Natural History of Indeterminate Liver Nodules in Patients with Advanced Liver Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear. METHODS: We conducted a multi-center retrospective cohort study among patients with ≥1 newly detected LI-RADS 3 (LR-3) lesion ≥1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks. RESULTS: Of 307 patients with ILNs, 208 had LR-3 lesions, 83 had LR-4 lesions, and 16 had both LR-3 and LR-4 lesions. HCC incidence rates for patients with LR-3 and LR-4 lesions were 110 (95%CI 70 - 150) and 420 (95%CI 310 - 560) per 1000 person-years, respectively. In multivariable analysis, incident HCC among patients with LR-3 lesions was associated with older age, thrombocytopenia (platelet count ≤150 x109/L), and elevated serum alpha-fetoprotein (AFP) levels. Among those with LR-4 lesions, incident HCC was associated with a maximum lesion diameter >1 cm. Although most patients had follow-up CT or MRI, 13.7% had no follow-up imaging and another 14.3% had follow-up ultrasound only. CONCLUSION: ILNs have a high but variable risk of HCC, with 4-fold higher risk in patients with LR-4 lesions than those with LR-3 lesions, highlighting a need for accurate risk stratification tools and close follow-up in this population.

Association between bridging therapy and posttransplant outcomes in patients with HCC within Milan criteria: A systematic review and meta-analysis.

Liver transplantation is the curative therapy of choice for patients with early-stage HCC. Locoregional therapies are often employed as a bridge to reduce the risk of waitlist dropout; however, their association with posttransplant outcomes is unclear. We conducted a systematic review using Ovid MEDLINE and EMBASE to identify studies published between database inception and August 2, 2023, which reported posttransplant recurrence-free survival and overall survival among patients transplanted for HCC within Milan criteria, stratified by receipt of bridging therapy. Pooled HRs were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 38 studies, including 19,671 patients who received and 20,148 patients who did not receive bridging therapy. Bridging therapy was not associated with significant differences in recurrence-free survival (pooled HR: 0.91, 95% CI: 0.77-1.08; I2 =39%) or overall survival (pooled HR: 1.09, 95% CI: 0.95-1.24; I2 =47%). Results were relatively consistent across subgroups, including geographic location and study period. Studies were discordant regarding the differential strength of association by pretreatment tumor burden and pathologic response, but potential benefits of locoregional therapy were mitigated in those who received 3 or more treatments. Adverse events were reported in a minority of studies, but when reported occurred in 6%-15% of the patients. Few studies reported loss to follow-up and most had a risk of residual confounding. Bridging therapy is not associated with improvements in posttransplant recurrence-free or overall survival among patients with HCC within Milan criteria. The risk-benefit ratio of bridging therapy likely differs based on the risk of waitlist dropout.

Stage migration as a surrogate of survival in hepatocellular carcinoma treated with transarterial chemoembolization.

BACKGROUND AIMS: Locoregional therapies, including transarterial chemoembolization (TACE), are recommended for the treatment of HCC; however, clinical trials evaluating their effectiveness have been complicated by a lack of validated surrogate outcomes. We aimed to evaluate if stage migration could serve as a potential surrogate of overall survival in patients undergoing TACE. APPROACH: We conducted a retrospective cohort study of adult patients with HCC who underwent TACE as initial therapy from 3 centers in the US from 2008 to 2019. The primary outcome was overall survival from the date of the first TACE treatment, and the primary exposure of interest was Barcelona Clinic Liver Cancer stage migration to a more advanced stage within 6 months of TACE. Survival analysis was completed using Kaplan-Meier and multiple Cox proportional hazard models adjusted by the site. RESULTS: Of 651 eligible patients (51.9% Barcelona Clinic Liver Cancer stage A and 39.6% stage B), 129 (19.6%) patients experienced stage migration within 6 months of TACE. Those with stage migration had larger tumors (5.6 vs. 4.2 cm, p < 0.01) and higher AFP levels (median 92 vs. 15 ng/mL, p < 0.01). In multivariate analysis, stage migration was significantly associated with worse survival (HR: 2.82, 95% CI: 2.66-2.98), with a median survival of 8.7 and 15.9 months in those with and without stage migration. Other predictors of worse survival included the White race, higher AFP levels, a higher number of tumors, and a larger maximum HCC diameter. CONCLUSION: Stage migration is associated with increased mortality after TACE in patients with HCC and could serve as a surrogate end point in clinical trials evaluating locoregional therapies such as TACE.

