Alanine Transferase Levels Research Articles

Jadenu® Substituting Exjade® in Iron Overloaded β-Thalassemia Major (BTM) Patients: A Preliminary Report of the Effects on the Tolerability, Serum Ferritin Level, Liver Iron Concentration and Biochemical Profiles.

IntroductionDue to the chronic nature of chelation therapy and the adverse consequences of iron overload, patient adherence to therapy is an important issue. Jadenu ® is a new oral formulation of deferasirox (Exjade ®) tablets for oral suspension. While Exjade® is a dispersible tablet that must be mixed in liquid and taken on an empty stomach, Jadenu ® can be taken in a single step, with or without a light meal, simplifying administration for the treatment of patients with chronic iron overload. This may significantly improve the compliance to treatment of patients with β-thalassemia major (BMT). The aim of this study was to evaluate the drug tolerability and the effects of chelation therapy on serum ferritin concentration, liver iron concentration (LIC) and biochemical profiles in patients with BMT and iron overload.Patients and MethodsTwelve selected adult patients BMT (mean age: 29 years; range:15–34 years) were enrolled in the study. All patients were on monthly regular red cell transfusion therapy to keep their pre-transfusional hemoglobin (Hb) level not less than 9 g/dL. They were on Exjade® therapy (30 mg/kg per day) for two years or more before starting Jadenu® therapy (14–28 mg/kg/day). The reason for shifting from Deferasirox® to Jadenu® therapy was lack of tolerability, as described by patients, such as nausea, vomiting, diarrhea, stomach pain. Most of them also reported that Deferasirox® was not palatable. Lab investigations included monthly urine analysis and measurement of their serum concentrations of creatinine, fasting blood glucose (FBG), serum ferritin, alkaline phosphatase (ALP), alanine transferase (ALT), aspartate transferase (AST) and albumin concentrations. LIC was measured using FerriScan ®. Thyroid function, vitamin D and serum parathormone, before and one year after starting Jadenu ® therapy, were also assessed.ResultsApart from some minor gastrointestinal complaints reported in 3 BMT patients that did not require discontinuation of therapy, other side effects were not registered during the treatment. Subjectively, patients reported an improvement in the palatability of Jadenu® compared to Exjade® therapy in 8 out of 12 BMT patients. A non-significant decrease in LIC measured by FerriScan® and serum ferritin levels was observed after one year of treatment with Jadenu®. A significant positive correlation was found between serum ferritin level and LIC measured by the FerriScan® method. LIC and serum ferritin level correlated significantly with ALT level (r = 0.31 and 0.45 respectively, p < 0.05). No significant correlation was detected between LIC and other biochemical or hormonal parameters.ConclusionsOur study shows that short-term treatment with Jadenu ® is safe but is associated with a non-significant decrease in LIC and serum ferritin levels. Therefore, there is an urgent need for adequately-powered and high-quality trials to assess the clinical efficacy and the longterm outcomes of new deferasirox formulation.

Alterations in lipid peroxidation, lipid profile, insulin sensitivity, and hepatic histopathological changes in diabetic rats following the treatment with Salvadora persica.

We examined the effects of various partitions of Salvadora persica extract on lipid profile (LP), lipid peroxidation, and insulin sensitivity (IS) of diabetic rats. The rats were divided into normal control, diabetic control (DC), standard, sham, and test groups. The test groups were treated with an oral dose of 200, 400, and 600 mg/kg of crude, aqueous, and ethyl acetate partition of S. persica extract. After 21 days of experiment, the fasting blood glucose (FBS), LPs, lipid peroxidation, IS, liver enzymes levels, liver histopathology, and body weight alteration were evaluated. A significant decrease in FBS and lipid profile (except HDL) were observed in rats treated with various dose of extract compared with the DC rats ( P < 0.05). Treating diabetic rats with various extracts of S. persica meaningfully decreased the level of malondialdehyde ( P < 0.05). Animals treated with various dose of aqueous extract showed better results ( P < 0.01). On the basis of used indirect indexes to determine IS, all partitions of extracts showed anti-insulin resistance effects in diabetic rats. On the basis of our statistical analyzing, treating diabetic rats with all of the three extracts of S. persica decreased the elevated levels of alanine phosphatase, aspartate aminotransferase, and alanine transferase. Also, pathological changes in the liver tissue were reduced following treatment with the S. persica. In conclusion, our results give evidence that the S. persica extract, especially aqueous partition, has a healing effect on diabetes and can be considered as an alternative therapy for this disease.

Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis.

In the multidrug resistance protein 2 (Mdr2)-/- mouse model, low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2-/- mice, intrahepatic CD8+ lymphocytes were expanded, and contraction of intrahepatic Tregs coincided with rising serum alanine transferase and alkaline phosphatase (ALP) levels between days 14-30 of life. Antibody-mediated depletion of intrahepatic CD8+ lymphocytes during that time reduced ALP levels and the expression of osteopontin (Opn), a pro-fibrogenic cytokine. Depletion of intrahepatic Tregs with anti-CD25 antibody between days 7-30 increased intrahepatic CD8+ T cells, Opn expression, and fibrosis. Conversely, expansion of intrahepatic Tregs with interleukin 2/anti-interleukin 2 immune complexes (IL-2c) downregulated hepatic expression of Opn and Tnf, reduced frequency of intrahepatic CD8+ lymphocytes, and diminished biliary injury and fibrosis. Treatment with IL-2c upregulated hepatic Treg expression of CD39, an ectonucleotidase capable of hydrolyzing pro-inflammatory adenosine triphosphate. In vitro, Tregs expressing CD39 suppressed the proliferation of hepatic CD8+ lymphocytes from Mdr2-/- mice more efficiently than those lacking CD39. In infants with BA, infiltration of interlobular bile ducts with CD8+ cells was associated with biliary expression of Opn and its transcription was negatively correlated with mRNA expression of Treg-associated genes. Conclusion: Hepatic CD8+ T lymphocytes drive biliary injury and fibrosis in murine SC. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL-2c, suggesting that Treg-directed low-dose Il-2 treatment may be considered as therapy for SC.

Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis.

Background Liver allograft preservation frequently involves static cold storage (CS) and machine perfusion (MP). With its increasing popularity, we investigated whether MP was superior to CS in terms of beneficial outcomes. Methods Human studies and large animal studies that optimized livers for transplantation using MP versus CS were assessed (PubMed/Medline/EMBASE). Meta-analyses were conducted for comparisons. Study quality was assessed according to the Newcastle-Ottawa quality assessment scale and SYRCLE's risk of bias tool. Results Nineteen studies were included. Among the large animal studies, lower levels of lactate dehydrogenase (SMD -3.16, 95% CI -5.14 to -1.18), alanine transferase (SMD -2.46, 95% CI -4.03 to -0.90), and hyaluronic acid (SMD -2.48, 95% CI -4.21 to -0.74) were observed in SNMP-preserved compared to CS-preserved livers. NMP-preserved livers showing lower level of hyaluronic acid (SMD -3.97, 95% CI -5.46 to -2.47) compared to CS-preserved livers. Biliary complications (RR 0.45, 95% CI 0.28 to 0.73) and early graft dysfunction (RR 0.56, 95% CI 0.34 to 0.92) also significantly reduced with HMP preservation in human studies. No evidence of publication bias was found. Conclusions MP preservation could improve short-term outcomes after transplantation compared to CS preservation. Additional randomized controlled trials (RCTs) are needed to develop clinical applications of MP preservation.

Semicarbazide-sensitive amine oxidase activity levels in patients with acute lymphoblastic leukemia after cytotoxic chemotherapy

