Forms Of Liver Damage Research Articles

Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders.

Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2',3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage.

Tactics with Prebiotics for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease via the Improvement of Mitophagy

Mitophagy/autophagy plays a protective role in various forms of liver damage, by renovating cellular metabolism linking to sustain liver homeostasis. A characterized pathway for mitophagy is the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-dependent signaling pathway. In particular, PINK1-mediated mitophagy could play an indispensable role in improving the metabolic dysfunction-associated fatty liver disease (MAFLD) which could precede to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. In addition, the PI3K/AKT/mTOR pathway might regulate the various characteristics of cellular homeostasis including energy metabolism, cell proliferation, and/or cell protection. Therefore, targeting mitophagy with the alteration of PI3K/AKT/mTOR or PINK1/Parkin-dependent signaling to eliminate impaired mitochondria might be an attractive strategy for the treatment of MAFLD. In particular, the efficacy of prebiotics for the treatment of MAFLD has been suggested to be useful via the modulation of the PI3K/AKT/mTOR/AMPK pathway. Additionally, several edible phytochemicals could activate mitophagy for the improvement of mitochondrial damages, which could also be a promising option to treat MAFLD with providing liver protection. Here, the potential therapeutics with several phytochemicals has been discussed for the treatment of MAFLD. Tactics with a viewpoint of prospective probiotics might contribute to the development of therapeutic interventions.

Adenosine receptor A2B mediates alcoholic hepatitis by regulating cAMP levels and the NF-KB pathway

Alcoholic hepatitis is a serious form of liver damage. Inflammation is a key factor in alcoholic hepatitis and plays a key role in the progression of alcoholic liver disease. Adenosine receptor A2B (A2BAR) is a member of the adenosine receptor family and generally considered to be a negative regulator of the inflammatory response. We found that A2BAR was the most highly expressed adenosine receptor in ETOH-fed mouse liver tissue and was also highly expressed in primary Kupffer cells and ETOH-induced RAW264.7 cells. In addition, injection of BAY 60-6583 stimulated A2BAR, induced upregulation of the expression levels of cAMP, and reduced ETOH-induced steatosis and inflammation in mice. At the same time, knockdown of A2BAR in vitro increased the inflammatory response in RAW264.7 cells triggered by ETOH. After knockdown of A2BAR in vitro, the release of the inflammatory cytokines IL-6, IL-1β and TNF-α was increased. After overexpression of A2BAR in vitro, the cAMP level was significantly increased, PKA expression was increased, the expression of phosphorylated proteins in the NF-kB signal transduction pathway was significantly affected, and the expression of the key phosphorylated protein p-P65 was decreased. However, after the simultaneous overexpression of A2BAR and inhibition of PKA, the expression of the key phosphorylated protein p-P65 was still significantly decreased. In addition, after the expression of A2BAR increased or decreased in RAW264.7 cells, AML-12 cells were cultured in the supernatant of RAW264.7 cells stimulated by ETOH, and the apoptosis rate was significantly changed by flow cytometry. These results suggest that A2BAR can reduce alcoholic steatohepatitis by upregulating cAMP levels and negatively regulating the NF-kB pathway. Overall, these findings suggest the significance of A2BAR-mediated inflammation in alcoholic liver disease.

Clinical Analysis of Liver Cirrhosis in Abdomen Ultrasound Examination at Dr, H Hospital, Marzoeki Mahdi Bogor

INTRODUCTION. Cirrhosis is a form of liver damage. Cirrhosis of the liver is the final stage of the process of liver fibrosis, which is the consistent from chronic liver disease that the liver cells lose their function. Cirrhosis is most often caused by alcoholism, hepatitis b, hepatitis c and fatty liver but many other charges (Digestive N, Information D. cirrhosis, 2014). OBJECTIVE . To know the effort to depict the cases of cirrhosis of the liver and its signs precisely and accurately by using ultrasound examination METHOD . This research was conducted by qualitative descriptive method. The population is patients who perform abdominal ultrasound examination in Marzuki Mahdi hospital. The sample used was a patient who examined his liver with a diagnosed liver cirrhosis. The number of samples used is 2 patients. RESULTS . After being analyzed and observed, ultrasonography is an appropriate and accurate examination in describing cases of liver cirrhosis. The use of Doppler or laboratory testing is sometimes needed to further confirm the diagnosis of visible signs. CONCLUSION . Based on this research, it can be expected that ultrasound modalities can be used as the first consideration in enforcing liver cirrhosis cases with accurate, fast, cheap and safe results.

