Attacking the public health crisis of hepatocellular carcinoma at its roots.

As the third most common cause of cancer-related death worldwide with significant mortality rates in the United States, hepatocellular carcinoma has strong association with cirrhosis and chronic hepatitis B virus (HBV) with a growing at-risk population from the rise in chronic liver disease from alcohol use and nonalcoholic fatty liver disease. Despite this, progress in identifying at-risk individuals and early detection of HCC in these populations have lagged behind treatment advances.The lack of consensus may undermine widespread adoption of surveillance programs, thus preventing HCC detection at a curable stage. This public policy corner piece focuses on opportunities for prevention of HCC by focusing on its principal risk factors: viral hepatitis, NAFLD, and alcohol-related liver disease, and three key action points to reverse the course of this public health crisis: 1) Awareness and education; 2) Screening and diagnosis, and 3) Partnerships and advocacy.

An Accurate and Automated Method for Adenoma Detection Rate and Report Card Generation Utilizing Common Electronic Health Records.

GOALS: To develop an automated method for Adenoma Detection Rate (ADR) calculation and report card generation using common electronic health records (EHRs). BACKGROUND: ADR is the most widely accepted colonoscopy quality indicator and is inversely associated with interval colorectal cancer incidence and mortality. However, ADR is difficult to efficiently measure and disseminate, due to need for data integration from distinct electronic databases. METHODS: We migrated data from an endoscopy reporting software (Endosoft) to Epic Reporting Servers where it was combined with anatomic pathology data (Beaker Lab Information System, EPIC Systems). A natural language processing expression was developed to search Beaker pathology reports for accurate identification of adenomatous polyps. A blinded physician manually validated a final cohort of 200 random procedures. ADR report cards were automatically generated utilizing the Crystal Reports feature within EPIC. RESULTS: Validation of the natural language processing algorithm for ADR showed a sensitivity, specificity, and accuracy of 100%. ADR was automatically calculated for 12 endoscopists over a calendar year. Two thousand two hundred seventy-six screening colonoscopies were performed with 775 procedures having a least one adenoma detected, for a total ADR of 34%. Report cards were successfully generated within the EPIC EHR and distributed to endoscopists by secure e-mail. CONCLUSION: We describe an accurate, automated and scalable process for ADR calculation and reporting utilizing commonly adopted EHRs and data integration methods. By integrating the process of ADR collection and streamlining dissemination of reports, this methodology is poised to enhance colonoscopy quality care across health care networks that use it.

A Vermont Statewide Educational Intervention to Improve Access to Hepatitis C Virus Treatment in a Rural State.

OBJECTIVES: Improved knowledge of hepatitis C virus (HCV) screening, linkage to care, and treatment is needed among nonspecialist medical professionals to combat the HCV epidemic. The authors sought to implement and analyze the impact of an HCV curriculum for primary care professionals (PCPs) across the state of Vermont, USA. METHODS: This investigation was a retrospective analysis of uptake of a Vermont HCV educational curriculum and its impact on HCV direct-acting antiviral (DAA) prescribing rates within the state before and after the study period. The curriculum was delivered online and in-person over 2 years from 2019 to 2020. The primary outcome was health care professional performance on a pre- and post-curriculum short-term knowledge assessment exam. The secondary outcome was assessing the number of unique healthcare professionals within a single payor database prescribing DAA treatment for HCV in Vermont before and after the study intervention, from January 1, 2017 until December 1, 2021. RESULTS: There were 31 unique respondents on the pre- and post-intervention examinations, which represented 9% of known participants. Respondents included physicians (n = 15), nurse practitioners (n = 8), and nurses (n = 8). Pre- and post-intervention knowledge scores increased significantly across all provider groups, from 3.2 (SD 0.6) to 4.5 (SD 0.4) 1 to 5 scale (P = .01). The total number of unique HCV DAA therapy prescribers decreased over the study period, from 17 in 2017 to 9 in 2021. CONCLUSIONS: A Vermont statewide HCV curriculum for PCPs was successful at increasing short-term HCV-related knowledge. However, this did not obviously translate to an increase in new professionals treating HCV.

