Nonalcoholic Steatohepatitis Cirrhosis Research Articles

Non-invasive biomarkers prognostic of decompensation events in NASH cirrhosis: a systematic literature review.

Liver cirrhosis due to nonalcoholic steatohepatitis (NASH) is a life-threatening condition with increasing incidence world-wide. Although its symptoms are unspecific, it can lead to decompensation events such as ascites, hepatic encephalopathy, variceal hemorrhage, and hepatocellular carcinoma (HCC). In addition, an increased risk for cardiovascular events has been demonstrated in patients with NASH. Pharmacological treatments for NASH cirrhosis are not yet available, one of the reasons being the lack in surrogate endpoints available in clinical trials of NASH cirrhosis. The feasibility of non-invasive prognostic biomarkers makes them interesting candidates as possible surrogate endpoints if their change following treatment would result in better outcomes for patients in future clinical trials of NASH cirrhosis. In this systematic literature review, a summary of the available literature on the prognostic performance of non-invasive biomarkers in terms of cardiovascular events, liver-related events, and mortality is outlined. Due to the scarcity of data specific for NASH cirrhosis, this review includes studies on NAFLD whose evaluation focuses on cirrhosis. Our search strategy identified the following non-invasive biomarkers with prognostic value in studies of NASH patients: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), enhanced liver fibrosis (ELF™), BARD (BMI, AST/ALT (alanine aminotransferase) ratio, diabetes), Hepamet Fibrosis Score (HFS), liver enzymes (AST + ALT), alpha-fetoprotein, platelet count, neutrophil to lymphocyte ratio (NLR), Lysyl oxidase-like (LOXL) 2, miR-122, liver stiffness, MEFIB (liver stiffness measured with magnetic resonance elastography (MRE) + FIB-4), and PNPLA3 GG genotype. The aim of the present systematic literature review is to provide the reader with a summary of the non-invasive biomarkers with prognostic value in NASH cirrhosis and give an evaluation of their utility as treatment monitoring biomarkers in future clinical trials.

High Concordance Between Nonalcoholic Fatty Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease in the TARGET-NASH Real-World Cohort.

This study investigates the applicability of the new metabolic dysfunction-associated steatotic liver disease (MASLD) nomenclature to the real-world TARGET-NASH US adult cohort. The new MASLD/metabolic steatohepatitis nomenclature was applied to patients enrolled with pragmatic diagnoses of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), and NASH cirrhosis and concordance were determined between the definitions. Approximately 99% of TARGET-NASH participants met the new MASLD diagnostic criteria. Approximately 1,484/1,541 (96.3%, kappa 0.974) nonalcoholic fatty liver patients (metabolic dysfunction-associated steatotic liver), 2,195/2,201 (99.7%, kappa 0.998) NASH patients (metabolic steatohepatitis), and 1,999/2,003 (99.8%, kappa 0.999) NASH cirrhosis patients met the new criteria. The new MASLD nomenclature is highly concordant with the previous TARGET-NASH pragmatic definitions.

Impact of Cirrhosis Etiology on the Risk for Venous Thromboembolism.

