Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: The patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship. APPROACH AND RESULTS: A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p =0.03, and p -value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p -value for interaction between PNPLA3 and each factor<0.01. CONCLUSIONS: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex.

Liver stiffness progression in biopsy-proven metabolic dysfunction-associated steatotic disease among people with diabetes versus people without diabetes: A prospective multicenter study.

BACKGROUND AND AIMS: There are limited data on the progression of liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in people with type 2 diabetes mellitus (T2DM) versus those without T2DM in biopsy-proven metabolic dysfunction-associated steatotic liver disease. We examined LSM progression in participants with T2DM versus those without T2DM in a large, prospective, multicenter cohort study. APPROACH AND RESULTS: This study included 1231 adult participants (62% female) with biopsy-proven metabolic dysfunction-associated steatotic liver disease who had VCTEs at least 1 year apart. LSM progression and regression were defined by a ≥20% increase and an upward or downward change, respectively, in the LSM category in the Baveno VII categories for compensated advanced chronic liver disease, compared between participants with T2DM (n = 680) versus no T2DM (n = 551) at baseline. The mean (±SD) age and body mass index were 51.8 (±12.0) years and 34.0 (±6.5) kg/m 2 , respectively. The median (IQR) time between the first and last VCTE measurements was 4.1 (2.5-6.5) years. Participants with T2DM had higher LSM progression at 4 years (12% vs. 10%), 6 years (23% vs. 16%), and 8 years (50% vs. 39%), p = 0.04. Using a multivariable Cox proportional hazards model adjusted for multiple confounders, the presence of T2DM remained an independent predictor of LSM progression (adjusted HR: 1.35, 95% CI: 1.01-1.81, p = 0.04). T2DM was not associated with LSM regression ( p = 0.71). Mean HbA1c was significantly associated with LSM progression ( p = 0.003) and regression ( p = 0.02). CONCLUSIONS: Using serial VCTE data from a multicenter study of participants with biopsy-proven metabolic dysfunction-associated steatotic liver disease, we demonstrate that T2DM and HbA1c are associated with LSM progression.

Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation.

BACKGROUND AND AIMS: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA. CONCLUSIONS: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.

Acute kidney injury in severe alcohol-associated hepatitis treated with anakinra plus zinc or prednisone.

BACKGROUND AND AIMS: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. APPROACH AND RESULTS: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005). CONCLUSIONS: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

PNPLA3 rs738409, environmental factors and liver-related mortality in the U.S. Population.

BACKGROUND & AIMS: Little is known about the interplay between patatin-like phospholipase domain protein 3 (PNPLA3 rs738409 C>G), environmental factors, and the risk of liver-related death (LRD). METHODS: 4,361 adults were selected from NHANES III, 1991-1994. All participants were linked to the National Death Index until 2019 (mean follow-up: 23.2 years). LRD was the study outcome. Associations of PNPLA3, diet, light alcohol intake, smoking, and BMI (kg/m2) with LRD were examined using competing risk regression models. RESULTS: PNPLA3 G-allele was significantly associated with LRD (adjusted subhazard ratio [adj.sHR]: 2.9, 95% CI: 1.4-5.8). Non-heavy alcohol intake (adj.sHR: 2.2, 95% CI: 1.1-4.5), top quartiles of monounsaturated fat (MUFA) (adj.sHR: 0.43, 95% CI: 0.12-0.99), and cholesterol (adj.sHR: 2.6, 95% CI: 1.00-8.8) and coffee intake ≥3 cups/day (adj.sHR: 0.05, 95% CI: 0.06-0.10), former/current smoking (adj.sHR: 1.8, 95% CI: 1.2-2.6), BMI (adj.sHR: 1.1, 95% CI: 1.03-1.2), and healthy eating index (HEI) (adj.sHR: 0.96, 95% CI: 0.93-0.98) were associated with LRD. Joint effects between PNPLA3 and environmental factors showed that the risk of LRD was significantly increased in carriers of the G-allele with non-heavy alcohol intake (adj.sHR: 3.7), higher consumption (top quartile) of cholesterol (adj.sHR: 4.1), former (adj.sHR: 4.3) or current (adj.sHR: 3.5) smoking, or BMI ≥30 (adj.sHR: 4.0) kg/m2. The effects of the G-allele on the risk of LRD were significantly attenuated in those with top quartile consumption of MUFA (adj.sHR: 0.5) or ≥3 cups/day of coffee (adj.sHR: 0.09). HEI was inversely associated with LRD across all PNPLA3 genotypes (adj.sHR: 0.94, 0.96, and 0.97 for CC, CG, and GG, respectively). CONCLUSIONS: PNPLA3 is associated with LRD and this relationship is significantly modified by anthropometric and environmental factors.

