Pharmacotherapeutic efficacy on noninvasive fibrosis progression in nonalcoholic fatty liver disease: a systematic review and network meta-analysis.

BACKGROUND: Fibrosis impacts long-term outcomes among patients with nonalcoholic fatty liver disease (NAFLD). Due to well-documented flaws associated with liver biopsy, there has been a recent emphasis on prioritizing noninvasive testing over liver biopsy for the assessment of fibrosis. METHODS: A comprehensive systematic review and frequentist random effects network meta-analysis was performed among randomized controlled trials reporting pharmacologic intervention in NAFLD. The primary endpoint was the absolute change in liver stiffness measurement (LSM) via elastography. Secondary endpoints included changes in noninvasive serologic tests including APRI, fibrosis-4 index, NAFLD fibrosis score, enhanced liver fibrosis (ELF) and FibroTest (FibroSure in the USA). RESULTS: Forty-five randomized controlled trials enrolling 6932 patients were identified for this network meta-analysis. Across the primary endpoint, firsocostat, semaglutide, montelukast, cilofexor plus firsocostat, obeticholic acid and diacerein (change in LSM via vibration controlled transient elastography), in addition to lubiprostone and pemafibrate (change in LSM via magnetic resonance elastography) were found to be the most effective and statistically significant treatment interventions. Similarly, the following interventions were determined to be most effective as compared to placebo among secondary endpoints: saroglitazar, lubiprostone, and obeticholic acid (change in APRI); saroglitazar, semaglutide, firsocostat and cilofexor plus firsocostat (change in ELF); obeticholic acid and belapectin [change in FibroTest/FibroSure]. CONCLUSION: This is the first systematic review and network meta-analysis reporting pharmacologic efficacy in the progression of fibrosis based on noninvasive testing among patients with NAFLD. Semaglutide, obeticholic acid, firsocostat, cilofexor plus firsocostat and lubiprostone were found to be the most effective treatments based on their consistent efficacy reproduced across multiple endpoints, both via elastography and noninvasive blood tests.

Pharmacotherapeutic Impact on Nonalcoholic Steatohepatitis Histology: A Systematic Review and Network Meta-analysis.

Background: Due to lack of targeted treatment options and inconsistent utilization of histologic endpoints among clinical trials, identifying efficacious pharmacotherapies for nonalcoholic steatohepatitis [NASH] has proven challenging. Methods: A thorough systematic review and frequentist random-effects network meta-analysis was performed across all randomized clinical trials reporting a pharmacotherapeutic intervention on biopsy-proven NASH. Primary outcomes were based on the most current, up-to-date recommended histologic endpoints. Results: A total of 40 RCTs were identified including 6593 total patients. The most effective and statistically significant treatment interventions for minimum two-point improvement in NAFLD Activity Score were aldafermin 1 mg [RR 7.69, 95% CI 2.00; 29.57], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 3.38, 95% CI 1.88; 6.07], pioglitazone 45 mg [RR 3.29, 95% CI 1.74; 6.22], vitamin E 800 IU [RR 2.06, 95% CI 1.33; 3.18], resmetirom 80 mg [RR 1.74, 95% CI 1.03; 2.94], obeticholic acid 25 mg [RR 1.63, 95% CI 1.32; 2.01], and obeticholic acid 10 mg [RR 1.31, 95% CI 1.02; 1.67]). The most robust pharmacotherapies for NASH resolution without worsening fibrosis were found to be aldafermin 1 mg [RR 5.77, 95% CI 1.48; 22.51], pioglitazone 45 mg [RR 2.65, 95% CI 1.43; 4.91], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 2.64, 95% CI 1.36; 5.12], pioglitazone 30 mg [RR 2.46, 95% CI 1.56; 3.88], vitamin E 800 IU [RR 1.90, 95% CI 1.20; 3.00], and obeticholic acid 25 mg [RR 1.52, 95% CI 1.03; 2.23]). Obeticholic acid had a significant improvement on fibrosis. Multiple interventions were found to improve individual histologic scores across secondary outcome analyses and are detailed below. Conclusion: This novel systematic review and network meta-analysis represents the most comprehensive investigation to date regarding the pharmacotherapeutic options for biopsy-proven NASH using current recommended histologic endpoints.

Peritransplant Renal Dysfunction in Liver Transplant Candidates.

