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Liver function tests are commonly obtained in symptomatic and asymptomatic patients. Various overlapping lab patterns can be seen due to derangement of hepatocytes and bile ducts function. Imaging tests are pursued to identify underlying etiology and guide management based on the lab results. Liver function tests may reveal mild, moderate, or severe hepatocellular predominance and can be seen in alcoholic and nonalcoholic liver disease, acute hepatitis, and acute liver injury due to other causes. Cholestatic pattern with elevated alkaline phosphatase with or without elevated γ-glutamyl transpeptidase can be seen with various causes of obstructive biliopathy. Acute or subacute cholestasis with conjugated or unconjugated hyperbilirubinemia can be seen due to prehepatic, intrahepatic, or posthepatic causes. We discuss the initial and complementary imaging modalities to be used in clinical scenarios presenting with abnormal liver function tests. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation. [ABSTRACT FROM AUTHOR]

The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation. [ABSTRACT FROM AUTHOR]

Patients with cirrhosis have an increased risk of postoperative mortality for a range of surgeries; however, they are also at risk of postoperative complications such as infection and cirrhosis decompensation. To date, there are no prediction scores that specifically risk stratify patients for these morbidities. This was a retrospective study using data of patients with cirrhosis who underwent diverse surgeries in the Veterans Health Administration. Validated algorithms and/or manual adjudication were used to ascertain postoperative decompensation and postoperative infection through 90 days. Multivariable logistic regression was used to evaluate prediction models in derivation and validation sets using variables from the recently-published Veterans Outcomes and Costs Associated with Liver Disease (VOCAL)-Penn cirrhosis surgical risk scores for postoperative mortality. Models were compared with the Mayo risk score, Model for End-stage Liver Disease (MELD)-sodium, and Child-Turcotte-Pugh (CTP) scores. A total 4712 surgeries were included; patients were predominantly male (97.2 %), white (63.3 %), and with alcohol-related liver disease (35.3 %). Through 90 postoperative days, 8.7 % of patients experienced interval decompensation, and 4.5 % infection. Novel VOCAL-Penn prediction models for decompensation demonstrated good discrimination for interval decompensation (C-statistic 0.762 vs 0.663 Mayo vs 0.603 MELD-sodium vs 0.560 CTP; P <.001); however, discrimination was only fair for postoperative infection (C-statistic 0.666 vs 0.592 Mayo [ P =.13] vs 0.502 MELD-sodium [ P <.001] vs 0.503 CTP [ P <.001]). The model for interval decompensation had excellent calibration in both derivation and validation sets. We report the derivation and internal validation of a novel, parsimonious prediction model for postoperative decompensation in patients with cirrhosis. This score demonstrated superior discrimination and calibration as compared with existing clinical standards, and will be available at www.vocalpennscore.com. [ABSTRACT FROM AUTHOR]

Patients with cirrhosis secondary to chronic hepatitis C virus (HCV) are at risk for hepatocellular carcinoma (HCC) despite a sustained virological response (SVR). We examined whether post-SVR liver stiffness measurement (LSM) could be used to stratify HCC risk. This was a retrospective cohort study of 1850 participants identified from the Veterans Health Administration, with HCV cirrhosis and SVR, followed up over 5099 person-years, from the time of post-SVR elastography until death, HCC, or the end of the study. The risk of HCC increased by 3% with every 1-kPa increase in LSM (adjusted hazard ratio [aHR], 1.03, 95% confidence interval [CI], 1.01–1.04; P <.001) and decreased with the number of years from SVR (aHR, 0.79; 95% CI, 0.70–0.90; P =.0003). The adjusted annual risk of HCC was 2.03% among participants with post-SVR LSM <10 kPa, 2.48% in LSM 10–14.9 kPa (aHR, 1.71; 95% CI, 1.01–2.88; P =.046), 3.22% for LSM 15–19.9 kPa (aHR, 1.59; 95% CI, 0.78–3.20; P =.20), 5.07% among LSM 20–24.9 kPa (aHR, 2.55; 95% CI, 1.30–5.01; P =.01), and 5.44% in LSM ≥25 kPa (aHR, 3.03; 95% CI, 1.74–5.26; P <.0001). The adjusted annual risk of HCC was < 0.4% in participants with LSM <5 kPa and without diabetes mellitus. LSM predicts rates of HCC in patients with HCV cirrhosis after SVR at multiple cutoff levels and offers a single test to predict portal hypertension–related complications and HCC. Patients with LSM <5 kPa in the absence of diabetes mellitus had a low risk of HCC in which surveillance could be discontinued. [Display omitted] [ABSTRACT FROM AUTHOR]

