Potential biomarkers screening of Polygonum multiflorum radix-induced liver injury based on metabonomics analysis of clinical samples.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Radix (PMR) is the dried root tuber of Polygonum multiflorum Thunb., which has been used in the clinic for a variety of pharmacological activities. However, Polygonum multiflorum Radix-induced liver injury (PMR-ILI) has been reported in recent years, which has limited its clinical use to some extent. The occurrence of PMR-ILI is not universal, so finding the different metabolic characteristics between PMR-ILI and Polygonum multiflorum Radix-tolerance group (PMR-T) is very important for the PMR rational clinical application and PMR-ILI early clinical diagnosis. METHODS: In this study, 6 clinical plasma samples of PMR-ILI and 13 PMR-T were collected and analyzed by high-resolution liquid chromatography-mass spectrometry. Firstly, the differential metabolites of the two groups were screened by conventional screening methods such as multivariate statistical analysis. Secondly, the characteristic metabolites with greater contribution, correlation with liver injury and high sensitivity were screened by correlation analysis with clinical liver injury indicators, random forest analysis, and receiver operating characteristic curve (ROC). RESULTS: After multivariate statistical analysis and screening analysis, 29 differential metabolites were identified. Compared with PMR-T group, the metabolism of glycerol and phospholipid, glutamine and glutamate, phenylalanine, sphingolipid and tryptophan in PMR-ILI group were disturbed. After correlation analysis with liver injury indexes and random forest screening, 8 potential biomarkers closely related to clinical liver injury were obtained. Finally, 3 potential biomarkers with high expression in PMR-ILI, hypoxanthine, LysoPC(P-16:0/0:0) and taurochenodesoxycholic acid, were screened out through the analysis of ROC, which can provide a basis for the early clinical diagnosis. CONCLUSION: Based on the analysis of the PMR-ILI and PMR-T plasma samples by LC-MS, three biomarkers of clinical liver injury of Polygonum multiflorum Radix were selected: hypoxanthine, LysoPC(P-16:0/0:0) and taurochenodeoxycholic acid.

Tu-San-Qi (Gynura japonica): the culprit behind pyrrolizidine alkaloid-induced liver injury in China.

Herbs and dietary supplement-induced liver injury (HILI) is the leading cause of drug-induced liver injury in China. Among different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-producing herb Gynura japonica contributes significantly to HILI by inducing hepatic sinusoidal obstruction syndrome (HSOS), a liver disorder characterized by hepatomegaly, hyperbilirubinemia, and ascites. In China, G. japonica has been used as one of the plant species for Tu-San-Qi and is often misused with non-PA-producing Tu-San-Qi (Sedum aizoon) or even San-Qi (Panax notoginseng) for self-medication. It has been reported that over 50% of HSOS cases are caused by the intake of PA-producing G. japonica. In this review, we provide comprehensive information to distinguish these Tu-San-Qi-related herbal plant species in terms of plant/medicinal part morphologies, medicinal indications, and chemical profiles. Approximately 2156 Tu-San-Qi-associated HSOS cases reported in China from 1980 to 2019 are systematically reviewed in terms of their clinical manifestation, diagnostic workups, therapeutic interventions, and outcomes. In addition, based on the application of our developed mechanism-based biomarker of PA exposure, our clinical findings on the definitive diagnosis of 58 PA-producing Tu-San-Qi-induced HSOS patients are also elaborated. Therefore, this review article provides the first comprehensive report on 2214 PA-producing Tu-San-Qi (G. japonica)-induced HSOS cases in China, and the information presented will improve public awareness of the significant incidence of PA-producing Tu-San-Qi (G. japonica)-induced HSOS and facilitate future prevention and better clinical management of this severe HILI.

Chronic liver injury induced by drugs and toxins.

Drug-induced liver injury (DILI) occurs in a small fraction of individuals exposed to drugs, herbs or dietary supplements and is a relatively rare diagnosis compared with other liver disorders. DILI can be serious, resulting in hospitalization and even life-threatening liver failure, death or need for liver transplantation. Toxic liver damage usually presents as an acute hepatitis viral-like syndrome or as an acute cholestasis that resolves upon drug discontinuation. However, un-resolving chronic outcome after acute DILI can ensue in some subjects, the mechanisms and risk factors for this particular evolution being yet scarcely known. Furthermore, the definition of chronicity after acute DILI is controversial, regarding both the time frame of liver injury persistence and the magnitude of the abnormalities required. Besides this, in some instances the phenotypes and pathological manifestations are those of chronic liver disease at the time of DILI diagnosis. These include non-alcoholic fatty liver disease, vascular lesions, drug-induced autoimmune hepatitis, chronic cholestasis leading to vanishing bile duct syndrome and even cirrhosis, and some drugs such as amiodarone or methotrexate have been frequently implicated in some of these forms of chronic DILI. In addition, all of these DILI phenotypes can be indistinguishable from those related to other etiologies, making the diagnosis particularly challenging. In this manuscript we have critically reviewed the more recent data on chronicity in DILI with a particular focus on the epidemiology, mechanisms and risk factors of atypical chronic DILI phenotypes.

