Obeticholic Acid Improves Aminotransferases Early during Treatment in Patients with Primary Biliary Cholangitis Not Responding to Ursodeoxycholic Acid: A Study in Clinical Practice

Obeticholic acid (OCA) improves cholestasis and is generally well tolerated in patients with primary biliary cholangitis (PBC) not responding, or intolerant, to ursodeoxycholic acid (UDCA). As PBC is mainly a cholestatic disorder, less attention is paid to aminotransferase behavior in the course of treatment. In this study we evaluated, in clinical practice, the efficacy of OCA treatment on both alkaline phosphatase (ALP) and alanine aminotransferase (ALT) using updated healthy ranges for aminotransferases. Fifteen PBC patients, non-responders to UDCA, were evaluated at baseline and during OCA treatment with serial measurement of cholestasis indexes and ALT, that were also assessed using updated normal ranges (<30 IU/L in males, <19 IU/L in females). Median ALP and ALT decreased from 2.16 to 1.27 × upper limit of normal (p = 0.003) and from 0.93 to 0.78 × upper limit of normal (p = 0.008), respectively, in the course of OCA treatment. At treatment day-15, median ALT decreased by 29.7% and ALP by 8.8%. Bilirubin and albumin were unmodified throughout treatment. Using updated normal ranges, ALT levels were normal in 6.7% of patients at baseline and in 33.3% of patients at 18 months of treatment. OCA treatment improves cholestasis and, also, indexes of hepatocyte necrosis, with a decline in necro-inflammatory activity even predating the improvement in cholestasis. Use of recalibrated healthy ranges for aminotransferases might be a useful tool to assess hepatic histological activity and its improvement with OCA treatment.

Hepatoprotective effect of trypsin/chymotrypsin against olanzapine-induced non-alcoholic steatohepatitis in rats

Metabolic side effects of atypical antipsychotics are an important cause of deterioration of cognitive function and failure of drug adherence. The antifatty effect trypsin/chymotrypsin (T/C) and their mechanisms of action remain unclear. To investigate possible therapeutic effect of T/C in rat model of chronic olanzapine (OLZ) – induced hepatic steatosis. Twenty rats were divided into two groups: control (C), given distilled water, and O, given 1 mg/kg of OLZ orally daily for 7 weeks. Then, both groups were given T/C 3 enzyme activity unit (EAU)/kg orally as an add-on treatment daily for the next 5 weeks and were named T/C or T/C+O groups. Rat performance in radial arm water maze was tested twice before and after T/C treatment. We measured liver enzymes, alpha-1 antitrypsin, albumin, total protein, direct and total bilirubin, inflammatory cytokines, and lipoprotein serum levels. Liver samples were collected for histopathology and Ki67 expression. The T/C add-on caused significant reduction in OLZ-induced elevation of alanine transaminase (ALT; P < 0.01), aspartate transaminase (AST; P < 0.001), alkaline phosphatase (ALP; P < 0.05), total cholesterol (Tc; P < 0.01), low-density lipoproteins (LDL-c; P < 0.05), steatosis score (P < 0.001), hepatocyte necrosis (P < 0.01), and significantly increased Ki67 expression (P < 0.01). The T/C add-on to OLZ provided protection against hepatic steatosis, elevated enzymes, and disturbed lipid profile and increased Ki67 without disturbing memory function.

Mercury Kushta Induced Histopathological Changes in Liver of Wister Rats

Background: Heavy metals are the natural constituents of the earth's crust but the indiscriminate human activities have drastically effected their biochemical balance and geochemical cycles. Heavy metals and their compounds have pharmacological importance. These are being used in south Asian countries as component of different medicines. These medicines may have serious side effects on liver. Objectives: To see the histological changes of Kushta which contains mercury, on liver of wister rats. Material and Methods: It was an animal experimental study in which a total of 42 Wistar rats were included and divided into five exposed and one control groups. Morphological changes were observed in liver of rats by using indigenous as well as patent mercury preparations. Results: Morphological changes in liver of exposed rats included hepatocyte swelling, hepatocyte necrosis, hepatocyte apoptosis, disarray of hepatic architecture, development of portal tract inflammation, central vein congestion, sinusoidal congestion and dilatation, development of fatty change and damage to hepatic vascular and liver capsule were seen at the end of 8 weeks. Conclusions: Indigenous herbo-mineral preparation (Kushta) of mercury produces deleterious morphological effects on liver of wister rats. Keywords: Mercury Kushta, Liver, Histopathology

