Stage F3-F4 Research Articles

Cardiovascular risk in US adults with nonalcoholic steatohepatitis (NASH) vs. matched non-NASH controls, National Health and Nutrition Examination Survey, 2017-2020.

NASH is considered a contributor to atherosclerotic cardiovascular disease (ASCVD) risk; however, its contribution beyond traditional risk factors for CVD, particularly diabetes, is less clearly understood. This study aimed to quantify the cardiovascular-event risk associated with NASH, independent of diabetes status. A cross-sectional analysis was conducted using the 2017-2020 NHANES pre-pandemic cycle. NASH was defined based on presence of steatosis without other causes of liver disease, and FibroScan+AST score from vibration-controlled transient elastography (VCTE). Significant fibrosis (stages F2-F4) was identified by liver stiffness measurement from VCTE. Predicted primary CV-event risk was estimated using both the Pooled Cohort Equations (PCE) and the Framingham Risk Score (FRS). NASH patients were matched with non-NASH controls on age, sex, race/ethnicity, and diabetes status. Weighted logistic regression was conducted, modeling elevated predicted CV risk (binary) as the dependent variable and indicators for NASH / fibrosis stages as independent variables. A sample of 125 NASH patients was matched with 2585 controls. NASH with significant fibrosis was associated with elevated predicted 10-year CV risk, although this association was only statistically significant in PCE analyses (odds ratio and 95% CI 2.34 [1.25, 4.36]). Analyses restricting to ages <65 years showed similar results, with associations of greater magnitude. Independent of diabetes, a significant association was observed between NASH with significant liver fibrosis and predicted primary CV-event risk in US adults, particularly for those <65. These findings suggest the importance of accounting for NASH and liver-fibrosis stage in predicting CV-event risk.

Metabolic dysfunction-associated steatohepatitis exhibits sex differences in people with HIV.

People with HIV are at increased risk for metabolic dysfunction-associated steatohepatitis (MASH). Although sex differences are documented in the general population, their role in the context of HIV is less understood. This was a multicentre cohort study including people with HIV without viral hepatitis coinfection. A FibroScan-AST (FAST) score >0.35 was used to diagnose MASH with significant liver fibrosis (stage F2-F4). We investigated sex-based differences in MASH trends as a function of age using a segmented linear mixed-effects model. Random effects accounted for clustering by the four sites. Adjusted models included ethnicity, diabetes, hypertension, and detectable HIV viral load. We included 1472 people with HIV (25% women). At baseline, the prevalence of MASH with fibrosis by FAST score was lower in women than in men (4.8% vs. 9.2%, p = 0.008). Based on the adjusted model, male sex (+0.034; p = 0.04), age per year (+0.003; p = 0.05), detectable HIV viral load (+0.034; p = 0.02), and hypertension (+0.03; p = 0.01) were positively associated with MASH with fibrosis. Although men exhibited generally higher FAST scores, FAST scores increased in women during the critical biological age of presumed perimenopause to menopause (between 40 and 50 years), reaching levels similar to those in men by the age of 55 years. Despite women with HIV having a lower prevalence of MASH with fibrosis than men, they exhibit an acceleration in FAST score increase around the perimenopausal age. Future studies should target adequate consideration of sex differences in clinical investigation of metabolic dysfunction-associated steatotic liver disease to fill current gaps and implement precision medicine for people with HIV.

Association of Blood NK Cell Phenotype with the Severity of Liver Fibrosis in Patients with Chronic Viral Hepatitis C with Genotype 1 or 3.

NK cells phenotype and functional state in different genotypes of chronic viral hepatitis C (CVHC), depending on liver fibrosis severity, have not been sufficiently studied, which limits the possibilities for the development of pathology therapy. The CVHC diagnosis was based on the EASL recommendations (2018). Clinical examination with liver elastometry was performed in 297 patients with genotype 1 and in 231 patients with genotype 3 CVHC. The blood NK cells phenotype was determined by flow cytometry in 74 individuals with genotype 1 and in 69 individuals with genotype 3 CVHC. The frequency of METAVIR liver fibrosis stages F3-F4 was 32.5% in individuals with genotype 3, and 20.5% in individuals with genotype 1 CVHC (p = 0.003). In patients with both genotype 1 and genotype 3 CVHC, a decrease in the total number of blood NK cells, CD56brightCD16+ NK cells and an increase in the proportion of CD56dimCD16+ NK cells, CD94+ and CD38 + CD73+ NK cells were registered in patients with fibrosis stage F3-F4 by METAVIR in comparison with persons with METAVIR fibrosis stage F0-F1. In patients with both genotype 1 and genotype 3 CVHC, an imbalance in the ratio between cytokine-producing and cytotoxic NK cells and an increase in the content of NK cells that express inhibitory molecules were determined in patients with severe liver fibrosis.