BackgroundThe role of Semicarbazide-sensitive amine oxidase (SSAO) in carcinogenesis is unknown; however, due to its function it may be involved in tumorigenesis via production of reactive aldehydes and hydrogen peroxide. ObjectiveThe study aimed to assess serum SSOA activity and to investigate the effect of cytotoxic chemotherapy on liver function in patients with acute lymphoblastic leukemia (ALL). Materials and MethodsSamples from 25 children with ALL were taken before and after finishing the induction phase of chemotherapy with (Daunorubicin, Vincristine VRC, L-asparaginase, Cyclophosphamide, Cytosar, Dexon, and Adriamycin). Activity of SSAO and liver function tests (alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP) and total serum bilirubin TSB) were measured using colorimetric methods before and after treatment. ResultsSignificant lower level in SSOA activity was found in 68% of the patients (P < 0.05) after chemotherapy. Significant higher levels were found after chemotherapy in ALT, AST, ALP activities and TSB levels in 92%, 80%, 72%, and 80% of the patients respectively. ConclusionThe decrease in SSAO activities after chemotherapy could be a mechanism for preventing the formation of the pro-inflammatory byproducts of SSAO. The increase in liver function could be a response to chemotherapy metabolism in liver cells.

Protection by the Total Flavonoids from Rosa laevigata Michx Fruit against Lipopolysaccharide-Induced Liver Injury in Mice via Modulation of FXR Signaling.

We previously reported the effects of the total flavonoids (TFs) from Rosa laevigata Michx fruit against carbon tetrachloride-induced liver damage, non-alcoholic fatty liver disease, and liver ischemia-reperfusion injury. However, there have been no papers reporting the role of R. laevigata TFs against lipopolysaccharide (LPS)-induced liver injury. In this paper, liver injury in mice was induced by LPS, and R. Laevigata extract was intragastrically administered to the mice for 7 days. Biochemical parameters in serum and liver tissue were examined, and pathological changes were observed by transmission electron microscopy, hematoxylin and eosin (H&E) and Oil Red O staining. The results showed that the TFs markedly reduced serum ALT (alanine transferase), AST (aspartate transaminase), TG (total triglyceride), and TC (total cholesterol) levels and relative liver weights and improved liver pathological changes. In addition, the TFs markedly decreased tissue MDA (malondialdehyde) level and increased the levels of SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase). A mechanistic study showed that the TFs significantly increased the expression levels of Nrf2 (nuclear erythroid factor2-related factor 2), HO-1 (heme oxygenase-1), NQO1 (NAD(P)H dehydrogenase (quinone 1), GCLC (glutamate-cysteine ligase catalytic subunit), and GCLM (glutamate-cysteine ligase regulatory subunit) and decreased Keap1 (Kelch-like ECH-associated protein 1) level by activating FXR (farnesoid X receptor) against oxidative stress. Furthermore, the TFs markedly suppressed the nuclear translocation of NF-κB (nuclear factor-kappa B) and subsequently decreased the expression levels of IL (interleukin)-1β, IL-6, HMGB-1 (high -mobility group box 1), and COX-2 (cyclooxygenase-2) by activating FXR and FOXO3a (forkhead box O3) against inflammation. Besides, the TFs obviously reduced the expression levels of SREBP-1c (sterol regulatory element-binding proteins-1c), ACC1 (acetyl-CoA carboxylase-1), FASN (fatty acid synthase), and SCD1 (stearoyl-coenzyme A desaturase 1), and improved CPT1 (carnitine palmitoyltransferase 1) level by activating FXR to regulate lipid metabolism. Our results suggest that TFs exhibited protective effect against LPS-induced liver injury by altering FXR-mediated oxidative stress, inflammation, and lipid metabolism, and should be developed as an effective food and healthcare product for the therapy of liver injury in the future.

Thymoquinone and diallyl sulfide protect against fipronil-induced oxidative injury in rats.

