A Rare Case of Drug Induced Liver Injury Secondary to Empagliflozin

Drug induced liver injury (DILI) is a condition with a wide clinical spectrum. The diagnosis represents a challenge not only due to the large number of known hepatotoxic products but especially when the substance involved is not known to induce liver damage. Empagliflozin is linked to several adverse effects but has not been convincingly associated to DILI. We report a case of a 70-year-old type 2 diabetic woman that presented with gastrointestinal symptoms 1 month after empagliflozin introduction. Elevated hepatic enzymes were found and despite ultrasound evidence of vesicular microlithiasis, no biliary obstruction was confirmed. Other causes of liver injury were excluded and the diagnosis of DILI secondary to empagliflozin was made after liver biopsy. Complete clinical and laboratorial resolution was verified after empagliflozin withdrawal. Only two cases of DILI were reported since empagliflozin licensure which makes this case more interesting, alerting clinicians to an early diagnosis and appropriate treatment.

Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism

Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from Gardenia jasminoides J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl4) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.

Cadmium Exposure Decreases Fasting Blood Glucose Levels and Exacerbates Type-2 Diabetes in a Mouse Model

Purpose Although the effects of cadmium (Cd) on the development of diabetes have been extensively investigated, the relationship between Cd exposure and the severity of established diabetes is unclear. Herein, we investigate the effects of long-term exposure to Cd in a streptozotocin-induced mouse model of type 2 diabetes and the underlying mechanism. Methods C57BL/6 Mice were divided into the following four groups: 1) control group; 2) Cd-exposed group; 3) diabetic group; 4) Cd-exposed diabetic group. Cd exposure was established by the administration of 155 ppm CdCl2 in drinking water. After 25 weeks of treatment, serum fasting glucose and insulin were measured. Meanwhile, the liver and pancreas specimens were sectioned and stained with Hematoxylin and eosin. Gluconeogenesis, glycolysis, lactate concentration and fibrosis in liver were evaluated. Results Clinical signs attributable to diabetes were more apparent in Cd-exposed diabetic mice. Interestingly, Cd exposure significantly decreased fasting blood glucose levels in diabetic group. We further demonstrated that the glycolysis related hepatic enzymes, pyruvate kinase M2 (PKM-2) and lactic dehydrogenase A (LDHA) were both increased, while the gluconeogenesis related hepatic enzymes, phosphoenolpyruvate-1 (PCK-1) and glucose-6-phosphatase (G6Pase) were both decreased in Cd exposed diabetic mice, indicating that Cd increased glycolysis and inhibited gluconeogenesis in diabetic model. Moreover, lactate accumulation was noted accompanied by the increased inflammation and fibrosis in the livers of diabetic mice following Cd exposure. Conclusions Cd exposure disturbed glucose metabolism and exacerbated diabetes, providing a biological relevance that DM patients are at greater risk when exposed to Cd.

Health concerns of lambs fed cottonseed hulls combined with chitosan by examining the blood metabolic profile and histopathology of the kidney, liver, and rumen

This study analysed the effect of cottonseed hulls and chitosan in diets for lambs by determining the blood metabolite profile, and the histopathology of the kidney, liver, and rumen. Eighty non-castrated Santa Inês lambs, approximately 120 days of age and a mean initial body weight (b.w.) of 22.6 (standard deviation ± 2.2 kg) were assigned to a completely randomised design, with a 2 × 2 factorial arrangement. Two chitosan levels and two cottonseed forms were evaluated. The experimental diets were following: diet containing whole cottonseed hulls (WC) without the addition of chitosan; diet containing WC with 136 mg/kg b.w. chitosan added; diet containing ground cottonseed hulls (GC) without the addition of chitosan; diet containing GC with 136 mg/kg b.w. chitosan added. The blood metabolites and hepatic enzymes ALT, AST, GGT were not significantly influenced in the treatment groups, except for the serum cholesterol concentration which was lower (P < 0.05) when the chitosan was combined with the whole cottonseed hulls. There were histopathological alterations (P < 0.05) in the liver and kidney tissue and moderate changes in the rumen samples in the animals fed cottonseed without chitosan, however, when chitosan was added, the changes were less marked. The combination of chitosan with cottonseed hulls (ground or whole) can be supplied safely to feedlot finishing lambs without compromising their health.

Effects of hyperthyroidism on serum alanine amino transferase and alkaline phosphatase levels in liver

Background: Hyperthyroidism is one of the most common endocrine disorders. Thyroid hormones are essential for normal metabolic function of body cells including the liver cells. Again, metabolism of thyroid hormones takes place in liver. Therefore, hyperthyroidism may affect liver cells and causes change in hepatic enzymes level. Objective: To assess serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in hyperthyroid patients. Methods: This cross sectional study was conducted in the Department of Physiology of Dhaka Medical College from July 2016 to June 2017. Total number of 50 subjects of both sexes aged from 18 to 50 years were selected. Among them, 25 hyperthyroid patients were considered as the study group (B) and 25 age matched healthy subject were considered as control group (A). Serum ALT and ALP were estimated in the Biochemistry & Molecular Biology Department of BSMMU. For statistical analysis, Unpaired student’s ‘t’ test and Chi Square test were done. Results: Serum ALT and ALP levels were significantly (p<0.001) increased in patients suffering from hyperthyroidism. Conclusions: This study showed that detection of changes in serum hepatic enzymes in hyperthyroidism useful for prediction of developing liver disease. J Bngladesh Soc Physiol 2021;16(1): 44-48