Cirrhosis is associated with an increased risk for both bleeding and venous thromboembolic (VTE) complications. The data regarding the impact of etiology of cirrhosis on VTE risk is poorly understood. In this retrospective observational analysis of the US Nationwide readmissions database 2019, we identified hospitalized patients who had cirrhosis from alcohol, viral, or nonalcoholic steatohepatitis (NASH) etiologies. We identified patients who had acute VTE, chronic/history of VTE, and portal venous thrombosis (PVT). Overall VTE risk was defined as the composite of acute and chronic VTE or PVT. The impact of etiology of cirrhosis on the crude and risk adjusted rates of VTE and PVT was studied. Of 432,383 patients with cirrhosis, 41.4% patients had NASH-cirrhosis, 39.7% had alcohol-related cirrhosis, and 18.9% had viral cirrhosis. The overall VTE rate was highest in patients with NASH cirrhosis (10.8%) followed by viral cirrhosis (9.7%) and alcohol-related cirrhosis (7.5%; P < 0.001). Similar results were observed for acute and chronic VTE. After risk adjustment, patients with NASH (OR 1.48 95% CI 1.42-1.54) and viral cirrhosis (OR 1.22 95% CI 1.17-1.29) had significantly higher overall VTE risk compared with alcohol-related cirrhosis. When separately evaluated, the adjusted risk for acute and chronic VTE was similar between patients with alcohol-related and viral cirrhosis but higher with NASH cirrhosis. PVT rate was highest with viral cirrhosis (4.3%) followed by NASH (2.8%) and alcohol-related cirrhosis (2.4%; P < 0.001). The adjusted risk of PVT was higher with viral (OR 1.61 95% CI 1.50-1.72) and NASH cirrhosis (OR 1.41 95% CI 1.31-1.52). NASH cirrhosis was associated with a higher VTE risk compared with alcohol-related and viral etiologies. As NASH cirrhosis increases in prevalence as the major etiology of cirrhosis, it is important to understand the increased VTE risk associated with this condition to improve management strategies and patient outcomes.

Disparities in Liver Transplantation for Nonalcoholic Steatohepatitis in Women.

Nonalcoholic steatohepatitis (NASH) is the fastest-growing indication for liver transplantation (LT). Sex disparities among patients with cirrhosis on the LT waitlist are well known. We wanted to understand these disparities further in women with end-stage liver disease patients listed for NASH cirrhosis in a contemporary cohort. We used data from the Scientific Registry of Transplant Recipients to assess sex racial, and ethnic differences in NASH patients listed for LT. Adults transplanted from August 1997 to June 2021 were included. Inferential statistics were used to evaluate differences with univariate and multivariate comparisons, including competitive risk analysis. During the study time period, we evaluated 12 844 LT for NASH cirrhosis. Women were transplanted at a lower rate (46.5% versus 53.5%; P < 0.001) and higher model for end-stage liver disease (MELD) (23.8 versus 22.6; P < 0.001) than men. Non-White women were transplanted at a higher MELD (26.1 versus 23.1; P < 0.001) than White women and non-White male patients (26.1 versus 24.8; P < 0.001). Graft and patient survivals were significantly different (P < 0.001) between non-White women and White women and men (White and non-White). Evaluation of LT candidates in the United States demonstrates women with NASH cirrhosis have a higher MELD than men at LT. Additional disparities exist among non-White women with NASH as they have higher MELD and creatinine at LT compared with White women. After LT, non-White women have worse graft and patient survival compared with men or White women. These data indicate that non-White women with NASH are the most vulnerable on the LT waitlist.

Chronic Liver Disease and Promising Therapeutic Strategy: A Concise Review

Abstract Background: Chronic liver dysfunction (CLD) is a significant global health issue; alcohol use, obesity, drugs, and antibiotic and viral infections contribute to its development. However, changes in gut microbiota composition, primarily as people grow older, can also play a role in initiating and progressing liver dysfunction. Purpose: This review summarizes the altered gut microbiota–mediated chronic liver dysfunction and promising therapeutic strategies for NAFLD, ALD, NASH, and liver cirrhosis. Discussion on the chronic liver disease and its therapeutic aspects: The gut microbiota influences physiological processes, including immune system regulation, by promoting the production of pro-inflammatory markers and elevating the expression of toll-like receptors (TLRs) on hepatocytes, metabolisms of bile acids and choline, alteration in saturated aliphatic organic acid (SCFA) production, and food absorption. These alterations increase intestinal permeability, chronic inflammation, and liver dysfunction. Dysbiosis triggers inflammatory pathways, oxidative stress, and the production of toxic compounds that damage liver cells and promote chronic liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis. Age-related changes in gut motility, secretory function, and immunological function can further decline beneficial bacterial diversity and abundance and shifts in pathogenic bacterial species’ relative abundance. Conclusion: Dysbiosis resulting from these age-related changes may contribute to the development of CLD. Numerous therapeutic approaches are available to restore the altered gut microbiota and reduce the risk of chronic liver dysfunction.