Fipronil (FPN) is a phenylpyrazole insecticide, widely used for agricultural and veterinary activities. Early reports indicated that FIP organ toxicity is primarily mediated by the induction of oxidative stress. Both thymoquinone (TQ) and diallyl sulfide (DAS) are natural antioxidants with established health benefits. This study investigated the potential ameliorative effects of DAS and TQ against FPN-induced toxicity in rats. Thirty-two male Wistar rats (150-180g) were randomized into four treatment groups, receiving (I) saline, (II) FPN (10mg/kg bw), (III) FPN with DAS (200mg/kg bw), and (IV) FPN with TQ (10mg/kg bw). All treatments were administered once daily for 28days. The results showed that compared to the control rats, FPN-treated rats had significantly increased (p < 0.05) serum levels of uric acid, urea, creatinine, cholesterol, aspartate transferase, alanine transferase, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyl transferase. Moreover, FPN significantly reduced (p < 0.05) the serum levels of total proteins, albumin, and triglycerides. In addition, compared with the control group, FPN-treated rats had significantly elevated (p < 0.05) malondialdehyde and nitric oxide levels, as well as significantly reduced glutathione concentration and activities of glutathione peroxidase, superoxide dismutase, and catalase enzymes in the hepatic, renal, and brain tissues. Cotreatment with DAS or TQ significantly ameliorated (p < 0.05) the FPN-induced alterations in all the previously mentioned parameters with more frequent restoration of normal control ranges in the TQ group. In conclusion, both DAS and TQ alleviated the oxidative injury of FPN, probably by enhancing tissue antioxidant defenses.

Metformin alleviates liver injury through mTOR-mediated T cell regulation in viral hepatitis in mice

Abstract Metformin is not only the first-line medication for the treatment of type 2 diabetes, but also has other effects, such as anti-inflammatory, anti-oxidative, and anti-tumor activities, in animal models. However, the therapeutic potential of metformin during viral hepatitis is uncertain. In this study, C57BL/6 mice were treated with oral administration of metformin (250 mg/kg) for 7 days daily, infected with different doses of adenovirus (i.v. inoculation), and then received metformin for another 7 days. All mice were sacrificed at 7 days post-infection. We found that metformin treatment ameliorated the liver injury induced by different doses of adenovirus infection, as judged by the significant decrease in liver alanine transferase levels, liver histopathology scores, as well as intrahepatic lymphocyte (IHL) and splenocyte counts. Compared to the PBS-treated groups, metformin-treated mice had significantly decreased numbers of activated T cells in the liver, as well as expression of IL-2, IFN-γ, and TNF-α in CD4+ and CD8+ T cells, especially among CD8+ T cells. Metformin treatment also significantly reduced phosphorylated S6 kinase beta 1 (S6K1)-positive CD4+ and CD8+ T cells in the liver, indicative of decreased mTORC1 activity in these cells. These data indicate that metformin can alleviate adenovirus-induced acute liver injury in mice, and that the beneficial effects of metformin may be mediated in part through mTORC1 pathway in T lymphocytes.

Inclusion of Moringa Leaf Powder (Moringa oleifera) in Fodder for Feeding Japanese Quail (Coturnix coturnix japonica)

ABSTRACT This research evaluated the nutritional, nutraceutical, antimicrobial, as well as the growing promoter effect of Moringa oleifera (MOR) leaves flour in fodders for fattening Japanese quails. The antimicrobial activity was measured using the method of Kirby-Bauer. A completely random design with 4x2 factorial arrangement was used, fodders included 0, 7, 14, and 21% of MOR, with and without Virginiamycin (100 ppm), during 35 d of fattening, 480 one-day old unsexed quails were used, each treatment had 5 replicates with 12 quails/cage. MOR inhibited the growth of bacteria gram (+) and gram (-). The inclusion of MOR in the period from 1 to 14 d inhibited the weight gain (p<0.001), increased feed conversion (p<0.001), without affecting the feed intake; however, in the period of 15 to 35 d MOR did not affect weight gain and the feed intake; the hematological and biochemical profile were within the normal range for quails. The inclusion of MOR decreased (p≤0.001) cholesterol and triglycerides concentrations. Levels of aspartate aminotransferase (AST), alanine transferase (ALT), and creatinine decreased (p≤0.001) when the amount of substitution of MOR was 21%. The carcass weight and its yield with MOR up to 14% were similar (p<0.001). The results of this experiment showed that flour from leaves of Moringa oleifera is a viable alternative to be included up to 14% in commercial diets of birds offering an option for AGP replacement without compromising the health of the animal and therefore its productivity.