Risk of Hepatocellular Carcinoma in Patients With Indeterminate (LI-RADS 3) Liver Observations.

Early hepatocellular cancer (HCC) detection is associated with curative treatment and improved survival.1 The American Association for the Study of Liver Diseases recommends semiannual ultrasound and α-fetoprotein (AFP) in patients with cirrhosis, and those with abnormal results should undergo diagnostic multiphase computed tomography (CT) or magnetic resonance imaging (MRI).2 The Liver Imaging Reporting and Data System (LI-RADS) was devised to standardize reporting of liver observations in at-risk individuals, ranging from LR-1 ("definitely benign") to LR-5 ("definitely HCC''), with indeterminate observations classified as LR-3 ("intermediate probability of malignancy").3 A study among 999 cirrhosis patients found that indeterminate liver observations are common, being reported on diagnostic CT or MRI in 98 (38.3%) of 256 patients with abnormal ultrasound results.4 Prior studies have reported a wide range in HCC risk, from 4% to 31%, for LR-3 observations, so there is insufficient evidence to recommend a standardized strategy for monitoring LR-3 observations.5,6.

Emerging liquid biopsy techniques for early detection of hepatocellular carcinoma, prognostication, and disease monitoring.

Content available: Author Interview and Audio Recording.

Risk of Cardiovascular Disease in Individuals With Nonobese Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is independently associated with obesity and cardiovascular disease (CVD). CVD is the primary cause of mortality in the predominantly obese population of adults with NAFLD. NAFLD is increasingly seen in individuals who are lean and overweight (i.e., nonobese), but it is unclear whether their risk of CVD is comparable to those with NAFLD and obesity. Using a prospective cohort of patients with NAFLD, we compared the prevalence and incidence of CVD in individuals with and without obesity. NAFLD was diagnosed by biopsy or imaging after excluding other chronic liver disease etiologies. Logistic regression was used to compare the odds of baseline CVD by obesity status. Cox proportional hazards regression was used to evaluate obesity as a predictor of incident CVD and to identify predictors of CVD in subjects with and without obesity. At baseline, adults with obesity had a higher prevalence of CVD compared to those without obesity (12.0% vs. 5.0%, P = 0.02). During follow-up, however, obesity did not predict incident CVD (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.69-2.22) or other metabolic diseases. Findings were consistent when considering body mass index as a continuous variable and after excluding subjects who were overweight. Age (adjusted HR [aHR], 1.05; 95% CI, 1.03-1.08), smoking (aHR, 4.61; 95% CI, 1.89-11.22), and decreased low-density lipoprotein levels (aHR, 0.98; 95% CI, 0.96-1.00) independently predicted incident CVD in the entire cohort, in subjects with obesity, and in those without obesity, respectively. Conclusion: Individuals with overweight or lean NAFLD are not protected from incident CVD compared to those with NAFLD and obesity, although CVD predictors appear to vary between these groups. Patients without obesity also should undergo rigorous risk stratification and treatment.

Hepatic Encephalopathy is Associated With Slow Speech on Objective Assessment.

INTRODUCTION: There are no available low-burden, point-of-care tests to diagnose, grade, and predict hepatic encephalopathy (HE). METHODS: We evaluated speech as a biomarker of HE in 76 English-speaking adults with cirrhosis. RESULTS: Three speech features significantly correlated with the following neuropsychiatric scores: speech rate, word duration, and use of particles. Patients with low neuropsychiatric scores had slower speech (22 words/min, P = 0.01), longer word duration (0.09 seconds/word, P = 0.01), and used fewer particles (0.85% fewer, P = 0.01). Patients with a history of overt HE had slower speech (23 words/min, P = 0.005) and longer word duration (0.09 seconds/word, P = 0.005). DISCUSSION: HE is associated with slower speech.

Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk. METHODS: We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI). RESULTS: Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86-0.97, I2 = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83-0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87-1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02-1.14, I2 = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02-1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89-1.60, I2 = 72%). CONCLUSIONS: Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.