Donor Diabetes and Steatosis Affects Recipient Survival Following Liver Transplantation Based on Etiology of Liver Cirrhosis.

Liver transplantation (LT) offers patients with decompensated cirrhosis the best chance at long-term survival. With the rising prevalence of diabetes, further clarity is needed on the impact of receiving a liver allograft from a donor with diabetes on post-LT outcomes. This study aims to evaluate the impact of donor diabetes on clinical outcomes after LT. This is a retrospective analysis of the United Network for Organ Sharing registry data of LT recipients from January 1, 2000, to December 31, 2021. Outcomes analysis was performed using Cox proportional model for all-cause mortality and graft failure. Confounding was reduced by coarsened exact matching causal inference analysis. Of 66 960 donors identified, 7178 (10.7%) had diabetes. Trend analysis revealed a longitudinal increase in the prevalence of donor diabetes ( P < 0.001). Importantly, donor diabetes was associated with increased all-cause mortality (hazard ratio [HR]: 1.13; 95% confidence interval [CI], 1.07-1.19; P < 0.001) and graft failure (HR: 1.16; 95% CI, 1.11-1.22; P < 0.001). Receiving donor organ with diabetes reduced graft survival in patients who received LT for nonalcoholic steatohepatitis cirrhosis (HR: 1.26; 95% CI, 1.13-1.41; P < 0.001) but not other etiologies of cirrhosis. Donor diabetes was associated with worse outcomes post-LT, particularly in patients receiving LT for nonalcoholic steatohepatitis cirrhosis. Future studies are needed to better understand the mechanism underlying this association to develop better risk stratification and clinical practice to improve the outcomes of the transplanted patients.

Increasing Prevalence and High Survival Rate of Liver Transplanted Patients with NASH and PSC Cirrhosis.

Epidemiological studies on liver transplant (LT) patients can provide valuable information about the etiology and trends of cirrhosis. The present study aimed to investigate the prevalence and trend of different etiologies and survival rates of LT patients at the Namazi Transplant Center in Shiraz, Iran, between 2001 and 2018. In this single-center, retrospective cohort study, the demographic and clinical characteristics of 3751 patients who underwent LT and met the study inclusion criteria, including age, gender, blood group, body mass index, model for end-stage liver disease (MELD) score, cause of cirrhosis, and diabetes, were extracted from patients' physical or electronic medical records between 2001 and 2018. The MELD scores of LT patients with primary sclerosing cholangitis (PSC), hepatitis B virus (HBV), and non-alcoholic steatohepatitis (NASH) cirrhosis significantly decreased over the study period (P<0.001). Among the LT patients, HBV infection had the highest frequency (21.09%), followed by cryptogenic (17.33%) and PSC (17.22%). The proportion of patients with PSC and NASH (both P<0.001) cirrhosis was significantly increased, so that PSC cirrhosis (2016: 19.4%, 2018: 18.8%) surpassed HBV (2016: 18.4%, 2018: 13.5%), autoimmune hepatitis (2016: 11.7%, 2018: 12.7%), and cryptogenic cirrhosis (2016: 16.1%, 2018:14%) as the leading indication for LT from 2016 to the end of the study period. Fortunately, these patients had a better survival rate than other common diseases (HR: 0.53, CI: 0.43‒0.66; P<0.001). The proportion of NASH and PSC cirrhosis significantly increased during the 18 years of study. However, these patients had an improved survival rate. Therefore, health organizations should pay more attention to non-communicable diseases, especially fatty liver disease and cholangitis.

Therapeutic targets for metabolic dysfunction-associated steatotic liver disease and their roles in hepatocellular carcinoma

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver diseases. Over time, there has been a significant increase in the prevalence of MASLD. It has become one of the leading causes of hepatocellular carcinoma (HCC) in the United States, France, and the United Kingdom. Globally, the incidence of HCC related to MASLD may further increase with the growing prevalence of obesity. Non-alcoholic steatohepatitis (NASH) is an important stage of MASLD, which is more likely to cause cirrhosis and even HCC. And patients with NASH cirrhosis have a much higher incidence of hepatocellular cancer than patients with non-cirrhotic MASLD. As a result, it is critical to investigate the targets of MASLD therapy in HCC. This article reviews therapeutic targets of MASLD, such as farnesoid X receptor (FXR), peroxisome proliferator activated receptor (PPAR), fibroblast growth factor-21 (FGF-21), etc., and introduces the drugs related to these targets and their mechanisms of action in HCC. In addition, the developmental process and pathogenesis of MASLD, as well as risk factors for HCC development, are discussed. These are of great significance for the prevention and treatment of HCC.