Nonalcoholic fatty liver disease and the risk of metabolic comorbidities: how to manage in clinical practice.

Nonalcoholic fatty liver disease (NAFLD) is a clinical condition that encompasses various forms of liver damage not caused by chronic alcohol consumption. In the absence of other etiologies, it ranges from steatosis to nonalcoholic steatohepatitis and cirrhosis. The prevalence of NAFLD has considerably increased over the last years owing to the current lifestyle (unhealthy diet and sedentarism). Besides, it is associated with metabolic risk factors such as obesity, arterial hypertension, dyslipidemia, and type 2 diabetes. Given the poor prognosis of patients with advanced NAFLD, a practical therapeutic approach is necessary to halt its natural history. However, no licensed drugs have been approved for this purpose to date. Nowadays, we are in a race to find the first drug able to stop the incidence of NAFLD and reverse the disease in patients at more advanced stages. Meanwhile, the management of the NAFLD metabolic overload, including weight loss, cardiovascular protection, insulin sensitization, and lipid reduction, is the only strategy to improve hepatic and extrahepatic outcomes. In this review, we aimed to describe the management of the main metabolic disorders related to NAFLD, such as type 2 diabetes, arterial hypertension, and dyslipidemia.

Characterization of release profile of ornithine carbamoyltransferase from primary rat hepatocytes treated with hepatotoxic drugs: Implications for its unique potential as a drug-induced liver injury biomarker

Ornithine carbamoyltransferase (OCT) is a mitochondrial protein expressed primarily in the liver. It has been shown that, like alanine aminotransferase (ALT), OCT is released from damaged hepatocytes in rats and humans, which has given rise to the possibility that OCT might provide a diagnostic biomarker of various forms of liver damage, including drug-induced liver injury (DILI). However, OCT release characteristics in DILI, as well as their diagnostic advantages, remain elusive. Therefore, this study aimed at clarifying whether and how OCT is released from rat primary hepatocytes in vitro using seven potentially hepatotoxic drugs. The results showed that OCT releases from damaged hepatocytes were observed for all tested drugs, and that those releases were not associated with mitochondrial membrane proteins. It should be underscored that the release dynamics were significantly larger than those of ALT. Furthermore, unlike ALT, the maximum OCT release levels showed differences depending on the drug being tested, suggesting that OCT release was susceptible to toxicity mechanisms. Taken together, these unique release characteristics highlight the possibility that OCT could provide a promising DILI biomarker that might contribute not only to diagnostic accuracy improvements, but also to a better understanding of toxicity types in clinical and drug development settings.

Hepatocellular Type of Liver Injury after the Use of Azithromycin: A Variant Form of Liver Damage

Hepatocellular Type of Liver Injury after the Use of Azithromycin: A Variant Form of Liver Damage

Liver damage induced by diabetes mellitus

There is a complicated association between the liver and diabetes mellitus.Diabetes mellitus may cause various forms of liver damage,such as nonalcoholic fatty liver disease (NAFLD),hepatic cirrhosis,hepatocellular carcinoma,liver abscess,and liver transplant complications.With the growing epidemic of diabetes mellitus,this review investigates diabetes mellitus induced liver damage. Key words: Diabetes mellitus; Liver injury

MicroRNAs in liver disease

Small, noncoding microRNAs (miRNAs) regulate diverse biological functions in the liver and increasing evidence suggests that they have a role in liver pathology. This Review summarizes advances in the field of miRNAs in liver diseases, inflammation and cirrhosis. MicroRNA-122, the most abundant miRNA in hepatocytes, has well-defined roles in HCV replication, and data indicate that it also serves as a viable therapeutic target. The role of miR-122 is also emerging in other liver diseases. Ample evidence exists for the important regulatory potential of other miRNAs in conditions associated with liver inflammation related to alcohol use, the metabolic syndrome or autoimmune processes. In addition, a broad array of miRNAs have been associated with the development of liver fibrosis both in animal models and human studies. The significance of the function and cellular distribution of miRNAs in the liver and the potential of miRNAs as a means of communication between cells and organs is discussed as well as the emerging utility of circulating miRNAs as biomarkers of different forms of liver damage and as early markers of disease and progression in hepatocellular carcinoma. Importantly, miRNA modulation in the liver represents a new therapeutic approach in the treatment armamentarium of hepatologists in the future.

