The leading cause of drug withdrawal from market and clinical trials failure is drug-induced liver injury (DILI). Varying clinical, histological and laboratory features of DILI, as well as undefined underlying mechanisms, hinder patients to be diagnosed in the early-stage of the disease and receive effective treatments. Conventional indicators, like serum transaminases and bilirubin, have inevitable limitations referring to sensitive prediction and specific detection of DILI. In order to reduce the occurrence of DILI, researchers have attempted to discover potential biomarkers with higher specificity and sensitivity from blood and urine in recent years. This article aims to review recent advances in biomarkers of DILI.
Biomarkers ; blood ; urine ; Chemical and Drug Induced Liver Injury ; diagnosis ; Humans ; Sensitivity and Specificity

Acute graft-versus-host disease (GVHD) following liver transplantation is a rare but fatal complication. The correct diagnosis and management of GVHD after liver transplantation are still major challenges. Herein, we reported successful salvage treatment of acute GVHD by withdrawal of immunosuppression in a patient who presented with fever, skin rashes, and decreased blood cell counts after liver transplantation. This case highlights the need for awareness of drug-induced liver injury if liver function tests are elevated during treatment, especially in patients taking multiple potentially hepatotoxic drugs, such as broad-spectrum antibiotics. When occurs, an artificial liver support system is a useful tool to provide temporary support of liver function for the patient in the event of drug-induced liver injury.
Anti-Bacterial Agents ; Blood Cell Count ; Diagnosis ; Drug-Induced Liver Injury ; Exanthema ; Fever ; Graft vs Host Disease* ; Humans ; Immunosuppression* ; Liver Function Tests ; Liver Transplantation* ; Liver* ; Liver, Artificial

Griseofulvin(GF) has become the drug of choice as an antifungal agent for patients who suffer from many kinds of fungal infection. In order to clarify hepatic injury by griseofulvin(GF) overload and the effect of UDCA on GF-induced hepatic injury, the authors carried out biochemical, histologic, and ultrastructural studies of liver following treatment with griseofulvin and ursodeoxycholic acid(UDCA) in mice. Urine porphobilinogen excretion in the group treated with GF alone was significantly increased and reached the highest level in the 4th week and declined thereafter. Biochemical studies of the liver function showed no remarkable changes of serum bilirubin levels throughout the experimental period in all groups, except for SGPT and alkaline phosphatase activities which were significantly elevated and reached the highest level in the second week. Then they slightly decreased in GF treated groups(GF alone and GF plus UDCA) in comparison with the control group. Pathologic findings in the group treated with GF alone include focal liver cell necrosis(esp, zone 3), Mallory bodies in hepatocytes(esp, zone 1), Kupffer cell activation, and brown protoporphyrin pigments in the hepatocytes, bile canaliculi and interlobular bile ducts with a marked inflammatory cell infiltration in the portal tracts. Under the polarizing light microscope, bile ductular and canalicular thrombi showed a "Maltese cross" birefringence in mice treated with GF alone. There is no definite finding of fatty change in hepatocyte. Under the microscope, the liver appeared normal with an intact lobular architecture in the GF plus UDCA treated group. Electron microscopically, GF-induced changes include swelling of mitochondria, globular protoporphyrin crystals in the hepatocyte cytoplasm, markedly dilated bile cannaliculi and bile ducts and the formation of a Mallory hyaline bodies in the hepatocytes. There were no noticeable structural changes in the GF plus UDCA-treated group. Therefore the results suggest that GF causes hepatic injury, namely porphyria and cholestasis, and the treatment of UDCA may have cytoprotective and choleretic effects on GF-induced hepatic injuries.
Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Bilirubin/blood ; *Drug-Induced Liver Injury ; Griseofulvin/*toxicity ; Liver Diseases/*drug therapy/pathology ; Mice ; Mice, Inbred ICR ; Microscopy, Electron ; Porphobilinogen/urine ; Porphyrias/*chemically induced/*drug therapy/pathology ; Ursodeoxycholic Acid/*therapeutic use

Adult ; Chemical and Drug Induced Liver Injury ; Dimethylformamide ; poisoning ; Humans ; Liver ; pathology ; Liver Diseases ; blood ; pathology ; Male ; Necrosis ; Occupational Diseases ; therapy ; Poisoning ; pathology ; therapy

Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range.
Actinomycosis/drug therapy ; Adult ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Amoxicillin/*adverse effects ; Anti-Bacterial Agents/*adverse effects ; Aspartate Aminotransferases/blood ; Cholestasis/*chemically induced ; Drug-Induced Liver Injury/*diagnosis/etiology ; Female ; Humans ; Liver/enzymology

Herbs are widely used as treatments for various symptoms. However, several herbs have been reported to be inducers of liver injury. We report herein a case of hepatotoxicity induced by Corydalis speciosa Max. A 37-year-old male complained of jaundice and mild abdominal discomfort. A thorough history was taken, and laboratory investigation, diagnostic imaging studies, and percutaneous liver biopsy sampling were conducted to determine the cause of liver injury. An accurate cause was not revealed. We administered supportive management for acute cholestatic hepatitis of unknown origin, after which his symptoms disappeared and serum aminotransferase levels decreased gradually to near normal levels. However, at 2 months after discharge, the symptoms and the elevation of aminotransferase levels recurred. At that time he told us that he had repeatedly but unintentionally eaten a herb called "Hwang-geun cho"(Corydalis speciosa Max.). Thus, we diagnosed his case as herbal hepatotoxicity.
Acute Disease ; Adult ; Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Corydalis/*chemistry ; Drug-Induced Liver Injury/*diagnosis/pathology ; Humans ; Male ; Plant Extracts/*toxicity ; Tomography, X-Ray Computed

Drug-induced liver injury (DILI) is a significant threat to patient health and a major concern during drug development. Recently, multiple circulating microRNAs (miRNAs) have been reported to be potential biomarkers for DILI. To adapt and validate miRNAs for clinical use, we investigated the time-course changes in miR-122 expression levels in an acetaminophen-induced liver injury model in rats. In addition, miR-155 and miR-21 were evaluated as makers of inflammation and regeneration, respectively, to characterize liver status. Our results revealed that miR-122 is an early and sensitive biomarker of hepatocellular injury at a stage when alanine transaminase, aspartate transaminase, and total bilirubin were not detectable. However, no significant differences in the expression levels of other miRNAs (miR-155 and -21) were observed between treatment and vehicle groups. Collectively, these time-course changes in the expression levels of miRNAs may be useful as markers for clinical decision-making, in the diagnosis and treatment of DILI.
Acetaminophen/*toxicity ; Animals ; Biomarkers/*blood ; Chemical and Drug Induced Liver Injury/*blood/*diagnosis/pathology ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Hepatocytes/*drug effects ; Inflammation/blood/diagnosis ; Liver Regeneration ; MicroRNAs/*blood/genetics ; Predictive Value of Tests ; Rats ; Time

OBJECTIVETo study early change features of microRNA (miRNA) in the peripheral blood of Sophorae Tonkinensis Radix et Rhizoma induced liver injury rats, and to look for the miRNA biomarkers in the peripheral blood of early liver injury.

METHODSSixty Wistar rats were randomly divided into the control group and the Sophorae Tonkinensis Radix et Rhizoma (abbreviated as STRR) group, 30 in each group. Rats in the STRR group was administered with STRR decoction at 12 g/kg (2 mL/100 g), while equal volume of the distilled water was given to those in the control group. Rats were anesthetized on day 3, 7, 14, and 28, and 28 days after withdrawal. The serum samples were withdrawn. The alanine aminotransferase (ALT), aspartate transaminase (AST), total bile (TBIL), alkaline phosphatase (ALP), total protein (TP), and albumin (ALB) were detected. The globulin (GLO) level was calculated. HE staining was performed on the liver tissue to observe the pathomorphological changes. The whole blood was collected on day 7, 14, and 28 to perform the microarray test. The differentially expressed miRNAs were screened and verified by RT-PCR.

RESULTSThe ALT activity obviously increased on day 7 - 28 in the STRR group (P <0.05). The histopathological results showed the degeneration and swelling of the liver cells on day 28. In the microarray test, there were 11, 22, and 13 up regulated expressed miRNAs on day 7, 14, and 28, respectively. There were 1, 13, 2 down regulated expressed miRNAs on day 7, 14, and 28, respectively. By target gene prediction and pathway analysis of differentially expressed miRNA on day 7, 14, and 28, they involved in regulating and controlling signal transduction, cellular interaction, cytoskeleton. Differentially expressed miRNA might possibly participate in the process of liver injury. The RT-PCR result of the expression of miR-291a-5p with the peak time efficiency on day 7 showed that the expressions of miR-291a-5p in the peripheral blood and the liver tissue were basically identical.

