Risk factors for HCC in contemporary cohorts of patients with cirrhosis.

BACKGROUND AND AIMS: Etiological risk factors for cirrhosis have changed in the last decade. It remains unclear to what extent these trends in cirrhosis risk factors have changed HCC risk. APPROACH AND RESULTS: We used data from two contemporary, prospective multiethnic cohorts of patients with cirrhosis: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston Veterans Administration Cirrhosis Surveillance Cohort. Patients with cirrhosis were enrolled from seven US centers and followed until HCC diagnosis, transplant, death, or June 30, 2021. We calculated the annual incidence rates for HCC and examined the effects of etiology, demographic, clinical, and lifestyle factors on the risk of HCC. We included 2733 patients with cirrhosis (mean age 60.1 years, 31.3% women). At enrollment, 19.0% had active HCV, 23.3% had cured HCV, 16.1% had alcoholic liver disease, and 30.1% had NAFLD. During 7406 person-years of follow-up, 135 patients developed HCC at an annual incidence rate of 1.82% (95% CI, 1.51-2.13). The annual HCC incidence rate was 1.71% in patients with cured HCV, 1.32% in patients with alcoholic liver disease, and 1.24% in patients with NAFLD cirrhosis. Compared to patients with NAFLD, the risk of progression to HCC was 2-fold higher in patients with cured HCV (HR, 2.04; 95% CI, 1.24-3.35). Current smoking (HR, 1.63; 95% CI, 1.01-2.63) and overweight/obesity (HR, 1.79; 95% CI, 1.08-2.95) were also associated with HCC risk. CONCLUSIONS: HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with HCV cirrhosis and lower risk in those with NAFLD cirrhosis. Current smoking and overweight/obesity increased HCC risk across etiologies.

Successful treatment of severe passenger lymphocyte syndrome with efgartigimod synergy.

INTRODUCTION: This case describes passenger lymphocyte syndrome (PLS) generating human platelet antigen 1a (HPA-1a) alloantibodies against the recipient's platelets after liver transplant. Given the rarity of PLS, especially in liver transplant with HPA-1a alloantibodies, disease course and management options are poorly described. METHODS: The patient had cirrhosis secondary to nonalcoholic steatohepatitis complicated by hepatocellular carcinoma, encephalopathy, and severe ascites. The model for end-stage liver disease (MELD) score was 15 at presentation. The patient developed hepatic artery thrombosis after an orthotopic liver transplant and was relisted for transplant with a MELD score of 40. The patient received a hepatitis C virus antibody positive, hepatitis C virus nucleic amplification test positive donor liver on postoperative day (POD) 7 after first transplant. On POD 7 after the second transplant, the patient developed profound thrombocytopenia refractory to platelet infusion. They were found to have serum antibody to HPA-1a based upon serum platelet alloantibody testing. The donor was later found to be negative for HPA-1a by genetic testing. However, the patient's native platelets were HPA-1a positive. The patient was diagnosed with PLS. RESULTS: The patient's treatment course included 57 units of platelets transfused, emergency splenectomy, rituximab, plasma exchange, intravenous immunoglobulin (IVIG), eltrombopag, romiplostim, and efgartigimod. DISCUSSION: The synergistic effect of efgartigimod with eltrombopag and romiplostim most likely resolved the patient's thrombocytopenia. This case represents a novel use of efgartigimod in the treatment of passenger lymphocyte syndrome following liver transplant.

Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial.

BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. APPROACH AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 µg/mL [0.3] vs. 1.3 µg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).

A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of nonalcoholic fatty liver disease, is characterized by hepatocellular injury and inflammation.1 Patients with NASH are at higher risk of progression to cirrhosis and it is therefore targeted for drug development efforts.2 Lifestyle modifications and weight loss are the only recommended modalities and no drug is yet approved for the treatment of patients with NASH. Saroglitazar is a dual PPAR α/γ agonist, which has shown promise for treatment of nonalcoholic fatty liver disease.3 Because of its combined PPAR-α/γ agonism, it has a clinically favorable impact of glucose and lipid metabolism. Saroglitazar has shown to improve liver-related histology in patients with NASH and was recently approved for treatment of NASH in India.4 The current study builds on the published literature in this proof of concept study to determine if there is a signal for histologic improvement of NASH with saroglitazar in a Western population.

Design of the Texas Hepatocellular Carcinoma Consortium Cohort Study.