Antibiotic exposure leads to changes in the gut microbiota. Our objective was to evaluate the association between antibiotic exposure and esophageal adenocarcinoma (EAC) risk. We performed a nested case-control study using data from the Veterans Health Administration from 2004 through 2020. The case group consisted of patients who received an incident diagnosis of EAC. For each case, up to 20 matched controls were selected using incidence density sampling. Our primary exposure of interest was any oral or intravenous antibiotic use. Our secondary exposures included cumulative number of days of exposure and classification of antibiotics by various subgroups. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (aORs) for the risk of EAC associated with antibiotic exposure. The case-control analysis included 8226 EAC cases and 140,670 matched controls. Exposure to any antibiotic was associated with an aOR for EAC of 1.74 (95% confidence interval [CI], 1.65–1.83) vs no antibiotic exposure. Compared with no antibiotic exposure, the aOR for EAC was 1.63 (95% CI, 1.52–1.74; P <.001) for cumulative exposure to any antibiotic for 1 to 15 days; 1.77 (95% CI, 1.65–1.89; P < 0.001) for 16 to 47 days; and 1.87 (95% CI, 1.75–2.01; P <.001) for ≥48 days, respectively (P for trend <.001). Exposure to any antibiotic is associated with an increased risk of EAC, and this risk increases as the cumulative days of exposure increase. This novel finding is hypothesis-generating for potential mechanisms that may play a role in the development or progression of EAC. [ABSTRACT FROM AUTHOR]

Background & Aims Little is known about provider and health system factors that affect receipt of active therapy and outcomes of patients with hepatocellular carcinoma (HCC). We investigated patient, provider, and health system factors associated with receipt of active HCC therapy and overall survival. Methods We performed a national, retrospective cohort study of all patients diagnosed with HCC from January 1, 2008 through December 31, 2010 (n = 3988) and followed through December 31 2014 who received care through the Veterans Administration (128 centers). Outcomes were receipt of active HCC therapy (liver transplantation, resection, local ablation, transarterial therapy, or sorafenib) and overall survival. Results In adjusted analyses, receiving care at an academically affiliated Veterans Administration hospital (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.60–2.41) or a multi-specialist evaluation (OR, 1.60; 95% CI, 1.15–2.21), but not review by a multidisciplinary tumor board (OR, 1.19; 95% CI, 0.98–1.46), was associated with a higher likelihood of receiving active HCC therapy. In time-varying Cox proportional hazards models, liver transplantation (hazard ratio [HR], 0.22; 95% CI, 0.16–0.31), liver resection (HR, 0.38; 95% CI, 0.28–0.52), ablative therapy (HR, 0.63; 95% CI, 0.52–0.76), and transarterial therapy (HR, 0.83; 95% CI, 0.74–0.92) were associated with reduced mortality. Subspecialist care by hepatologists (HR, 0.70; 95% CI, 0.63–0.78), medical oncologists (HR, 0.82; 95% CI, 0.74–0.91), or surgeons (HR, 0.79; 95% CI, 0.71–0.89) within 30 days of HCC diagnosis, and review by a multidisciplinary tumor board (HR, 0.83; 95% CI, 0.77–0.90), were associated with reduced mortality. Conclusions In a retrospective cohort study of almost 4000 patients with HCC cared for at VA centers, geographic, provider, and system differences in receipt of active HCC therapy are associated with patient survival. Multidisciplinary methods of care delivery for HCC should be prospectively evaluated and standardized to improve access to HCC therapy and optimize outcomes. [ABSTRACT FROM AUTHOR]

