Diagnosis and treatment of drug-related liver injury
Renji Hospital, Shanghai Jiaotong University School of Medicine
Yimin Mao
Drugs are a double-edged sword. While they are clinically effective in treating diseases, their adverse effects also cause harm to human health. With the development of a large number of new drugs and their clinical application, human exposure to various drugs has greatly increased, and therefore, the safety of drugs has received more and more attention. The liver is the main organ of drug metabolism and is also the main target organ of drug injury. Drug-related liver injury belongs to the category of adverse drug reactions, which refers to the direct or indirect liver damage of different degrees caused by the drug itself or its metabolites during the application of therapeutic doses of drugs. Mao Yimin, Department of Gastroenterology, Shanghai Renji Hospital
I. Epidemiology
The incidence of drug-related liver injury is second only to drug-induced skin and mucous membrane damage and drug fever. In Europe and the United States, drug-related liver injury accounts for about 2%-5% of hospitalized patients with jaundice and 10% of hospitalized patients with “acute hepatitis”; in elderly patients with liver disease, drug-related liver injury can reach more than 20%; in Europe and the United States, about 30%-40% of acute liver failure is caused by drugs. According to the statistics of the United States in 2001, about 2000 cases of acute liver failure occur each year, more than 50% of which are caused by drugs, 36% of which are non-steroidal anti-inflammatory drugs, and 16% of liver injury is caused by idiosyncratic substances. China currently lacks the corresponding epidemiological information.
Second, susceptibility factors
There are many susceptibility factors for drug-related liver disease, and the susceptibility factors are different for different kinds of drugs. The most common susceptibility factors from the host perspective include old age or childhood, female, genetic background, nutritional status, alcoholism and combined diabetes, renal failure, HIV infection and other liver diseases, etc. From a drug perspective, susceptibility factors often include the dose of the drug, reactions to other drugs, and the combined application of multiple drugs. If you have one or more susceptibility factors, you should consider carefully when choosing drugs and avoid using drugs that may increase hepatotoxicity.
Third, the metabolism of drugs and the factors affecting them
The metabolism of drugs in the body is divided into two phases. The first phase is the oxidation reaction, mainly involving the cytochrome P450 system, which metabolizes the non-polar lipid-soluble drugs into water-soluble metabolites containing polar groups through oxidation, reduction and hydrolysis; the second phase is the binding reaction, involving glucuronidase and glutathione, which metabolizes the above metabolites into highly water-soluble metabolites that can be easily excreted.
Cytochrome P450 (CYP450) oxidase is the most important hepatic drug enzyme involved in drug metabolism and has many isozymes. 28 isozymes of human CYP have been identified, mainly in mitochondria, microsomes or both. CYP450 has significant individual differences and has considerable genetic polymorphism. Due to the genetic polymorphism, the phenotypes of drug metabolism are different, i.e. strong (normal) metabolic type (EM), weak (slow) metabolic type (PM), intermediate metabolic type (IM), ultra-fast metabolic type (UM), and the area under the curve (AUC) of PM and EM can be increased by 10~100 times when comparing drugs, and adverse reactions can occur with conventional drug dosage, which should attract clinical attention. Therefore, the genetic polymorphism of CYP450 directly affects the metabolic pathway and metabolic rate of drugs, thus affecting the efficacy and safety of drugs.
At present, it is known that more than 90% of drug metabolism and detoxification are done in hepatic microsomal CYP450, of which CYP1, 2 and 3 account for more than 70% of the total CYP450 in the liver, mainly metabolizing exogenous poisons (drugs and poisons), with poor conservatism; CYP4 mainly metabolizes endogenous substances, with high specificity and conservatism.
Individual differences, diet, alcohol, smoking, cow’s milk (Ca++), tea (tannic acid) and drug interactions are the main factors affecting drug metabolism.