Systemic Effects of White Adipose Tissue Dysregulation and Obesity‐Related Inflammation

Systemic Effects of White Adipose Tissue Dysregulation and Obesity‐Related Inflammation

Is spleen circulation impaired in systemic sclerosis and what is the role of liver fibrosis?

To investigate the spleen vascular involvement and the presence of liver fibrosis in a population of subjects with established systemic sclerosis (SSc). In a cross-sectional fashion, 17 patients with SSc were compared with 18 patients suffering from hepatitis C virus (HCV)-related liver cirrhosis, grade A and B Child-Pugh classification. Eighteen non elderly subjects, apparently healthy, were used as the control group. Splenic artery resistivity index (SARI) at Doppler ultrasound, transient elastography of liver and nailfold capillaroscopy were the main outcomes. Transient elastography values of SSc patients were similar to those of controls; 5.2 ± 1.1 vs 4.5 ± 1, (P = 0.07). Median Alanine amino transferase (ALT) concentrations of cirrhotic patients were greater than those of controls and SSc patients, i.e. 66.5 (36-89) U/L vs 29 (22-34) U/L and 31 (22-41) U/L, respectively, (P = 0.005). SARI determinations in cirrhotic patients, although significantly higher than those found in controls and SSc patients, showed some degree of overlap with SSc patients, i.e. 0.59 vs 0.52 and 0.57, respectively, (P = 0.04). Mean systolic blood pressure was significantly higher in SSc patients than in cirrhotics and controls, i.e. 142 mmHg vs 128.2 mmHg and 127 mmHg, respectively, (P = 0.005). Mean diastolic blood pressure behaved in a similar fashion, i.e. 84 mmHg vs 72.2 mmHg and 76.9 mmHg (P = 0.005). Nailfold Capillaroscopy grades and diastolic blood pressure values correlated well with SARI results. An enhanced resistivity of the splenic artery was found in patients suffering from SSc; they did not have evidence of splenomegaly as well as no liver fibrosis or any other form of liver damage.

The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer

Nonalcoholic steatohepatitis (NASH) is a form of liver damage that can progress to cirrhosis. NASH is associated with obesity and diabetes. The condition also may be associated with some medications, including tamoxifen. Early case reports and small series have documented NASH in patients who received tamoxifen. The records of patients registered in the St. Vincent Hospital Cancer Registry of Green Bay Wisconsin from January 1, 1992 to December 31, 2000 were reviewed. In total, 1105 patients with breast cancer were evaluated for NASH, and 24 cases of NASH were documented (2.2%). Seven patients had NASH before their diagnosis of breast cancer, and 17 patients developed NASH after their diagnosis of breast cancer. In multivariate analysis, the factors associated with NASH were tamoxifen use (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.06-63.72), body mass index (BMI) (OR, 1.13; 95% CI, 1.06-1.20), and age (OR, 95% CI, 0.91-0.99). NASH improved after tamoxifen was stopped. After discontinuation of tamoxifen, transaminase levels returned to normal in 14 of 16 patients. NASH was present in 24 of 1105 patients with breast cancer (2.2%). Seven patients had NASH before they were diagnosed with breast cancer, and 17 patients developed NASH after their diagnosis. NASH was associated with the use of tamoxifen and improved when tamoxifen was stopped.

Non-alcoholic steatohepatitis (NASH) in patients with breast cancer and association with tamoxifen

11528 Background: Non-alcoholic steatohepatitis is a form of liver damage that can progress to cirrhosis of the liver. NASH is microscopically identical to steatohepatitis that is noted in alcoholics. The condition is associated with obesity and diabetes. NASH may also be associated with some medications including tamoxifen. Early case reports and small series documented NASH in patients who received tamoxifen. Methods: The St Vincent Hospital Cancer Registry of Green Bay Wisconsin was used to identify breast cancer patients for this retrospective review. Clinic records of patients with breast cancer diagnosed from January 1, 1992 until December 31, 2000 were reviewed. NASH was diagnosed if documented by liver biopsy or if documented by transaminases 2 times the upper range of normal on two occasions and computerized tomography scan or ultrasound documentation of a fatty liver. Results: 1,105 patients with breast cancer were evaluated for NASH. 24 cases of NASH were documented (2.2%). 7 patients had NASH ...