Increases and decreases in liver stiffness measurement are independently associated with the risk of liver-related events in NAFLD.

BACKGROUND & AIMS: The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs). METHODS: Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status. RESULTS: In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p <0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p <0.01). CONCLUSIONS: Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD. IMPACT AND IMPLICATIONS: The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD.

Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis.

BACKGROUND & AIMS: Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. METHODS: In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. RESULTS: Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14-0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13-0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). CONCLUSIONS: Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. IMPACT AND IMPLICATIONS: There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. TRIAL REGISTRATION: NCT04072822.

Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease.

BACKGROUND: The prognoses with respect to mortality and hepatic and nonhepatic outcomes across the histologic spectrum of nonalcoholic fatty liver disease (NAFLD) are not well defined. METHODS: We prospectively followed a multicenter patient population that included the full histologic spectrum of NAFLD. The incidences of death and other outcomes were compared across baseline histologic characteristics. RESULTS: A total of 1773 adults with NAFLD were followed for a median of 4 years. All-cause mortality increased with increasing fibrosis stages (0.32 deaths per 100 person-years for stage F0 to F2 [no, mild, or moderate fibrosis], 0.89 deaths per 100 persons-years for stage F3 [bridging fibrosis], and 1.76 deaths per 100 person-years for stage F4 [cirrhosis]). The incidence of liver-related complications per 100 person-years increased with fibrosis stage (F0 to F2 vs. F3 vs. F4) as follows: variceal hemorrhage (0.00 vs. 0.06 vs. 0.70), ascites (0.04 vs. 0.52 vs. 1.20), encephalopathy (0.02 vs. 0.75 vs. 2.39), and hepatocellular cancer (0.04 vs. 0.34 vs. 0.14). As compared with patients with stage F0 to F2 fibrosis, patients with stage F4 fibrosis also had a higher incidence of type 2 diabetes (7.53 vs. 4.45 events per 100 person-years) and a decrease of more than 40% in the estimated glomerular filtration rate (2.98 vs. 0.97 events per 100 person-years). The incidence of cardiac events and nonhepatic cancers were similar across fibrosis stages. After adjustment for age, sex, race, diabetes status, and baseline histologic severity, the incidence of any hepatic decompensation event (variceal hemorrhage, ascites, or encephalopathy) was associated with increased all-cause mortality (adjusted hazard ratio, 6.8; 95% confidence interval, 2.2 to 21.3). CONCLUSIONS: In this prospective study involving patients with NAFLD, fibrosis stages F3 and F4 were associated with increased risks of liver-related complications and death. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; NAFLD DB2 ClinicalTrials.gov number, NCT01030484.).

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD.

BACKGROUND & AIMS: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD. METHODS: A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG). RESULTS: PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% CI, 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013-1.026), CG (OR, 1.024; 95% CI, 1.018-1.030), and GG (OR, 1.03; 95% CI, 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m2 was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both). CONCLUSIONS: Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD.

Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). METHODS: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. RESULTS: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. CONCLUSIONS: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study.

BACKGROUND & AIMS: There are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies. METHODS: This study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM. RESULTS: The mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24). CONCLUSIONS: In this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design.

Effects of Food Insecurity on Hepatic Steatosis and Fibrosis in People With HIV.

BACKGROUND & AIMS: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. METHODS: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥ 18 years on antiretroviral therapy, HIV RNA <200 copies/mL, and without other known liver diseases were screened for NAFLD (controlled attenuated parameter ≥263 decibels/meter) and advanced fibrosis (liver stiffness measurement ≥11 kilopascals) by vibration controlled transient elastography at 8 U.S. CENTERS: Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD and advanced fibrosis by FI status. RESULTS: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 of participants (31%), including 97/348 with NAFLD (28%) and 18/41 with advanced fibrosis (44%). In multivariable analysis, FI was associated with lower odds of NAFLD (OR, 0.57; 95% CI, 0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR, 1.38; 95% CI, 0.65-2.90). We identified a significant interaction between FI and diabetes (P = .02) on fibrosis risk, with greater odds of fibrosis among food insecure PWH and diabetes (OR, 3.83; 95% CI, 1.15-12.73) but not among food insecure nondiabetics (OR, 1.12; 95% CI, 0.47-2.98). CONCLUSIONS: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, there is greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH.

HLA-B*53:01 Is a Significant Risk Factor of Liver Injury due to Phenytoin and Other Antiepileptic Drugs in African Americans.

