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.

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.

Body mass index trajectories, weight gain and risks of liver and biliary tract cancers.

BACKGROUND: Little is known about the role of early obesity or weight change during adulthood in the development of liver cancer and biliary tract cancer (BTC). METHODS: We investigated the associations of body mass index (BMI) and weight trajectories with the risk of liver cancer and BTC in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). BMI was self-reported at ages 20, 50, and at enrollment. BMI trajectories were determined using latent class growth models. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 15.9 years among 138,922 participants, 170 liver cancer and 143 BTC cases were identified. Compared with those whose BMI does not exceed 25 kg/m2, participants with BMI exceeding 25 kg/m2 at age 20 had increased risks of liver cancer (HR = 2.03, 95% CI: 1.26-3.28) and BTC (HR = 1.99, 95% CI: 1.16-3.39). Compared to participants maintaining normal BMI until enrollment, trajectory of normal weight at age 20 to obesity at enrollment was associated with increased risk for liver cancer (HR = 2.50, 95% CI: 1.55-4.04) and BTC (HR = 1.83, 95% CI: 1.03-3.22). Compared to adults with stable weight (+/-5kg) between age 20 to 50 years, weight gain ≥20 kg between ages 20 to 50 years had higher HRs of 2.24 (95%CI: 1.40-3.58) for liver cancer and 1.86 (95% CI: 1.12-3.09) for BTC. CONCLUSIONS: Being overweight/obese at age 20, and BMI trajectories that result in being overweight and/or obese, may increase risk for both liver cancer and BTC.

Comparison of transient elastography and Model for End-Stage Liver Disease-sodium to Model for End-Stage Liver Disease-sodium alone to predict mortality and liver transplantation.

OBJECTIVES: Model for End-Stage Liver Disease (MELD) alone and with sodium (MELD-Na) have decreasing predictive capacity as trends in liver disease evolve. We sought to combine transient elastography (TE) with MELD-Na to improve its predictive ability. METHODS: This is a retrospective cohort study comparing the use of TE, MELD-Na, and composite MELD-Na-TE to predict liver transplantation and all-cause mortality, with hepatic decompensation as a secondary outcome. Cox proportional hazards regression was used to measure predictive ability and control for confounders. RESULTS: Of the 214 patients, the mean age was 53 years with 35% being female and 76% being Caucasian. Hepatitis C (59%) and nonalcoholic fatty liver disease (22%) were the most frequent liver disease etiologies. On univariable analysis, MELD-Na [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.06-1.2, P < 0.001], TE (HR 1.04, 95% CI 1.03-1.06, P < 0.001) and composite MELD-Na-TE (HR 1.13, 95% CI 1.08-1.19, P < 0.001) were associated with death or transplant. On multivariable analysis, MELD-Na was no longer significant (HR 1.08, 95% CI 0.95-1.22, P = 0.27) after adjusting for TE (HR 1.05, 95% CI 1.03-1.07, P < 0.001) while composite MELD-Na-TE remained significant (HR 1.16, 95% CI 1.09-1.24, P < 0.001). Composite MELD-Na-TE predicts mortality or liver transplant with the highest C-statistic of 0.81. Age (HR 1.05, 95% CI 1-1.09, P = 0.04), TE (HR 1.04, 95% CI 1.03-1.06, P < 0.001) and composite MELD-Na-TE (HR 1.11, 95% CI 1.06-1.15, P < 0.001) were significantly associated with hepatic decompensation. CONCLUSION: Composite MELD-Na-TE better predicts liver transplantation, death, and hepatic decompensation compared to MELD/MELD-Na or TE alone.

A Dynamic Aspartate-to-Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease.

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.

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.

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.