Statewide Assessment of the Hepatitis C Virus Care Cascade for Incarcerated Persons in Vermont.

OBJECTIVES: Incarcerated persons in the United States have a high burden of hepatitis C virus (HCV) infection. This study assessed the impact of a statewide effort in Vermont to treat HCV in this group. METHODS: We performed a retrospective, observational cohort study of all HCV-infected persons who were imprisoned in Vermont during the 19-month study period (December 2018-June 2020). The cascade of care comprised opt-out HCV screening, full access to direct-acting antiviral treatment (without hepatic fibrosis-based treatment restrictions), HCV specialist involvement, and medication-assisted treatment for patients with opioid use disorder. The primary outcome was sustained virologic response at 12 weeks after treatment completion (SVR12). RESULTS: The study included 217 HCV-infected patients; the median age was 35 years (range, 18-73 years), 89% were male, 76% had opioid use disorder, 67% had a psychiatric comorbidity, and 9% had cirrhosis. Of the 217 patients, 98% had a liver fibrosis assessment, 59% started direct-acting antiviral treatment, 55% completed direct-acting antiviral treatment, and 51% achieved documented SVR12. Of the 129 HCV-infected persons who started direct-acting antiviral treatment, 92% completed therapy and 86% achieved documented SVR12. Psychiatric comorbidity was not significantly associated with achieving SVR12 (odds ratio = 0.67; 95% CI, 0.27-1.65; P = .38), nor was receiving medication-assisted treatment for patients with opioid use disorder (odds ratio = 1.45; 95% CI, 0.62-2.56; P = .45). CONCLUSIONS: This study reports the highest SVR12 rate achieved in a state incarcerated population to date. HCV treatment in incarcerated populations is a practical and efficacious strategy that should serve a foundational role in HCV elimination.

Nonalcoholic fatty liver disease and cognitive impairment: A prospective cohort study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is prevalent and may affect cognitive function. We studied associations of NAFLD with risk of cognitive impairment. Secondarily we evaluated liver biomarkers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), their ratio, and gamma-glutamyl transpeptidase). METHODS: In a prospective cohort study, the REasons for Geographic and Racial Differences in Stroke, among 30,239 black and white adults aged ≥45,495 cases of incident cognitive impairment were identified over 3.4 years follow up. Cognitive impairment was identified as new impairment in two of three cognitive tests administered every two years during follow up; word list learning and recall, and verbal fluency. 587 controls were selected from an age, race, sex-stratified sample of the cohort. The fatty liver index was used to define baseline NAFLD. Liver biomarkers were measured using baseline blood samples. RESULTS: NAFLD at baseline was associated with a 2.01-fold increased risk of incident cognitive impairment in a minimally adjusted model (95% CI 1.42, 2.85). The association was largest in those aged 45-65 (p interaction by age = 0.03), with the risk 2.95-fold increased (95% CI 1.05, 8.34) adjusting for cardiovascular, stroke and metabolic risk factors. Liver biomarkers were not associated with cognitive impairment, except AST/ALT >2, with an adjusted OR 1.86 (95% CI 0.81, 4.25) that did not differ by age. CONCLUSIONS: A laboratory-based estimate of NAFLD was associated with development of cognitive impairment, particularly in mid-life, with a tripling in risk. Given its high prevalence, NAFLD may be a major reversible determinant of cognitive health.

Screening for pancreatic cancer in a high-risk population with serum CA 19-9 and targeted EUS: a feasibility study.

