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Concept: Alanine transaminase

171

Elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) is prominent in acute dengue illness. The World Health Organization (WHO) 2009 dengue guidelines defined AST or ALT ≥ 1000 units/liter (U/L) as a criterion for severe dengue. We aimed to assess the clinical relevance and discriminatory value of AST or ALT for dengue hemorrhagic fever (DHF) and severe dengue.

Concepts: Malaria, Liver function tests, Aspartate transaminase, Alanine transaminase, Fever, Dengue fever, World Health Organization, EC 2.6.1

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BACKGROUND: Cichorium glandulosum Boiss. et Huet is used for treatment of liver disorders, and its effects are attributed to sesquiterpenes. This study aims to investigate the hepatoprotective effects of a sesquiterpene-rich fraction (SRF) from the aerial part of C. glandulosum on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in mice, and on priming with Bacillus Calmette–Guerin (BCG) followed by lipopolysaccharide (LPS)-induced immunological liver injury in mice. METHODS: SRF was suspended in water and administered to mice at 0.05, 0.10 and 0.20 g/kg body weight for 7 consecutive days. An active control drug (bifendate pills) was suspended in distilled water and administered to mice at 0.40 g/kg body weight for 7 consecutive days. Hepatotoxicity was induced by intraperitoneal injection of 0.1% CCl4 (0.2 mL/mouse) at 13 h before the last drug administration, or by tail intravenous injection of BCG (0.2 mL/mouse) before the first drug administration and LPS (0.2 mL/mouse; 8 mug) at 15 h before the last drug administration. Blood samples and the livers were collected for evaluation of the biochemical parameters of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBIL). RESULTS: SRF significantly reduced the impact of CCl4 toxicity. The highest dose of SRF (0.20 g/kg) was the most effective, reflected by significant reductions in the levels of AST (P = 0.001), ALT (P = 0.000) and TBIL (P = 0.009). The serum enzymatic levels induced by BCG and subsequent LPS injection were significantly and dose-dependently restored by SRF, reflected by significant reductions in the levels of AST (P = 0.003), ALT (P = 0.003) and TBIL (P = 0.007) for the highest dose of SRF (0.20 g/kg). CONCLUSION: SRF is hepatoprotective in animal models of chemical and immunological acute liver injury.

Concepts: Liver, Liver function tests, Aspartate transaminase, Alanine transaminase, Hepatology, Bilirubin, Hepatotoxicity, Chemical pathology

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BACKGROUND: Studies have shown psychological distress in patients with cirrhosis, yet no studies have evaluated the laboratory and physiologic correlates of psychological symptoms in cirrhosis. This study therefore measured both biochemistry data and heart rate variability (HRV) analyses, and aimed to identify the physiologic correlates of depression, anxiety, and poor sleep in cirrhosis. METHODS: A total of 125 patients with cirrhosis and 55 healthy subjects were recruited. Each subject was assessed through routine biochemistry, 5-minutes ECG monitoring, and psychological ratings of depression, anxiety, and sleep. HRV analysis were used to evaluate autonomic functions. The relationship between depression, sleep, and physiologic correlates was assessed using a multiple regression analysis and stepwise method, controlling for age, duration of illness, and severity of cirrhosis. RESULTS: Reduced vagal-related HRV was found in patients with severe liver cirrhosis. Severity of cirrhosis measured by the Child-Pugh score was not correlated with depression or anxiety, and only had a weak correlation with poor sleep. The psychological distress in cirrhosis such as depression, anxiety, and insomnia were correlated specifically to increased levels of aspartate aminotransferase (AST), increased ratios of low frequency to high frequency power, or reduced nonlinear properties of HRV (alpha1 exponent of detrended fluctuation analysis). CONCLUSIONS: Increased serum AST and abnormal autonomic nervous activities by HRV analysis were associated with psychological distress in cirrhosis. Because AST is an important mediator of inflammatory process, further research is needed to delineate the role of inflammation in the cirrhosis comorbid with depression.

Concepts: Inflammation, Psychology, Regression analysis, Cirrhosis, Liver, Aspartate transaminase, Alanine transaminase, Hepatic encephalopathy

168

Steatotic grafts are excluded for use in partial liver transplantation (LT) due to increased risk of primary non-function. This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT. Rat livers were harvested after acute ethanol treatment (6 g/kg, i.g.), reduced in size to ~1/3, and transplanted. Serum alanine aminotransferase (ALT) and total bilirubin, and hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG). Suramin (5 mg/kg, i.p.) decreased ALT by ~60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation. Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 h and mitotic index increased to 7% in LPG but was only 0.2% in FPG, indicating suppressed regeneration in FPG. Suramin increased BrdU incorporation and mitotic index to 43% and 9%, respectively, in FPG. All FPG recipients died within 5 days. Suramin recovered survival of FPG to 62%. TNFα mRNA was 2.2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and -3 in FPG. Suramin decreased TNFα and caspase activation in FPG. TGF-β, phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-β formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNFα and TGF-β formation.

Concepts: Apoptosis, Cirrhosis, Liver, Liver function tests, Alanine transaminase, Hepatology, Bilirubin, Jaundice

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A paper-based, multiplexed, microfluidic assay has been developed to visually measure alanine aminotransferase (ALT) in a fingerstick sample, generating rapid, semi-quantitative results. Prior studies indicated a need for improved accuracy; the device was subsequently optimized using an FDA-approved automated platform (Abaxis Piccolo Xpress) as a comparator. Here, we evaluated the performance of the optimized paper test for measurement of ALT in fingerstick blood and serum, as compared to Abaxis and Roche/Hitachi platforms. To evaluate feasibility of remote results interpretation, we also compared reading cell phone camera images of completed tests to reading the device in real time.