A Pathophysiologic Approach Combining Genetics and Insulin Resistance to Predict the Severity of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a complex disease dictated by both genetic and environmental factors. While insulin resistance (IR) is a key pathogenic driver, two common genetic variants in patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) also impart significant risk for disease progression. Traditional approaches to NAFLD risk stratification rely on biomarkers of fibrosis, an end result of disease progression. We hypothesized that by combining genetics and a novel measurement for IR we could predict disease progression by the NAFLD activity score (NAS) and histologic presence of significant fibrosis. A total of 177 patients with biopsy-proven NAFLD were enrolled in this cross-sectional study. PNPLA3 I148M and TM6SF2 E167K genotypes were determined by TaqMan assays. The enhanced lipoprotein IR index (eLP-IR) was calculated from serum biomarkers using nuclear magnetic resonance (NMR) spectroscopy. Multivariate regression models were used to study the relationships between genetics, IR, and histologic features of NAFLD. In the multivariate analysis, the eLP-IR was strongly associated with histologic features of NAFLD activity and hepatic fibrosis (P < 0.001 to 0.02) after adjustment for potential confounders. PNPLA3 148M and TM6SF2 E167K genotypes were significantly associated with steatosis (P = 0.003 and P = 0.02, respectively). A combination of the eLP-IR and genetic score was able to predict the presence of NAS ≥3 with an area under the receiver operating characteristic curve (AUROC) of 0.74. Adding age to this model predicted stages 3-4 liver fibrosis with an AUROC of 0.82. Conclusion: This proof-of-concept study supports the hypothesis that genetics and IR are major determinants of NAFLD severity and demonstrates the feasibility of a new risk stratification paradigm using exclusively pathogenic factors.

Non-alcoholic fatty liver disease: a narrative review of genetics.

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition, candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance, inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.

Osteoporosis in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC 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 PBC and summarizes current and emerging therapies.

Risk factors for hepatocellular carcinoma in cirrhosis due to nonalcoholic fatty liver disease: A multicenter, case-control study.

AIM: To identify risk factors associated with hepatocellular carcinoma (HCC), describe tumor characteristics and treatments pursed for a cohort of individuals with nonalcoholic steatohepatitis (NASH) cirrhosis. METHODS: We conducted a retrospective case-control study of a well-characterized cohort of patients among five liver transplant centers with NASH cirrhosis with (cases) and without HCC (controls). RESULTS: Ninety-four cases and 150 controls were included. Cases were significantly more likely to be male than controls (67% vs 45%, P < 0.001) and of older age (61.9 years vs 58 years, P = 0.002). In addition, cases were more likely to have had complications of end stage liver disease (83% vs 71%, P = 0.032). On multivariate analysis, the strongest association with the presence of HCC were male gender (OR 4.3, 95%CI: 1.83-10.3, P = 0.001) and age (OR = 1.082, 95%CI: 1.03-1.13, P = 0.001). Hispanic ethnicity was associated with a decreased prevalence of HCC (OR = 0.3, 95%CI: 0.09-0.994, P = 0.048). HCC was predominantly in the form of a single lesion with regional lymph node(s) and distant metastasis in only 2.6% and 6.3%, respectively. Fifty-nine point three percent of individuals with HCC underwent locoregional therapy and 61.5% underwent liver transplantation for HCC. CONCLUSION: Male gender, increased age and non-Hispanic ethnicity are associated with HCC in NASH cirrhosis. NASH cirrhosis associated HCC in this cohort was characterized by early stage disease at diagnosis and treatment with locoregional therapy and transplant.

Managing the Burden of Non-NASH NAFLD.

PURPOSE OF REVIEW: The purpose of this review article is to raise awareness of the significance of steatosis that exist within the spectrum of nonalcoholic fatty liver disease (NAFLD). While the impact of nonalcoholic steatohepatitis (NASH), and its potential for histologic progression to cirrhosis and hepatocellular carcinoma is widely appreciated, the impact of non-NASH NAFLD (steatosis) on morbidity and mortality is less well recognized. RECENT FINDINGS: NAFLD is a spectrum of hepatic pathology with a rising prevalence worldwide. Steatosis without fibrosis carries a low risk of progression to cirrhosis but likely confers an increased risk of diabetes mellitus and cardiovascular disease. SUMMARY: About a quarter of the world population is affected by NAFLD. NAFLD represents a burden to affected individuals, economics of the health care system and contributes significantly to morbidity and mortality worldwide. An increased level of awareness and knowledge about risk factors and diagnostic strategies is needed to identify patients affected with disease.