BACKGROUND: Earlier detection of pancreatic adenocarcinoma is needed. OBJECTIVE: To determine whether early pancreatic neoplasia can be detected in a high-risk population by using CA 19-9 followed by targeted EUS. DESIGN: Prospective cohort study. SETTING: Two academic medical centers. PATIENTS: Eligible patients met age criteria and had at least 1 first-degree relative with pancreatic adenocarcinoma. INTERVENTIONS: A serum CA 19-9 was performed on all patients. EUS was performed if the CA 19-9 level was elevated. FNA of identified lesions was performed. Patients with pancreatic cancer detected by using this screening protocol were compared with patients presenting off-protocol for staging data. Medicare reimbursement rates were used to derive cost data. MAIN OUTCOME MEASUREMENTS: Detection of early pancreatic neoplasia. RESULTS: A total of 546 patients were enrolled. CA 19-9 was elevated in 27 patients (4.9%, 95% CI, 3.2%-7.1%). Neoplastic or malignant findings were detected in 5 patients (0.9%, 95% CI, 0.3%-2.1%), and pancreatic adenocarcinoma in 1 patient (0.2%, 95% CI, 0.005%-1.02%). The patient with pancreatic cancer detected as part of this protocol was 1 of 2 patients presenting to the University of Vermont with stage 1 cancer. The cost to detect 1 pancreatic neoplasia was $8431. The cost to detect 1 pancreatic adenocarcinoma was $41,133. LIMITATIONS: The sample size is adequate only to demonstrate the feasibility of this approach. CONCLUSIONS: Potentially curative pancreatic adenocarcinoma can be identified with this screening protocol. Stage 1 pancreatic cancer is more likely to be detected by using this screening protocol than by using standard means of detection.

Nonalcoholic fatty liver disease: diagnosis and relation to metabolic syndrome and approach to treatment.

Nonalcoholic fatty liver disease is an increasingly prevalent disorder that spans a range of conditions from hepatic steatosis to cirrhosis. It is commonly associated with obesity and diabetes, two components of the metabolic syndrome. Although hepatic steatosis may be reversible, disease progression appears to be triggered by overproduction of reactive oxygen species and mitochondrial injury in hepatocytes. Evolving treatments are focused on reversing insulin resistance, which underlies many of the metabolic derangements in this disease.

Adherence to surveillance endoscopy following hospitalization for index esophageal variceal hemorrhage.

AIM: To investigate patient adherence to surveillance endoscopy after index esophageal variceal hemorrhage and the extent to which adherence influences outcomes. METHODS: We reviewed the records of patients with cirrhosis admitted to the medical intensive care unit between 2000 and 2014 for first time esophageal variceal hemorrhage treated with endoscopic variceal ligation who were subsequently discharged and scheduled for surveillance endoscopy at our medical center. Demographic and clinical data were obtained through the medical records, including etiology of cirrhosis, completion of variceal obliteration, attendance at surveillance endoscopy, zip code of primary residence, distance from home to hospital, insurance status, rehospitalization for variceal hemorrhage, beta-blocker at discharge, pharmacologically treated psychiatric disorder, and transplant free survival. RESULTS: Of 99 consecutive survivors of esophageal variceal bleeding, the minority (33) completed variceal obliteration and fewer (12) adhered to annual surveillance. Completion of variceal obliteration was associated with fewer rehospitalizations for variceal rebleeding (27% vs 56%, P = 0.0099) and when rehospitalizations occurred, they occurred later in those who had completed obliteration (median 259 d vs 207 d, P = 0.0083). Incomplete adherence to endoscopic surveillance was associated with more rehospitalizations for variceal rebleeding compared to those fully adherent to annual endoscopic surveillance (51% vs 17%, P = 0.0328). Those adherent to annual surveillance were more likely to be insured privately or through Medicare compared to those who did not attend post-hospital discharge endoscopy (100% vs 63%, P = 0.0119). CONCLUSION: Most patients do not complete variceal obliteration after index esophageal variceal hemorrhage and fewer adhere to endoscopic surveillance, particularly the uninsured and those insured with Medicaid.

Non-alcoholic fatty liver disease, liver biomarkers and stroke risk: The Reasons for Geographic and Racial Differences in Stroke cohort.