Exclusive liquor and cocktail consumption is associated with at-risk fibrosis among nonheavy alcohol users with metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol consumption have both increased in recent years, and there is debate as to whether nonheavy alcohol use is safe in MASLD. We analyzed the association between different nonheavy alcohol use patterns and at-risk liver fibrosis among individuals with MASLD. We conducted a cross-sectional study of 1072 eligible National Health and Nutrition Examination Survey participants with MASLD who reported nonheavy alcohol consumption. We used vibration-controlled transient elastography to define the primary outcome of at-risk liver fibrosis as >8.2 kPa (stage F2-F4). Multivariable logistic regression models were used to determine the association of different alcohol consumption patterns (average drinks/day, drinking days/week, weekly alcohol intake, type of alcoholic beverage) and at-risk hepatic fibrosis, controlling for demographic/socioeconomic, lifestyle/dietary, and metabolic risk factors. Exclusive liquor or cocktail drinkers had a 5.02-fold odds of at-risk fibrosis (95% CI: 1.15-21.95) compared with non-drinkers when controlling for potential confounders. While consuming an average of 2 drinks/day, ≥3 drinking days/week, or 1-3 drinks/week appeared to have a lower association with at-risk fibrosis when controlling for demographic/socioeconomic risk factors, the association was not present after controlling for lifestyle/dietary and metabolic risk factors. There is an association between exclusive liquor/cocktail consumption and at-risk liver fibrosis in patients with MASLD who report nonheavy alcohol consumption.

Abstract 18543: Association of Nonalcoholic Steatohepatitis With Predicted 10-Year Cardiovascular Risk, Independent of Diabetes Status (NHANES 2017-2020)

Introduction: Evidence suggests patients with nonalcoholic steatohepatitis (NASH), particularly those with significant fibrosis (stages ≥F2), have elevated CV-event risk. Hypothesis: The association of NASH with diabetes may confound the relationship between NASH and CV-event risk. Goals/Aims: To estimate primary CV-event risk associated with presumed NASH, adjusting for diabetes. Methods: A cross-sectional analysis of the 2017-March 2020 NHANES cycle was conducted. Presumed NASH was defined as evidence of steatosis (controlled attenuation parameter [CAP] ≥302 dB/m), exclusion of excessive alcohol consumption or hepatitis B/C, and FibroScan-AST (FAST) score ≥0.48. Non-NASH controls were matched 3:1 based on age, sex, and race. The 10-year probability of a primary CV event was estimated using the Framingham Heart Study risk equations. Linear models were used to estimate the association of presumed NASH with CV risk, with and without adjustment for diabetes, and distinguishing fibrosis stages F0-F1 vs F2-F4 within presumed NASH. Results: The analysis included 123/369 matched participants with/without presumed NASH. Mean (SE, P value) incremental probability of a primary CV event associated with presumed NASH was 1.4% (1.2%, P =0.26) before adjustment for diabetes, and 1.8% (1.0%, P =0.10) after adjustment. In participants ages &lt;65, the association with presumed NASH was statistically significant at 2.3% (1.1%, P =0.05) before adjustment for diabetes, and 2.1% (1.0%, P =0.04) after adjustment, and elevated in fibrosis stages F2-F4 (see Table). Limited sample size challenged reliability of estimates for ages ≥65. Conclusions: Among individuals ages &lt;65, a significant association of presumed NASH and primary CV-event risk was observed, before and after adjusting for diabetes. The incremental risk was greater for fibrosis stages F2-F4, suggesting the importance of accounting for fibrosis stage in predicting CV risk.

Weaker SARS-CoV-2 vaccine responses in nonalcoholic fatty liver disease with advanced liver fibrosis

BackgroundSARS-CoV-2 vaccine responses that could harbor potential risks to chronic liver diseased patients. AimsTo assess immune response following Pfizer's SARS-CoV-2 vaccine in patients with different liver fibrosis severities of nonalcoholic fatty liver disease (NAFLD). MethodsClinical and histological (NAS-score and fibrosis stage) characteristics of NAFLD patients before vaccine were correlated with serologic vaccine responses of two doses of the BNT162b2. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed on day seven following immunization (Liaison assay). ResultsThe mean-age of patients (n = 157) was 56.9 ± 13.2 years (46.5 % males). 94.8 % had a positive response (anti-S levels ≥ 19 AU/ml). The anti-S cutoff of 200 AU/ml used to separate strong vs. weak responses. A strong response (anti-S titers ≥ 200 AU/ml) was observed in 93/157 (59.2 %) patients with a mean-age of 53.1 ± 13.8 years (45.2 % males). A weak response (anti-S titers < 200 AU/ml) was observed in 64/157 (40.8 %) cases with a mean-age of 62.3 ± 10.2 years (p < 0.0001). The strong response subgroup had lower metabolic comorbidities, including glucose hemostasis, hypertension, and dyslipidemia (p < 0.04). Moreover, the strong response subgroup had fibrosis stages F0-F2 (75.3 % vs. 56.3 %) and lower rates of advanced stages F3-F4 (24.7 % vs. 43.8 %). The F0-F2 subgroups had significantly higher rates of strong responses than the F3-F4 stages. The anti-S ≥ 200 and anti-S ≥ 400 AU/ml response achieved in 66 % and 36.8 % of the F0-F2 population was significantly higher than the 45.1 % (p = 0.006) and 23.5 % (p = 0.05) in the F3-F4 population, respectively. The Fib-4 calculations and Fibroscan evaluations were consistent with histologic fibrosis assessment. ConclusionAdvanced liver fibrosis (assessed by histology, Fib-4, or Fibroscan) is a risk factor for lower response to Pfizer's BNT162b2 vaccine, and patients should be prioritized for the vaccine booster against SARS-CoV-2.