Nuclear factor-κB in the liver of patients with chronic hepatitis C: Decreased RelA expression is associated with enhanced fibrosis progression

The mechanisms of liver damage in chronic hepatitis C virus (HCV) infection are poorly understood. The transcription factor, nuclear factor-κB (NF-κB), regulates the expression of genes involved in apoptosis, inflammation, and antiviral response. It plays a protective role in several forms of liver damage. In this study, we analyzed NF-κB by gel mobility shift assay and immunohistochemistry in liver biopsies from HCV-infected patients, and we have determined the hepatic levels of the components of the NF-κB system by semiquantitative polymerase chain reaction (PCR). We found that NF-κB was activated in the liver of patients with chronic hepatitis C. Neither NF-κB activity nor the RNA levels of NF-κB subunits showed correlation with liver inflammatory activity, viral load, or HCV genotype. By contrast, hepatic mRNA values of RelA, the main element of active NF-κB, correlated inversely with apoptosis (r = −.68; P < .05) and with the rate of fibrosis progression (r = −.51; P < .04). In intermediate/rapid fibrosers, RelA mRNA levels were significantly decreased as compared with slow fibrosers (P < .003) and with normal livers (P < .03). In conclusion, we found that NF-κB is activated in chronic HCV-infected livers, and that the expression of RelA is inversely correlated with liver cell apoptosis and with the rate of fibrosis progression. Our data thus suggest that RelA expression may protect against liver fibrosis and hepatocellular damage. (HEPATOLOGY 2001;34:1041-1048.)

Drug and toxin‐induced bile duct disorders

Various drugs of toxins have been implicated in the development of a particular form of liver damage predominantly involving the bile ducts. Such liver toxicity is often associated with a clinical picture of prolonged cholestasis and may even evolve in rare instances, into the full picture of the vanishing bile duct syndrome, eventually complicated with biliary cirrhosis. Drug and toxins potentially responsible for bile duct injury are reviewed as well as the characteristics of its clinical presentation. The pathophysiologic aspects of the syndrome are also reviewed including recent data, which are strongly in favor of the role of a genetic predisposition.

Prevention of Endotoxin-Induced Lethality, but Not of Liver Apoptosis in Poly(ADP-ribose) Polymerase-Deficient Mice

Activation of poly-(ADP-ribose) polymerase (PARP) is often associated with cytotoxicity, but its precise role in shock-induced lethality and in different modes of tissue injury is still unknown. We took advantage of the existence of mice with a targeted deletion of the PARP gene (PARP−/−) to examine the differential sensitivity of wild-type (wt) and PARP−/− mice toward endotoxin (LPS)-induced lethality and different forms of liver damage. All PARP−/− animals survived high-dose (20 mg/kg) LPS-mediated shock, which killed 60% of wt animals. Moreover, LPS-induced necrotic liver damage was significantly reduced. In contrast, when apoptotic liver damage was induced via injection of low concentrations of LPS (30 μg/kg) into D-galactosamine-sensitized mice, or via activation of hepatic cell death receptors, PARP−/− animals were not protected. We conclude that PARP is involved in systemic LPS toxicity, while it plays a minor role in apoptotic liver damage mediated by TNF or CD95.

Premorbid hair growth over the trunk and severity of alcohol-related liver disease.

It is unclear why only a minority (<15%) of alcoholics develop liver disease. No predisposing host factor other than gender (women are more susceptible than men) has been identified. The present study was carried out to examine the association of another host factor, hair growth over the trunk, and alcoholic liver disease. Forty-four chronic alcohol abusers were categorized into group I (scanty hair growth) and group II (profuse hair growth) based on premorbid hair distribution over the trunk. The results of laboratory tests, liver histology, and incidence of portal hypertension were compared between the two groups. There were 21 patients in group I and 23 in group II. The mean (+/- SD) daily alcohol consumption was greater in group II (230 +/- 146 g) vs group I patients (152 +/- 56 g; P < 0.05), as was the duration of alcohol abuse (17.3 +/- 7.4 vs 11.9 +/- 4.9 years; P < 0.01). Despite lower alcohol consumption, liver tests showed greater derangement in group I compared to group II patients. At histology, severe forms of liver damage were seen more frequently in group I vs group II patients (P < 0.001). Our results indicate a close association between the premorbid truncal hair growth and severity of alcoholic liver disease. These findings provide an easily recognizable clinical sign identifying individuals at increased risk of developing alcohol-related liver damage.