[Effect of notoginseng extracts and their components on lipopolysaccharide and galactosamine mixture-induced impaired hepatic function in mice].

The protective effects of notoginseng against hepatic damage were investigated in mice. To prepare a model animal of hepatitis, a mixture of lipopolysaccharide and galactosamine (LPS/GAlN) was administered intraperitoneally, leading to the impairment of hepatic function. Extracts of notoginseng or its components (ginsenoside Rb1 and ginsenoside Rg1) were orally administered 2 h before LPS/GalN injection. Eight hours after LPS/GalN injection, blood and liver tissue samples were collected. The levels of serum aspartate amino transferase (AST), alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured using commercial assay kits. Histologic changes in the tissue samples were also observed after hematoxylin-eosin staining. LPS/GalN administration increased the serum levels of AST and ALT, and histologic changes were noted, indicating hepatic cell damage. Prior to the increase in ALT, the serum levels of TNF-α and IFN-γ were elevated after LPS/GalN injection. Pretreatment of the mice with either notoginseng extract or gensenoside Rb1 and Rg1 attenuated the LPS/GalN-induced hepatic damage markedly. The protective effects of the components against hepatic damage appeared to be less potent than those of the crude extract and prescription of notoginseng. Notoginseng may be clinically useful in patients with hepatitis.

Complementary and alternative medicine in hepatology: review of the evidence of efficacy.

There is an increase in the use of complementary and alternative medicine (CAM), especially herbal therapy, among patients with liver disease. The most commonly used herbal agent is silymarin. In animal models, many of the commonly used agents have shown anti-inflammatory and antifibrotic effects. Although many human studies have shown improvements in subjective symptoms (well being) and liver biochemistry, there are no convincing data to suggest a definite histologic and/or virologic improvement with most of these agents. Poorly designed studies, heterogeneous patient populations, lack of standardized preparations, and poorly defined nonobjective end points may partly explain the conflicting reports in the literature. Hepatotoxicity and drug interactions are common with many herbal medications, and therefore physicians need to be cognizant of known or occult use of CAM by their patients. Only well-designed, randomized, controlled trials will be able to ascertain whether CAM has any role in the management of patients with acute or chronic liver diseases. Until such time, the use of CAM cannot be recommended as a therapy for patients with liver disease.

[Severe drug hepatitis caused by Chelidonium]. / 58-jähriger Patient mit schwerer cholestatischer Hepatitis.

We report the case of a 58-year-old male patient who was admitted with severe acute cholestatic hepatitis. Liver biopsy showed signs of drug-induced hepatitis. Other causes of acute hepatitis were excluded. Therefore, the ingestion of a Chelidonium-containing preparation (celandine) was thought to be responsible for the hepatitis. Shortly after stopping the administration of Chelidonium, the highly pathological levels of several liver parameters began to normalise. As no autoantibodies were detectable, an idiosyncratic reaction as the cause of drug-induced hepatitis is probable. In cases of unknown hepatitis, herbal medications should be taken into account as a possible cause.

Comparative hepatic toxicity: prechronic/chronic liver toxicity in rodents.

The morphologic assessment of the gross and microscopic appearance of the liver can provide a broad base of knowledge concerning the potential toxicity of a drug or chemical. This information may either lead to an understanding of the underlying mechanism of toxicity or guide further study to discern the mode of action of the hepatotoxicity. In standard regulatory bioassays, toxicity studies are conducted during phase 1 and phase 2 of the development process to define the acute, subchronic and chronic toxicity of the test compound. In the liver, there are a limited number of morphologic changes that can be identified using conventional light microscopy. These morphologic alterations are often characterized as "adaptive," consisting of an exaggerated normal physiologic response; "pharmacologic," consisting of an expected alteration in response to the desired action of the test article; or "adverse," consisting of morphologic alterations that are generally undesired, progressive and deleterious to the normal function of the cell(s) involved. Morphologic evidence of adverse effects may involve hepatocytes, the biliary system, hepatic vasculature, Kupffer cells, or stellate cells (Ito cells). In drug discovery and development programs, it is necessary to utilize a multidisciplinary approach, using different endpoints, to investigate the same or similar biological responses in the liver. This results in large amounts of data that must be organized in a retrievable fashion. In order for such a multidisciplinary approach to succeed, each discipline must organize and generate their data in a manner that is easily used by others in the process. The toxicologic pathologist must develop and use standardized nomenclature and diagnostic criteria when examining the liver so that data from various investigators can be compared in a useful manner.