DIAGNOSTIC VALUE OF NITROGEN METABOLISM DISORDERS IN NON-ALCOHOLIC FATTY LIVER DISEASE IN COMORBID PATIENTS WITH METABOLIC SYNDROME AND STRATIFICATION OF DISEASE STAGES

The aim of the study is to determine the significance of hyperammonemia for the diagnosis of non-alcoholic fatty liver disease (NAFLD) in patients with metabolically associated comorbid pathology.&#x0D; Materials and Methods. A single-stage cohort randomized study was conducted to examine NAFLD in patients with metabolically associated pathology – type 2 diabetes, obesity, hypertension, coronary artery disease, and dyslipidemia. The study included 96 patients, who were divided into 3 groups: patients with steatotic liver disease (n=33), patients with non-alcoholic steatohepatitis (n=47) and patients with newly diagnosed liver cirrhosis (n=16). For NAFLD diagnosis, non-invasive methods were also applied (APRI, FIB4, NAFLD fibrosis score). To diagnose hepatocellular insufficiency, the authors evaluated ammonia level in capillary blood. Statistical processing was carried out by parametric and nonparametric methods, correlation and cluster analysis (Statistica 10.0). We also calculated odds ratio.&#x0D; Results. Metabolic syndrome in patients aged 64.2±0.85 (64.9 % females and 35.1 % males, Charleson comorbidity index 4.57±0.12) was represented by type 2 diabetes (100 %), insulin-treated diabetes (2/3 of patients), hypertension (1/3 of patients, stage 3 of NAFLD), obesity (87.5 %), coronary heart disease (90.6 %), steatotic liver disease (34.4 %), non-alcoholic steatohepatitis (49 %) and asymptomatic liver cirrhosis (16,6 %). According to NFS results, stage F3–F4 fibrosis was diagnosed in 52.1 % of patients, F2 fibrosis in 47.9 %; hyperammonemia was found in 91.7 % (up to 111.1±4.86 (101.3–120.7) µmol/l). Hyperammonemia developed from steatosis to non-alcoholic steatohepatitis and liver cirrhosis and correlated with the stage of liver fibrosis, hepatitis activity, and metabolic syndrome key criteria. NFS calculator and hyperammonemia diagnosis made it possible to stratify the stages of non-alcoholic fatty liver disease.

Potential Hepatic Lipid Markers Associated with Nonalcoholic Steatohepatitis and Fibrosis in Morbid Obesity Patients.

This study investigated differences in lipidomic profile features in nonalcoholic steatohepatitis (NASH) between mild and significant liver fibrosis cases among patients with morbid obesity. Wedge liver biopsy was performed during sleeve gastrectomy and significant liver fibrosis was defined as a fibrosis score ≥ 2. We selected patients with NASH with non/mild fibrosis (stage F0-F1; n = 30) and NASH with significant fibrosis (stage F2-F4; n = 30). The results of the liver tissue lipidomic analysis revealed that the fold changes of triglyceride (TG) (52:6); cholesterol ester (CE) (20:1); phosphatidylcholine (PC) (38:0) and (50:8); phosphatidic acid (PA) (40:4); phosphatidylinositol (PI) (49:4); phosphatidylglycerol (PG) (40:2); and sphingomyelin (SM) (35:0) and (37:0) were significantly lower in patients with NASH with F2-F4 than those with NASH with F0-F1 (p < 0.05). However, the fold changes of PC (42:4) were relatively higher in patients with NASH with stage 2-4 fibrosis (p < 0.05). Moreover, predictive models incorporating serum markers levels, ultrasonographic studies, and levels of specific lipid components [PC (42:4) and PG (40:2)] yielded the highest area under receiver operating curve (0.941), suggesting a potential correlation between NASH fibrosis stages and liver lipid accumulation among specific lipid species subclasses. This study demonstrated that the concentrations of particular lipid species in the liver correlate with NASH fibrosis stages and may indicate hepatic steatosis regression or progression in patients with morbid obesity.

Clinical characteristics and management of patients with nonalcoholic steatohepatitis in a real-world setting: analysis of the Ipsos NASH therapy monitor database

