Mohammad S. Siddiqui

The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) detection is difficult because of the unavailability of short screening tools. Therefore, MHE patients can remain undiagnosed and untreated. The aim of this study was to use a Stroop smartphone application (app) (EncephalApp_Stroop) to screen for MHE. The app and standard psychometric tests (SPTs; 2 of 4 abnormal is MHE, gold standard), psychometric hepatic encephalopathy score (PHES), and inhibitory control tests (ICTs) were administered to patients with cirrhosis (with or without previous overt hepatic encephalopathy; OHE) and age‐matched controls from two centers; a subset underwent retesting. A separate validation cohort was also recruited. Stroop has an “off” state with neutral stimuli and an “on” state with incongruent stimuli. Outcomes included time to complete five correct runs as well as number of trials needed in on (Ontime) and off (Offtime) states. Stroop results were compared between controls and patients with cirrhosis with or without OHE and those with or without MHE (using SPTs, ICTs, and PHES). Receiver operating characteristic analysis was performed to diagnose MHE in patients with cirrhosis with or without previous OHE. One hundred and twenty‐five patients with cirrhosis (43 previous OHE) and 134 controls were included in the original cohort. App times were correlated with Model for End‐Stage Liver Disease (Offtime: r = 0.57; Ontime: r = 0.61; P < 0.0001) and were worst in previous OHE patients, compared to the rest and controls. Stroop performance was also significantly impaired in those with MHE, compared to those without MHE, according to SPTs, ICTs, and PHES (all P < 0.0001). A cutoff of >274.9 seconds (Ontime plus Offtime) had an area under the curve of 0.89 in all patients and 0.84 in patients without previous OHE for MHE diagnosis using SPT as the gold standard. The validation cohort showed 78% sensitivity and 90% specificity with the >274.9‐seconds Ontime plus Offtime cutoff. App result patterns were similar between the centers. Test‐retest reliability in controls and those without previous OHE was good; a learning effect on Ontime in patients with cirrhosis without previous OHE was noted. Conclusion: The Stroop smartphone app is a short, valid, and reliable tool for screening of MHE. (Hepatology 2013;58:1122‐1132)

Covert Hepatic Encephalopathy Is Independently Associated With Poor Survival and Increased Risk of Hospitalization

OBJECTIVES:Despite the high prevalence of covert hepatic encephalopathy (CHE) in cirrhotics without previous overt HE (OHE), its independent impact on predicting clinically relevant outcomes is unclear. The aim of this study was to define the impact of CHE on time to OHE, hospitalization, and death/transplant in prospectively followed up patients without previous OHE.METHODS:Outpatient cirrhotics without OHE were enrolled and were administered a standard paper–pencil cognitive battery for CHE diagnosis. They were systematically followed up and time to first OHE development, hospitalization (liver-related/unrelated), and transplant/death were compared between CHE and no-CHE patients at baseline using Cox regression.RESULTS:A total of 170 cirrhotic patients (55 years, 58% men, 14 years of education, Model for End-Stage Liver Disease (MELD 9), 53% hepatitis C virus (HCV), 20% nonalcoholic etiology) were included, of whom 56% had CHE. The entire population was followed up for 13.0±14.6 months, during which time 30% developed their first OHE episode, 42% were hospitalized, and 19% had a composite death/transplant outcome. Age, gender, etiology, the MELD score, and CHE status were included in Cox regression models for time to first OHE episode, hospitalization, death, and composite death/transplant outcomes. On Cox regression, despite controlling for MELD, those with CHE had a higher risk of developing OHE (hazard ratio: 2.1, 95% confidence interval 1.01–4.5), hospitalization (hazard ratio: 2.5, 95% confidence interval 1.4–4.5), and death/transplant (hazard ratio: 3.4, 95% confidence interval 1.2–9.7) in the follow-up period.CONCLUSIONS:Covert HE is associated with worsened survival and increased risk of hospitalization and OHE development, despite controlling for the MELD score. Strategies to detect and treat CHE may improve these risks.