INTRODUCTION: To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA). METHODS: In this study, 21 AA with AED drug-induced liver injury (DILI), 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included. RESULTS: HLA-B*53:01 was significantly associated with aromatic AED-DILI (odds ratio: 4.52, 95% confidence interval: 2.42-8.44, P = 1.46 × 10 -5 ). Phenytoin DILI showed the strongest association with HLA-B*53:01 (odds ratio: 9.17; 95% confidence interval: 3.61-23.28, P = 1.1 × 10 -5 ). The HLA-B*53:01 allele was carried by 8 of 9 AA phenytoin DILI cases. DISCUSSION: HLA-B*53:01 is a significant risk factor of liver injury due to antiepileptics, particularly phenytoin, in AA.

Non-Hispanic Black Persons With Nonalcoholic Fatty Liver Disease Have Lower Rates of Advanced Fibrosis, Cirrhosis, and Liver-Related Events Even After Controlling for Clinical Risk Factors and PNPLA3 Genotype.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is less frequent in non-Hispanic persons (NHB), but there are knowledge gaps in our understanding of disease severity and outcomes of NAFLD in NHB. We compared liver histology and clinical outcomes of NAFLD in non-Hispanic Black persons (NHB) and non-Hispanic White persons (NHW). METHODS: We compared liver histology and outcomes of 109 NHB and 1,910 NHW adults with biopsy-proven NAFLD participating in the Nonalcoholic Steatohepatitis Clinical Research Network observational studies. The relationship between self-reported NHB race/ethnicity and advanced fibrosis was assessed through multivariable logistic regression after controlling for clinical covariates and PNPLA3 genotype. RESULTS: NHB and NHW with NAFLD had similar NAFLD activity scores (NAS, 4.4 vs 4.3, P = 0.87) and proportions with definite metabolic dysfunction-associated steatohepatitis (59% vs 58%, P = 1.0), but NHB had significantly lower rates of advanced fibrosis (22% vs 34%, P = 0.01) or cirrhosis (4.6% vs 12.1%, P = 0.010). Compared with NHW, NHB had significantly lower frequency of advanced fibrosis (Odds Ratio: 0.48, 95% Confidence Interval: 27-0.86, P = 0.01). In a comparison between 24 NHB and 655 NHW with advanced fibrosis, the NAS (5.6 vs 4.9, P = 0.01) and lobular inflammation grade (2.2 vs 1.7, P < 0.002) were significantly higher among NHB with advanced fibrosis. One NHB and 23 NHW died during follow-up (0.30 vs 0.28 per 100 person-year follow-up). Seven and zero liver-related deaths occurred in NHW and NHB with NAFLD, respectively. DISCUSSION: The risk of advanced fibrosis in NHB with NAFLD is significantly lower, after controlling for clinical risk factors and PNPLA3 genotype. Although their risk of advanced fibrosis was low, NHB with NAFLD and advanced fibrosis had higher NAS and lobular inflammation, indicating a difference in their relationship between necroinflammation and fibrosis.

Early Diagnostic Paracentesis Improves Outcomes of Hospitalized Patients With Cirrhosis and Ascites: A Systematic Review and Meta-Analysis.

INTRODUCTION: Diagnostic paracentesis is recommended for patients with cirrhosis admitted to the hospital, but adherence is suboptimal with unclear impact on clinical outcomes. The aim of this meta-analysis was to assess the outcomes of early vs delayed diagnostic paracentesis among hospitalized patients with cirrhosis and ascites. METHODS: We searched multiple databases for studies comparing early vs delayed diagnostic paracentesis among hospitalized patients with cirrhosis and ascites. The pooled odds ratio (OR) and mean difference with confidence intervals (CIs) for proportional and continuous variables were calculated using the random-effects model. Early diagnostic paracentesis was defined as receiving diagnostic paracentesis within 12-24 hours of admission. The primary outcome was in-hospital mortality. Secondary outcomes were length of hospital stay, acute kidney injury, and 30-day readmission. RESULTS: Seven studies (n = 78,744) (n = 45,533 early vs n = 33,211 delayed diagnostic paracentesis) were included. Early diagnostic paracentesis was associated with lower in-hospital mortality (OR 0.61, 95% CI 0.46-0.82, P = 0.001), length of hospital stay (mean difference -4.85 days; 95% CI -6.45 to -3.20; P < 0.001), and acute kidney injury (OR 0.62, 95% CI 0.42-0.92, P = 0.02) compared with delayed diagnostic paracentesis, with similar 30-day readmission (OR 1.11, 95% CI 0.52-2.39, P = 0.79). Subgroup analysis revealed consistent results for in-hospital mortality whether early diagnostic paracentesis performed within 12 hours (OR 0.51, 95% CI 0.32-0.79, P = 0.003, I2 = 0%) or within 24 hours of admission (OR 0.67, 95% CI 0.45-0.98, P = 0.04, I2 = 82%). Notably, the mortality OR was numerically lower when diagnostic paracentesis was performed within 12 hours, and the results were precise and homogenous ( I2 = 0%). DISCUSSION: Findings from this meta-analysis suggest that early diagnostic paracentesis is associated with better patient outcomes. Early diagnostic paracentesis within 12 hours of admission may be associated with the greatest mortality benefit. Data from large-scale randomized trials are needed to validate our findings, especially if there is a greater mortality benefit for early diagnostic paracentesis within 12 hours.