Background & Aims We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies. Methods We performed a prospective study of treatment-naive (n = 47) and treatment-experienced (n = 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000–1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy. Results Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%–88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%–97%) and 36 were treatment naive (77%; 95% confidence interval, 62%–88%). All patients had at least 1 comorbidity. Thirty-five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment. Conclusions In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov , Number: NCT02128542 [ABSTRACT FROM AUTHOR]

The impact of proton pump inhibitory (PPI) medications on adverse outcomes in cirrhosis remains controversial. We aimed to evaluate the association between PPI exposure and all-cause mortality, infection, and decompensation in a large national cohort. This was a retrospective study of patients with cirrhosis in the Veterans Health Administration. PPI exposure was classified as a time-updating variable from the index time of the cirrhosis diagnosis. Inverse probability treatment weighting–adjusted Cox regression was performed with additional adjustment for key time-varying covariates, including cardiovascular comorbidities, gastrointestinal bleeding (GIB), and statin exposure. The study included 76,251 patients, 23,628 of whom were on a PPI at baseline. In adjusted models, binary (yes/no) PPI exposure was associated with reduced hazard of all-cause mortality in patients with hospitalization for GIB (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.84–0.91; P <.001) but had no significant association in all others (HR, 0.99; 95% CI, 0.97–1.02; P =.58). However, cumulative PPI exposure was associated with increased mortality in patients without hospitalization for GIB (HR, 1.07 per 320 mg-months [omeprazole equivalents]; 95% CI, 1.06–1.08; P <.001). PPI exposure was significantly associated with severe infection (HR, 1.21; 95% CI, 1.18–1.24; P <.001) and decompensation (HR, 1.64; 95% CI, 1.61–1.68; P <.001). In a cause-specific mortality analysis, PPI exposure was associated with increased liver-related mortality (HR, 1.23; 95% CI, 1.19–1.28) but with decreased nonliver-related mortality (HR, 0.88; 95% CI, 0.85–0.91). PPI exposure is associated with increased risk of infection and decompensation in cirrhosis, which may mediate liver-related mortality. However, PPI use was associated with reduced all-cause mortality in those with prior GIB, suggesting benefit in the presence of an appropriate indication. Proton pump inhibitor use in cirrhosis is associated with increased risk of liver-related adverse outcomes, but may reduce mortality in patients hospitalized with gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Abstract: Dark matter with mass below about a GeV is essentially unobservable in conventional direct detection experiments. However, newly proposed technology will allow the detection of single electron events in semiconductor materials with significantly lowered thresholds. This would allow detection of dark matter as light as an MeV in mass. Compared to other detection technologies, semiconductors allow enhanced sensitivity because of their low ionization energy around an eV. Such detectors would be particularly sensitive to dark matter with electric and magnetic dipole moments, with a reach many orders of magnitude beyond current bounds. Observable dipole moment interactions can be generated by new particles with masses as great as ∼103 TeV, providing a window to scales beyond the reach of current colliders. [Copyright &y& Elsevier]

Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61–0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35–0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure. [ABSTRACT FROM AUTHOR]

Background /Aims: Interleukin-10 (IL-10) has been ascribed pro-viral but anti-fibrotic properties in chronic hepatitis C virus (HCV) infection. In this study, we examined the role of HCV-specific T-cell IL-10 response in patients with acute and chronic HCV infection. Methods: Peripheral HCV-specific T-cell IL-10 and IFNγ responses were measured in cytokine Elispot assay using overlapping HCV-derived peptides in patients with chronic (n =61), resolved (n =15) and acute (n =8) hepatitis C, looking for their onset, quantity, breadth and durability relative to clinical and virological outcomes. The source and effect of HCV-specific IL-10 response were determined in depletion and IL-10 neutralization experiments. Results: Both HCV-specific IL-10 and IFNγ responses were detected early within 1–2months of acute clinical hepatitis C. However, only HCV-specific IL-10 response correlated with elevated liver enzymes, increased viremia and suppressed HCV-specific CD4+ T-cell proliferation in acute infection. While these associations were lost in established chronic infection, HCV-specific IL-10 responses were increased in patients without cirrhosis while IL-10 blockade enhanced antiviral effector IFNγ responses. Conclusions: HCV-specific IL-10 Tr1 responses may play a dual role in HCV infection, dampening effector T-cells to promote viral persistence in acute infection but also protecting against progressive fibrosis in chronic infection. [Copyright &y& Elsevier]