Severity of Nonalcoholic Fatty Liver Disease and Progression to Cirrhosis Are Associated With Atherogenic Lipoprotein Profile

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD. METHODS We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository. RESULTS Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis. CONCLUSIONS Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.

The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids

The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASH patients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy‐proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis‐driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534‐548).

Preserved hemostatic status in patients with non-alcoholic fatty liver disease

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of thrombosis. However, it remains unclear if hypercoagulability contributes to this risk. We, therefore, determined an in-depth hemostatic profile in a cohort of well-defined patients with NAFLD. METHODS We drew blood samples from 68 patients with biopsy-proven NAFLD (simple steatosis n=24, NASH n=22, and NASH cirrhosis n=22), 30 lean controls, 30 overweight controls (body mass index (BMI) >25kg/m2), and 15 patients with alcoholic (ASH) cirrhosis, and performed in-depth hemostatic profiling. RESULTS Basal and agonist-induced platelet activation, plasma levels of markers of platelet activation, and plasma levels of the platelet adhesion regulators von Willebrand factor and ADAMTS13 were comparable between patients with non-cirrhotic NAFLD and controls. Agonist-induced platelet activation was decreased in patients with cirrhosis. Thrombomodulin-modified thrombin generation was comparable between all patients and controls, although patients with cirrhosis had a reduced anticoagulant response to thrombomodulin. Thromboelastography test results were comparable between controls and non-cirrhotic NAFLD patients, but revealed moderate hypocoagulability in cirrhosis. Plasma fibrinolytic potential was decreased in overweight controls and non-cirrhotic NAFLD, but accelerated fibrinolysis was observed in ASH cirrhosis. Clot permeability was decreased in overweight controls and patients with NAFLD. CONCLUSIONS The overall hemostatic profile is comparable between patients with non-cirrhotic NAFLD and controls. Additionally, pro-thrombotic features (hypofibrinolysis and a pro-thrombotic structure of fibrin clot) in patients with NAFLD are likely driven by obesity. Our study suggests a limited role for hyperactive hemostasis in the increased thrombotic risk in NAFLD. LAY SUMMARY The combined results of this study show that the overall hemostatic status is comparable between healthy individuals and patients with a fatty liver disease.

Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease

Vibration‐controlled transient elastography estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), which are noninvasive assessments of hepatic fibrosis and steatosis, respectively. However, prior vibration‐controlled transient elastography studies reported high failure rates in patients with nonalcoholic fatty liver disease. We examined the performance characteristics of the FibroScan 502 Touch with two probes, medium (M+) and extra large (XL+), in patients with nonalcoholic fatty liver disease in a multicenter setting. A total of 1,696 exams were attempted in 992 patients (body mass index, 33.6 ± 6.5 kg/m2) with histologically confirmed nonalcoholic fatty liver disease. Simultaneous assessment of LSM and CAP was performed using the FibroScan 502 Touch with an automatic probe selection tool. Testing was conducted twice in patients by either a single operator (87%) or two operators (13%). Failure was defined as the inability to obtain a valid examination. An examination was considered unreliable if LSM interquartile range/median was >30%. Significant disagreement between two readings was defined as >95% limits of agreement between two readings. A total of 1,641 examinations yielded valid results with a failure rate of 3.2% (55/1,696). The proportion of unreliable scans for LSM was 3.9%. The proportion of unreliable scans with operator experience in the top quartile (≥59 procedures) was significantly lower than that in the lower three quarters combined (1.6% versus 4.7%, P = 0.02 by Fishers exact test). The significant disagreement between first and second readings for LSM and CAP when obtained back to back was 18% and 11%, respectively. Conclusion: Vibration‐controlled transient elastography for estimation of LSM and CAP can be successfully deployed in a multicenter setting with low failure (3.2%) and high reliability (>95%) rates and high reproducibility. (Hepatology 2018;67:134‐144).

Performance of non-invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non-alcoholic fatty liver disease.