Oral Administration of Escherichia coli Endotoxin Caused Liver - Kidney Dysfunction and Death in Rabbits

This study was carried out to determine the effects of ingested endotoxin on cellular and histological parameters in European albino rabbits - Oryctolagus cuniculus. Twenty-four (24) rabbits of either sexes weighing 1.5-1.8 kg each were randomly grouped into four of six (6) rabbits per group. The control group, A was orally administered with 5 % w/v dextrose containing 0 EU/ml and hence received 0 EU/kg body weight; groups B, C and D received 50, 500 and 1000 EU/kg body weight respectively, once daily by 10 am prior feeding for a total of 21 days. On a daily basis, blood samples were taken from each animal and serum levels of alanine transferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and catalase activities; bilirubin, malondialdehyde, total protein, albumin (ALB), urea, uric acid and creatinine levels were assayed for. At the end of the 21 days a mortality of 20.83 % was recorded in the groups administered with endotoxin (500 and 1000 EU/kg bw). Also, there was significant increase (p &lt;0.05) in the serum activities of ALT, AST and ALP; significantly reduced total protein and ALB levels with significant (p&lt;0.05) increase in endotoxin doses and duration of the administration. There was significant increase (p&lt;0.05) in bilirubin, urea and creatinine levels in the serum. Histopathology examinations show tissue degeneration in the liver, heart, kidney and lung related to increased dosages and durations of the orally administered endotoxin. We therefore conclude that oral ingestion of endotoxin causes damage to the liver, kidney, heart and the lungs in rabbits, especially when prolonged.

English

Paracetamol toxicity due to overdose amongst people living in the developing countries has been on the increase. This study investigated the amelioration potentials of Vernonia calvaona ethanol leaf extract in paracetamol-treated rats. Thirty five Wistar rats were divided into five groups of seven rats each. Hepatic damage was induced by administering 2 g/kg b.wt of paracetamol p.o for four day to all the groups except group 1 (normal control). This was followed by 21 days treatment with crude ethanol extract of V. calvaona (VC) leaf as well as vitamin E. Group 2 received 2 g/kg b.wt of paracetamol while groups 3 and 4 received 200 and 400 mg VC extracts/kg b.wt, respectively. Group 5 received vitamin E 100 mg/kg b.wt. and histology of the liver, respectively. The result showed a significant (p˂0.05) increase in serum alanine transferase (ALT), aspartate transferase (AST) and ALP during the pre-treatment phase while the treatment phase indicated a significant (p˂0.05) reduction in the serum ALT, AST and alkaline phosphatase (ALP) levels in a dose dependent pattern relative to the controls. The 400 mg VC extract/kg b.wt and the vitamin E 100 mg/kg b.wt reversed the levels of these enzymes to a non-significant (p˂0.05) difference relative to the controls. The histology of the liver in the VC extract treated groups indicated regeneration of the hepatocytes when compared to the control. It is therefore suggested that crude extract of V. calvaona leaf possesses protective effect against paracetamol induced hepatic damage in rats. &nbsp; Key words: Amelioration potentials, liver function biomarkers, Vernonia calvoana.

Effect of the acute heat stress on serum endotoxin concentration and the expression of TLR4 mRNA in liver of Arbor Acres broiler chickens

This study was undertaken to investigate the relationship between gut-derived endotoxin and the Toll-like receptor 4 (TLR4) expression in the liver of broilers under acute heat stress (AHS). For this purpose, 120 Arbor Acres chicks were randomised into two groups: control temperature group (CT group, 22 ± 1°C) and high temperature group (HT group, 38 ± 1°C). The chicks received AHS at Day 28 and their small intestine, liver and blood samples were collected after 2 h, 5 h and 10 h to examine the histopathology, biochemical parameters, endotoxin concentrations and TLR4 expression. The results showed that damaged intestinal villi and severe congestion of the hepatic sinusoids were observed, especially after 10 h of AHS in the HT group. In addition, the levels of alanine transferase, aspartate transaminase, and direct bilirubin, except alkaline phosphataseafter were significantly elevated (P &lt; 0.05) and total bilirubin (P &lt; 0.01) and albumin (P &lt; 0.05) were decreased after 10 h of AHS as compared with the CT group, which are associated with liver function. Moreover, the mRNA expression of TLR4 in the liver was noticeably upregulated (P &lt; 0.05) during AHS with significantly increased in endotoxin concentration (P &lt; 0.01) of broilers. Altogether, these findings suggest that the upregulated expression of TLR4 mRNA was triggered via gut-derived endotoxin in heat stress-induced liver injury.