Case-control analysis of venous thromboembolism risk in non-alcoholic steatohepatitis diagnosed by transient elastography.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Studies have shown a strong association between non-alcoholic steatohepatitis (NASH) cirrhosis and portal vein thrombosis. Specifically, there is paucity of data on the association of NASH and venous thromboembolism (VTE), with one such study predicting a 2.5-fold increased risk for VTE compared to other liver diseases in hospitalized patients. The mechanism is believed to be a hepatocellular injury, which causes a chronic inflammatory state leading to the unregulated activation of procoagulant factors. There has been no prior analysis of the degree of steatosis and fibrosis (measured using transient elastography, commonly known as FibroScan) in NASH and its association with VTE. To examine the association between the degree of hepatic steatosis and fibrosis, quantified by transient elastography, and the incidence of VTE in patients with NASH. In our case-control study, we included patients with a documented diagnosis of NASH. We excluded patients with inherited thrombophilia, hemoglobinopathy, malignancy, alcohol use disorder, autoimmune hepatitis, and primary biliary cirrhosis. The collected data included age, demographics, tobacco use, recreational drug use, medical history, and vibration controlled transient elastography scores. VTE-specific data included the location, type of anticoagulant, need for hospital stay, and history of VTE recurrence. Steatosis was categorized as S0-S1 (mild) and S2-S3 (moderate to severe) based on the controlled attenuation parameter score. Fibrosis was classified based on the kilopascal score and graded as F0-F1 (Metavir stage), F2, F3, and F4 (cirrhosis). χ2 and Mann-Whitney U tests were used for the qualitative and quantitative variable analyses, respectively. Furthermore, we performed a logistic regression using VTE as the dependent variable. A total of 415 patients were analyzed, and 386 met the inclusion criteria. 51 and 335 patients were included in the VTE and non-VTE groups, respectively. Patients with VTE had a mean age of 60.63 years compared to 55.22 years in the non-VTE group (P < 0.014). Patients with VTE had a higher body mass index (31.14 kg/m² vs 29.30 kg/m²) and a higher prevalence of diabetes mellitus (29.4% vs 13.1%). The history of NASH was significantly higher in the VTE group (45.1% vs 30.4%, P < 0.037). Furthermore, moderate-to-severe steatosis was significantly higher in the VTE group (66.7% vs 47.2%, P < 0.009). Similarly, the F2-F4 fibrosis grade had a prevalence of 58.8% in the VTE group compared to 38.5% in the non-VTE group (P < 0.006). On logistic regression, using VTE as a dependent variable, diabetes mellitus had an odds ratio (OR) =1.702 (P < 0.015), and F2-F4 fibrosis grade had an OR = 1.5 (P < 0.033). Our analysis shows that NASH is an independent risk factor for VTE, especially deep vein thrombosis. There was a statistically significant association between the incidence of VTE, moderate-to-severe steatosis, and fibrosis. All hospitalized patients should be considered for medical thromboprophylaxis, particularly those with NASH.

From Non-Alcoholic Steatohepatitis (NASH) to Hepatocellular Carcinoma (HCC): Epidemiology, Incidence, Predictions, Risk Factors, and Prevention.

Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. The incidence of NASH is projected to increase by up to 56% over the next 10 years. There is growing epidemiological evidence that NAFLD has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of HCC varies between patients with NASH cirrhosis and patients with noncirrhotic NAFLD. In this review, NAFLD/NASH-associated HCC will be described, including its epidemiology, risk factors promoting hepatocarcinogenesis, and management of HCC in patients with obesity and associated metabolic comorbidities, including preventive strategies and therapeutic approaches to address this growing problem.