Renal function is intricately tied to Model for End-Stage Liver Disease score and overall prognosis among patients with cirrhosis. The estimation of glomerular filtration rate (GFR) and etiology of renal impairment are even more magnified among cirrhotic patients in the period surrounding liver transplantation. Novel biomarkers including cystatin C and urinary neutrophil gelatinase-associated lipocalin have been demonstrated to more accurately assess renal dysfunction and aid in the diagnosis of competing etiologies. Accurately identifying the severity and chronicity of renal dysfunction among transplant candidates is an imperative component with respect to stratifying patients toward simultaneous liver-kidney transplantation versus liver transplantation alone.

Noninvasive assessment of fibrosis among patients with nonalcoholic fatty liver disease [NAFLD].

Nonalcoholic fatty liver disease [NAFLD] is a condition affecting a vast portion of the worldwide population. The presence of underlying fibrosis is the strongest predictor of long-term outcomes and mortality, with a graduated increase in liver-related morbidity and mortality with progression from moderate fibrosis tobiomarkers targeting collagen turnover and extracellular matrix remodeling FibroTest FAST™, Velacur™, MRE]. While many of these provide a robust, stand alone value, the accuracy of these noninvasive tests markedly increase when used in combination or in sequential order with one another. There is not a uniform consensus demonstrating superiority of any specific test. Given the growing role and accuracy of these tests, they should have an expanding role in the assessment of fibrosis across this patient population and obviate the need for liver biopsy in a large portion of patients. Future clinical studies should focus on validating these novel biomarkers, as well as optimizing the sequential or algorithmic testing when combining these noninvasive tests.

Impact of Chronic Hepatitis C virus co-infection on outcomes of infective endocarditis in people who inject drugs.

Injection drug use (IDU) is a risk factor for infective endocarditis (IE) and hepatitis C virus (HCV) infection. This retrospective cohort study assessed HCV's impact on outcomes of adult people who inject drugs (PWID). Those admitted due to IE using modified Duke criteria from January 2012 through May 2018 were identified. The cohort was divided into HCV seropositive and seronegative groups. The seropositive group was further stratified according to HCV viremia. Complications and mortality during the IE hospitalization, at 10 weeks, and 1 year were compared across groups. Clinical factors were similar between the cohorts, except patients without viremia (29, 81%) required more ICU admissions than with viremia (30, 60%) (P < 0.05). There was no difference in mortality at all time periods between the groups. Although several factors affect mortality in PWID with IE, neither HCV antibody positivity nor viremia appear to increase the risk for complications or death.

Clinical and Genetic Risk Factors of Recurrent Nonalcoholic Fatty Liver Disease After Liver Transplantation.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been increasingly reported among recipients of liver transplantation (LT). We aimed to identify clinical and genetic risk factors responsible for the development of early recurrent NAFLD in nonalcoholic steatohepatitis transplant recipients. METHODS: Forty-six total single nucleotide polymorphisms with known association with NAFLD were tested among both recipient and donor liver samples in 66 LT recipients with nonalcoholic steatohepatitis to characterize influences on NAFLD recurrence at ∼1 year post-LT (median interval from LT to biopsy: 377 days). RESULTS: Recurrent NAFLD was identified in 43 (65.2%) patients, 20 (30.3%) with mild recurrence, and 23 (34.8%) with moderate to severe NAFLD. On adjusted analysis, change in the body mass index (BMI) (ΔBMI) was significantly associated with NAFLD recurrence, whereas post-LT diabetes mellitus was associated with increased severity of NAFLD recurrence. ADIPOR1 rs10920533 in the recipient was associated with increased risk of moderate to severe NAFLD recurrence, whereas the minor allele of SOD2 rs4880 in the recipient was associated with reduced risk. Similar reduced risk was noted in the presence of donor SOD2 rs4880 and HSD17B13 rs6834314 polymorphism. DISCUSSION: Increased BMI post-LT is strongly associated with NAFLD recurrence, whereas post-LT diabetes mellitus was associated with increased severity of NAFLD recurrence. Both donor and recipient SOD2 rs4880 and donor HSD17B13 rs6834314 single nucleotide polymorphisms may be associated with reduced risk of early NAFLD recurrence, whereas presence of the minor allele form of ADIPOR1 rs10920533 in the recipient is associated with increased severity NAFLD recurrence.