In non‐alcoholic fatty liver disease, presence of fibrosis is predictive of long‐term liver–related complications. Currently, there are no reliable and non‐invasive means of quantifying fibrosis in those with non‐alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non‐invasive models in predicting fibrosis in non‐alcoholic fatty liver disease.

Nonalcoholic Steatohepatitis (NASH) Is Associated With A Decline In Pancreatic Beta Cell (β-Cell) Function

BackgroundNonalcoholic fatty liver disease (NAFLD) represents a histological spectrum ranging from benign hepatic steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD is closely associated with insulin resistance (IR), and although the role of IR in NAFLD has been an area of intense investigation, there are limited data on pancreatic β-cell function.AimTo evaluate the pancreatic β-cell function in NAFLD using the homeostatic model assessment-β (HOMA-β) and β-cell index (BI).MethodsHOMA-β was measured in ninety-nine non-diabetic subjects with histologically confirmed NAFLD and compared to lean (age- and gender-matched) and obese (age-, gender-, and BMI-matched) controls. Using the values from an oral glucose tolerance test, BI was compared in 31 non-diabetic, non-cirrhotic subjects with NASH and gender- and BMI-matched controls.ResultsThe subjects with NAFLD had higher HOMA-β compared to both lean and obese controls (43.1 vs. 9 vs. 22.1 %, respectively, P < 0.05). HOMA-β was directly related to serum alkaline phosphate, total bilirubin, and weight and inversely related to age. There was no difference in HOMA-β between subjects with NAFL and NASH. Subjects with NASH had lower β-cell function as measured by a lower BI (2.09 ± 1.64 vs. 7.74 ± 25.12; P = 0.04). In patients with NASH, BI was inversely associated with fibrosis independent of age, BMI, and serum ALT levels. In contrast, HOMA-β was directly associated with fibrosis stage.ConclusionNASH is associated with strained pancreatic β-cell function in non-diabetic subjects. Future studies are necessary to evaluate the temporal relationship between β-cell function and hepatic histology.

The Patient Buddy App Can Potentially Prevent Hepatic Encephalopathy-Related Readmissions

Readmissions are a major burden in cirrhosis. A proportion of readmissions in cirrhosis, especially because of hepatic encephalopathy (HE) could be avoided through patient and caregiver engagement. We aimed to define the feasibility of using the Patient Buddy App and its impact on 30‐day readmissions by engaging and educating cirrhotic inpatients and caregivers in a pilot study.

Coronary artery disease in decompensated patients undergoing liver transplantation evaluation

Coronary artery disease (CAD) is an important contributor to morbidity and mortality in patients undergoing liver transplantation (LT). However, the current literature is limited by sampling bias and nondefinitive assessment of CAD. The current study examines the prevalence of CAD via per protocol coronary angiography and its relationship to etiology of liver disease in patients undergoing liver transplantation evaluation (LTE). Data on 228 patients were prospectively collected who had coronary angiography as part of LTE between 2011 and 2014. Coronary angiography was done in all patients age ≥50 years or with CAD risk factors. CAD was defined as any coronary artery stenosis, whereas stenosis ≥ 70% in distribution of 1 or 3 major coronary arteries was considered as single‐ or triple‐vessel disease. CAD was detected in 36.8% of patients, with the highest prevalence among nonalcoholic steatohepatitis (NASH) patients with cirrhosis (52.8%). Prevalence of single‐vessel disease was higher among patients with NASH compared with hepatitis C virus (HCV) and alcoholic cirrhosis (15.1% versus 4.6% versus 6.6%; P = 0.02). Similarly, patients with NASH were more likely to have triple‐vessel disease when compared with HCV and alcoholic cirrhosis (9.4% versus 0.9% versus 0%; P = 0.001). While adjusting for traditional risk factors for CAD, only NASH as etiology of liver disease remained significantly associated with CAD. Complications from diagnostic coronary angiography or percutaneous coronary intervention were low (2.6%). In conclusion, patients undergoing LTE have a high prevalence of CAD, which varies widely depending on etiology of liver cirrhosis. The procedural complications from coronary angiography are low. Liver Transplantation 24 333–342 2018 AASLD.