Fourth, the mechanism of drug-related liver injury
Drug-related liver injury can be divided into two types: predictable and unpredictable. The former is mainly due to the direct toxic effects of drugs; the latter can be divided into metabolic abnormalities and allergic reactions according to their mechanisms, that is, metabolic and allergic specific body. The mechanisms of drug-induced liver injury mainly include cell membrane destruction, bile depression, damage caused by metabolites produced by CYP450 activation, formation of target antigen-activated immune response, TNFα activation-induced apoptosis, and mitochondrial damage. Mitochondrial damage is an early common event of drug- and toxin-induced cellular injury, and oxygen stress is involved in the pathogenesis of direct drug injury, immune-mediated injury, and metabolism-specific injury.
V. Clinical features
Clinically, drug-related liver injury involves almost all types of liver injury, including acute or chronic parenchymal cell injury, bile depression, steatosis, liver fibrosis, cirrhosis, vascular lesions, benign and malignant tumors, etc. The clinical manifestations of drug-related liver injury vary from asymptomatic mild biochemical changes in liver function to acute fulminant liver failure or even death, usually related to the type of liver-damaging drugs and the different mechanisms that cause liver injury. Acute drug-related liver injury may also show extrahepatic manifestations, such as fever, rash, hemolytic anemia, bone marrow damage, kidney damage, gastrointestinal ulcers, pancreatitis, and eosinophilia, lymphocytosis, etc.
Abnormal liver function caused by drug-related liver disease can be divided into hepatocellular injury type, biliary depression type and mixed type. In hepatocellular injury type, ALT≥3×ULN or ALT/AKP≥5, the clinical features are significant elevation of ALT and AST, while ALP may be normal or slightly elevated, and bilirubin may be elevated to varying degrees, and the clinical manifestations are similar to those of acute viral hepatitis in general, with prodromal symptoms such as malaise, decreased fatigue, epigastric discomfort, nausea, vomiting, jaundice, and dark urine. AKP≥2×ULN or ALT/AKP≤2 is called biliary depression type, and its clinical manifestations, signs and laboratory manifestations are similar to intrahepatic biliary sludge, extrahepatic biliary obstruction and acute cholangitis. The clinical picture is characterized by elevated AKP, GGT, 5′-nucleotidase and other indicators of bile duct injury such as bile acids, mildly elevated transaminases, elevated bile salts, lipoprotein X and cholesterol, and negative anti-mitochondrial antibodies. Clinical manifestations include jaundice, rash, and symptoms reflecting varying degrees of substantial liver damage, including anorexia, fatigue, epigastric pain, itching, right upper abdominal tenderness, and hepatomegaly, with itching being the more specific symptom of cholestasis and occurring in 20-50% of jaundiced patients. In the mixed form, ALT/AKP = 2-5, with clinical features of both the hepatocellular injury type and the cholestasis type.
In 1975, Hyman zimmerman proposed Hy, s rule that drug-related liver injury with ALT ≥3ULN+TBil ≥2ULN can result in a mortality rate of up to 10% even if the drug is discontinued in the absence of biliary obstruction. This rule is the reference standard for evaluating hepatotoxicity in the development of new drugs assessed by the FDA. Recently, it has been shown that the Hy,s rule of ALT ≥3ULN lacks specificity, and the addition of TBil ≥2ULN may improve the specificity but is not very sensitive. Recently, it has been validated that AST+TBil is more valuable for assessing clinical outcomes and liver transplantation prognosis.