BackgroundNonalcoholic steatohepatitis (NASH) is the more severe, inflammatory type of nonalcoholic fatty liver disease (NAFLD). NASH, a leading indication for liver transplantation, is growing in prevalence. The extent of liver fibrosis, ranging from fibrosis stage (FS) of none (F0) to cirrhosis (F4), is a strong predictor of health outcomes. There is little information on patient demographics and clinical characteristics by fibrosis stage and NASH treatment outside of academic medical centers.MethodsWe conducted a cross-sectional observational study using Ipsos’ syndicated NASH Therapy Monitor database, consisting of medical chart audits provided by sampled NASH-treating physicians in the United States in 2016 (n = 174) and 2017 (n = 164). Data was collected online.ResultsOf 2,366 patients reported on by participating physicians and included in the analysis, 68% had FS F0–F2, 21% had bridging fibrosis (F3), and 9% had cirrhosis (F4). Common comorbidities were type 2 diabetes (56%), hyperlipidemia (44%), hypertension (46%), and obesity (42%). Patients with more advanced fibrosis scores (F3-F4) had higher comorbidity rates than patients with F0-F2. Commonly used diagnostic tests included ultrasound (80%), liver biopsy (78%), AST/ALT ratio (43%), NAFLD fibrosis score (25%), transient elastography (23%), NAFLD liver fat score (22%), and Fatty Liver Index (19%). Most commonly prescribed medications were vitamin E (53%), statins (51%), metformin (47%), angiotensin converting enzyme inhibitors (28%), and beta blockers (22%). Medications were commonly prescribed for reasons other than their known effects.ConclusionPhysicians in this study, drawn from a spectrum of practice settings, relied on ultrasound and liver biopsy for diagnosis and vitamin E, statins, and metformin for pharmacological treatment of NASH. These findings imply poor adherence to guidelines in the diagnosis and management of NAFLD and NASH.Plain language summaryNonalcoholic steatohepatitis (NASH) is a liver disease caused by excess fat in the liver which can lead to liver inflammation and scarring (fibrosis), ranging from stage F0 (no scarring) to F4 (advanced scarring). The stage of liver scarring can predict the likelihood of future health problems, including liver failure and liver cancer. However, we do not fully understand how patient characteristics may vary at different stages of liver scarring. We looked at medical information from physicians treating patients diagnosed with NASH to understand how patient characteristics might differ based on the severity of their liver scarring. The majority (68%) of patients were stage F0-F2, with 30% having advanced scarring (F3-F4). In addition to NASH, many patients also had type 2 diabetes, high cholesterol, high blood pressure, and obesity. Patients with more advanced scarring (F3-F4) were more likely to have these diseases than patients with less severe disease (F0-F2). Diagnosis of NASH by participating physicians was based on tests including imaging (ultrasound, CT scan, MRI), liver biopsy, blood tests, and whether patients had other conditions that would put them at risk for NASH. The medications that the doctors prescribed most often to their patients included vitamin E and drugs to treat high cholesterol, high blood pressure, or diabetes. Medications were frequently prescribed for reasons other than their known effects. By understanding how patient characteristics vary by stages of liver scarring and how NASH is currently managed may help guide the evaluation and treatment of NASH when NASH-specific therapies become available.

The combination of the enhanced liver fibrosis and FIB-4 scores to determine significant fibrosis in patients with nonalcoholic fatty liver disease.

The presence of fibrosis in NAFLD is the most significant risk factor for adverse outcomes. We determined the cutoff scores of two non-invasive te sts (NITs) to rule in and rule out significant fibrosis among NAFLD patients. Clinical data and liver biopsies were used for NAFLD patients included in this analysis (2001-2020). The enhanced liver fibrosis (ELF) and FIB-4 NITs were calculated. Liver biopsies were read by a single hematopathologist and scored by the NASH CRN criteria. Significant fibrosis was defined as stage F2-F4. There were 463 NAFLD patients included: 48 ± 13 years old, 31% male, 35% type 2 diabetes; 39% had significant fibrosis; mean ELF score was 9.0 ± 1.2, mean FIB-4 score was 1.22 ± 1.05. Patients with significant fibrosis were older, more commonly male, had lower BMI but more components of metabolic syndrome, higher ELF and FIB-4 (p < 0.0001). The performance of the two NITs in identifying significant fibrosis was: AUC (95% CI)=0.78 (0.74-0.82) for ELF, 0.79 (0.75-0.83) for FIB-4. The combination of ELF score ≥9.8 and FIB-4 ≥ 1.96 returned a positive predictive value of 95% which can reliably rule in significant fibrosis (sensitivity 22%, specificity >99%), while an ELF score ≤7.7 or FIB-4 ≤ 0.30 had a negative predictive value of 95% ruling out significant fibrosis (sensitivity 98%, specificity 22%). The combination of ELF and FIB-4 may provide practitioners with easily obtained information to risk stratify patients with NAFLD who could be referred to specialists or for enrollment in clinical trials.

Extracellular volume fraction obtained by dual-energy CT depicting the etiological differences of liver fibrosis.

To assess etiological differences in extracellular volume fraction (ECV) and evaluate its influence on staging performance. A total of 166 patients with normal liver (n = 14) and chronic liver disease related to viral hepatitis (n = 71), alcohol (n = 44), and nonalcoholic steatohepatitis (NASH) (n = 37) underwent dual-energy CT (DECT) of the liver (5-min equilibrium-phase images) between January 2020 and July 2022. The iodine densities of the parenchyma and aorta were measured and ECV was calculated. Comparisons of ECV between each etiology and METAVIR fibrosis stage were statistically analyzed (p < 0.05). ECV in each etiology and all patients significantly increased with higher fibrosis stage (p < 0.001) and showed a strong or moderate correlation with fibrosis stage (Spearman's ρ; all patients, 0.701; viral hepatitis, 0.638; alcoholic, 0.885; NASH, 0.791). In stages F2-F4, ECV in alcoholic liver disease was significantly larger than those for viral hepatitis and NASH (p < 0.05); however, no significant difference in stage F1 was found among the three etiologies. The cutoff values and areas under the receiver operating characteristic curve (AUC-ROCs) for discriminating fibrosis stage (≥ F1- ≥ F4) were higher for alcohol (cutoff values and AUC-ROC; 20.1% and 0.708 for ≥ F1, 23.8% and 0.990 for ≥ F2, 24.3% and 0.968 for ≥ F3, and 26.6% and 0.961 for ≥ F4, respectively) compared with those for the others. ECV in alcoholic liver disease is higher than that in other etiologies in the advanced stages of fibrosis, and etiological differences in ECV affect the staging performance of fibrosis.