OBJECTIVES: The Texas Hepatocellular Carcinoma Consortium cohort study investigates risk factors of hepatocellular carcinoma (HCC) and biomarkers for early HCC detection in patients with liver cirrhosis. METHODS: Adult patients with liver cirrhosis are enrolled at 5 clinical centers from 3 cities in Texas, with a target of 5,000 patients. Clinical history, risk factor questionnaires, liver imaging, laboratory data, and blood samples were collected at enrollment and at each 6-month follow-up visit. RESULTS: The primary outcome was the development of HCC. Biomarkers were tested in banked blood samples using prospective specimen collection, retrospective blinded evaluation design. CONCLUSIONS: We describe study design, eligibility criteria, recruitment, study cores, and sample size and analysis considerations.

Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH. METHODS: In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis. RESULTS: The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF. CONCLUSION: In an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.

Liver and Spleen Stiffness Measurements by Point Shear Wave Elastography via Acoustic Radiation Force Impulse: Intraobserver and Interobserver Variability and Predictors of Variability in a US Population.

OBJECTIVES: Measurements of liver stiffness and spleen stiffness are useful noninvasive ways to assess fibrosis and portal hypertension in patients with chronic liver disease. One method for assessing stiffness is by point shear wave elastography via acoustic radiation force impulse imaging (ARFI). Its advantage is that sites where stiffness is measured are visualized sonographically. However, its reliability has not been well established, and all studies done to date evaluating the use of ARFI in chronic liver disease have been performed outside the United States. We aimed to characterize the intraobserver and interobserver variability of ARFI-measured liver and spleen stiffness. METHODS: Two hepatologists evaluated unselected hepatology outpatients with ARFI. Exclusions were hepatocellular carcinoma, ascites, a surgical shunt or transjugular intrahepatic portosystemic shunt, portal thrombosis, and cholestatic disease. Each operator obtained 20 measurements from the right liver lobe and spleen. Intraclass correlation coefficients (ICC) were calculated. RESULTS: A total of 177 patients were included: median age, 61 years; 85% male; and 43% obese. Intraobserver ICCs were the same for both observers for liver stiffness (0.89; 95% confidence interval [CI], 0.85-0.92) and spleen stiffness (0.72; 95% CI, 0.61-0.80). Interobserver agreement was excellent for liver stiffness (ICC, 0.85; 95% CI, 0.76-0.90) but not as good for spleen stiffness (ICC, 0.73; 95% CI, 0.60-0.83). A body mass index of 30 kg/m2 or greater, waist circumference of greater than 105 cm, and skin-to-capsule distance of 2 cm or greater negatively affected the ICC for liver stiffness; small spleen size negatively affected the ICC for spleen stiffness. CONCLUSIONS: To our knowledge, this article is the first report of ARFI findings in a US population with chronic liver disease. Liver stiffness reproducibility was excellent, particularly in nonobese patients. Spleen stiffness reproducibility was excellent in those with larger spleens and therefore may be most useful in patients with cirrhosis and portal hypertension.

Low level of hepatitis B virus screening among patients receiving chemotherapy.

BACKGROUND & AIMS: Chemotherapy of patients with inactive hepatitis B virus (HBV) infection can lead to viral reactivation and hepatitis flares. We investigated the proportion of patients screened for HBV infection before chemotherapy over time and the outcomes of screened patients. METHODS: In a retrospective study, we collected data from a pharmacy database on patients who underwent cytotoxic chemotherapy for solid or hematologic malignancies at the Mayo Clinic in Rochester, Minnesota, from January 1, 2006, through September 30, 2011. Laboratory data were collected from electronic medical records. Screening was identified based on tests for hepatitis B surface antigen, for any reason at any time before chemotherapy. RESULTS: Of 8005 patients undergoing chemotherapy, 1279 (16%) were screened for HBV infection before chemotherapy, including 668 of 1805 patients with hematologic malignancies (37%). The proportion of patients screened for HBV increased from 14.3% in 2006 to 2008 to 17.7% in 2009 to 2011 (P < .01). This trend was attributed mostly to an increase in the proportion of patients with hematologic malignancies, from 32.7% in 2006 to 2008 to 40.6% in 2009 to 2011 (P < .01). Of 13 patients who tested positive for HBV, 5 did not receive prophylactic antiviral therapy; HBV infection was reactivated in 2 of these patients. None of the 8 patients who received an antiviral agent before chemotherapy experienced HBV reactivation. Of 58 unscreened patients who had increases in their alanine aminotransferase level (>300 U/L), only 1 patient appeared to have an undiagnosed HBV infection. CONCLUSIONS: Only a small percentage of patients receiving chemotherapy are screened for HBV infection. However, a larger proportion of patients was screened during 2009 to 2011 than during 2006 to 2008, especially patients with hematologic malignancies. Strategies are needed to ensure that patients receiving chemotherapy are protected from the consequences of undiagnosed HBV infection.

Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score.

BACKGROUND: Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies. METHODS: We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic. RESULTS: During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35-3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22-3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52-0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64-0.76), increasing from 0.68 without the PRS (p = 0.0012). CONCLUSIONS: Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients.

Exploring hepatitis B: a neglected disease.

Chronic hepatitis B viral (HBV) infection can lead to cirrhosis, liver failure, or hepatocellular carcinoma. In the United States, HBV infection is commonly associated with high-risk behaviors such as intravenous drug use or unprotected sex; but it is not as well-known among health care providers that HBV can be transmitted from mother to baby during birth. Worldwide, the majority of cases of chronic HBV infection are in people who contracted the virus during birth. There is a lack of awareness in the United States that immigrants from HBV-endemic countries may be at high risk for chronic HBV. Thus, at-risk individuals may not be screened for HBV. The most recent Centers for Disease Control and Prevention guidelines recommend HBV screening for all people born in Asia, all U.S.-born persons who were unvaccinated as infants and whose parents were born in regions of high HBV endemicity (> or = 8%), and individuals with parenteral risk factors. Screening for HBV starts with HBsAg (hepatitis B surface antigen), HBsAb (antibody to hepatitis B surface antigen), and total anti-HBc (total antibody to hepatitis B core antigen) testing. For those who are HBV-negative (HBsAg-negative) and have no evidence of prior immunity, the three-part HBV vaccination series is recommended.

Cholestasis in Benign Recurrent Intrahepatic Cholestasis 2.

Benign recurrent intrahepatic cholestasis represents a rare class of autosomal recessive chronic cholestasis disorders, usually presenting with recurrent episodes of intense pruritus and jaundice. We report a 27-year-old woman presenting with benign recurrent intrahepatic cholestasis type 2 due to heterozygosity in ABCB11. Interestingly, she was also found to be heterozygous in cystic fibrosis transmembrane conductance regulator, NPHP4, and A1ATD (SERPINA1), which may explain the severe nature of her disease expression because heterozygosity in each of these genes has been associated with cholestasis. Finally, she exhibited a response to steroids that may have implications for future treatment of bile salt export pump-related diseases.

The burden associated with thrombocytopenia and platelet transfusions among patients with chronic liver disease.

Background: Thrombocytopenia (TCP), a common complication of chronic liver disease (CLD), can cause uncontrolled bleeding during procedures. As such, CLD patients with TCP and platelet counts <50,000/µL often receive prophylactic platelet transfusions before invasive procedures. However, platelet transfusions are associated with clinical complications, which may result in increased healthcare utilization and costs.Objective: This retrospective database analysis describes the clinical and economic burden in CLD patients with TCP, CLD patients without TCP, and CLD patients with TCP who receive platelet transfusions.Methods: Adult CLD patients with or without TCP were identified in the IBM MarketScan Commercial Claims and Medicare Supplemental data from 1 January 2012 to 31 December 2015. CLD patients with or without TCP were propensity-score matched (1:1) for the analysis of annual healthcare utilization and costs. Platelet transfusions among CLD patients with TCP were identified using procedure codes.Results: Of the 601,626 patients with CLD, 8,292 (1.4%) patients with TCP were matched to patients without TCP. Among CLD patients with TCP, 981 (11.8%) patients received ≥1 platelet transfusions and met inclusion/exclusion criteria. Compared to patients without TCP, CLD patients with TCP had more complications, including higher prevalence of neutropenia (11.4% vs 2.9%) and bleeding events (21.4% vs 10.9%), greater resource utilization including greater average hospital admissions (1.2 vs 0.7, p < .01), greater average ER visits (2.1 vs 1.3, p < .01), higher average outpatient office visits (20.1 vs 18.4, p < .01), and higher average healthcare costs including total costs (p < .01), inpatient costs (p < .01), ER visit costs (p < .01), and outpatient office visit costs (p < .01). The mean annual total costs in CLD and TCP patients with platelet transfusions were $206,396.Conclusions: CLD patients with TCP, and particularly those who received platelet transfusions, experienced significantly greater clinical and economic burden compared to CLD patients without TCP. Safer and more cost-effective treatments to increase platelets are necessary.

Ombitasvir/paritaprevir/ritonavir + dasabuvir +/- ribavirin in real world hepatitis C patients.