Elevated Liver Biochemistries in Hospitalized Chinese Patients With Severe COVID-19: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Several recent studies have reported an abnormal liver chemistry profile among patients with coronavirus disease 2019 (COVID-19), although its clinical significance remains unknown. APPROACH AND RESULTS: This systematic review and meta-analysis identified six studies of 586 patients delineating liver chemistries among patients with severe/critical illness versus mild cases of COVID-19 infection. Patients with severe/critical illness with COVID-19 infection have increased prevalence of coronary artery disease, cerebrovascular disease, and chronic obstructive pulmonary disease as compared with mild cases. A significant association between severe/critical COVID-19 infections with elevations in aspartate aminotransferase (pooled mean difference [MD], 11.70 U/L; 95% confidence interval [CI], 2.97, 20.43; P = 0.009), elevated total bilirubin (pooled MD, 0.14 mg/dL; 95% CI, 0.06, 0.22; P = 0.0005), and decreased albumin (pooled MD, -0.68 g/L; 95% CI, -0.81, -0.55; P < 0.00001) was noted. There was also a trend toward elevated alanine aminotransferase levels among these severe cases (pooled MD, 8.84 U/L; 95% CI, -2.28, 19.97; P = 0.12); however, this did not reach statistical significance. More severe/critically ill cases were associated with leukocytosis, neutrophilia, lymphopenia, elevated creatinine kinase, elevated lactate dehydrogenase (LDH), and elevated prothrombin time (PT). CONCLUSIONS: Comorbidities, including coronary artery disease, cerebrovascular disease and chronic obstructive pulmonary disease, are more prevalent in hospitalized Chinese patients with severe/critical illness from COVID-19, and these patients are more likely to manifest with abnormal liver chemistries. Further prospective studies are crucial to understand the pathophysiologic mechanisms underlying the hepatic manifestations of the novel COVID-19 infection and its clinical significance.

Systematic review with meta-analysis: abnormalities in the international normalised ratio do not correlate with periprocedural bleeding events among patients with cirrhosis.

BACKGROUND: Cirrhotic coagulopathy is a delicate interplay comprising deficiencies of both procoagulant and anticoagulant factors. AIM: To identify the relationship between international normalised ratio [INR] with periprocedural bleeding risk among patients with cirrhosis. METHODS: Following a thorough database search of the primary literature, 29 studies were targeted for analysis, including 13 276 patients with cirrhosis undergoing indicated procedures. RESULTS: There was no significant association between periprocedural bleeding events and pre-procedural INR [pooled odds ratio 1.52; 95% CI 0.99, 2.33; P = 0.06]. Furthermore, there was no significant difference in mean INR [pooled mean difference 0.05; 95% CI -0.03, 0.13; P = 0.23] upon comparison of patients who either did or did not experience a periprocedural bleeding event. Significant heterogeneity among some studies was primarily fuelled by significant subgroup effects of both specific procedure types performed. Additionally, there were markedly inconsistent transfusion practices across studies. CONCLUSIONS: INR fails to serve as a significant correlate for periprocedural bleeding events among patients with cirrhosis. Ideally, these new findings will help serve as a springboard for future studies, as well as to minimize transfusion of blood products, which command a myriad of adverse effects among patients with cirrhosis.

Prevalence of chronic liver disease in patients with COVID-19 and their clinical outcomes: a systematic review and meta-analysis.

Abnormal liver enzymes are seen in 20% of hospitalized patients with COVID-19. The etiology of elevated liver enzymes is thought to be multifactorial including medications and underlying liver disease. The true prevalence and clinical significance of underlying chronic liver diseases (CLD) in COVID-19 remains poorly defined. In this systematic review and meta-analysis, we included 74 clinical studies that were identified after a thorough literature search across three databases. The prevalence of CLD patients (73 studies, 24,299 patients) was 3% among all COVID-19 patients. The prevalence of CLD patients was similar in COVID-19 positive and negative population (pooled OR 0.79 [95% CI 0.60, 1.05], p = 0.10). The presence of CLD was significantly associated with more severe COVID-19 infection (pooled OR 1.48 [95% CI 1.17, 1.87], p = 0.001) and overall mortality (pooled OR 1.78 [95% CI 1.09, 2.93], p = 0.02). Additionally, there was a non-significant trend noted for increased ICU admissions and need for invasive mechanical ventilation among COVID-19 patients with CLD. To date, the clinical importance of chronic liver diseases among COVID-19 infection has remained undefined. In this novel systematic review and meta-analysis, the presence of underlying chronic liver disease was significantly associated with more severe COVID-19 infections and mortality.