Background & Aims: The immunoinhibitory receptor programmed death-1 (PD-1) is up-regulated on dysfunctional virus-specific CD8 T cells during chronic viral infections, and blockade of PD-1/PD-ligand (PD-L) interactions can restore their function. As hepatitis C virus (HCV) persists in the liver with immune-mediated disease pathogenesis, we examined the role of PD-1/PD-L pathway in antigen-specific CD8 T-cell dysfunction in the liver and blood of HCV-infected patients. Methods: PD-1 expression and function of circulating CD8 T cells specific for HCV, Epstein–Barr virus, and influenza virus were examined ex vivo and following antigenic stimulation in vitro in patients with acute, chronic, and resolved HCV infection using class I tetramers and flow cytometry. Intrahepatic CD8 T cells were examined from liver explants of chronically HCV-infected transplant recipients. Results: Intrahepatic HCV-specific CD8 T cells from chronically HCV-infected patients were highly PD-1 positive, profoundly dysfunctional, and unexpectedly refractory to PD-1/PD-L blockade, contrasting from circulating PD-1–intermediate HCV-specific CD8 T cells with responsiveness to PD-1/PD-L blockade. This intrahepatic functional impairment was HCV-specific and directly associated with the level of PD-1 expression. Highly PD-1–positive intrahepatic CD8 T cells were more phenotypically exhausted with increased cytotoxic T-lymphocyte antigen 4 and reduced CD28 and CD127 expression, suggesting that active antigen-specific stimulation in the liver induces a profound functional exhaustion not reversible by PD-1/PD-L blockade alone. Conclusions: HCV-specific CD8 T-cell dysfunction and responsiveness to PD-1/PD-L blockade are defined by their PD-1 expression and compartmentalization. These findings provide new and clinically relevant insight to differential antigen-specific CD8 T-cell exhaustion and their functional restoration. [Copyright &y& Elsevier]

Background & Aims: Acute hepatitis C virus (HCV) infection becomes chronic in the majority of patients. Although HCV-specific CD4 T-cell response is associated with HCV clearance, less is known about virus-specific CD8 T-cell or neutralizing antibody (nAb) responses and the role of CD4 help in their induction during acute infection. Methods: HCV-specific CD4, CD8, and HCV pseudoparticle (HCVpp) nAb responses were monitored in acutely HCV-infected patients to define their relative contributions to viral clearance. Results: Our results show that the outcome of acute hepatitis C is associated with a functional hierarchy in HCV-specific CD4 T-cell response and the scope of virus-specific, total T-cell interferon-γ response. HCV-specific CD8 T-cell response was readily detectable in acutely HCV-infected patients regardless of virologic outcome or virus-specific CD4 T-cell response. In contrast, HCVpp-specific nAbs were readily detected in patients with chronic evolution and impaired virus-specific CD4 T-cell response but not in patients who cleared infection with robust virus-specific CD4 T-cell response. Conclusions: The outcome of acute hepatitis C is associated with efficient virus-specific CD4 T-cell response(s) without which HCV-specific CD8 T-cell and heterologous nAb responses may develop but fail to clear viremia. Furthermore, HCV-specific nAb responses may not be induced despite robust virus-specific CD4 T-cell response. [Copyright &y& Elsevier]

The hepatitis C virus affects 2–3% of the world''s population. The inability to efficiently propagate the virus in cell-culture greatly impaired the study of the viral life cycle. Recent advances have facilitated extensive study of viral entry, translation, proteolysis, and replication that will foster intelligent drug design for this infection, a major cause of cirrhosis and hepatocellular carcinoma worldwide. [Copyright &y& Elsevier]