S3260 A Case of Smoldering Multiple Myeloma in a Patient With Gaucher’s Disease Diagnosed on Liver Biopsy

Introduction: We describe a rare case of Gaucher Disease (GD) diagnosed on liver biopsy in a patient with thrombocytopenia and hepatic steatosis with subsequent findings of smoldering multiple myeloma (SMM). Case Description/Methods: 59-year-old male with history of chronic thrombocytopenia presented to the clinic for mild elevation in liver enzymes. At the time of evaluation, patient was asymptomatic and denied any history or risk factors for liver disease. Labs were notable for ALT 53, AST 43, Total bilirubin 0.5, alkaline phosphatase 111, INR 1, platelet 73, and ferritin 1157. Serology for hemochromatosis, autoimmune hepatitis, and viral hepatitis were negative. A CT scan of abdomen revealed hepatic steatosis and splenomegaly. Transient elastography was consistent with stage F3-F4 fibrosis. Subsequent liver biopsy showed features of steatohepatitis and sinusoidal cells with pale-gray striated cytoplasm characteristic of Gaucher’s cells. No evidence of iron overload and cirrhosis on trichome stain. The degree of thrombocytopenia and splenomegaly were out of proportion to the liver disease, prompting further hematological evaluation. Serum protein electrophoresis showed 1300 mg/dL IgA kappa monoclonal protein spike. Bone marrow biopsy revealed hypercellular marrow (50%), Gaucher cells, and plasma cell neoplasm ( >20%) consistent with Type I GD with smoldering multiple myeloma given absence of end organ damage. He was treated conservatively with close monitoring for disease progression. (Figure) Discussion: GD is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme glucocerebrosidase that leads to accumulation of glycophospholipids in the cells of the reticuloendothelial system. It is a multisystem progressive disorder with involvement of bone marrow, liver and spleen. Type 1 GD is the most common non-neuropathic variant in adults with prevalence of 1:1000. Predominant clinical features include thrombocytopenia, hepatosplenomegaly with variable patterns of liver involvement ranging from sub-clinical to decompensated cirrhosis. GD is often associated with laboratory abnormalities including hyperferritinemia or hypergammaglobulinemia that may lead to misdiagnosis with other chronic liver conditions. Additionally, there is an increased risk of multiple myeloma and other gammopathies in type 1 GD. Lack of awareness of early clinical course and its associated conditions can lead to delay in diagnosis and treatment.Figure 1.: (A) There is mild pericellular fibrosis, but no periportal or bridging fibrosis. Mild steatosis supportive of a component of NASH accompany the Gaucher's cells is seen (Trichrome, 100X). (B) Sinusoidal cells are enlarged and show pale-gray striated cytoplasm representing Gaucher's cells whereas the hepatocytes are ballooned. Inflammatory infiltrates are absent(hematoxylin and eosin, 200X). (C) The Gaucher's cell are positive for the histiocytic marker CD68 (Immunohistochemistry, 200X).

Chronic hepatitis C in hemodialysis patients: Prevalence and liver fibrosis impact in the National Center for Renal Health in Peru

Hepatitis C (HCV) remains a serious public health problem in high-risk persons such as patients on chronic hemodialysis. We aimed to estimate the serological prevalence of HCV, the HCV viral load and genotype, and liver fibrosis stage among patients on chronic hemodialysis at the National Renal Health Center in Lima, Peru. From June 2019 to March 2021, all patients who received chronic hemodialysis were invited to participate. Subjects who provided written informed consent were enrolled. Patients with HCV-positive serology underwent determination of HCV viral load. Samples from subjects with detectable viral load, underwent determination of HCV genotype. Then, HCV infected subjects underwent determination of liver fibrosis using transitional elastography (Fibroscan 402): Metavir score: F0–F1: 2.5–7.5 kPa, F2: 7.6–9.5 Kpa, F3: 9.6–12 Kpa, F4 (Cirrhosis): 12.1–75 Kpa. Of the 303 subjects invited to participate, 174 (57.4%) subjects gave their written consent. Mean age was 52 years (range 22–91) and 116 (66.6%) were male. HCV serology was positive in 35.1% of patients (61/174); however, the prevalence of positive serology with detectable viral load was 20.11% (35/174). Genotype 1a was the most prevalent (85%). The majority (83.6%) of subjects with detectable viral load had values lower than 800.000 IU/mL. Twenty-nine of those 35 subjects underwent elastography evaluation, and 13 (44.8%) of them were found to have stage F2–F4 fibrosis. The prevalence of HCV at the largest reference center for hemodialysis in Lima remains high, with GT1a predominance, viral load usually below 800,000 IU/mL and significant liver fibrosis.