Accuracy of Noninvasive Fibrosis Scoring Systems in African American and White Patients With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) score, aspartate aminotransferase (AST)-to-platelet ratio index (APRI) score, and AST-alanine aminotransferase (ALT) ratio are noninvasive fibrosis scoring systems for the staging of liver fibrosis in patients with chronic liver disease. METHODS: In a large cohort of patients with nonalcoholic fatty liver disease, we compared AST-ALT ratio, NFS, FIB-4 score, and APRI score in predicting advanced fibrosis (defined as fibrosis stage ≥ 3) in histologically confirmed African American (AA) and white patients. We identified 907 patients: 677 (74.6%) white and 230 (25.3%) AA patients with nonalcoholic fatty liver disease. RESULTS: Of the 907 patients, 115 (12.8%) patients had advanced fibrosis (stages 3 and 4) in the total cohort: 6 (2.6%) AAs, and 109 (16.2%) whites. In AAs, the area under the receiver operating characteristic (area under the curve) for predicting advanced fibrosis was 0.58 by NFS, 0.86 by APRI score, 0.77 by FIB-4 score, and 0.65 by AST-ALT ratio. In whites, the area under the receiver operating characteristic for predicting advanced fibrosis was 0.82 by NFS, 0.82 by APRI score, 0.88 by FIB-4 score, and 0.76 by AST-ALT ratio. In the AA population, NFS > 0.675, FIB-4 score > 2.67, and APRI score > 1.5 each has a negative predictive value of 98%, whereas the negative predictive values in whites are 91%, 88%, and 85%, respectively. DISCUSSION: Noninvasive fibrosis scoring systems can reliably exclude advanced fibrosis in both AAs and whites and have acceptable discriminatory ability to predict advanced fibrosis in whites. The utility of noninvasive fibrosis scoring systems in predicting advanced fibrosis in AAs needs further validation in a larger multicenter cohort.

Similarities and Differences Between Nonalcoholic Steatohepatitis and Other Causes of Cirrhosis.

Nonalcoholic fatty liver disease includes a spectrum of liver disorders that range from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Risk factors such as obesity, hypertension, hyperlipidemia, chronic kidney disease, and smoking status increase risk of progression to cirrhosis among patients with NASH. Cirrhosis derived from non-NASH causes may share similar features with patients with NASH but embody distinct pathogenetic mechanisms, genetic associations, prognosis, and outcomes. This article discusses in detail the comparison of clinical, genetic, and outcome characteristics between patients with NASH cirrhosis as opposed to alternative causes of chronic liver disease.

Thromboelastography versus standard coagulation testing in the assessment and reversal of coagulopathy among cirrhotics: a systematic review and meta-analysis.

The utility of thromboelastography/thromboelastometry currently has unvalidated clinical benefit in the assessment and reversal of coagulopathy among cirrhotic patients as compared to standard coagulation testing. A novel systematic review and meta-analysis was conducted in order to assess pooled outcome data among patients receiving thromboelastography/thromboelastometry as compared to standard coagulation testing. As compared to standard coagulation testing, there was a significant reduction in the number of patients requiring pRBC, platelet, and fresh frozen plasma transfusions among thromboelastography/thromboelastometry group with pooled OR 0.53 (95% CI 0.32-0.85; P = 0.009), 0.29 (95% CI 0.12-0.74; P = 0.009), and 0.19 (95% CI 0.12-0.31; P < 0.00001), respectively. Similarly, there was a significant reduction in number of pRBC, platelet, and fresh frozen plasma units transfused in the thromboelastography/thromboelastometry group with pooled MD -1.53 (95% CI -2.86 to -0.21; P = 0.02), -0.57 (95% CI -1.06 to -0.09; P = 0.02), and -2.71 (95% CI -4.34 to -1.07; P = 0.001), respectively. There were significantly decreased total bleeding events with pooled OR 0.54 (95% CI 0.31-0.94; P = 0.03) and amount of intraoperative bleeding during liver transplantation with pooled MD -1.46 (95% CI -2.49 to -0.44; P = 0.005) in the thromboelastography/thromboelastometry group. Overall, there was no significant difference in mortality between groups with pooled OR 0.91 (95% CI 0.63-1.30; P = 0.60). As compared to standard coagulation testing, a thromboelastography/thromboelastometry-guided approach to the assessment and reversal of cirrhotic coagulopathy improves overall number of patients exposed to blood product transfusions, quantity of transfusions, and bleeding events.

Nonalcoholic fatty liver disease and alcoholic liver disease: metabolic diseases with systemic manifestations.