The Impact of Iron Overload in Patients with Acute Leukemia and Myelodysplastic Syndrome on Hepatic and Endocrine functions.

Patients with hematologic malignancies undergoing chemotherapy and requiring blood transfusion usually have an elevated serum ferritin. These findings have led to the suggestion that iron overload is common and may have deleterious effects in these patients. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. Therefore, we measured the liver iron content (LIC) by the FerriScan® method and investigated the liver function and some endocrine tests in 27 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS). Using FerriScan® method, the normal mean LIC levels are: 4.3±2.9 mg Fe/g dry weight (d.w.). In our patients, the mean serum ferritin level was 1965±2428 ng/mL. In our patients, the mean total iron in the blood received by them was 7177±5009 mg. In 6 out of 27 patients LIC was >7 mg Fe/g d.w. and in 11/27 serum ferritin was >1000 ng/ml. Measuring fasting blood glucose revealed 3/27 with diabetes mellitus and 4/27 with impaired fasting glucose (IFG). All patients had normal serum concentrations of calcium, parathormone (PTH), free thyroxine (FT4) and thyrotropin (TSH). Four patients had elevated serum alanine transferase (ALT). LIC was correlated significantly with ferritin level (r=0.5666; P<0.001) and the cumulative amount of iron in the transfused blood (r=0.523; P<0.001). LIC was correlated significantly with ALT (r=0.277; P = 0.04) and fasting blood glucose (FBG) was correlated significantly with the amount of iron transfused (r=0.52, p<0.01) and ALT level (r=0.44; P<0.01). The age of patients did not correlate with LIC, FBG or ALT. In conclusions, these results contribute to our understanding of the prevalence of dysglycemia and hepatic dysfunction in relation to parenchymal iron overload in patients with hematologic malignancies undergoing chemotherapy and requiring blood transfusions. (www.actabiomedica.it)

Effects of Dietary Supplementation of Fermented Rice Bran (FRB) or Fermented Broken Rice (FBR) on Laying Performance, Egg Quality, Blood Parameter, and Cholesterol in Egg Yolk of Hy-Line Brown Laying Hens

This experiment was aimed at investigating the effects of dietary supplementation with fermented rice bran (FRB) or fermented broken rice (FBR) on egg-laying performance, egg quality, blood parameters, and cholesterol level in egg yolk of Hy-Line Brown egg-laying hens. Altogether, 144 Hy-Line Brown egg-laying hens (32-week-old) were randomly allocated to one of 4 dietary treatment groups, with 4 replicates per treatment. Of them, 3 treatments diets were prepared by supplementing the basal diet with 0.1% probiotics (PRO), 1% fermented rice bran (FRB), or 1% fermented broken rice (FBR) at the expense of corn. Hen-day egg production was higher (<italic>P</italic>&lt;0.05) in PRO and FRB treatment groups than in the basal treatment groups. However, feed intake, egg weight, egg mass, and feed conversion ratio did not differ among the treatment groups. Additionally, supplementation with FRB or FBR did not affect eggshell strength, eggshell thickness, egg yolk color, and Haugh unit during the feeding trial. There was no significant difference in leukocyte count. Total cholesterol level was lower (<italic>P</italic>&lt;0.05) in the FRB treatment group than in the basal treatment groups. Asparate aminotransferase, alanine transferase, glucose, and albumin levels were unaffected by dietary supplementation with FRB or FBR. Egg yolk cholesterol level was lower (<italic>P</italic>&lt;0.05) in the FRB and FBR treatment groups than in the basal treatment groups. In conclusion, dietary supplementation with FRB or FBR improved egg-laying performance, and reduced the levels of total serum cholesterol and cholesterol in egg yolk of Hy-Line Brown egg-laying hens.