A Comprehensive Evaluation of Emergency Department Utilization by Patients With Cirrhosis.

INTRODUCTION: Emergency department (ED)-based care is required for cirrhosis management, yet the burden of cirrhosis-related ED healthcare utilization is understudied. We aimed to describe ED utilization within a statewide health system and compare the outcomes of high ED use (HEDU) vs non-HEDU in individuals with cirrhosis. METHODS: We retrospectively reviewed charts of adults with cirrhosis who presented to any of 16 EDs within the Indiana University Health system in 2021. Patient characteristics, features of the initial ED visit, subsequent 90-day healthcare use, and 360-day outcomes were collected. Multivariable logistic regression models were used to identify predictors HEDU status which was defined as ≥2 ED visits within 90 days after the index ED visit. RESULTS: There were 2,124 eligible patients (mean age 61.3 years, 53% male, and 91% White). Major etiologies of cirrhosis were alcohol (38%), metabolic dysfunction-associated steatohepatitis (27%), and viral hepatitis (21%). Cirrhosis was newly diagnosed in the ED visit for 18.4%. Most common reasons for ED visits were abdominal pain (21%), shortness of breath (19%), and ascites/volume overload (16%). Of the initial ED visits, 20% (n = 424) were potentially avoidable. The overall 90-day mortality was 16%. Within 90 days, there were 366 HEDU (20%). Notable variables independently associated with HEDU were model for end-stage liver disease-sodium (adjusted odds ratio [aOR] 1.044, 95% confidence interval [CI] 1.005-1.085), prior ED encounter (aOR 1.520, 95% CI 1.136-2.034), and avoidable initial ED visit (aOR 1.938, 95% CI 1.014-3.703). DISCUSSION: Abdominal pain, shortness of breath, and ascites/fluid overload are the common presenting reasons for ED visits for patients with cirrhosis. Patients with cirrhosis presenting to the ED experience a 90-day mortality rate of 16%, and among those who initially visited the ED, 20% were HEDU. We identified several variables independently associated with HEDU. Our observations pave the way for developing interventions to optimize the care of patients with cirrhosis presenting to the ED and to lower repeated ED visits.

Diagnostic Ability of Simple Noninvasive Blood Tests to Predict Increased Liver Stiffness in People Living With HIV and Steatotic Liver Disease.

INTRODUCTION: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM). METHODS: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS). RESULTS: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF. DISCUSSION: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

CAP and LSM as determined by VCTE are independent predictors of all-cause mortality in the US adult population.

BACKGROUND AND AIM: Data retrospective cohort studies have shown that liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) can predict mortality in patients with NAFLD, however, its ability to predict mortality at a population level is unknown. We investigated the ability of LSM and controlled-attenuation parameter (CAP) by TE to predict mortality in a prospective US cohort. APPROACH AND RESULTS: A total of 4192 US adults aged ≥18 years enrolled in the National Health, and Nutrition Examination Survey (NHANES) (2017-2018) with reliable information on CAP and LSM by TE were included in this analysis. All-specific and cause-specific mortality were ascertained by linkage to National Death Index records through December 31, 2019. Cox models were used to estimate HR and 95% CI. During a mean follow-up of 24.4 months, there were 68 deaths (1.6%). CAP (adjusted HR: 1.01, 95% CI: 1.0-1.05), and LSM (adjusted HR: 1.06, 95% CI: 1.02-1.11) were independently associated with overall mortality. NAFLD by CAP ≥285 had a 2.2-fold (95% CI: 1.0-4.7) increased odds of mortality compared with non-NAFLD. Cumulative mortality rates were significantly higher in participants with LSM of 9.7-13.5 (advanced fibrosis) and LSM ≥13.6 (cirrhosis) as compared with LSM <9.7; p value for trend across groups <0.01. LSM ≥13.6 displayed the highest mortality risk (adjusted HR: 3.2, 95% CI: 1.3-7.8). Compared with LSM <10 [absence of advanced chronic liver disease (ACLD)], LSM 10-19.9 (likely ACLD), and ≥20 kPa (likely ACLD with clinically significant portal hypertension) conferred a 3.4-fold (95% CI: 1.0-13.8) and 5.2-fold (95% CI: 1.2-22.3) increase in hazards of mortality. CONCLUSIONS: Our study findings highlight the importance of liver health as a predictor of overall mortality at a population level.