The development of decompensation in cirrhosis demarcates a marked change in the natural history of chronic liver disease. HMG-CoA reductase inhibitors (statins) exert pleiotropic effects that reduce inflammation and fibrosis as well as improve vascular reactivity. Retrospective studies uniformly have associated statin utilization with improved outcomes for patients with cirrhosis. Prospective human studies have shown that statins reduce portal hypertension and reduce death in patients with decompensated cirrhosis after variceal hemorrhage when added to standard therapy with an acceptable safety profile. This proposal aims to extend these findings to demonstrate that simvastatin reduces incident hepatic decompensation events among cirrhotic patients at high risk for hepatic decompensation. We will perform the SACRED Trial (NCT03654053), a phase III, prospective, multi-center, double-blind, randomized clinical trial at 11 VA Medical Centers. Patients with compensated cirrhosis with clinically significant portal hypertension will be stratified based upon the concomitant use of nonselective beta-blockers and randomized to simvastatin 40 mg/day versus placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Ancillary studies will evaluate patient-reported outcomes and pharmacogenetic corollaries of safety and/or efficacy. Statins have a long track-record of safety and tolerability. This class of medications is generic and inexpensive, and thus, if the hypothesis is proven, there will be few barriers to widespread acceptance of the role of statins to prevent decompensation in patients with compensated cirrhosis. ClinicalTrials.gov Identifier: NCT03654053 [ABSTRACT FROM AUTHOR]

Expert consensus mandates retesting for eradication of Helicobacter pylori infection after treatment, but it is not clear how many patients are actually retested. We evaluated factors associated with retesting for H pylori in a large, nationwide cohort. We performed a retrospective cohort study of patients with H pylori infection (detected by urea breath test, stool antigen, or pathology) who were prescribed an eradication regimen from January 1, 1994 through December 31, 2018 within the Veterans Health Administration (VHA). We collected data on demographic features, smoking history, socioeconomic status, facility poverty level and academic status, and provider specialties and professions. The primary outcome was retesting for eradication. Statistical analyses included mixed-effects logistic regression. Of 27,185 patients prescribed an H pylori eradication regimen, 6486 patients (23.9%) were retested. Among 7623 patients for whom we could identify the provider who ordered the test, 2663 patients (34.9%) received the order from a gastroenterological provider. Female sex (odds ratio, 1.22; 95% CI, 1.08–1.38; P =.002) and history of smoking (odds ratio, 1.24; 95% CI, 1.15–1.33; P <.001) were patient factors associated with retesting. There was an interaction between method of initial diagnosis of H pylori infection and provider who ordered the initial test (P <.001). There was significant variation in rates of retesting among VHA facilities (P <.001). In an analysis of data from a VHA cohort of patients with H pylori infection, we found low rates of retesting after eradication treatment. There is significant variation in rates of retesting among VHA facilities. H pylori testing is ordered by nongastroenterology specialists two-thirds of the time. Confirming eradication of H pylori is mandatory and widespread quality assurance protocols are needed. [ABSTRACT FROM AUTHOR]

Conventional teaching is that Helicobacter pylori infection is required for the development of non-cardia gastric adenocarcinoma (NCGC) through a sequence of atrophic gastritis, intestinal metaplasia, dysplasia, and finally, cancer.1–3 However, studies have not demonstrated a 100% rate of H pylori infection in gastric malignancy, hypothesized to be due to false negatives, gastric atrophy leading to apparent loss of infection, and inclusion of cardia, nonintestinal cancers.1–3 [ABSTRACT FROM AUTHOR]