Efficacy and Safety of Mycophenolate Mofetil in Patients With Autoimmune Hepatitis and Suboptimal Outcomes After Standard Therapy

Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine. We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment. The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P = .07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events. In this retrospective study of patients with AIH who received mycophenolate mofetil as a rescue therapy, we found the drug to be well tolerated and moderately effective, inducing biochemical remission in 60% of subjects. Rates of response are lower and rates of infection are higher in patients with AIH and cirrhosis. Prospective studies of mycophenolate mofetil are warranted for this population.

The influence of the serum liver function, α-glutathione S-transferase and α-hydroxybutyrate dehydrogenase on pregnancy outcome in patients with intrahepatic cholestasis of pregnancy

Objective To explore the influence of the serum liver function, α-glutathione S-transferase(α-GST) and α-hydroxybutyrate dehydrogenase(α-HBDH) on pregnancy outcome in patients with intrahepatic cholestasis of pregnancy(ICP). Methods Retrospective analysis was conducted on the clinical data of 80 cases with ICP who admitted in our hospital from January 2013 to December 2015.The patients were divided into mild group and severe group.Biochemical indicators and the indicators reflecting poor pregnancy outcomes were analyzed. Results The levels of alanine transferase(ALT), aspartate transferase(AST), total bile acid(TBA) and direct bilirubin(DB) in the severe group were significantly higher than those in the mild group(t=4.07, 3.45, 3.50, 2.11, P=0.04, P<0.01). The incidence rate of fetal distress, premature delivery and pollution of amniotic fluid above II degree was significantly higher in the severe group(χ2=8.352, all P<0.01). There were no significant differences in gestational weeks, cesarean section rate, the amount of postpartum hemorrhage and neonatal birth weight between the two groups (χ2=4.178, P=0.892). Logistic regression analysis showed that gestational weeks, neonatal birth weight and the levels of TBA, AST, ALT, α-GST and α-HBDH were associated with the severity of ICP(all P<0.01). α-GST had higher sensitivity and specificity in predicting adverse perinatal outcomes, such as amniotic fluid, premature rupture of membranes, preterm birth, low birth weight and fetal distress. Conclusion The perinatal outcomes of pregnant women with severe ICP can be improved by grading management according to their serum biochemical indicators and active clinical intervention treatment.α-GST and α-HBDH can be used to evaluate the severity of ICP, which have higher clinical value in predicting poor pregnancy outcomes. Key words: Cholestasis, intrahepatic; Pregnancy; Glutathione s-transferase; Hydroxybutyrate dehydrogenase; Pregnancy outcomes

Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis C patients treated with all-oral direct-acting antivirals: Analysis of a Japanese prospective cohort.

Several case reports have shown that hepatitis B virus (HBV) reactivation developed in hepatitis C patients with a current or previous HBV infection during direct-acting antiviral (DAA) treatment, which led to severe hepatitis or death in some cases. However, its precise frequency and risk factors are not entirely clear. We analyzed a prospective cohort. We analyzed HBV reactivation in 461 consecutive hepatitis C patients who received 12weeks of ledipasvir/sofosbuvir for genotype 1 or sofosbuvir plus ribavirin for genotype 2 at multiple centers. By the examination of the preserved sera at baseline, 159 patients (34%) were identified as seropositive for HBV core antibody (anti-HBc) and were included in the subsequent analysis; 4 patients were positive for HBV surface antigen (HBsAg), and the others were negative. Serum HBV DNA was undetectable or was detectable but <20IU/mL at baseline for all patients. Serial measurement of HBV DNA at 4weeks and 12weeks in the preserved serum samples was available in 147 patients and identified HBV reactivation (defined as the appearance of serum HBV DNA ≥20IU/mL) in 2 HBsAg-positive and 3 HBsAg-negative patients. No patient developed HBV-associated hepatitis. Patients who developed HBV reactivation had significantly lower anti-HBs titers and higher serum alanine transferase levels before treatment. Hepatitis B virus reactivation during direct-acting antiviral therapies occurs in 3.4% (5/147) of patients who are positive for anti-HBc. A low titer of anti-HBs and a high serum alanine transferase level prior to treatment are associated with reactivation in this patient group.