Abstract 14822: Portopulmonary Hypertension Unveiled: Effects of Transjugular Intrahepatic Portopulmonary Shunt Placement

Introduction: Transjugular intrahepatic portosystemic shunts (TIPS) treat portal hypertension by connecting the portal vein to the hepatic vein in the liver. The resultant shunting of portal venous flow to the systemic circulation helps reduce the portosystemic gradient and is used to treat complications of portal hypertension. Right heart failure and the development of pulmonary hypertension after TIPS are known complications; however, portopulmonary hypertension (POPH) is rare. Description of Case: A 61-year-old male presents to the clinic for six months of exertional dyspnea, weight gain, and lower extremity edema. He has a history of coronary artery disease and nonalcoholic steatohepatitis cirrhosis, with TIPS placement four years prior for esophageal variceal bleeding. An echocardiogram revealed right ventricular (RV) dilatation with moderately reduced function, a flattened left ventricular septum, and an estimated pulmonary artery systolic pressure of 91 mmHg. An echocardiogram and right heart catheterization (RHC) performed before his TIPS showed normal RV function and pulmonary artery pressures (PAP). Decision Making: The patient was promptly started on furosemide and spironolactone, and after adequate diuresis, a repeat RHC was obtained, which showed significantly elevated PAP, and normal left-sided filling pressures and cardiac output. Other causes of pulmonary hypertension were ruled out, and the patient was started on tadalafil monotherapy for severe POPH, with significant improvement in his PAP (Table 1). Conclusion: POPH after TIPS is a rare complication that should be suspected in patients presenting with signs of right-sided volume overload. The mechanism by which TIPS leads to POPH is not entirely understood. The degree of RV dysfunction correlates with mortality, and prompt treatment is warranted.

OR24-01 Characteristics Of Patients With Type 1 Or 2 Diabetes And Non-alcoholic Fatty Liver Disease: A Retrospective Cohort Study

Abstract Disclosure: A. Liu: None. S. Brar: None. K. McKenzie: None. M. Beaton: Advisory Board Member; Self; Abbvie, Takeda, Janssen Research &amp; Development Company, Pfizer, Inc., Novo Nordisk. Research Investigator; Self; Abbvie, Novo Nordisk, Takeda, Boehringer Ingelheim, Janssen Research &amp; Development Company, Pfizer, Inc., AstraZeneca. H. Lapier: None. I. Hramiak: None. M. Brahmania: None. T. Spaic: Advisory Board Member; Self; Sanofi. Research Investigator; Self; Novo Nordisk, Lilly USA, LLC. Speaker; Self; Sanofi. K.K. Clemens: None. Background: Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis to non-alcoholic steatohepatitis (NASH) cirrhosis, which is the second leading cause of liver transplant in the United States. Though the association between T2D and NAFLD is well-known, there is a paucity of data on patients with T1D who live with this condition. We aimed to describe the characteristics of adult patients with NAFLD and T1D. Methods: We conducted a retrospective cohort study of patients 18 years old at a single academic center with gastroenterologist diagnosed NAFLD and T1D between 2010 and 2022. As a comparator, we also included adults with T2D and NAFLD. We used descriptive statistics to summarize their characteristics and compared data between groups. Results: There were 11 patients with T1D and NAFLD (54% female, mean age 37±12 years) and 166 with T2D and NAFLD (57% female, mean age 64±11 years). Mean diabetes duration before NAFLD diagnosis was 16.6±13 years in T1D and 16.6 ±8 years in T2D patients. The most common comorbidities were dyslipidemia (T1D=73%, T2D=79%) and hypertension (T1D=55%, T2D=78%). None with T1D had macrovascular complications. In those with T2D, 36 (22%) had macrovascular complications. Microvascular complications were present in 6 (55%) with T1D and in 83 (50%) T2D patients. At the time of their NAFLD diagnosis, mean BMI of those with T1D was 31.7±5.8 kg/m2 vs 35.8±10 kg/m2 in T2D patients. Mean HbA1c was 9.1±1.7% vs 7±1.2% in T1D and T2D patients respectively. In patients with T1D vs T2D, respective mean triglycerides were 3.7±4.7 vs 2±1.0 (&amp;lt;/=1.7) mmol/L, LDL 2.6±0.9 vs 2±0.9 (&amp;lt;/=2.0) mmol/L, and HDL 1.1±0.4 vs 1.2±0.4 (&amp;lt;/=1.3) mmol/L. In patients with T1D and T2D, liver enzymes were on average elevated with respective ALT 49.5±58.1 and 46.3±40.2 (&amp;lt;/=33) U/L, AST 42.3±49.4 SD and 41.6±28.8 (&amp;lt;/=32) U/L, ALP 115.1±39.9 and 92.9±42.3 (35-104) U/L. One patient with T1D (9%) and 78 (47%) patients with T2D developed cirrhosis. Conclusion: Patients with T1D and T2D with NAFLD appeared to develop disease at similar diabetes duration. Relative to those with T2D, patients with T1D had suboptimal glycemic control. Patients with T1D and T2D demonstrated metabolic syndrome with obesity, high triglycerides and low HDL. None of the patients with T1D had macrovascular complications, however microvascular complications were present in approximately half of patients with T1D and T2D. We have demonstrated that NAFLD is present in patients with T1D who may have features of metabolic syndrome and suboptimal glycemic control. Further studies are needed to explore the characteristics of patients with T1D who are at risk of developing NAFLD. Presentation: Saturday, June 17, 2023

Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver-targeted thyroid hormone receptor-β selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo. To present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO-NAFLD-1 [NCT04197479], MAESTRO-NAFLD-OLE [NCT04951219], MAESTRO-NASH [NCT03900429], MAESTRO-NASH-OUTCOMES [NCT05500222]). MAESTRO-NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy-confirmed at-risk NASH. Patients are randomised to a once-daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO-NAFLD-1 is a 52-week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non-invasive testing); ~700 patients from MAESTRO-NAFLD-1 are enrolled in MAESTRO-NAFLD-OLE, a 52-week active treatment extension to further evaluate safety. MAESTRO-NASH-OUTCOMES is enrolling 700 adults with well-compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non-invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient-reported outcomes. The MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long-term clinical liver-related outcomes in MAESTRO-NASH (month 54) and MAESTRO-NASH-OUTCOMES (time to event).

Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.

Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFβ1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP-degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFβ1 levels were highly correlated with PDE4 expression. TGFβ1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC-specific agonist decreased TGFβ1-mediated cell migration in vitro. In vivo, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis-related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.

Global Epidemiology of Cirrhosis: Changing Etiological Basis and Comparable Burden of Nonalcoholic Steatohepatitis between Males and Females

Introduction: The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019. Methods: We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology. Results: In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8). Conclusion: The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males.

Estimating the cost of illness of non-alcoholic fatty liver disease in Bangladesh.

Non-alcoholic fatty liver disease (NAFLD) is a growing concern, affecting about 45 million of the Bangladeshi population. There is a paucity of research on the economic burden of NAFLD. The study aims to estimate the cost of illness of NAFLD in Bangladesh. In this prospective, cross-sectional study, a total of 250 patients of NAFLD, non-alcoholic steatohepatitis (NASH), and NASH cirrhosis were included from public and private hospitals. Costs of hospitalization, physician fees, investigation costs, expenditures on medical procedures, drugs; and nonmedical costs such as transport expenses and other informal payments (tips) were estimated. The overall cost per patient per evaluation was (16.90-46 942.00) USD. The cost in public and private hospitals was 384.76 and 1146.93 USD, respectively. The cost per patient of NAFLD was 157.91 (16.90-955.08) USD, and for NASH cirrhosis was 1783.80 (422.48-46 942) USD. The cost of illness increased to USD 281.18 for diabetics and 254.52 USD for hypertensive. If all the NAFLD patients are evaluated once in healthcare settings, the projected cost will be 7.11 billion USD. In NAFLD, cost for investigations, medicines, transportation, and consultation of physicians was 49.08%, 32.41%, 11.11%, and 6.67%, respectively. NAFLD is causing a huge economic burden to the healthcare system. The cost of illness is increased with NASH cirrhosis. Overall, this study provides valuable insights into the economic burden of NAFLD in Bangladesh and emphasizes the several ways of intervention to reduce the cost by preventive measures and accessible healthcare for affected individuals.

