Sherry Boyett

Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.

Patients with minimal hepatic encephalopathy (MHE) have impaired driving skills, but association of MHE with motor vehicle crashes is unclear. Standard psychometric tests (SPT) or inhibitory control test (ICT) can be used to diagnose MHE. The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1‐year follow‐up. Patients with cirrhosis were diagnosed with MHE by ICT (MHEICT) and SPT (MHESPT). Self and department‐of‐transportation (DOT)‐reports were used to determine crashes and violations over the preceding year. Agreement between self and DOT‐reports was analyzed. Patients then underwent 1‐year follow‐up for crash/violation occurrence. Crashes in those with/without MHEICT and MHESPT were compared. 167 patients with cirrhosis had DOT‐reports, of which 120 also had self‐reports. A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self‐report (17% vs 0.0%, P = 0.0004) and DOT‐reports (17% vs 3%, P = 0.004, relative risk: 5.77). SPT did not differentiate between those with/without crashes. A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT, both self‐reported (100% vs 50%, P = 0.03) and DOT‐reported (89% vs 44%, P = 0.01). There was excellent agreement between self and DOT‐reports for crashes and violations (Kappa 0.90 and 0.80). 109 patients were followed prospectively. MHEICT patients had a significantly higher future crashes/violations compared to those without (22% vs 7%, P = 0.03) but MHESPT did not. MHEICT (Odds ratio: 4.51) and prior year crash/violation (Odds ratio: 2.96) were significantly associated with future crash/violation occurrence. Conclusion: Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospective follow‐up compared to patients without MHE. ICT, but not SPT performance is significantly associated with prior and future crashes and violations. There was an excellent agreement between self‐ and DOT‐reports. (HEPATOLOGY 2009.)

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.

Association Between High-Normal Levels of Alanine Aminotransferase and Risk Factors for Atherogenesis

BACKGROUND & AIMS Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting. METHODS We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease. RESULTS Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high-normal range (19-40 IU/L in women and 31-40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high-normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 μU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all). CONCLUSIONS In an analysis of asymptomatic individuals, increased serum levels of ALT (even high-normal levels) are associated with markers of cardiovascular disease.

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 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.

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

BACKGROUND & AIMS: Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. METHODS: We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. RESULTS: Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory‐Denk bodies than men and also at an increased risk of lobular inflammation and Mallory‐Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory‐Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05). CONCLUSIONS: Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

Validation of Noninvasive Methods for Detecting Hepatic Steatosis in Patients With Human Immunodeficiency Virus Infection

Nonalcoholic fatty liver disease (NAFLD) is common among patients with human immunodeficiency virus (HIV) infection; a reliable noninvasive method of detection is needed. We aimed to validate noninvasive means of identifying steatosis in HIV-positive patients. We performed a single-center retrospective study to validate the abilities of the liver fat score (LFS) and the lipid accumulation product (LAP) to detect hepatic steatosis in HIV-positive patients, compared with HIV-negative individuals (controls); NAFLD was confirmed by histology, and findings were compared with those from ultrasonography. These models then were validated in HIV-positive patients with NAFLD vs patients co-infected with HIV and hepatitis C virus (HCV) infection, without hepatic steatosis. LFS identified hepatic steatosis in HIV-positive subjects, compared with controls, with an area under the receiver operating curve value of 0.971 ± 0.027 (95% confidence interval, 0.91-1.000). At a cut-off value of -0.945, the LFS identified patients with steatosis with 100% sensitivity and 84% specificity. At a cut-off of value of -0.234, the LFS differentiated between HIV-positive subjects with NAFLD and patients co-infected with HIV and HCV with 100% sensitivity and 74% specificity. LAP scores ≥38 identified HIV-positive patients with steatosis with 89% sensitivity and 83% specificity. LAP scores ≥42 differentiated between HIV-positive subjects with steatosis and patients co-infected with HIV and HCV with 89% specificity and 70% sensitivity. We validated the accuracy of LFS and LAP in detecting hepatic steatosis in HIV-positive patients.

Changes of in vitro potency of anticoagulant drugs are similar between patients with cirrhosis due to alcohol or non-alcoholic fatty liver disease

• In vitro potency of common anticoagulants differs substantially between patients with cirrhosis and controls.