BACKGROUND AND PURPOSE: Liver disease, particularly non-alcoholic fatty liver disease (NAFLD), is a risk factor for cardiovascular disease, but little is known about its relationship with ischemic stroke. METHODS: In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort of 30,239 American black and white adults, we assessed baseline NAFLD as fatty liver index (FLI) >60, and assessed liver biomarkers aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), and the AST/ALT ratio and risk of incident ischemic stroke over 5.8 years using a case-cohort study design. RESULTS: Considering 572 strokes and a 1,017-person cohort sample, NAFLD was inversely associated with stroke risk in men (HR: 0.50; 95% CI: 0.26, 0.96), as was being in the highest ALT quintile versus the lowest (HR: 0.39; 95% CI: 0.19, 0.78) and the highest versus lowest GGT quintile (HR: 0.45, 95% CI: 0.24, 0.85), but not in women. Conversely, FLI score above the 90th percentile was associated with increased stroke risk among women (HR: 2.26; 95% CI: 1.14-4.47), but not men. AST was not associated with stroke risk in either sex. AST/ALT ratio >2 was strongly associated with increased stroke risk in whites, but not blacks (HRs: 3.64; 95% CI: 1.42-9.35 and 0.97; 95% CI: 0.45-1.99, respectively; p for interaction = 0.03). CONCLUSIONS: The relationships between NAFLD, liver biomarkers, and ischemic stroke are complex, and sex and race differences we observed require further study and confirmation.

Impact of physician specialty on quality care for patients hospitalized with decompensated cirrhosis.

BACKGROUND: Decompensated cirrhosis is a common precipitant for hospitalization, and there is limited information concerning factors that influence the delivery of quality care in cirrhotic inpatients. We sought to determine the relation between physician specialty and inpatient quality care for decompensated cirrhosis. DESIGN: We reviewed 247 hospital admissions for decompensated cirrhosis, managed by hospitalists or intensivists, between 2009 and 2013. The primary outcome was quality care delivery, defined as adherence to all evidence-based specialty society practice guidelines pertaining to each specific complication of cirrhosis. Secondary outcomes included new complications, length-of-stay, and in-hospital death. RESULTS: Overall, 147 admissions (59.5%) received quality care. Quality care was given more commonly by intensivists, compared with hospitalists (71.7% vs. 53.1%, P = .006), and specifically for gastrointestinal bleeding (72% vs. 45.8%, P = .03) and hepatic encephalopathy (100% vs. 63%, P = .005). Involvement of gastroenterology consultation was also more common in admissions in which quality care was administered (68.7% vs. 54.0%, P = .023). Timely diagnostic paracentesis was associated with reduced new complications in admissions for refractory ascites (9.5% vs. 46.6%, P = .02), and reduced length-of-stay in admissions for spontaneous bacterial peritonitis (5 days vs. 13 days, P = .02). CONCLUSIONS: Adherence to quality indicators for decompensated cirrhosis is suboptimal among hospitalized patients. Although quality care adherence appears to be higher among cirrhotic patients managed by intensivists than by hospitalists, opportunities for improvement exist in both groups. Rational and cost-effective strategies should be sought to achieve this end.

Hospitalization for variceal hemorrhage in an era with more prevalent cirrhosis.