1121-P: The Combination of the ELF and FIB-4 Scores Have High Predictive Performance for Significant or Advanced Fibrosis in Patients with NAFLD

Background: Patients with nonalcoholic fatty liver disease (NAFLD) and fibrosis stage ≥ 2 (F2-F4) are at risk for adverse outcomes and considered to be candidates for clinical trials. We aimed to use two NITs combined to rule in and rule out fibrosis stages F2-F4 among patients with NAFLD. Methods: Data were collected from patients with NAFLD diagnosis. The Enhanced Liver Fibrosis (ELF) and FIB-4 NITs were calculated. Liver biopsies were read by 1 hepatologist; scored by NASH CRN criteria. Significant fibrosis stage was ≥ F2, advanced fibrosis was ≥ F3. Results: There were 463 NAFLD patients: 48±13 years old, 31% male, 35% type 2 diabetes, 39% had significant fibrosis and 24% advanced fibrosis. In comparison to those without significant fibrosis, patients with significant fibrosis were older (mean age 52 vs. 45 years) , more commonly male (38% vs. 26%) , and had more components of metabolic syndrome (type 2 diabetes, hypertension, hyperlipidemia) as well as higher ELF and FIB-4 scores; similar trends were observed for patients with vs. without advanced fibrosis (p&amp;lt;0.05) . The performance of the two NITs in identifying NAFLD patients with significant fibrosis was as follows: AUC (95% CI) = 0.78 (0.74-0.82) for ELF, 0.79 (0.75-0.83) for FIB-4; for advanced fibrosis AUC = 0.81 (0.77-0.85) for ELF, 0.83 (0.79 - 0.86) for FIB-4. A combination of ELF score ≥9.8 and FIB-4 ≥1.96 returned PPV of 95% which can reliably rule in significant fibrosis (sensitivity 22%, specificity &amp;gt;99%) , while an ELF score ≥7.7 and FIB-4 ≥0.30 had NPV of 95% which can be used to rule out significant fibrosis (sensitivity 98%, specificity 22%) . For advanced fibrosis, similar rules were ELF ≥9.8 and FIB-4 ≥2.90 (PPV 95%, sensitivity 18%, specificity &amp;gt;99%) to rule in; ELF ≥7.2 and FIB-4 ≥0.74 (NPV 95%, sensitivity 92%, specificity 49%) to rule out. Conclusions: The combination of ELF and FIB-4 can provide an easy algorithm with high predictive value to detect significant or advanced fibrosis in NAFLD. Disclosure Z.Younossi: Consultant; Bristol-Myers Squibb Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Quest Diagnostics, Siemens. S.Felix: None. T.Jeffers: Stock/Shareholder; Neurometrix. E.Younossi: None. F.Nader: None. A.Racila: None. B.P.Lam: Consultant; Intercept Pharmaceuticals, Inc. M.Stepanova: None.

Diagnostic Feasibility of Magnetic Resonance Elastography Radiomics Analysis for the Assessment of Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

The aim of the study was to investigate the diagnostic feasibility of radiomics analysis using magnetic resonance elastography (MRE) to assess hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). One hundred patients with suspected NAFLD were retrospectively enrolled. All patients underwent a liver parenchymal biopsy. Magnetic resonance elastography was performed using a 3.0-T scanner. After multislice segmentation of MRE images, 834 radiomic features were analyzed using a commercial program. Radiologic features, such as median and mean values of the regions of interest and variable clinical features, were analyzed. A random forest regressor was used to extract important radiomic, radiological, and clinical features. A random forest classifier model was trained to use these features to classify the fibrosis stage. The area under the receiver operating characteristic curve was evaluated using a classifier for fibrosis stage diagnosis. The pathological hepatic fibrosis stage was classified as low-grade fibrosis (stages F0-F1, n = 82) or clinically significant fibrosis (stages F2-F4, n = 18). Eight important features were extracted from radiomics analysis, with the 2 most important being wavelet-high high low gray level dependence matrix dependence nonuniformity-normalized and wavelet-high high low gray level dependence matrix dependence entropy. The median value of the multiple small regions of interest was identified as the most important radiologic feature. Platelet count has been identified as an important clinical feature. The area under the receiver operating characteristic curve of the classifier using radiomics was comparable with that of radiologic measures (0.97 ± 0.07 and 0.96 ± 0.06, respectively). Magnetic resonance elastography radiomics analysis provides diagnostic performance comparable with conventional MRE analysis for the assessment of clinically significant hepatic fibrosis in patients with NAFLD.

Cost-effectiveness and potential value of pharmaceutical treatment of nonalcoholic fatty liver disease

Background Nonalcoholic fatty liver disease (NAFLD) is associated with substantial morbidity, mortality, and economic burden. With currently no approved treatment, an effective pharmaceutical intervention for this disease must be both clinically- and cost-effective. Methods A Markov model was constructed to estimate the clinical outcomes, costs, and quality of life impact of a hypothetical pharmaceutical intervention. Lifetime clinical outcomes, life-years, quality-adjusted life-years (QALYs), costs (2020 $US), incremental cost-effectiveness ratios (ICERs), and economically justifiable prices (EJPs) were quantified. Only patients with fibrosis stage F2–F4 were assumed eligible to initiate pharmaceutical treatment. Results Over a mean life expectancy of approximately 21 years in the simulated cohort, drug treatment reduced liver-related mortality by 6.0% (2.7% absolute reduction). Assuming an annual drug cost of $36,000, total discounted medical costs were $574,238 and $120,312 for drug and usual care, respectively, with discounted QALYs estimated to be 9.452 and 9.272 for the two comparators. This yielded an ICER of $2,517,676/QALY gained. The EJP of the drug at an ICER threshold of $150,000/QALY gained was $2,633, a 93% reduction from a base case. Sensitivity analyses suggest that, without a substantial decrease in the drug price, ICERs would exceed $500,000/QALY gained even with the most favorable efficacy assumptions. Conclusions For a pharmaceutical intervention to be considered cost-effective in the NAFLD fibrosis population, the substantial clinical benefit will need to be coupled with a modest annual price. Annual drug costs exceeding $12,000 likely will not provide reasonable value, even with favorable efficacy. More work is needed to estimate the cost-effectiveness of lifestyle modifications.