Hepatoprotective Impact of Ghrelin against Cyclophosphamide-Induced Toxicity in the Male Mice

Background Despite its vast spectrum of clinical usage, cyclophosphamide (CP) exerts many adverse impacts, including hepatotoxicity. Antioxidant properties of ghrelin might protect the liver from CP-induced toxicity. The current study aimed to assess the protective impacts of ghrelin on CP-induced liver toxicity. Methods Forty male mice were randomly divided into four groups (n=10) Group 1 as control received no intervention,group 2 received cyclophosphamide (CP) (100 mg/kg, i.p.) for five weeks and once a week. Group 3 received CP+ghrelin (CP+G), (80 µg/kg daily, i.p.) for five weeks. Group 4 received ghrelin with above-mentioned dose. At the end of the experiment, the mice were sacrificed to remove liver tissuesfor histological and biochemical examination. Results Malondialdehyde (MDA) level increased after CP treatment but ghrelin administration significantly decreased the level of MDA (P<0.05). Measurement of the total antioxidant capacity (TAC) noted a significant decrease in the CP group against the control group (P<0.05). Ghrelin treatment in the CP+G group considerably increased the TAC activity when compared to the CP group (P<0.05). Histological examinations also confirmed the hepatocyte necrosis, local bleeding and inflammation, vacuolation, and sinusoidal dilation in the CP group, ghrelin administration reduced the destructive effects of CP on the liver significantly (P<0.05). Conclusion Our results reveal the hepatoprotective effect of ghrelin against CP. Therefore, ghrelin might be useful in protecting the body against the adverse impacts of injuries induced by chemotherapeutic drugs.

Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.

Effect of Alcornea cordifolia Aqueous and Methanolic Leaf Extracts against Antituberculosis Drugs Induced Liver Damage in Rats

The hepatoprotective properties of Alchornea cordifolia, a medicinal plant was studied in hepatotoxicity induced animal model with a high dose of paracetamol or carbon tetrachloride. Knowing that antituberculosis drugs also represent a risk factor for hepatotoxicity, could A. cordifolia play a key role to limit their hepatotoxicity? The objective of this study was to assess the histological changes of antituberculosis drugs in rat livers and their evolution after administration of an aqueous and a methanolic leaf extracts of A. cordifolia and therefore estimate their polyphenol and flavonoid contents. Rats were divided into three (3) groups: group 1 was treated with isoniazid; group 2 received the combination of isoniazid and rifampicin and group 3 was given the combination of isoniazid, rifampicin and pyraziamide. For each group of rats, the hepatotoxicant was either administered alone or two hours before administration of an aqueous (200, 400, or 800 mg/kg) or a methanolic (200, 400, or 800 mg/kg) leaf extracts of A. cordifolia each day for 10 days. Animals were sacrificed on day 11 and their livers removed for histolopathological analysis. In addition, total polyphenol and flavonoid contents were estimated in both extracts. Antituberculosis drug combinations caused peliosis lesions, steatosis and hepatocyte necrosis. The liver histology of rats that received extracts after administration of antituberculosis drug combinations showed the ability of extracts to annihilate or alleviate hepatocellular damage caused by such drugs. The methanolic extract, richer in total polyphenols (0.55 ± 0.02 mg EGA) than the aqueous extract (0.35 ± 0.01 mg EGA) demonstrated a greater hepatoprotective effect. Thus, according to liver histological analysis, the aqueous and methanolic leaf extracts of A. cordifolia could attenuate the hepatotoxicity induced by antituberculosis drugs in rats.