AIM: To examine hospitalization rates for variceal hemorrhage and relation to cause of cirrhosis during an era of increased cirrhosis prevalence. METHODS: We performed a retrospective review of patients with cirrhosis and gastroesophageal variceal hemorrhage who were admitted to a tertiary care referral center from 1998 to 2009. Subjects were classified according to the etiology of their liver disease: alcoholic cirrhosis and non-alcoholic cirrhosis. Rates of hospitalization for variceal bleeding were determined. Data were also collected on total hospital admissions per year and cirrhosis-related admissions per year over the same time period. These data were then compared and analyzed for trends in admission rates. RESULTS: Hospitalizations for cirrhosis significantly increased from 611 per 100000 admissions in 1998-2001 to 1232 per 100000 admissions in 2006-9 (P value for trend < 0.0001). This increase was seen in admissions for both alcoholic and non-alcoholic cirrhosis (P values for trend < 0.001 and < 0.0001 respectively). During the same time period, there were 243 admissions for gastroesophageal variceal bleeding (68% male, mean age 54.3 years, 62% alcoholic cirrhosis). Hospitalizations for gastroesophageal variceal bleeding significantly decreased from 96.6 per 100000 admissions for the time period 1998-2001 to 70.6 per 100000 admissions for the time period 2006-2009 (P value for trend = 0.01). There were significant reductions in variceal hemorrhage from non-alcoholic cirrhosis (41.6 per 100000 admissions in 1998-2001 to 19.7 per 100000 admissions in 2006-2009, P value for trend = 0.007). CONCLUSION: Hospitalizations for variceal hemorrhage have decreased, most notably in patients with non-alcoholic cirrhosis, and this may reflect broader use of strategies to prevent bleeding.

Myosin light chain kinase and Src control membrane dynamics in volume recovery from cell swelling.

The expansion of the plasma membrane, which occurs during osmotic swelling of epithelia, must be retrieved for volume recovery, but the mechanisms are unknown. Here we have identified myosin light chain kinase (MLCK) as a regulator of membrane internalization in response to osmotic swelling in a model liver cell line. On hypotonic exposure, we found that there was time-dependent phosphorylation of the MLCK substrate myosin II regulatory light chain. At the sides of the cell, MLCK and myosin II localized to swelling-induced membrane blebs with actin just before retraction, and MLCK inhibition led to persistent blebbing and attenuated cell volume recovery. At the base of the cell, MLCK also localized to dynamic actin-coated rings and patches upon swelling, which were associated with uptake of the membrane marker FM4-64X, consistent with sites of membrane internalization. Hypotonic exposure evoked increased biochemical association of the cell volume regulator Src with MLCK and with the endocytosis regulators cortactin and dynamin, which colocalized within these structures. Inhibition of either Src or MLCK led to altered patch and ring lifetimes, consistent with the concept that Src and MLCK form a swelling-induced protein complex that regulates volume recovery through membrane turnover and compensatory endocytosis under osmotic stress.

Ca2+-activated IK1 channels associate with lipid rafts upon cell swelling and mediate volume recovery.

Restoration of cell volume in the continued presence of osmotic stimuli is essential, particularly in hepatocytes, which swell upon nutrient uptake. Responses to swelling involve the Ca2+-dependent activation of K+ channels, which promote fluid efflux to drive volume recovery; however, the channels involved in hepatocellular volume regulation have not been identified. We found that hypotonic exposure of HTC hepatoma cells evoked the opening of 50 pS K+-permeable channels, consistent with intermediate conductance (IK) channels. We isolated from rat liver and HTC cells a cDNA with sequence identity to the coding region of IK1. Swelling-activated currents were inhibited by transfection with a dominant interfering IK1 mutant. The IK channel blockers clotrimazole and TRAM-34 inhibited whole cell swelling-activated K+ currents and volume recovery. To determine whether IK1 underwent volume-sensitive localization, we expressed a green fluorescent protein fusion of IK1 in HTC cells. The localization of IK1 was suggestive of distribution in lipid rafts. Consistent with this, there was a time-dependent increase in colocalization between IK1 and the lipid raft ganglioside GM1 on the plasma membrane, which subsequently decreased with volume recovery. Pharmacological disruption of lipid rafts altered the plasma membrane distribution of IK1 and inhibited volume recovery after hypotonic exposure. Collectively, these findings support the hypothesis that IK1 regulates compensatory responses to hepatocellular swelling and suggest that regulation of cell volume involves coordination of signaling from lipid rafts with IK1 function.

Src regulates distinct pathways for cell volume control through Vav and phospholipase Cgamma.

