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.

Diagnosis of covert hepatic encephalopathy without specialized tests.

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) impairs quality of life (QOL) and can be difficult to diagnose. Patient-administered methods that do not require specialized tests or equipment might increase rates of detection. We performed a longitudinal study to determine whether demographic data and responses to a validated QOL questionnaire, the Sickness Impact Profile (SIP), can identify patients with CHE. METHODS: Patients with cirrhosis without prior overt HE were recruited from outpatient liver clinics at the Virginia Commonwealth University Medical Center, from August 2008 through February 2012. We performed cognitive tests on 170 patients (mean age, 55 y; mean model for end-stage liver disease score, 9; 50% with hepatitis C-associated and 11% with alcohol-associated cirrhosis). Patients also were given the SIP questionnaire (136 questions on 12 QOL topics, requiring a yes or no answer) at enrollment, at 6 months, and at 12 months. The proportion of patients that responded "yes" to each question was compared between those with and without CHE. Patient variables (noncognitive), demographics (age, education, sex, alcoholic etiology), and SIP questions that produced different responses between groups were analyzed by logistic regression and receiver operating characteristic analyses. RESULTS: Based on cognitive test results, 93 patients (55%) had CHE when the study began. They had a higher proportion of "yes" responses to 54 questions on the SIP questionnaire, across all categories. We developed a formula to identify patients with CHE based on age, sex, and responses to 4 SIP questions (a SIP CHE score). Baseline SIP CHE scores greater than 0 identified patients with CHE with 80% sensitivity and 79% specificity. Of the 98 patients who returned for the 6-month evaluation, 50% had CHE (the SIP CHE identified these patients with 88% sensitivity). Of the 50 patients who returned for the 12-month evaluation, 32% had CHE (the SIP CHE score identified these patients with 81% sensitivity). CONCLUSIONS: We developed a system to identify patients with CHE based on age, sex, and responses to 4 SIP questions; this formula identified patients with CHE with more than 80% sensitivity over a 12-month period after the initial enrollment. Patient-administered CHE screening strategies that do not include specialized tests could increase the detection of CHE and improve therapy.

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

UNLABELLED: 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.

Differential impact of hyponatremia and hepatic encephalopathy on health-related quality of life and brain metabolite abnormalities in cirrhosis.

BACKGROUND & AIMS: Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality of life (HRQOL) and cognition in cirrhosis. We aimed at studying the effect of hyponatremia on cognition, HRQOL, and brain MR spectroscopy (MRS) independent of HE. METHODS: Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium <130 mEq/L), HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psychosocial and physical sub-scores) and brain MRS (myoinositol (mI) and glutamate+glutamine (Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. RESULTS: 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN, and 10 HN, MELD 12, 63% hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN: 3, HN: 3.5, HE: 6.5, HE+HN: 7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP (p<0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE, HE+HN, and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psychosocial SIP scores. CONCLUSIONS: Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL.

Asymmetric dimethylarginine is strongly associated with cognitive dysfunction and brain MR spectroscopic abnormalities in cirrhosis.

BACKGROUND & AIMS: Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide synthase that accumulates in liver disease and may contribute to hepatic encephalopathy (HE). We aimed at evaluating the association of ADMA with cognition and brain MR spectroscopy (MRS) in cirrhosis. METHODS: Cirrhotic patients with/without prior HE and non-cirrhotic controls underwent cognitive testing and ADMA determination. A subgroup underwent brain MRS [glutamine/glutamate (Glx), myoinositol (mI), N-acetyl-aspartate (NAA) in parietal white, occipital gray, and anterior cingulated (ACC)]. Cognition and ADMA in a cirrhotic subgroup before and one month after transjugular intrahepatic portosystemic shunting (TIPS) were also tested. Cognition and MRS values were correlated with ADMA and compared between groups using multivariable regression. ADMA levels were compared between those who did/did not develop post-TIPS HE. RESULTS: Ninety cirrhotics (MELD 13, 54 prior HE) and 16 controls were included. Controls had better cognition and lower ADMA, Glx, and higher mI compared to cirrhotics. Prior HE patients had worse cognition, higher ADMA and Glx and lower mI compared to non-HE cirrhotics. ADMA was positively correlated with MELD (r=0.58, p<0.0001), abnormal cognitive test number (r=0.66, p<0.0001), and Glx and NAAA (white matter, ACC) and negatively with mI. On regression, ADMA predicted number of abnormal tests and mean Z-score independent of prior HE and MELD. Twelve patients underwent TIPS; 7 developed HE post-TIPS. ADMA increased post-TIPS in patients who developed HE (p=0.019) but not in others (p=0.89). CONCLUSIONS: A strong association of ADMA with cognition and prior HE was found independent of the MELD score in cirrhosis.

Management of hepatocellular carcinoma: treatment options and indications for orthotopic liver transplantation.

Hepatocellular carcinoma (HCC) is the most common tumor worldwide and the leading cause of death amongst patients with cirrhosis. There are an estimated 500,000 or more new cases diagnosed each year in the world, with recent data suggesting an increase in incidence in the United State. Since the majority of HCC occurs in the setting of cirrhosis, an effective protocol for treatment needs to be in place addressing both management of underlying cirrhosis and cancer.

Rates of surveillance and management of hepatocellular carcinoma in patients evaluated at a liver transplant center.

OBJECTIVES: The treatment of choice for HCC with cirrhosis is liver transplantation (LT). We assessed if patients evaluated for hepatocellular carcinoma are being diagnosed by surveillance, the proportion of patients meeting Milan criteria at diagnosis, and rates of liver transplantation. METHODS: All HCC cases in cirrhotic patients at Duke University Medical Center in the MELD era (Feb 2002-Oct 2008) were identified. Surveillance was defined as an imaging exam for detection of HCC in the 12 months prior to diagnosis of HCC. Logistic regression was used to examine predictors of LT. RESULTS: There were 319 cases meeting diagnostic criteria for HCC. Only 30.7% were diagnosed by surveillance and 43.7% met Milan criteria at diagnosis. Patients diagnosed by surveillance were more likely to meet Milan criteria and to receive LT (p < 0.0001 for both outcomes). Surveillance was associated with higher rates of LT with an OR 2.6 (95% CI 1.2-5.7, p = 0.02). Patients managed by a hepatologist were more likely to be diagnosed by surveillance (65.9 vs. 19.0%, p < 0.0001). Patients meeting Milan criteria managed by a hepatologist were more likely to receive LT than those referred from other providers (26.4 vs. 8%, p = 0.009). CONCLUSIONS: A minority of HCC cases in cirrhotic patients were diagnosed by surveillance, and only 12.5% underwent LT. Patients diagnosed by surveillance were more likely to meet Milan criteria and to undergo LT. These findings highlight the need for increased identification of patients with chronic liver disease and for subsequent referral to hepatologists for enrollment in HCC surveillance programs.

Management of nonalcoholic fatty liver disease: weight control.

With obesity reaching epidemic proportions in the United States, it is imperative that hepatologists have an understanding of the medical ramifications and methods of treatment. Evaluation of nonalcoholic fatty liver disease may get the patient into the office,but weight reduction may provide a therapeutic hurdle. This article provides an overview of current obesity treatment.