Histopathological features of liver tissue in non-alcoholic and alcoholic steatohepatitis depending on the presence of concomitant anemia

The aim: to study some histopathological changes in the liver affected by steatohepatitis of various etiologies with the presence of anemia. Material and methods. Liver biopsies were analyzed in 30 patients with non-alcoholic steatohepatitis (NASH) and 20 patients with alcoholic steatohepatitis (ASH). The morphological examination of the liver was carried out according to the standard methods. The histopathological features of the liver were established on the basis of hematoxylin and eosin staining method, with confirmation, if necessary, by the histochemical methods - staining for fat (method with Sudan-III) and collagen fibers (method with chromotropic-water blue by NZ Slinchenko). Microspectrophotometric studies were performed using a cytological analyzer with software "VideoTest - Size 5.0" (2000). Results. A number of parameters revealed the statistical differences in the average trends with the use of the nonparametric Mann-Whitney method (p<0.05). The highest rate of hepatocyte necrosis was observed in the patients with ASH with anemia, in particular, more than a third of hepatocytes in these patients had signs of colic necrosis, which was more pronounced in ASH than in NASH. NASH with anemia was accompanied by more pronounced necrosis of hepatocytes than NASH without anemia. In ASH without anemia, the percentage of affected hepatocytes was on average approximately the same as in NASH without anemia. Fatty dystrophy of hepatocytes was observed in all the patients with NASH and ASH, but the severity of the general pathological process was not the same. Conclusions. Due to the comorbidity of fatty liver disease with anemia in both NASH and ASH, a much higher percentage of hepatocytes affected by reversible swelling are formed, which coincides with the tendency for hepatocyte oncosis. Anemia affects the nature of connective tissue growth in NASH and ASH (in ASH, the specific volume of connective tissue was higher than in NASH). At the same time, the intensity of regenerative processes in the liver (ductal reactions of the liver) is most pronounced in patients with anemia, and most - in ASH.

Liver Profile of Artemether-lumefantrine-tinidazole in Healthy and Parasitized Mice

Artemether/lumefantrine/tinidazole (A/L/T) has shown additive antiplasmodial activity; therefore its safety assessment is imperative. This study examined its hepatotoxic effect on healthy and diseased mice. Fifty four Swiss albino mice of n=6 were used. The mice were diseased with Plasmodium berghei ( ) and treated with T (28.6 mg/kg), A/L (2.3/13.7mg/kg) and A/L/T for 4 days, respectively. Healthy mice were treated with T (28.6 mg/kg), A/L (2.3/13.7mg/kg) and A/L/T for 28 days, respectively. After drug treatment; the mice were weighed and anesthetized. Liver samples were excised, weighed and evaluated for oxidative stress indices and histology. Blood samples were assessed for serum liver function indices. Treatment with T, A/L and A/L/T produced no significant (p>0.05) effects on all evaluated parameters in parasitized mice when compared to control. Significant decrease in body weight with significant increase in liver weight occurred in healthy mice treated with A/L (p<0.05) and A/L/T (p<0.01) when compared to control. Impaired liver function characterized by significantly increased serum aminotranferases, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transferase, and bilirubin levels with significantly decreased total protein and albumin levels occurred in healthy mice treated with T (p<0.05), A/L (p<0.01) and A/L/T (p<0.001) when compared to control. Significantly decreased glutathione peroxidase, superoxide dismutase, glutathione, and catalase levels with significantly increased malondialdehyde levels occurred in healthy mice treated with T (p<0.05), A/L (p<0.01) and A/L/T (p<0.001) when compared to control. A/L/T caused hepatocyte necrosis in healthy mice. The use of A/L/T for malaria treatment seems safe on the liver, but may impair liver function with prolonged use.