Aspirin Use Is Associated with a Reduced Incidence of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death worldwide, with a growing incidence and poor prognosis. While some recent studies suggest an inverse association between aspirin use and reduced HCC incidence, other data are conflicting. To date, the precise magnitude of risk reduction-and whether there are dose-dependent and duration-dependent associations-remains unclear. To provide an updated and comprehensive assessment of the association between aspirin use and incident HCC risk, we conducted a systematic review and meta-analysis of all observational studies published through September 2020. Using random-effects meta-analysis, we calculated the pooled relative risks (RRs) and 95% confidence intervals (CIs) for the association between aspirin use and incident HCC risk. Where data were available, we evaluated HCC risk according to the defined daily dose of aspirin use. Among 2,389,019 participants, and 20,479 cases of incident HCC, aspirin use was associated with significantly lower HCC risk (adjusted RR, 0.61; 95% CI, 0.51-0.73; P ≤ 0.001; I2 = 90.4%). In subgroup analyses, the magnitude of benefit associated with aspirin was significantly stronger in studies that adjusted for concurrent statin and/or metformin use (RR, 0.45; 95% CI, 0.28-0.64) versus those that did not (P heterogeneity = 0.02), studies that accounted for cirrhosis (RR, 0.49; 95% CI, 0.45-0.52) versus those that did not (P heterogeneity = 0.02), and studies that confirmed HCC through imaging/biopsy (RR, 0.30; 95% CI, 0.15-0.58) compared with billing codes (P heterogeneity < 0.001). In four studies, each defined daily dose was associated with significantly lower HCC risk (RR, 0.98; 95% CI, 0.97-0.98), corresponding to an 8.4% risk reduction per year of aspirin use. Conclusion: In this comprehensive systematic review and meta-analysis, aspirin use was associated with a significant reduction in HCC risk. These benefits appeared to increase with increasing dose and duration of aspirin use.

Cognitive Tests and Stool Frequency at Hospital Discharge Do Not Predict Outcomes in Hepatic Encephalopathy.

OBJECTIVES: Hepatic encephalopathy (HE) is associated with hospital readmissions and mortality. We sought to determine whether cognitive testing and stool frequency at discharge predicted 30-day readmission or death in cirrhotic patients admitted with overt HE. METHODS: We approached consecutive inpatients with cirrhosis and overt HE when they were within 48 hours of discharge. Patients underwent cognitive tests, including Psychometric Hepatic Encephalopathy Score (PHES), and stool frequency was documented. Chart review identified Model for End-Stage Liver Disease-sodium (MELD-Na) and the presence of non-HE extrahepatic organ failures. Cox proportional hazards models were used to evaluate predictors of time to the primary composite outcome of hospital readmission for HE or death within 30 days, censoring for liver transplantation. RESULTS: Of 51 patients consented and enrolled, 14 patients met the primary composite outcome. In unadjusted Cox models, 4 variables predicted HE readmission or death: MELD-Na (hazard ratio [HR] 1.10 [1.01-1.20], P = 0.03), respiratory failure (HR 4.26 [1.47-12.35], P = 0.008), total number of HE extrahepatic organ failures (HR 1.79 [1.12-2.88], P = 0.02), and score on a PHES subtest, Number Connection Test A (per 30 seconds; HR 1.25 [1.06-1.47], P = 0.01). PHES and 24-hour stool frequency did not predict the primary outcome. When controlling for MELD-Na, respiratory failure predicted the primary outcome (HR 3.67 [1.24-10.86], P = 0.02). CONCLUSION: Cognitive testing and stool frequency at discharge did not predict poor outcomes in patients admitted with HE, while respiratory failure appeared to be a strong predictor.

A Smartphone App to Manage Cirrhotic Ascites Among Outpatients: Feasibility Study.

BACKGROUND: Ascites is a common, painful, and serious complication of cirrhosis. Body weight is a reliable proxy for ascites volume; therefore, daily weight monitoring is recommended to optimize ascites management. OBJECTIVE: This study aims to evaluate the feasibility of a smartphone app in facilitating outpatient ascites management. METHODS: In this feasibility study, patients with cirrhotic ascites requiring active management were identified in both inpatient and outpatient settings. Patients were provided with a Bluetooth-connected scale, which transmitted weight data to a smartphone app and then via the internet to an electronic medical record (EMR). Weights were monitored every weekday. In the event of a weight change of ≥5 lbs in 1 week, patients were called and administered a short symptom questionnaire, and providers received an email alert. The primary outcomes of this study were the percentage of enrolled days during which weight data were successfully transmitted to an EMR and the percentage of weight alerts that prompted responses by the provider. RESULTS: In this study, 25 patients were enrolled: 12 (48%) were male, and the mean age was 58 (SD 13; range 35-81) years. A total of 18 (72%) inpatients were enrolled. Weight data were successfully transmitted to an EMR during 71.2% (697/979) of the study enrollment days, with technology issues reported on 16.5% (162/979) of the days. Of a total of 79 weight change alerts fired, 41 (52%) were triggered by weight loss and 38 (48%) were by weight gain. Providers responded in some fashion to 66 (84%) of the weight alerts and intervened in response to 45 (57%) of the alerts, for example, by contacting the patient, scheduling clinic or paracentesis appointments, modifying the diuretic dose, or requesting a laboratory workup. Providers responded equally to weight increase and decrease alerts (P=.87). The staff called patients a mean of 3.7 (SD 3.5) times per patient, and the number of phone calls correlated with technology issues (r=0.60; P=.002). A total of 60% (15/25) of the patients chose to extend their participation beyond 30 days. A total of 17 patient readmissions occurred during the study period, with only 4 (24%) related to ascites. CONCLUSIONS: We demonstrated the feasibility of a smartphone app to facilitate the management of ascites and reported excellent rates of patient and provider engagement. This innovation could enable early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among patients with cirrhosis.

Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: Implications for therapeutic planning.

The practice of transplanting hepatitis C (HCV)-infected livers into HCV-uninfected recipients has not previously been recommended in transplant guidelines, in part because of concerns over uncontrolled HCV infection of the allograft. Direct-acting antivirals (DAAs) provide an opportunity to treat donor-derived HCV-infection and should be administered early in the posttransplant period. However, evidence on the safety and efficacy of an immediate DAA treatment approach, including how to manage logistical barriers surrounding timely DAA procurement, are required prior to broader use of HCV-positive donor organs. We report the results of a trial in which 14 HCV-negative patients underwent successful liver transplantation from HCV-positive donors. Nine patients received viremic (nucleic acid testing [NAT]-positive) livers and started a 12-week course of oral glecaprevir-pibrentasvir within 5 days of transplant. Five patients received livers from HCV antibody-positive nonviremic donors and were followed using a reactive approach. Survival in NAT-positive recipients is 100% at a median follow-up of 46 weeks. An immediate treatment approach for HCV NAT-positive liver transplantation into uninfected recipients is safe and efficacious. Securing payer approval for DAAs early in the posttransplant course could enable need-based allocation of HCV-positive donor organs irrespective of candidate HCV status, while averting chronic HCV allograft infection.

Hiatal Hernia Presenting with Recurrent Non-ST Elevation Myocardial Infarction and Cardiac Tamponade.

Hiatal hernia is a common pathology, particularly among the elderly or obese populations. Occasionally, markedly dilated hernias can impinge on surrounding structures, notably the heart or lung. In such cases, morbidity can be considerable. We present a case of an enlarging hiatal hernia that compressed the heart, leading to recurrent non-ST elevation myocardial infarction with cardiac tamponade. The patient was successfully managed with nasogastric decompression and surgical repair. We recommend that extrapericardial pathology be considered in tamponade patients with concurrent hiatal hernia and that surgery should be considered the definitive treatment modality.

Asthma and lung cancer, after accounting for co-occurring respiratory diseases and allergic conditions: a systematic review protocol.

INTRODUCTION: Asthma is one of the most frequently diagnosed respiratory diseases in the UK, and commonly co-occurs with other respiratory and allergic diseases, such as chronic obstructive pulmonary disease (COPD) and atopic dermatitis. Previous studies have shown an increased risk of lung cancer related to asthma, but the evidence is mixed when accounting for co-occurring respiratory diseases and allergic conditions. A systematic review of published data that investigate the relationship between asthma and lung cancer, accounting for co-occurring respiratory and allergic diseases, will be conducted to investigate the independent association of asthma with lung cancer. METHODS AND ANALYSIS: A systematic review will be conducted, and include original reports of cohort, cross-sectional and case-control studies of the association of asthma with lung cancer after accounting for co-occurring respiratory diseases. Articles published up to June 2016 will be included, and their selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A standardised data extraction form will be developed and pretested, and descriptive analyses will be used to summarise the available literature. If appropriate, pooled effect estimates of the association between asthma and lung cancer, given adjustment for a specific co-occurring condition will be estimated using random effects models. Potential sources of heterogeneity and between study heterogeneity will also be investigated. ETHICS AND DISSEMINATION: The study will be a review of published data and does not require ethical approval. Results will be disseminated through a peer-reviewed publication. TRIAL REGISTRATION NUMBER: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42016043341.