Nearly all studies of gastric adenocarcinoma in the United States have relied on national cancer databases, which do not include data on Helicobacter pylori infection, the most well-known risk factor for gastric cancer. We collected data from a large cohort of patients in the United States to calculate the incidence of and risk factors for nonproximal gastric adenocarcinomas after detection of H pylori. Secondary aims included identifying how treatment and eradication affect cancer risk. We performed a retrospective cohort study, collecting data from the Veterans Health Administration on 371,813 patients (median age 62 years; 92.3% male) who received a diagnosis of H pylori infection from January 1, 1994, through December 31, 2018. The primary outcome was a diagnosis of distal gastric adenocarcinoma 30 days or more after detection of H pylori infection. We performed a time to event with competing risk analysis (with death before cancer as a competing risk). The cumulative incidence of cancer at 5, 10, and 20 years after detection of H pylori infection was 0.37%, 0.5%, and 0.65%, respectively. Factors associated with cancer included older age at time of detection of H pylori infection (subhazard ratio [SHR], 1.13; 95% confidence interval [CI], 1.11–1.15; P <.001), black/African American race (SHR, 2.00; 95% CI, 1.80–2.22), Asian race (SHR, 2.52; 95% CI, 1.64–3.89) (P <.001 for race), Hispanic or Latino ethnicity (SHR, 1.59; 95% CI, 1.34–1.87; P <.001), and history of smoking (SHR, 1.38; 95% CI, 1.25–1.52; P <.001). Women had decreased risk of gastric adenocarcinoma compared with men (SHR, 0.52; 95% CI, 0.40–0.68; P <.001); patients whose H pylori infection was detected based on serum antibody positivity also had a reduced risk of cancer (SHR 0.74; 95% CI, 0.54–1.04; P =.04). Patients who received treatment for their H pylori infection still had an increased risk of gastric cancer (SHR, 1.16; 95% CI, 0.74–1.83; P =.51) but confirmed H pylori eradication after treatment reduced risk of gastric cancer (SHR, 0.24; 95% CI, 0.15–0.41; P <.001). In a study of 371,813 veterans with a diagnosis of H pylori infection, we found significantly higher risks of gastric cancer in racial and ethnic minorities and smokers. Treatment of H pylori infection decreased risk only if eradication was successful. Studies are needed on the effects of screening high-risk persons and to identify quality measures for diagnosis, resistance patterns, and treatment efficacy. [ABSTRACT FROM AUTHOR]

It is unclear if hepatocellular carcinoma (HCC) risk declines over time after hepatitis C virus (HCV) eradication. We analyzed changes in HCC annual incidence over time following HCV eradication and identified dynamic markers of HCC risk. We identified 48,135 patients who initiated HCV antiviral treatment from 2000 through 2015 and achieved a sustained virologic response (SVR) in the Veterans Health Administration (29,033 treated with direct-acting antiviral [DAA] agents and 19,102 treated with interferon-based regimens). Patients were followed after treatment until February 14, 2019 (average 5.4 years), during which 1509 incident HCCs were identified. Among patients with cirrhosis before treatment with DAAs (n = 9784), those with pre-SVR fibrosis-4 (FIB-4) scores ≥3.25 had a higher annual incidence of HCC (3.66%/year) than those with FIB-4 scores <3.25 (1.16%/year) (adjusted hazard ratio 2.14; 95% confidence interval 1.66–2.75). In DAA-treated patients with cirrhosis and FIB-4 scores ≥3.25, annual HCC risk decreased from 3.8%/year in the first year after SVR to 2.4%/year by the fourth year (P =.01). In interferon-treated patients with FIB-4 scores ≥3.25, annual HCC risk remained above 2%/year, even 10 years after SVR. A decrease in FIB-4 scores from ≥3.25 pre-SVR to <3.25 post-SVR was associated with an approximately 50% lower risk of HCC, but the absolute annual risk remained above 2%/year. Patients without cirrhosis before treatment (n = 38,351) had a low risk of HCC, except for those with pre-SVR FIB-4 scores ≥3.25 (HCC risk 1.22%/year) and post-SVR FIB-4 scores ≥3.25 (HCC risk 2.39%/year); risk remained high for many years after SVR. Patients with cirrhosis before an SVR to treatment for HCV infection continue to have a high risk for HCC (>2%/year) for many years, even if their FIB-4 score decreases, and should continue surveillance. Patients without cirrhosis but with FIB-4 scores ≥3.25 have a high enough risk to merit HCC surveillance, especially if FIB-4 remains ≥3.25 post-SVR. [ABSTRACT FROM AUTHOR]