BACKGROUND: The hepatitis C virus (HCV) NS5A inhibitor ABT-267 (ombitasvir, OBV), the HCV NS4/4A protease inhibitor ABT-450 (paritaprevir, PTV), the CYP3A inhibitor ritonavir (r) and the non-nucleoside NS5B polymerase inhibitor ABT-333 (dasabuvir, DSV) (OBV/PTV/r + DSV) with or without ribavirin (RBV) is a direct-acting antiviral regimen approved in the United States and other major countries for the treatment of HCV in genotype 1 (GT1) infected patients. Patients with HCV who are considered "hard-to-cure" have generally been excluded from registration trials due to rigorous study inclusion criteria, presence of comorbidities and previous treatment failures. AIM: To investigate the efficacy of this regimen in HCV G1-infected patients historically excluded from clinical trials. METHODS: Patients were ≥ 18 years old and chronically infected with HCV GT1 (GT1a, GT1b or GT1a/1b). Patients were treatment-naïve or previously failed a regimen including pegylated interferon/RBV +/- telaprevir, boceprevir, or simeprevir. One hundred patients were treated with the study drug regimen, which was administered for 12 or 24 wk +/- RBV according to GT1 subtype and presence/absence of cirrhosis. Patients were evaluated every 4 wk from treatment day 1 and at 4 and 12 wk after end-of-treatment. RESULTS: Many of the patients studied had comorbidities (44.2% hypertensive, 33.7% obese, 20.2% cirrhotic) and 16% previously failed HCV treatment. Ninety-six patients completed study follow-up and 99% achieved 12-wk sustained virologic response. The majority (88.4%) of patients had undetectable HCV RNA by week 4. The most common adverse events were fatigue (12%), headache (10%), insomnia (9%) and diarrhea (8%); none led to treatment discontinuation. Physical and mental patient reported outcomes scores significantly improved after treatment. Almost all (98%) patients were treatment compliant. CONCLUSION: In an all-comers HCV GT1 population, 12 or 24-wk of OBV/PTV/r + DSV +/- RBV is highly effective and tolerable and results in better mental and physical health following treatment.

Real-world observational experience with direct-acting antivirals for hepatitis C: baseline resistance, efficacy, and need for long-term surveillance.

The aim of this study was to obtain real-world, US, observational data on the effect of baseline resistance-associated substitutions (RASs) on achieving sustained virologic response (SVR) in hepatitis C (HCV) patients treated with direct-acting antiviral (DAA) regimens; the need for long-term follow-up in post-SVR patients.It is uncertain if the presence of RASs limits efficacy to DAAs. Once SVR is achieved, society guidelines recommend long-term surveillance for hepatocellular carcinoma in certain patients. Real-world data are limited on these topics.Adult patients treated with DAAs at community hepatitis clinics between January 2015 and April 2017 were included in this study. Baseline resistance testing was performed before treatment. Per guidelines, post-SVR long-term monitoring was required in patients with F3 to F4 fibrosis before treatment or with elevated ALT levels (>19 U/L females; >30 U/L males).A total of 875 chronic, mostly GT1a (60%) HCV patients were treated with an approved DAA regimen. Average baseline AST and ALT were 75 and 67 U/L, respectively, and 47% had F3 to F4 fibrosis at baseline. SVR was achieved in 863 (98.6%) patients despite a high presence of baseline RASs (61%). Long-term monitoring was required post-SVR in 539 patients (62%).In a real-life, US cohort of HCV-infected patients, nearly all patients achieved SVR with available DAA regimens regardless of baseline RASs. Approximately two-thirds of these patients required long-term follow-up, despite viral eradication.

Non-hemorrhagic acute complications associated with cirrhosis and portal hypertension.

Timely recognition and management of acute complications of cirrhosis is of significant importance in order to reduce morbidity and mortality, especially in the hospitalized patient. In this review, we present a practical approach to the identification and management of non-hemorrhagic acute complications of cirrhosis, specifically bacterial infections, acute kidney injury, and acute exacerbation of hepatic encephalopathy, focusing on patient stratification.

Biosensor detection of botulinum toxoid A and staphylococcal enterotoxin B in food.

Immunoassays were developed for the simultaneous detection of staphylococcal enterotoxin B and botulinum toxoid A in buffer, with limits of detection of 0.1 ng/ml and 20 ng/ml, respectively. The toxins were also spiked and measured in a variety of food samples, including canned tomatoes, sweet corn, green beans, mushrooms, and tuna.