors (2), colchicine (1), methotrexate (1), cyclosporine (1), modafinil (1), and obeticholic acid (1). On meta-analysis, UDCA was not associated with a reduction in risk of fatigue (RR = 0.86, 95% CI 0.69-1.08, p = 0.19, I2 = 56.2%). While liver transplantation did reduce degree of fatigue (SMD - 0.57, 95% CI - 0.89 to - 0.24, p = 0.001, I2 = 67.3%), fatigue did not return to baseline indicating the underlying cause may not be addressed. CONCLUSIONS: While there is some improvement in fatigue with liver transplantation, there is a lack of high-quality evidence supporting the efficacy of any other intervention in the treatment of PBC-related fatigue. Further research into the underlying pathophysiology may help guide future trials.

Clinical Implications of a Multivariate Stratification Model for the Estimation of Prognosis in Ventricular Septal Defect.

OBJECTIVES: To derive and validate a multivariate stratification model for prediction of survival free from intervention (SFFI) in ventricular septal defect (VSD). A secondary aim is for this model to serve as proof of concept for derivation of a more general congenital heart disease prognostic model, of which the VSD model will be the first component. STUDY DESIGN: For 12 years, 2334 subjects with congenital heart disease were prospectively and consecutively enrolled. Of these, 675 had VSD and form the derivation cohort. One hundred seven other subjects with VSD followed in another practice formed the validation cohort. The derivation cohort was serially stratified based on clinical and demographic features correlating with SFFI. RESULTS: Six strata were defined, the most favorable predicting nearly 100% SFFI at 10 years, and the least favorable, a high likelihood of event within weeks. Strata with best SFFI had many subjects with nearly normal physiology, muscular VSD location, or prior intervention. In the validation cohort, the relation between predicted and actual SFFI at 6 months, 1 year, 2 years, and 5 years follow-up had areas under the receiver operating characteristic curves 0.800 or greater. CONCLUSIONS: A prediction model for SFFI in VSD has been derived and validated. It has potential for clinical application to the benefit of patients and families, medical trainees, and practicing physicians.

A comparative evaluation of ChatGPT 3.5 and ChatGPT 4 in responses to selected genetics questions.

OBJECTIVES: To evaluate the efficacy of ChatGPT 4 (GPT-4) in delivering genetic information about BRCA1, HFE, and MLH1, building on previous findings with ChatGPT 3.5 (GPT-3.5). To focus on assessing the utility, limitations, and ethical implications of using ChatGPT in medical settings. MATERIALS AND METHODS: A structured survey was developed to assess GPT-4's clinical value. An expert panel of genetic counselors and clinical geneticists evaluated GPT-4's responses to these questions. We also performed comparative analysis with GPT-3.5, utilizing descriptive statistics and using Prism 9 for data analysis. RESULTS: The findings indicate improved accuracy in GPT-4 over GPT-3.5 (P < .0001). However, notable errors in accuracy remained. The relevance of responses varied in GPT-4, but was generally favorable, with a mean in the "somewhat agree" range. There was no difference in performance by disease category. The 7-question subset of the Bot Usability Scale (BUS-15) showed no statistically significant difference between the groups but trended lower in the GPT-4 version. DISCUSSION AND CONCLUSION: The study underscores GPT-4's potential role in genetic education, showing notable progress yet facing challenges like outdated information and the necessity of ongoing refinement. Our results, while showing promise, emphasizes the importance of balancing technological innovation with ethical responsibility in healthcare information delivery.

Evaluating ChatGPT as an Agent for Providing Genetic Education.

Genetic disorders are complex and can greatly impact an individual's health and well-being. In this study, we assess the ability of ChatGPT, a language model developed by OpenAI, to answer questions related to three specific genetic disorders: BRCA1, MLH1, and HFE. ChatGPT has shown it can supply articulate answers to a wide spectrum of questions. However, its ability to answer questions related to genetic disorders has yet to be evaluated. The aim of this study is to perform both quantitative and qualitative assessments of ChatGPT's performance in this area. The ability of ChatGPT to provide accurate and useful information to patients was assessed by genetic experts. Here we show that ChatGPT answered 64.7% of the 68 genetic questions asked and was able to respond coherently to complex questions related to the three genes/conditions. Our results reveal that ChatGPT can provide valuable information to individuals seeking information about genetic disorders, however, it still has some limitations and inaccuracies, particularly in understanding human inheritance patterns. The results of this study have implications for both genomics and medicine and can inform future developments in this area. AI platforms, like ChatGPT, have significant potential in the field of genomics. As these technologies become integrated into consumer-facing products, appropriate oversight is required to ensure accurate and safe delivery of medical information. With such oversight and training specifically for genetic information, these platforms could have the potential to augment some clinical interactions.

Association of per- and polyfluoroalkyl substance exposure with fatty liver disease risk in US adults.

Background & Aims: Per- and polyfluoroalkyl substances (PFAS) are widespread pollutants with demonstrated hepatotoxicity. Few studies have examined the association between PFAS and fatty liver disease (FLD) risk in an adult population. Methods: In this cross-sectional study of participants from the 2017-2018 National Health and Nutrition Examination Survey, serum PFAS were measured, and FLD cases were ascertained by vibration-controlled transient elastography. Logistic regression models were used to examine the association between circulating PFAS levels and FLD risk. Analyses were stratified into non-alcoholic FLD and alcoholic FLD risk groups by alcohol intake status, as well as controlling for other risk factors, including personal demographics, lifestyle factors, and related health factors. Results: Among 1,135 eligible participants, 446 had FLD. For FLD risk, the multivariable-adjusted odds ratio per log-transformed SD increase (ORSD) in perfluorohexane sulfonate (PFHxS) was 1.13 (95% CI 1.01-1.26). The association between PFHxS and FLD appeared stronger among individuals with obesity or high-fat diets (both p interaction <0.05). When limiting the analysis to 212 heavy drinkers (≥2 drinks/day for women and ≥3 drinks/day for men), significantly higher risk of alcoholic FLD was found for higher levels of perfluorooctanoic acid (ORSD 1.79; 95% CI 1.07-2.99), PFHxS (ORSD 2.06; 95% CI 1.17-3.65), and perfluoroheptane sulfonic acid (ORSD 1.44; 95% CI 1.00-2.07), and marginally significant higher risk for total PFAS (ORSD 2.12; 95% CI 0.99-4.54). In never or light drinkers, we did not observe any significant association between PFAS and non-alcoholic FLD. Significant positive associations were found for PFAS with aspartate aminotransferase, gamma-glutamyl transaminase, total bilirubin, and albumin (ß ranged from 0.008 to 0.101, all p <0.05). Conclusions: Higher serum PFAS was moderately associated with FLD risk and worse liver function in the general population, and among those with independent risk factors, including heavy alcohol intake, obesity, or high-fat diets, PFAS increased the risk. These results suggest synergistic effects on hepatic steatosis between PFAS exposures as measured through biomonitoring data and lifestyle risk factors in a nationally representative US population. Impact and Implications: The per- and polyfluoroalkyl substances (PFAS) may convey higher risk for chronic liver disease in humans. Among 1,135 US adults in the 2017-2018 National Health and Nutrition Examination Survey, we found that higher serum PFAS was associated with higher fatty liver disease risk and worse liver function, especially among those with liver disease risk factors, including heavy alcohol intake, obesity, or high-fat diets. Continuously monitoring PFAS in the population and examining how they potentiate risk to the liver are essential.