Fibrosis-4 index is associated with the risk of hepatocellular carcinoma in patients with cirrhosis and nonalcoholic steatohepatitis.

Identification of high-risk patients for hepatocellular carcinoma (HCC) is essential for long term monitoring of nonalcoholic steatohepatitis (NASH) cirrhosis progression. We sought to evaluate the association between Fibrosis-4 (FIB-4) index and incidence of HCC risk among patients with NASH cirrhosis. We conducted a retrospective cohort study of adult patients with NASH cirrhosis (n= 1,338) who were evaluated in a single medical center between 2005 and 2015. Those who developed HCC were identified through electronic medical records using International Classification of Diseases (ICD) 9 and 10 codes until the end of September 2021. During a median follow-up time of 3.7 years, 157 (11.7%) patients with NASH cirrhosis developed HCC. At index visit, the study population had a median age 57 years, 43% males, 78.8% White, and mean FIB-4 index 4.2. The final multivariable Cox regression model revealed that male sex, BMI 25-29.9 kg/m2, and hypertension were independent factors associated with development of HCC in patients with NASH cirrhosis. Compared to patients with FIB-4 ¾ 1.45, patients with FIB-4 between 1.45-3.25 had a similar hazard of HCC (Hazard Ratio [HR] 1.12, 95% CI: 0.67-1.86, p=0.670), whereas patients with FIB-4 >3.25 had a 1.93 (95% CI: 1.22-3.05, p=0.005) increased hazard of HCC. FIB-4 > 3.25 was an independent factor associated with increased HCC risk among NASH cirrhosis patients. FIB-4 index is a promising tool for determining high-risk patients and may be used in routine clinical practice to monitor risk of HCC in patients with NASH cirrhosis.

Hepatic venous pressure gradient and rebleeding risk of patients with nonalcoholic steatohepatitis cirrhosis after variceal bleeding.

Hepatic venous pressure gradient (HVPG) has a strong predictive value for variceal rebleeding in cirrhotic patients, but the accuracy of HVPG may be compromised in nonalcoholic steatohepatitis (NASH) cirrhosis. This study aimed to evaluate the accuracy of HVPG and portal pressure gradient (PPG) for predicting rebleeding in NASH cirrhosis after acute variceal bleeding. Thirty-eight NASH cirrhosis patients and 82 hepatitis B virus (HBV) cirrhosis patients with acute variceal bleeding were included in this study. All patients recived transjugular intrahepatic portalsystemic shunt (TIPS). The prognostic value of HVPG and PPG for variceal rebleeding was evaluated. Compared with HBV cirrhosis, NASH cirrhosis demonstrated a lower HVPG (15.3 ± 3.8 vs. 18.0 ± 4.8; p = 0.003) and lower PPG (18.0 ± 3.7 vs. 20.0 ± 3.4; p = 0.005). HVPG (AUC = 0.82; p = 0.002) and PPG (AUC = 0.72; p = 0.027) had promising prognostic value among NASH cirrhosis patients. The optimal threshold of HVPG and PPG for predicting rebleeding in NASH cirrhosis was 17 mmHg and 20 mmHg. At multivariate analysis, HVPG ≥17 mmHg was a significant predictor of variceal rebleeding (HR 9.40; 95% CI 1.85-47.70; p = 0.007). In the patients with cirrhosis and vairceal bleeding, the levels of HVPG and PPG were found to be low in NASH cirrhosis than HBV cirrhosis. However, the prevalence of rebleeding was similar between two groups. HVPG measurement is still an accurate way to assess the risk of variceal rebleeding in NASH cirrhosis.

Impact of Liver Transplantation on Adipose Tissue Compartments and Its Association With Metabolic Sequela.