Background & Aims Concerns related to hepatotoxicity frequently lead to discontinuation or non-initiation of 3-hydroxy-3-methylglutaryl–coenzyme A reductase therapy in patients with cirrhosis despite data supporting statin use. We investigated the independent effects of hyperlipidemia and statin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma development in a large national cohort of patients with cirrhosis. Methods We performed a retrospective cohort study of patients with newly diagnosed cirrhosis from January 1, 2008 through June 30, 2016 in the Veterans Health Administration. Subjects were divided into 2 cohorts: 21,921 patients with prior statin exposure (existing users) and 51,023 statin-naïve individuals, of whom 8794 subsequently initiated statin therapy (new initiators) and 44,269 did not (non-initiators). Multivariable Cox proportional hazard models with inverse probability weighting were constructed to assess the effects of time-updating lipid profiles and cumulative exposure to statins on survival and hepatic decompensation. Statin-naïve new initiators were propensity matched with non-initiators to simulate a randomized controlled trial of statin use in cirrhosis. Results In statin-naïve subjects, every 10-mg/dL increase in baseline total cholesterol was associated with a 3.6% decrease in mortality. In existing users, each year of continued statin exposure was associated with a hazard ratio of 0.920 (95% confidence interval 0.0.897–0.943) for mortality. After risk-set matching, each year of statin exposure among new initiators was associated with a hazard ratio of 0.913 (95% confidence interval 0.890–0.937) for mortality. Conclusions In a retrospective cohort study of veterans with a new diagnosis of cirrhosis, we associated hypercholesterolemia with well-preserved hepatic function and decreased mortality. Nonetheless, each cumulative year of statin exposure was associated with an independent 8.0%–8.7% decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and B. Graphical abstract [ABSTRACT FROM AUTHOR]

Purpose: The impact of transarterial chemoembolization after initiation of sorafenib (SOR) has not been prospectively compared with SOR alone in unresectable hepatocellular carcinoma (HCC). The objective of this study was to assess whether SOR + transarterial chemoembolization provides benefit over SOR alone in this setting.Materials and Methods: A retrospective cohort study with propensity matching using data from patients prescribed SOR for HCC at Veterans Health Administration hospitals from 2007 to 2015. The primary outcome was overall survival from the time of SOR prescription and stratified by receipt of transarterial chemoembolization within 90 days of SOR initiation.Results: A total of 4,896 patients received SOR for HCC, of whom 232 (4.7%) underwent transarterial chemoembolization within 90 days. Patients receiving transarterial chemoembolization + SOR were highly selected, being younger and with less significant hepatic dysfunction, earlier Barcelona Clinic Liver Cancer stage (P < .0001), and fewer tumors with lower rates of macrovascular invasion (MVI) and metastases (all P < .0001) than SOR-alone patients. In unadjusted analysis, SOR + transarterial chemoembolization was associated with reduced mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.53-0.71; P < .0001). After propensity matching, SOR + transarterial chemoembolization continued to show significant associations with reduced mortality with HR 0.75 (95% CI 0.62-0.92; P = .0005). Subgroup analysis suggests that the addition of transarterial chemoembolization to SOR improves outcomes in most patients, particularly those with Model for End-Stage Liver Disease score <15, platelets >50,000/μL, and >3 tumors with or without macrovascular invasion, without local invasion or metastases.Conclusions: Patients with unresectable HCC started on systemic therapy with SOR appear to benefit from adjuvant transarterial chemoembolization. Optimal application of multimodal therapy in this setting should be prospectively investigated. [ABSTRACT FROM AUTHOR]