Changes in plasma proteins in rats treated for short periods with hepatotoxins or with agents which induce cytochrome P450 isoenzymes.

We have compared the alterations in plasma proteins following treatment of rats with the centrilobular hepatotoxin carbon tetrachloride, the periportal hepatotoxin allyl alcohol and two inducers of hepatic microsomal drug metabolising enzymes, phenobarbitone and a mixture of polychlorinated biphenyls (Aroclor 1254). The results are compared with changes observed in animals treated with agents which caused proliferation of rat liver peroxisomes and described in an earlier publication. Our results indicate that: There is a marked induction of a minor glycoprotein which migrates as a prealbumin following treatment with both inducers of microsomal mixed function oxidases and inducers of peroxisome proliferation. There is a marked increase in a minor alpha 1-glycoprotein when there is chemically-induced mitosis in the liver but not in mitosis following liver damage. Two major alpha 1-glycoprotein are depressed in all forms of liver damage. There are indications of specific protein responses to allyl alcohol, to inducers of microsomal mixed function oxidases and to inducers of peroxisome proliferation.

Long-term studies on chemically induced liver enlargement in the rat I. Sustained induction of microsomal enzymes with absence of liver damage on feeding phenobarbitone or butylated hydroxytoluene

As part of a study on the relationships between liver enlargement, induction of drug-metabolising enzymes and certain forms of liver damage, sequential biochemical and morphological observations were made on the livers of female rats fed diets containing 0.4% butylated hydroxytoluene (BHT) or 0.25% phenobarbitone for periods of up to 80 weeks. Both compounds increased the relative liver weight and produced marked enhancement of the activities of ethylmorphine N-demthylase, aniline 4-hydroxylase, biphenyl 4-hydroxylase and NADPH-cytochrome c reductase and the contents of cytochromes P-450 and b 5 and microsomal protein. These changes were evident after 1 week of treatment and persisted until treatment was stopped after 80 weeks. The only morphological changes observed throughout the period of treatment were centrilobular cell enlargment and hypertrophy of the smooth endoplasmic reticulum (SER). Histochemical examination revealed a centrilobular depression of glucose-6-phosphatase but there was no disturbance of the normal pericanalicular distribution of lysosomes. All changes observed with either compound were reversible on cessation of treatment at week 80. These results support the concept that liver enlargement accompanied by induction of drug-metabolising enzymes represents an adaptive response and they provide a basis for the interpretation of pathological changes developing in the enlarged liver unaccompanied by drug-metabolising enzyme induction.

Effect of experimental biliary obstruction on respiratory function

Since liver damage due to alcoholic cirrhosis and viral hepatitis may influence respiration, we have studied biliary obstruction in the rat to see if this form of liver damage could also influence respiratory function. Three weeks after sham surgery or common bile duct division, the effect of liver damage on red cell morphology, red cell 2,3-diphosphoglycerate, blood gases with room air and 100% and 10% oxygen, respiratory rate, oxygen consumption, blood ammonia and pulmonary morphology were studied. Experimental biliary obstruction was associated with impaired weight gain, hypoxemia, respiratory alkalosis, intrapulmonary shunting of blood, elevated arterial but not venous ammonia, decreased oxygen consumption, elevated venous lactate, normal pulmonary diffusion of oxygen, microscopic abnormalities of the lung, and a macrocytic anemia. Histological examination of the lung revealed thickening of the alveolar septal walls with proliferation of alveolar cells and increased content of collagen. The anemia was unaffected by splenectomy and folic acid but the macrocytosis was corrected by folic acid. Hyperventilation may have been related to the elevated arterial ammonia, hypoxia and possible abnormal circulatory metabolic degradation products. The hypoxia was due to intrapulmonary shunting of blood. The anemia appeared unrelated to hypersplenism and only modified by folic acid.