Development and validation of an ensemble machine learning framework for detection of all-cause advanced hepatic fibrosis: a retrospective cohort study

Cirrhosis is the result of advanced scarring (or fibrosis) of the liver, and is often diagnosed once decompensation with associated complications has occurred. Current non-invasive tests to detect advanced liver fibrosis have limited performance, with many indeterminate classifications. We aimed to identify patients with advanced liver fibrosis of all-causes using machine learning algorithms (MLAs). In this retrospective study of routinely collected laboratory, clinical, and demographic data, we trained six MLAs (support vector machine, random forest classifier, gradient boosting classifier, logistic regression, artificial neural network, and an ensemble of all these algorithms) to detect advanced fibrosis using 1703 liver biopsies from patients seen at the Toronto Liver Clinic (TLC) between Jan 1, 2000, and Dec 20, 2014. Performance was validated using five datasets derived from patient data provided by the TLC (n=104 patients with a biopsy sample taken between March 24, 2014, and Dec 31, 2017) and McGill University Health Centre (MUHC; n=404). Patients with decompensated cirrhosis were excluded. Performance was benchmarked against aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), transient elastography, and an independent panel of five hepatology experts (MB, GS, HK, KP, and RSK). MLA performance was evaluated using the area under the receiver operating characteristic curve (AUROC) and the percentage of determinate classifications. The best MLA was an ensemble algorithm of support vector machine, random forest classifier, gradient boosting classifier, logistic regression, and neural network algorithms, which achieved 100% determinate classifications (95% CI 100·0-100·0), an AUROC score of 0·870 (95% CI 0·797-0·931) on the TLC validation set (fibrosis stages F0 and F1 vs F4), and an AUROC of 0·716 (95% CI 0·664-0·766) on the MUHC validation set (fibrosis stages F0, F1, and F2 vs F3 and F4). The ensemble MLA outperformed all routinely used biomarkers and achieved comparable performance to hepatologists as measured by AUROC and percentage of indeterminate classifications in both the TLC validation dataset (APRI AUROC score 0·719 [95% CI 0·611-0·820], 83·7% determinate [95% CI 76·0-90·4]; FIB-4 AUROC score 0·825 [95% CI 0·730-0·912], 72·1% determinate [95% CI 63·5-80·8]) and the MUHC validation dataset (APRI AUROC score 0·618 [95% CI 0·548-0·691], 75·5% determinate [95% CI 71·5-79·2]; FIB-4 AUROC score 0·717 (95% CI 0·652-0·776), 75·5% determinate [95% CI 0·713-0·797]), and achieving only slightly lower AUROC than transient elastography (0·773 [95% CI 0·699-0·834] vs 0·826 [95% CI 0·758-0·889]). We have shown that an ensemble MLA outperforms non-imaging-based methods in detecting advanced fibrosis across different causes of liver disease. Our MLA was superior to APRI, FIB-4, and NFS with no indeterminate classifications, while achieving performance comparable to an independent panel of experts. MLAs using routinely collected data could identify patients at high-risk of advanced hepatic fibrosis and cirrhosis among patients with chronic liver disease, allowing intervention before onset of decompensation. Toronto General Hospital Foundation.

Stage-dependent expression of fibrogenic markers in alcohol-related liver disease