CONCLUSIONmiR-291a-5p could early indicate the liver injury, which could be taken as one of an early marker in STRR induced liver injury.

Animals ; Chemical and Drug Induced Liver Injury ; metabolism ; pathology ; Drugs, Chinese Herbal ; adverse effects ; Female ; Liver ; metabolism ; pathology ; Male ; MicroRNAs ; blood ; metabolism ; Rats ; Rats, Wistar

OBJECTIVETo investigate the clinical significance of liver function and autoantibodies in patients with acute or chronic drug-induced liver injury.

METHODS51 patients with drug-induced liver injury were divided into acute drug induced liver injury group and chronic drug induced liver injury group, liver function and autoantibodies were compared between these two groups.

RESULTSThere was no significant difference (P more than 0.05) in alanine aminotransferase [(412.1+/-387.5) U/L and (376.0+/-319.7) U/L], aspartate aminotransferase [(352.5+/-457.9) U/L and (198.8+/-142.7) U/L], total bilirubin [(109.7+/-104.80)micromol/L and(102.4+/-135.7)micromol/L], direct bilirubin [(66.4+/-73.3)micromol/L and (61.2+/-72.1)micromol/L], alkaline phosphatase [(133.4+/-50.1) U/L and (147.4+/-97.3) U/L], gamma-glutamyltransferase [(139.9+/-134.1) U/L and (180.6+/-227.9) U/L], and albumin [(41.3+/-4.9) g/L and (39.8+/-5.3)g/L] between these two groups, however, the level of globulin [(25.1+/-5.3) g/L and (28.6+/-5.1) g/L] was significantly different between these two groups (P less than 0.05). The titers of Anti-nuclear antibody (ANA) and smooth muscle antibody (SMA) were less than or equal to 1:320 in patients with acute drug induced liver injury. The titers of ANA, antimitochondrial antibody (AMA), and SMA were more than or equal to 1:320 in most of the patients with chronic drug induced liver injury.

CONCLUSIONLiver function has no value in the diagnosis of acute or chronic drug induced liver injury. High titer autoantibodies are found in patients with chronic drug induced liver injury.

Acute Disease ; Adult ; Antibodies, Antinuclear ; blood ; Autoantibodies ; blood ; Chemical and Drug Induced Liver Injury ; blood ; diagnosis ; immunology ; Diagnosis, Differential ; Drug-Related Side Effects and Adverse Reactions ; Female ; Humans ; Liver ; pathology ; physiopathology ; Liver Function Tests ; Male ; Microsomes ; immunology ; Middle Aged ; Muscle, Smooth ; immunology

OBJECTIVETo Study the protective effect of curcumin on three models of experimental liver injury in mice.

METHODThe experimental models of live injury were induced by carbon tetrachloride (CCl4), D-galactosamine (D-Gal N), and Bacillus Calmette-Guerin (BCG) Plus lipolysaccharides (LPS), respectively, in mice. The serum ALT, AST, NO and liver MDA were measured to evaluate the protective effect of curcumin on experimental injury in mice.

RESULTCurcumin (50 mg.kg-1, 100 mg.kg-1, 150 mg.kg-1), like biophenyldicarboxylate, were shown to significantly inhibit the increase of serum ALT, AST, NO and liver molondialdehyde (MDA) content induced by CCl4, D-Gal N, BCG + LPS.

CONCLUSIONCurcumin showed protective effect against liver injury induced by CCl4, D-Gal N, BCG plus LPS.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Carbon Tetrachloride Poisoning ; Chemical and Drug Induced Liver Injury ; Curcumin ; pharmacology ; Galactosamine ; Lipopolysaccharides ; Liver ; metabolism ; Liver Diseases ; blood ; metabolism ; Male ; Malondialdehyde ; metabolism ; Mice ; Nitric Oxide ; blood ; Protective Agents ; pharmacology