Concepts: Measurement, Metrology, Alanine transaminase, Psychometrics, Test method, Java, Mobile phone, Camera phone

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Liver function test (LFT) increase is an early sign of acetaminophen (APAP) toxicity. Typically, when an acute overdose patient is evaluated and has an initial undetectable APAP level and normal liver enzymes, the patient is not treated with N-acetylcysteine, and liver enzymes are not expected to increase later. We report a case of moderate LFT increase despite normal LFTs and an undetectable APAP level after delayed presentation of an APAP ingestion. A 22-year-old male with no medical history ingested 15-25 hydrocodone/APAP tablets (5 mg/500 mg). His suicide note and his bunkmate corroborated the overdose time. He arrived at the emergency department 16 hours after ingestion. At that time, his APAP level was <10 μg/mL, and his liver enzymes were normal [aspartate transaminase (AST) 31 U/L and alanine transaminase (ALT) 34 U/L]. Twenty-nine hours after ingestion, the psychiatry team obtained LFTs (AST 45, ALT 61). He had persistent nausea and diffuse abdominal pain. On repeat analysis, the APAP level at 36 hours was found to be <10 μg/mL, AST 150, and ALT 204. After 2 more days of increasing LFTs and persistent abdominal pain and nausea, the toxicology department was consulted, the patient was transferred to the medicine department, and intravenous N-acetylcysteine was started 66 hours after ingestion. He was treated for 16 hours and had a significant decline in LFTs and symptom resolution. His prothrombin time, bilirubin, lactate, creatinine, and mental status were normal throughout the admission. Other cases of LFT increase were excluded. Our case report illustrates that a moderate increase in liver transaminase may occur despite an initial undetectable APAP level and normal transaminases after a delayed presentation. In our case, no serious clinical effects were reported.

Concepts: Liver, Liver function tests, Aspartate transaminase, Alanine transaminase, Hepatology, Bilirubin, Liver disease, Chemical pathology

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BACKGROUND & AIMS: Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients. METHODS: This analysis included HBsAg-seropositive and anti-HCV-seronegative participants from R.E.V.E.A.L.-HBV cohort. The newly-developed cirrhosis and hepatocellular carcinoma was ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBeAg serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels and HBV genotypes. The family history was included in prediction model for hepatocellular carcinoma additionally. Cox’s proportional hazards regression coefficients for cirrhosis and hepatocellular carcinoma predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Results: Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA and HBsAg were all significantly associated with an increased risk of cirrhosis and hepatocellular carcinoma. The risk scores estimated from the derivation set could accurately categorize participants with low, medium and high cirrhosis and hepatocellular carcinoma risk in validation set (p<0.001). The AUROCs for predicting 3-, 5- and 10-year cirrhosis risk ranged 0.83-0.86 and 0.79-0.82 for the derivation and validation set, respectively. The AUROC for predicting 5-, 10-, 15-year risk of hepatocellular carcinoma ranged 0.86-0.89 and 0.84-0.87 in the derivation and validation set, respectively. CONCLUSIONS: The risk prediction models of cirrhosis and hepatocellular carcinoma by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients. (HEPATOLOGY 2013.).

Concepts: Regression analysis, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Alanine transaminase, Hepatitis C, Hepatitis B, Hepatitis A

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OBJECTIVE: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. DESIGN: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. RESULTS: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log(10) (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. CONCLUSIONS: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

Concepts: DNA, Molecular biology, Cirrhosis, Liver, Alanine transaminase, Hepatitis C, Ribavirin, Hepatitis A

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BACKGROUND & AIMS:: Studies of primary biliary cirrhosis (PBC) phenotypes have largely been performed using small and used selected populations. Study size has precluded investigation of important disease sub-groups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes. METHODS:: We performed a cross-sectional study using the United Kingdom-PBC patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures). RESULTS:: Seventy-nine percent of the patients reported current UDCA therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response, P <.05); male sex was an independent predictor of non-response on multivariate analysis. Age at diagnosis was strongly and independently associated with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than 70 y, to less than 50% for those younger than 30 y ( P <.0001). Patients who presented at younger ages were also significantly more likely not respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's ( P <.0001). The increase in fatigue severity in women was strongly related (r=0.58, P <.0001) to higher levels of autonomic symptoms ( P <.0001). CONCLUSIONS:: Among patients with PBC, response to UDCA treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at <50 years of age. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.

Concepts: Cirrhosis, Symptoms, Symptom, Alanine transaminase, Hepatology, Post-concussion syndrome, Primary biliary cirrhosis, Ursodiol

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The present study investigated the acute, subchronic and genotoxicity of turmeric essential oil (TEO) from Curcuma longa L. Acute administration of TEO was done as single dose up to 5 g of TEO per kg body weight and subchronic toxicity study for thirteen weeks was done by daily oral administration of TEO at doses 0.1, 0.25 and 0.5 g/kg b.wt. in Wistar rats. There were no mortality, adverse clinical signs or changes in body weight; water and food consumption during acute as well as subchronic toxicity studies. Indicators of hepatic function such as aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were unchanged in treated animals compared to untreated animals. Oral administration of TEO for 13 weeks did not alter total cholesterol, triglycerides, markers of renal function, serum electrolyte parameters and histopathology of tissues. TEO did not produce any mutagenicity to Salmonella typhimurium TA-98, TA-100, TA-102 and TA-1535 with or without metabolic activation. Administration of TEO to rats (1 g/kg b.wt) for 14 days did not produce any chromosome aberration or micronuclei in rat bone marrow cells and did not produce any DNA damage as seen by comet assay confirming the non toxicity of TEO.

Concepts: Bone, Mutation, Bone marrow, Liver function tests, Aspartate transaminase, Alanine transaminase, Mutagen, Curcuma