Alcohol-related liver disease (ALD) is the primary cause of liver-related mortality and morbidity. Liver fibrosis remains the best validated surrogate marker for patient prognosis and is usually assessed in liver biopsies using histochemical stains detecting collagen as the major extracellular matrix (ECM) component in ALD. Distinction of collagen subtypes is of clinical interest, as they, including their cleavage products, have different functions. Changes in production, distribution, and composition of specific collagen subtypes and other extracellular matrix (ECM) components as well as markers for their main cellular source (activated hepatic stellate cells (aHSCs) and myofibroblasts (MFBs)) have not been fully elucidated in ALD. Our aims were to investigate the stage-dependent expression of collagen subtypes and markers for aHSCs and MFBs in ALD. We included liver biopsies from 49 ALD patients with fibrosis stages F0–F4. Biopsies were classified according to the semi-quantitative non‐alcoholic fatty liver disease (NAFLD) activity score (NAS‐CRN). Slides were stained with H&E, Sirius Red, and immunohistochemically with antibodies against collagen types I, III, IV and VI, and aHSC/MFB markers α-SMA, osteonectin, and CD271. Expression was examined using automated digital imaging analysis (DIA), by calculating the positive area relative to the total liver biopsy area (proportionate area). Likewise, collagen-proportionate area (CPA) was assessed using DIA of Sirius Red stained slides. CPA correlated highly with fibrosis stage (rs = 0.88, P = 5.9E-17) and moderately with activity score (rs = 0.58, P = 0.00001). Collagen type I proportionate area increased from 0.3% (± 0.1) at F1 to 10.2% (± 1.6) at F4 (P < 0.001). Collagen type III proportionate area increased from 0.6% (± 0.2) at F0 to 11.9% (± 1.7) at F4 (P < 0.001). Collagen type IV proportionate area increased from 17.0% (± 2.5) at F0 to 27.0% (± 3.9) at F4 (P = 0.079). Collagen type VI proportionate area increased from 14.8% (± 1.4) at F0 to 31.4% (± 2.4) at F4 (P < 0.001). Proportionate areas for α-SMA and CD271 increased from 10.7% (± 1.6) and 6.5% (± 1.0) at F0 to 29.5% (± 3.4) and 22.1% (± 2.2) at F4 (P < 0.001). Proportionate area for osteonectin increased from 1.4–1.8% at F0–F2 to 3.1% (± 0.5) at F3 and 3.2% (± 0.6) at F4 (P < 0.05). In conclusion, our data indicate that collagen types I, III and VI and the aHSC/MFB markers α-SMA and CD271 show a stage-dependent increase in ALD. In early ALD, collagen types IV and VI are important components of the perisinusoidal and pericellular fibrosis. Immunohistochemistry is a valuable additional tool to characterize the ECM changes in ALD. Further research is needed to explore the functional role of CD271 and the stage-dependent expression of other collagen subtypes in ALD.

Клиническая характеристика и частота фиброза печени у больных с хроническим вирусным гепатитом C или с инвазией Opisthorchis felineus

Study Objective: To study the clinical symptoms and prevalence of hepatic fibrosis in patients with chronic virus hepatitis C (CVHC), genotype 1, or Opisthorchis felineus invasion. Study Design: Cross-sectional comparative study of random groups of inpatient or outpatient patients. Material and Methods. We examined 297 patients with CVHC, genotype 1, and 214 patients with chronic opisthorchiasis. CVHC was diagnosed in accordance with the guidelines of the European Association for the Study of the Liver. Opisthorchiasis was diagnosed when eggs or mature parasites were found in duodenal content and/or faeces of the patient. Hepatic fibrosis was assessed with shear wave elastography using the METAVIR scale. Study Results. We have found differences in clinical symptoms: prevailing cytolytic syndrome (82.8% vs 9.8%; p &lt; 0.001), hepatomegaly (20.9% vs 10.3%; p = 0.002), and stage F3-F4 hepatic fibrosis (METAVIR) (20.5% vs 8.4%; p &lt; 0.001) in patients with CVHC and higher prevalence of cholestatic syndrome (14.5% vs 0.3%; p &lt; 0.001), chronic cholecystitis (18.2% vs 8.8%; р = 0.002), gallstones (4.7% vs 0.7%; р = 0.008) in patients with opisthorchiasis. Conclusion. Highly significant is frequently diagnosed F2, F3 and F4 hepatic fibrosis (METAVIR) in patients with opisthorchiasis (20.5%). These evidences point out that O. felineus invasion is a hepatic pre-cancer condition. Taking into account the high prevalence of O. felineus invasion in some regions of Siberia, the available data show that opisthorchiasis is a relevant medical and social issue which must be addressed. Keywords: virus hepatitis С, Opisthorchis felineus, hepatic fibrosis.

Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States.

One fifth of patients with nonalcoholic fatty liver disease (NAFLD) may progress to nonalcoholic steatohepatitis (NASH), which can increase the risk of cirrhosis, cancer, and death. To date, reported predictors of NASH progression have been heterogeneous.We identified determinants of fibrosis progression in patients with NASH in the United States using physician-reported data from the real-world Global Assessment of the Impact of NASH (GAIN) study, including demographics and clinical characteristics, NASH diagnostic information, fibrosis stage, comorbidities, and treatment. We developed a logistic regression model to assess the likelihood of fibrosis progression since diagnosis, controlling for sociodemographic and clinical variables. An iterative nested model selection approach using likelihood ratio test determined the final model.A total of 989 patients from the GAIN US cohort were included; 46% were women, 58% had biopsy-proven NAFLD, and 74% had fibrosis stage F0–F2 at diagnosis. The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, Vitamin E, and liver transplant proposed at diagnosis. Odds of progression were 17% higher (odds ratio, 1.17 [95% CI: 1.11–1.23]; P < .001) with each year since NASH diagnosis, 41% lower (0.59 [0.38–0.90]; P = .016) for women than men, 131% higher (2.31 [1.30–4.03]; P = .004) for smokers versus non-smokers, and 89% higher (1.89 [1.26–2.86]; P = .002) with obesity. Odds of progression were also higher with part-time, retired, unemployed, and unable to work due to NASH status versus full-time employment, and when a liver transplant was proposed at diagnosis.Disease duration and severity, obesity, smoking, and lack of full-time employment were significant determinants of fibrosis progression. These findings can support clinical and health-policy decisions to improve NASH management in the US.