Background & Aims It is important to quantify medical costs associated with hepatocellular carcinoma (HCC), the incidence of which is rapidly increasing in the United States, for development of rational healthcare policies related to liver cancer surveillance and treatment of chronic liver disease. We aimed to comprehensively quantify healthcare costs for HCC among patients with cirrhosis in an integrated health system and develop a model for predicting costs that is based on clinically relevant variables. Methods Three years subsequent to liver cancer diagnosis, costs accrued by patients included in the Veteran’s Outcome and Cost Associated with Liver disease cohort were compiled by using the Department of Veterans Affairs Corporate Data Warehouse. The cohort includes all patients with HCC diagnosed in 2008–2010 within the VA with 100% chart confirmation as well as chart abstraction of tumor and clinical characteristics. Cancer cases were matched 1:4 with non-cancer cirrhosis controls on the basis of severity of liver disease, age, and comorbidities to estimate background cirrhosis-related costs. Univariable and multivariable generalized linear models were developed and used to predict cancer-related overall cost. Results Our analysis included 3188 cases of HCC and 12,722 controls. The mean 3-year total cost of care in HCC patients was $154,688 (standard error, $150,953–$158,422) compared with $69,010 (standard error, $67,344–$70,675) in matched cirrhotic controls, yielding an incremental cost of $85,679; 64.9% of this value reflected increased inpatient costs. In univariable analyses, receipt of transplantation, Barcelona Clinic Liver Cancer (BCLC) stage, liver disease etiology, hospital academic affiliation, use of multidisciplinary tumor board, and identification through surveillance were associated with cancer-related costs. Multivariable generalized linear models incorporating transplantation status, BCLC stage, and multidisciplinary tumor board presentation accurately predicted liver cancer–related costs (Hosmer-Lemeshow goodness of fit; P value ≅ 1.0). Conclusions In a model developed to comprehensively quantify healthcare costs for HCC among patients with cirrhosis in an integrated health system, we associated receipt of liver transplantation, BCLC stage, and multidisciplinary tumor board with higher costs. Models that predict total costs on the basis of receipt of liver transplantation were constructed and can be used to model cost-effectiveness of therapies focused on HCC prevention. [ABSTRACT FROM AUTHOR]

Background & Methods The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. The CTP score is a composite of 5 subscores, 3 based on objective clinical laboratory values and 2 subjective variables quantifying the severity of ascites and hepatic encephalopathy. To date, no system to quantify CTP score from administrative databases has been validated. The Veterans Outcomes and Costs Associated with Liver Disease study is a multicenter collaborative study to evaluate the outcomes and costs of hepatocellular carcinoma in the U.S. Veterans Health Administration. We developed and validated an algorithm to calculate electronic CTP (eCTP) scores by using data from the Veterans Health Administration Corporate Data Warehouse. Methods Multiple algorithms for determining each CTP subscore from International Classification of Diseases version 9, Common Procedural Terminology, pharmacy, and laboratory data were devised and tested in 2 patient cohorts. For each cohort, 6 site investigators (Boston, Bronx, Brooklyn, Philadelphia, Minneapolis, and West Haven VA Medical Centers) were provided cases from which to determine validity of diagnosis, laboratory data, and clinical assessment of ascites and encephalopathy. The optimal algorithm (designated eCTP) was then applied to 30,840 cirrhotic patients alive in the first quarter of 2008 for whom 5-year overall and transplant-free survival data were available. The ability of the eCTP score and other disease severity scores (Charlson-Deyo index, Veterans Aging Cohort Study index, Model for End-Stage Liver Disease score, and Cirrhosis Comorbidity) to predict survival was then assessed by Cox proportional hazards regression. Results Spearman correlations for administrative and investigator validated laboratory data in the HCC and cirrhotic cohorts, respectively, were 0.85 and 0.92 for bilirubin, 0.92 and 0.87 for albumin, and 0.84 and 0.86 for international normalized ratio. In the HCC cohort, the overall eCTP score matched 96% of patients to within 1 point of the chart-validated CTP score (Spearman correlation, 0.81). In the cirrhosis cohort, 98% were matched to within 1 point of their actual CTP score (Spearman, 0.85). When applied to a cohort of 30,840 patients with cirrhosis, each unit change in eCTP was associated with 39% increase in the relative risk of death or transplantation. The Harrell C statistic for the eCTP (0.678) was numerically higher than those for other disease severity indices for predicting 5-year transplant-free survival. Adding other predictive models to the eCTP resulted in minimal differences in its predictive performance. Conclusion We developed and validated an algorithm to extrapolate an eCTP score from data in a large administrative database with excellent correlation to actual CTP score on chart review. When applied to an administrative database, this algorithm is a highly useful predictor of survival when compared with multiple other published liver disease severity indices. [ABSTRACT FROM AUTHOR]