Liver Histophysiological Alterations in Pelagic and Benthic Fish as Biomarkers for Marine Environmental Assessment

The present study aimed to evaluate changes in liver tissue and vitamin E, plasma levels of alanine transferase (ALT) and aspartate transferase (AST) in Acanthopagrus latus and Euryglossa orientalis. The fish were collected from six different Iranian fish landing stations and concentrations of Zn, Pb, Hg, Cu, and Cd were determined in the water and sediment samples taken from each station. Pronounced liver histological alterations, highest plasma levels of ALT and AST, and the lowest levels of vitamin E and total proteins were observed in both fish species caught at the most polluted petrochemical site. These results were in agreement with the increased levels of the metals in water and sediment from this station. There was a high correlation (average R 2 = 0.8) between Hg concentration in water from these stations and biochemical and histological alterations in A. latus. In conclusion, the alterations of the tissue structure and function of the liver could potentially be used as suitable biomarkers for marine environmental monitoring.

Detrimental effects of nicotine on thioacetamide-induced liver injury in mice

Aim: Nicotine exerts a number of physiological effects. The purpose of this study was to determine the effects of nicotine on thioacetamide (TAA)-induced liver fibrosis in mice.Materials and methods: For in vivo experiments, hepatic fibrosis was induced by TAA (0.25 g/kg, i.p.) three times a week for 6 weeks. Mice of TAA treated groups were administered daily with distilled water and nicotine (50 or 100 μg/mL) via gastrogavage throughout the experimental period. For in vitro experiments, HepG2 (human liver cancer cell line) and LX-2 (human hepatic stellate cell line) were used to determine oxidative stress and fibrosis, respectively.Results: Compared to control groups, TAA treated groups had significantly differences in serum alanine transferase and aspartate aminotransferase levels and nicotine accentuated liver injury. Moreover, nicotine increased the mRNA levels of TAA-induced transforming growth factor-β (TGF-β) and collagen type I alpha 1 in the liver. Nicotine also increased TAA-induced oxidative stress. Histological examination confirmed that nicotine aggravated the degree of fibrosis caused by TAA treatment. Additionally, nicotine enhanced hepatic stellate cell activation via promoting the expression of α-smooth muscle actin.Conclusions: Oral administration of nicotine significantly aggravated TAA-induced hepatic fibrosis in mice through enhancing TGF-β secretion and TAA-induced oxidative stress. The increase in TGF-β levels might be associated with the strengthening of oxidative processes, subsequently leading to increased hepatic stellate cell activation and extracellular matrix deposition. These results suggest that patients with liver disease should be advised to abandon smoking since nicotine may exacerbate hepatic fibrosis.

Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid

Tannic acid (TA) is the polyphenol that has beneficial health effects against oxidative stress. However, the hepatoprotective effects of TA are still relatively unknown. In the present study, we evaluated the effects of TA on an acetaminophen (APAP)-induced hepatotoxicity model, which was established by administration of 400mg/kg of APAP. The levels of alanine transferase (ALT), aspartate transferase (AST), dendothelin-1 (ET-1), nitric oxide (NO) and malondialdehyde (MDA) in the APAP-induced hepatotoxicity mice were significantly increased (up to ~200%), while their levels were reduced by pretreatment with TA (25 and 50mg/kg) (P<0.05). The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the APAP-induced hepatotoxicity mice were significantly reduced (lower to ~65%), while their activities were increased by pretreatment with TA (25 and 50mg/kg) (P<0.05). In addition, pretreatment with oral TA (25 and 50mg/kg) for 3days before the APAP administration dose-dependently ameliorated changes in hepatic histopathology, suppressed overexpression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), c-fos, c-jun, NF-κB (p65) and caspase-3 (all P<0.05), downregulated bax and upregulated bcl-2, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) (all P<0.05) in the liver. These results indicate that TA exhibits significant hepatoprotective effects against APAP-induced hepatotoxicity and suggest that the hepatoprotective mechanisms of TA may be related to anti-oxidation, anti-inflammation and anti-apoptosis.