The Effect of Alcoholic Extract of Thymus Vulgaris on Hepatic Enzymes Activity and Apoptosis-Related Gene Expression in Streptozotocin-Induced Diabetic Rats

Many diseases, including diabetes, are involve in the development of liver disorders through changes in the expression of genes such as apoptosis-related gene. In the present study, the effect of alcoholic extract of Thymus Vulgaris on Hepatic Enzymes Activity and apoptosis-related gene expression in streptozotocin-induced diabetic rats. In this study, 50 adult male Wistar rats weighing approximately 200–220 g were divided into five groups. Diabetes was induced by intraperitoneal injection of STZ (60 mg/kg). Following 18 days, all the animals in different groups were weighed and blood samples were taken from their cardiac veins. GC analysis revealed 45 different compounds in the Thymus Vulgaris, including; thymol (39.1%), p-cymene (20.63%), γ-Terpinene (14.85%). The results showed a significant increase in liver enzymes (AST, ALT and ALP) in diabetic or streptozoic mice compared to the control group (healthy mice) (p < 0.0001). The level of liver enzymes (AST, ALT and ALP) in rats treated with doses 200 mg/kg and 400 mg/kg of thymus vulgaris extract showed a significant decrease in these enzymes in comparison with diabetic rats (p < 0.0001). The expression of caspase 3 and 9 genes in the groups treated with thyme significantly decreased compared to diabetic mice (P < 0.0001) and the expression of Bcl in the group receiving 400 mg / kg of thyme significantly increased compared to diabetic mice (P = 0.0001). Due to its antioxidant compounds, thyme improves the liver tissue cells in streptozotocin-induced diabetic mice by reducing caspases 3 and 9 as well as increasing Bcl-2.

Bariatric Surgery Affects Plasma Levels of Alanine Aminotransferase Independent of Weight Loss: A Registry-Based Study

Patients that undergo bariatric surgery experience weight loss and a reduction in the plasma levels of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We used the Israeli national bariatric registry, which includes demographic, clinical, and biochemical data on 19,403 patients, of which 1335 patients had two-year follow-up data on ALT, AST, A1C, and BMI, to test the dependence of the reduction in the levels of ALT and AST on weight loss. The data were analyzed using regression models, retrospective matching, and time course analyses. Changes in liver enzymes did not correlate with change in BMI, and linear regression models did not demonstrate that the change in ALT and AST values were dependent on pre-operative levels of BMI or the extent of weight loss. ALT and AST levels were reduced two years after surgery compared with a cohort of retrospectively matched patients for ethnicity, sex, age, BMI, and A1C. Finally, patients who regained weight displayed a reduction in levels of liver enzymes. Our results suggest that bariatric surgery affects AST and ALT levels via weight loss dependent and independent mechanisms. Mechanistic studies that will identify the nature of this effect and the clinical relevance of ALT and AST levels to the post-bariatric liver function are warranted.

Probiotics Do Not Alter Liver Function Markers and Clinical Parameters in Patients With Nonalcoholic Steatohepatitis and Low Degree of Fibrosis

Objectives Evaluate the effect of probiotic supplementation on liver function markers, and clinical parameters, in nonalcoholic steatohepatitis (NASH) patients. Methods This double-blind, randomized clinical trial included adult outpatients with biopsy-proven NASH. The intervention: 24 weeks of supplementation with probiotic mix (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1 × 109 CFU for each) or placebo, twice a day. At baseline and 24-weeks after treatment, the following parameters were evaluated: demographic and clinical data, hepatic enzymes, laboratory assessment, serum concentration of toll-like receptor-4 (TLR-4), cytokeratin 18 (CK-18) biomarker and anthropometric data assessment. Results Forty-four patients completed the trial (51.4 ± 11.6 years, 59% women). At baseline, 87% had low hepatic fibrosis degree (26% F0; 61% F1 at biopsy), values of hepatic enzymes close to normal [AST 32 (24–46) U/L, ALT 42 (28–63) U/L, GGT 46 (28–84) U/L], increased waist circumference (104.7 ± 12 cm), body mass index (BMI) with obesity classification 30.97 (28.36–33.75) kg/m2 and 76% with Metabolic Syndrome (MetS). After 24 weeks, no differences were observed between the Probiotic and Placebo groups in the components of the MetS, waist circumference, BMI or liver enzymes (P &gt; 0.05 for all). CK-18 was reduced in both groups after the intervention: in the probiotic group from 981.09 (738.34–1134.73) to 639.46 (509.50–817.23) mIU/ml (P ≤ &lt; 0.01) and in the placebo group from 789.74 (540.80–985.65) to 605.45 (472.13–837.22) mIU/ml (P = 0.013), however with no significant difference between groups (P = 0.109). Likewise, TLR-4 was reduced in both groups after the intervention, also with no difference between groups (P = 0.885). Conclusions The intervention with probiotics for 24 weeks in patients with NASH with low degree of fibrosis demonstrated to be unable to promote significant changes in the reduction of liver injury and inflammation biomarkers, nutritional and clinical parameters. Funding Sources Research and Events Fund from the Hospital de Clínicas de Porto Alegre (FIPE), Coordination for the Improvement of Higher Education Personnel (CAPES/PROAP), National Council for Scientific and Technological Development – Brazil (CNPq).