Cell volume recovery in response to swelling requires reorganization of the cytoskeleton and fluid efflux. We have previously shown that electrolyte and fluid efflux via K+ and Cl- channels is controlled by swelling-induced activation of phospholipase Cgamma (PLCgamma). Recently, integrin engagement has been suggested to trigger responses to swelling through activation of Rho family GTPases and Src kinases. Because both PLCgamma and Rho GTPases can be regulated by Src during integrin-mediated cytoskeletal reorganization, we sought to identify swelling-induced Src effectors. Upon hypotonic challenge, Src was rapidly activated in transient plasma membrane protrusions, where it colocalized with Vav, an activator of Rho GTPases. Inhibition of Src with PP2 attenuated phosphorylation of Vav. PP2 also attenuated phosphorylation of PLCgamma, and inhibited swelling-mediated activation of K+ and Cl- channels and cell volume recovery. These findings suggest that swelling-induced Src regulates cytoskeletal dynamics, through Vav, and fluid efflux, through PLCgamma, and thus can coordinate structural reorganization with fluid balance to maintain cellular integrity.

Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.

BACKGROUND/AIMS: Treatment regimens with pegylated interferons have yielded improved response rates, compared with conventional interferon-based regimens, for chronic hepatitis C. However, little is known about the utility of such regimens for individuals who failed to respond to prior conventional interferon-based treatment. METHODS: 182 patients who had previously failed to eliminate circulating hepatitis C virus 24 weeks after completion of a multi-week course of either interferon monotherapy or interferon in combination with ribavirin were treated with peginterferon alfa-2b weekly and ribavirin daily for 48 weeks. RESULTS: The sustained viral response, was 20% (23/116) in previous non-responders and 55% (36/66) in previous relapsers (P<0.001). In previous non-responders, the sustained viral response in those with viral genotype 1 was 17% (19/109) compared to 57% (4/7) in those with genotypes 2 and 3 (P=0.03). In previous relapsers, the sustained viral response in those with viral genotype 1 was 53% (26/49) compared to 59% (10/17) with genotypes 2 and 3 (P=0.78). CONCLUSIONS: The response to pegylated interferon and ribavirin in previous non-responders with genotypes 2 and 3 and in prior relapsers with chronic hepatitis C is comparable to overall sustained viral response rates seen in previously untreated patients.

Calcium mobilization evoked by hepatocellular swelling is linked to activation of phospholipase Cgamma.

Recovery from swelling of hepatocytes and selected other epithelia is triggered by intracellular Ca(2+) release from the endoplasmic reticulum, which leads to fluid and electrolyte efflux through volume-sensitive K(+) and Cl(-) channels. The aim of this study was to determine the mechanisms responsible for swelling-mediated hepatocellular Ca(2+) mobilization. Swelling of HTC rat hepatoma cells, evoked by exposure to hypotonic medium, elicited transient increases in intracellular levels of inositol 1,4,5-trisphosphate (IP(3)) and cytosolic [Ca(2+)]. The latter was attenuated by inhibition of phospholipase C (PLC) with and by IP(3) receptor blockade with 2-aminoethoxydiphenyl borate, but it was unaffected by ryanodine, an inhibitor of intracellular Ca(2+)-induced Ca(2+) release channels. Hypotonic swelling was associated with a transient increase in tyrosine phosphorylation of PLCgamma, with kinetics that paralleled the increases in intracellular IP(3) levels and cytosolic [Ca(2+)]. Confocal imaging of HTC cells exposed to hypotonic medium revealed a swelling-induced association of tyrosine-phosphorylated PLCgamma with the plasma membrane. These findings suggest that activation of PLCgamma by hepatocellular swelling leads to the generation of IP(3) and stimulates discharge of Ca(2+) from the endoplasmic reticulum via activation of IP(3) receptors. By extension, these data support the concept that tyrosine phosphorylation of PLCgamma represents a critical step in adaptive responses to hepatocellular swelling.