The progression of liver disease is portrayed by several common, overarching signs and symptoms. Classically, these include findings such as spider angiomata, jaundice, palmar erythema, and as cirrhosis decompensates, ascites, variceal hemorrhage (VH), hepatic encephalopathy (HE), and hepatocellular carcinoma (HCC). Aside from these universal hallmarks among cirrhotics, patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) harbor their own distinct systemic associations and manifestations. NAFLD is tightly linked to metabolic syndrome, which appears to be a driving force for a multitude of comorbidities, such as insulin resistance, cardiovascular disease, chronic kidney disease (CKD), obstructive sleep apnea (OSA), as well as increased malignancy risk. ALD also maintains a variety of comorbidities congruent with systemic effects of chronic alcohol use. These findings are highlighted by cardiovascular conditions, neuronal damage, myopathy, nutritional deficiencies, chronic pancreatitis, in addition to increased malignancy risk. While a general, guideline-driven management for all cirrhotic patients remains imperative for minimizing risk of complications, a tailored treatment strategy is useful for patients with NAFLD and ALD who entertain their own constellation of unique systemic manifestations.

A Low Iron Diet Protects from Steatohepatitis in a Mouse Model.

High tissue iron levels are a risk factor for multiple chronic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). To investigate causal relationships and underlying mechanisms, we used an established NAFLD model-mice fed a high fat diet with supplemental fructose in the water ("fast food", FF). Iron did not affect excess hepatic triglyceride accumulation in the mice on FF, and FF did not affect iron accumulation compared to normal chow. Mice on low iron are protected from worsening of markers for non-alcoholic steatohepatitis (NASH), including serum transaminases and fibrotic gene transcript levels. These occurred prior to the onset of significant insulin resistance or changes in adipokines. Transcriptome sequencing revealed the major effects of iron to be on signaling by the transforming growth factor beta (TGF-ß) pathway, a known mechanistic factor in NASH. High iron increased fibrotic gene expression in vitro, demonstrating that the effect of dietary iron on NASH is direct. Conclusion: A lower tissue iron level prevents accelerated progression of NAFLD to NASH, suggesting a possible therapeutic strategy in humans with the disease.

Genetic and Epigenetic Culprits in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic Fatty Liver Disease (NAFLD) constitutes a wide spectrum of liver pathology with hepatic steatosis at the core of this pathogenesis. Variations of certain genetic components have demonstrated increased susceptibility for hepatic steatosis. Therefore, these inciting variants must be further characterized in order to ultimately provide effective, targeted therapies for NAFLD and will be the focus of this review. Several genetic variants revealed an association with NAFLD through Genome-wide Association Study, meta-analyses, and retrospective case-control studies. PNPLA3 rs738409 and TM6SF2 rs58542926 are the two genetic variants providing the strongest evidence for association with NAFLD. However, it remains to be determined if these genetic variants serve as the primary culprit which induces the pathogenesis of NAFLD. Prospective and intervention studies are urgently needed to firmly establish a cause-and-effect relationship between the presence of certain genetic variants and risk of NAFLD development and progression.

Targeting incretin hormones and the ASK-1 pathway as therapeutic options in the treatment of non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is currently one of the leading forms of chronic liver disease, and its rising frequency worldwide has reached epidemic proportions. NAFLD, particularly its progressive variant NASH (non-alcoholic steatohepatitis), can lead to advanced fibrosis, cirrhosis, and HCC. The pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex, and as such myriad therapies are under investigation targeting different pathophysiological mechanisms. Incretin-based therapies, including GLP-1RAs and DPP-4 inhibitors and the inhibition of ASK1 pathway have provided two such novel mechanisms in the management of this disease, and will remain focus of this review.

The Role of Nonalcoholic Fatty Liver Disease on Cardiovascular Manifestations and Outcomes.

Cardiovascular disease has been postulated as the leading cause of mortality among patients with nonalcoholic fatty liver disease (NAFLD), rather than from sequalae of liver disease specifically. While there is ample evidence validating the association between NAFLD and increased cardiovascular comorbidities, events, and mortality, current data presents a challenge in attributing this effect solely due to NAFLD given the rampant presence of insulin resistance and type 2 diabetes mellitus (T2DM). Endpoints of increased cardiovascular risk remains tightly linked to the concomitant presence of insulin resistance and T2DM. Prospective studies accentuating early detection of NAFLD are imperative to institute early intervention and prevent future cardiovascular events.