Loss of skeletal muscle can be accompanied by an increase in adipose tissue leading to sarcopenic obesity. There are limited data on how liver transplantation (LT) might impact adipose tissue compartments, particularly among patients with metabolically active disease, such as nonalcoholic steatohepatitis (NASH) and subsequent metabolic sequela. Skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured using cross-sectional imaging performed in 190 patients pre-LT, 6 mo post-LT and 12 mo post-LT. Changes in adipose tissue and their impact on metabolic diseases were determined in patients transplanted for NASH versus non-NASH. Skeletal muscle, VAT, and SAT were similar in patients with NASH and non-NASH pre-LT despite a higher burden of metabolic diseases in patients with NASH. Following LT, no significant differences between skeletal muscle and SAT were observed in the entire cohort and among patients with NASH (versus non-NASH). LT recipients with the highest muscle mass pre-LT were at the greatest risk for muscle loss post-LT. A time-dependent increase in VAT was noted post-LT, which was more robust among patients with a history of NASH cirrhosis. In adjusted multivariate analysis, NASH versus non-NASH was a strong predictor of post-LT increase in VAT (β-coefficient 3.00, P = 0.04). Pre-LT VAT was an independent predictor of post-LT serum triglycerides (β-coefficient 5.49 ± 2.78, P = 0.05) and low-density lipoprotein cholesterol (β-coefficient 1.80 ± 0.75, P = 0.02). A trend between pre-LT VAT and diabetes was noted but did not reach statistical significance. VAT but not SAT increases rapidly after LT, especially among patients transplanted for NASH cirrhosis and predicts future metabolic burden.

Natural history of NASH cirrhosis in liver transplant waitlist registrants

Non-alcoholic steatohepatitis (NASH) cirrhosis is rapidly growing as an indication for liver transplant(ation) (LT). However, the natural history of NASH cirrhosis among LT waitlist registrants has not been established. The present study aimed to define the natural history of NASH cirrhosis using the Scientific Registry of Transplant Recipients database. The study cohort comprised patients registered on the LT waitlist between 1/1/2016 to 12/31/2021. The primary outcomes included probability of LT and waitlist mortality, comparing NASH (n= 8,120) vs. non-NASH (n= 21,409) cirrhosis. Patients with NASH cirrhosis were listed with lower model for end-stage liver disease (MELD) scores despite bearing a greater burden of portal hypertension, especially at lower MELD scores. The overall transplant probability in LT waitlist registrants with NASH [vs. non-NASH] cirrhosis was significantly lower at 90 days (HR 0.873, p <0.001) and 1 year (HR 0.867, p <0.001); this was even more pronounced in patients with MELD scores >30 (HR 0.705at 90 days and HR 0.672at 1 year, p <0.001 for both). Serum creatinine was the key contributor to MELD score increases leading to LT among LT waitlist registrants with NASH cirrhosis, while bilirubin was in patients with non-NASH cirrhosis. Finally, waitlist mortality at 90 days (HR 1.15, p <0.001) and 1 year (1.25, p <0.001) was significantly higher in patients with NASH cirrhosis compared to those with non-NASH cirrhosis. These differences were more pronounced in patients with lower MELD scores at the time of LT waitlist registration. LT waitlist registrants with NASH cirrhosis are less likely to receive a transplant compared to patients with non-NASH cirrhosis. Serum creatinine was the major contributor to MELD score increases leading to LT in patients with NASH cirrhosis. This study provides important insights into the distinct natural history of non-alcoholic steatohepatitis (NASH) cirrhosis among liver transplant (LT) waitlist registrants, revealing that patients with NASH cirrhosis face lower odds of transplantation and higher waitlist mortality than those with non-NASH cirrhosis. Our study underscores the significance of serum creatinine as a crucial contributor to model for end-stage liver disease (MELD) score in patients with NASH cirrhosis. These findings have substantial implications, emphasizing the need for ongoing evaluation and refinement of the MELD score to more accurately capture mortality risk in patients with NASH cirrhosis on the LT waitlist. Moreover, the study highlights the importance of further research investigating the impact of the implementation of MELD 3.0 across the US on the natural history of NASH cirrhosis.