Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.

BACKGROUND: Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown. OBJECTIVE: We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS. DESIGN: Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included. RESULTS: Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations. CONCLUSIONS: In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and insulin resistance. Hence, to maintain homeostasis, the liver upregulates these enzymes, leading to changes in the amounts of amino acids released into the circulation.

Predominance of released mitochondrial enzymes by partial hepatectomy-induced rat regenerating liver is controlled by hemodynamic changes and not related to mitochondrial damage.

OBJECTIVE: Serum activities of assumed organ-specific enzymes are useful protein markers in the diagnosis of necrotic liver diseases. However, after partial hepatectomy (PH) in rats, remaining hepatocytes proliferate to restore the lost liver mass, even when there is a drastic but selective elevation of serum enzyme activities. The aim of the present study was to elucidate the underlying mechanisms involved in this PH-induced enhancement of enzyme release. MATERIAL AND METHODS: Routine spectrophotometric methods were used to measure nine "marker" enzyme activities in sera, in effluents from isolated perfused livers, as well as in the incubation media used for liver slices and isolated cells from either sham-operated or 70%-PH rats. RESULTS: PH induced a drastic increase in serum activities of liver enzymes, predominantly of mitochondrial localization. In the control and 70%-PH groups, liver enzymes were differentially released by varying in vitro flow rate/liver mass ratio, using livers perfused at variable flow rates. This event was reversible and not associated with liver structural or functional alterations, but was dependent on the flow-bearing physical forces and independent of production of extra-hepatic factors. Liver slices and isolated cells were used to identify additional flow-independent enzyme release. The 70%-PH-induced drastic release of specific enzymes (predominantly those from mitochondria) could be mimicked in control livers by changing the hepatic blood flow/mass ratio, and closely resembled urea production by these livers. CONCLUSIONS: PH-induced effects were not associated with liver necrosis or mitochondrial dysfunction and evidenced previously unrecognized mechanisms controlling the rate of enzyme release into the bloodstream, which might have clear clinical implications.

Levels and interactions of plasma xanthine oxidase, catalase and liver function parameters in Nigerian children with Plasmodium falciparum infection.

Elevated plasma levels of xanthine oxidase and liver function parameters have been associated with inflammatory events in several human diseases. While xanthine oxidase provides in vitro protection against malaria, its pathophysiological functions in vivo and interactions with liver function parameters remain unclear. This study examined the interactions and plasma levels of xanthine oxidase (XO) and uric acid (UA), catalase (CAT) and liver function parameters GOT, GPT and bilirubin in asymptomatic (n=20), uncomplicated (n=32), and severe (n=18) falciparum malaria children aged 3-13 years. Compared to age-matched control (n=16), significant (p<0.05) elevation in xanthine oxidase by 100-550%, uric acid by 15.4-153.8%, GOT and GPT by 22.1-102.2%, and total bilirubin by 2.3-86% according to parasitaemia (geometric mean parasite density (GMPD)=850-87100 parasites/microL) was observed in the malarial children. Further comparison with control revealed higher CAT level (16.2+/-0.5 vs 14.6+/-0.4 U/L; p<0.05) lacking significant (p>0.05) correlation with XO, but lower CAT level (13.4-5.4 U/L) with improved correlations (r=-0.53 to -0.91; p<0.05) with XO among the asymptomatic and symptomatic malaria children studied. 75% of control, 45% of asymptomatic, 21.9% of uncomplicated, and none of severe malaria children had Hb level>11.0 g/dL. Multivariate analyses further revealed significant (p<0.05) correlations between liver function parameters and xanthine oxidase (r=0.57-0.64) only in the severe malaria group. We conclude that elevated levels of XO and liver enzymes are biochemical features of Plasmodium falciparum parasitaemia in Nigerian children, with both parameters interacting differently to modulate the catalase response in asymptomatic and symptomatic falciparum malaria.

Copper concentrations in tap water and possible effects on infant's health--results of a study in Lower Saxony, Germany.

Copper in drinking water has been associated with non-Indian childhood cirrhosis (NICC), a form of liver cirrhosis in childhood. This epidemiological study examines the exposure of infants to increased copper concentrations through drinking water from public water supplies in southern Lower Saxony, Germany, and whether this dietary copper intake causes liver damage in early childhood. In total, water samples from 1674 households with infants were tested for copper. The mean copper concentration was 0.18 mg/L in the 1619 collected stagnation samples and 0.11 mg/L in the 1660 random daytime samples. There were notable regional differences in copper values. In 10.3% of all sampled households a copper value of 0.5 mg/L or more was found. These families were requested to additionally collect 2 composite samples. An increased level of copper in the drinking water with copper concentrations at or above 0.8 mg/L in the composite samples and a defined minimum ingestion of tap water was followed by a recommendation of a pediatric examination. Fourteen infants were examined by a pediatrician and of these 11 received a blood serum analysis. None of the examined infants showed any signs of liver malfunction. From the results of the study, no indication of a hazard due to copper pipes connected to public water supplies could be found.

[A study of serum mitochondrial enzymes(mCK, mAST, mMDH) in rotavirus and adenovirus gastroenteritis in pediatric patients].

Rotavirus and adenovirus antigens in feces from 77 cases of gastroenteritis in pediatric patients were examined. Mitochondrial enzymes, mitochondrial creatine kinase(mCK), mitochondrial aspartate amino-transferase(mAST) and mitochondrial malate dehydrogenase(mMDH) activities in their sera were also measured and compared with the results of rotavirus and adenovirus antigens in the feces. Thirty-one cases were rotavirus antigen-negative(rota-negative)/adenovirus antigen-negative(adeno-negative), 5 were rota-negative/adenovirus antigen-positive(adeno-positive), 40 were rotavirus antigen-positive(rota-positive)/adeno-negative, and only one case showed positive for both antigens. The mean activities of these three enzymes were compared among 3 groups except one both positive case mentioned above and control group(n = 105) by Mann-Whitney U-test. The serum mCK activity was significantly higher in rota-positive/adeno-negative patients than in other groups(p < 0.01). On the other hand, no significant differences were observed for mAST and mMDH activities among any groups. It is suggested that these phenomena are caused by the differences of localization of these enzymes in mitochondria, that mCK is located the outer surface of inner membrane of mitochondria, and mAST and mMDH are located on the inner surface. The difference of serum mCK activity between rotavirus infection and adenovirus infection suggests that intestinal epithelial cell injury by rotavirus is stronger than that by adenovirus.