IV. Diagnosis
Drug-related liver disease is often misdiagnosed or missed because of the wide variation in time of onset, the hidden relationship between clinical manifestations and drug use, the lack of clinicians’ understanding of drug safety, and the clinical presence of other diseases or factors that cause liver injury. Usually, the clinical diagnosis of drug-related liver disease requires the following basic conditions: (1) a history of drug exposure and an incubation period consistent with it, which varies according to the type of drug hepatotoxicity, ranging from 1-5 weeks in immune-specific cases to a few weeks, months or more than 1 year in metabolism-specific cases; (2) liver damage or liver function abnormalities due to other causes or diseases can be excluded; (3) once the diagnosis of drug-related liver disease is made, it is possible to stop the drug after discontinuing it. (3) once the diagnosis of drug-related liver disease is made, the serum ALT should start to decrease gradually after 8 days and stop increasing within 30 days after the drug is stopped, and other serum liver function indexes should also improve. The reference conditions for the diagnosis of drug-related liver disease include: (1) extrahepatic system manifestations, such as fever, rash, arthralgia or lymph node enlargement, etc., with systemic vasculitis; (2) blood picture showing eosinophilia (>6%), pseudomonocytosis, etc.; (3) immunological examination, application of relevant drug-sensitized macrophage (or leukocyte) movement inhibition test and/or lymphocyte transformation test (4) histological changes suggestive of drug-induced liver disease, which may present with zone necrosis of liver lobules or alveoli, microvesicular fatty liver, eosinophilic infiltration, simple biliary sludge, destructive bile duct lesions, hepatic vascular damage lesions, and granulomatous hepatitis; (5) occasionally, the disease is rapidly triggered to reignite due to re-administration of drugs.
Currently, there are no uniform and accepted diagnostic criteria for drug-related liver disease. Identification of whether liver injury is caused by drug factors requires following Karach and Lasagna evaluation guidelines, i.e., whether the chronological sequence of drug administration and reaction appearance is reasonable, whether there are previous reports of reactions to the drug, the outcome of withdrawal of the drug after the occurrence of reaction, the appearance of readministration of the drug after clearance of reaction symptoms, and whether there are other causes or confounding factors. The more commonly used diagnostic criteria include the Maria Diagnostic Scale, the Modified Danan Scale and the 2004 Japanese DDW Modified Scale.
V. Treatment
Immediate discontinuation of liver-damaging drugs and suspected drugs is the primary treatment for drug-induced liver disease, and most mild drug-induced liver injury can be recovered in the short term. However, if the liver-damaging drugs used to treat the underlying disease cannot be discontinued or even replaced by other drugs, it is necessary to weigh the advantages and disadvantages, and can be achieved by reducing the dose of drugs and changing the usage of drugs to both effectively control the original underlying disease and minimize the degree of liver damage.
In patients with acetaminophen overdose, N-acetylcysteine can detoxify the reactive metabolites that have been formed and can be administered early with good results.
In patients with severe disease or liver failure, strengthen the supportive treatment, according to liver failure for active treatment, artificial liver support and liver transplantation can be considered.
VI. Outlook
Hepatotoxicity of drugs is a clinical issue of increasing concern, and it is of great significance to strengthen the attention and research in this area to ensure the safety of drugs and to implement early warning to predict the risk of future drug use.
Mastering the indications of drug use and rational use of drugs are the main measures to reduce drug-related liver disease. Pay attention to the use of drugs in children, the elderly, patients with a history of liver disease and other special groups; pay attention to drug interactions and avoid the simultaneous use of drugs with the same metabolic pathway; fully understand the metabolic characteristics, dosage and safety information of drugs before treatment; fully understand the adverse reactions and allergic history of patients with previous drug use before treatment is an effective means to reduce drug-drug liver injury. Drug concentration monitoring should be established in units with conditions, and the role of clinical pharmacists should be brought into play.
Once the diagnosis of drug-related liver disease is established, it should be promptly reported according to the requirements of adverse drug reactions, according to statistics, only about 10% of liver damage cases are included in the statistics. According to the comparison of adverse drug reaction reports between China and the United States in 2002, the United States has a population of 250 million and reports 290,000 adverse reactions annually, while China has a population of 1.3 billion and reports less than 10,000 adverse reactions annually, of which 9 provinces and cities are 0. It is urgent to pay attention to drug-related liver injury, drug safety, and the establishment of China’s DILI database.
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