The most common form of pharmacologic liver injury is atopic liver injury, which by definition occurs within a therapeutic dose but only in susceptible individuals. Susceptibility to atopic liver injury depends on genetic and environmental risk factors, both of which determine the in vivo distribution and metabolism of the drug as well as tissue susceptibility and adaptation to toxicity. Risk Factors for Pharmacologic Liver Disease At present, there are limited predictive risk factors for liver injury, and those that have been relatively well characterized are: age, gender, genetic and familial predisposition, drug-drug interactions, cross-reactivity, alcohol abuse, nutritional status, underlying liver disease, and other disorders. Age 20% of hepatitis in the elderly is caused by drugs. Data suggest that 30% of adults aged 19-64 years use prescription medications, while 74% of adults over 65 years use prescription medications. As a result, adverse effects are multiplied in older adults. approximately 19% of 19-64 year olds use two or more medications, compared to 51% of 65-74 year olds, of which 12% use five or more prescription drugs. The risk of drug interactions increases with polypharmacy. Increased or repeated exposure to a drug with age may also produce an immune-specific response. Impaired drug distribution and metabolism are also age-related. With age, there is a progressive decline in hepatic and renal function, leading to increased accumulation of drugs in the body. In the elderly, hepatic blood flow is reduced; the major drug carrier proteins in the blood are serum albumin and alpha 1 acid glycoprotein, both of which are also decreased. A study that included 1,000 patients showed that the rate of transaminase elevation was more than five times higher in the elderly than in the normal age group when treated with isoniazid, while another study found that age factors were associated with pyrazinamide liver damage. Gender In two large-scale studies, 61% to 66% of drug-induced liver damage occurred in women, about 1.5 times more than in men. According to the Health and Nutrition Census, the gender difference in the use of prescription medications to produce drug-induced liver damage occurs after age 20. Drug-induced chronic liver injury is more common in women and is a specific type of liver injury. This type of liver damage has several features of autoimmune liver damage, such as autoantibodies (antinuclear antibodies, anti-smooth muscle antibodies), hyperglobulinemia, and response to steroids. Drug-Drug Interactions A drug enhances the hepatotoxicity of another drug by inducing the production of toxic metabolites that inhibit or compete for detoxification. The combination of rifampicin and isoniazid produced earlier toxicity and higher serum alanine aminotransferase (ALT) levels than isoniazid alone. The mean time to onset of liver damage was 1 month with isoniazid compared to 15 days with the combination of rifampicin. In one clinical study, the incidence of liver damage was 1.6% with isoniazid alone, 1.1% with rifampicin alone, and 2.6% with both. Reactive toxic metabolites are produced by CYP microsomal enzymes. Cross-reactivity For certain structurally similar drugs, a history of drug liver damage should be considered an important risk factor. These reactions are referred to as cross-reactivity, cross-sensitization, or cross hepatotoxicity. Cross-reactivity may be caused by structural similarities that elicit immunomutagenic responses; or by shared genetic polymorphisms in metabolism. Cross-reactivity has been reported between angiotensin-converting enzyme inhibitors (ACEIs); between erythromycin salts, ampicillin, and cefuroxime; between the furans furotoxin and furazolidone; between haloalkane anesthetics and nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen and fenuglifloxacin; and between the tricyclic antidepressants aminopterin and clomipramine, as well as between trimipramine, dexipramine, and the phenothiazine cyanomemazine. reactions have been reported. Alcoholism Alcoholism lowers the threshold for acetaminophen intoxication by inducing CYP2E1, whose toxic metabolites reduce glutathione detoxification. Alcoholism Alcoholism induces CYP2E1 to produce more N-acetyl-p-benzoquinone imine (NAPQI), and this induction gradually disappears after abstinence from alcohol. Ethanol prevents mitochondrial uptake of glutathione from the cytosol, leading to selective mitochondrial depletion of glutathione. Selective mitochondrial depletion of the detoxifying effects of glutathione and subsequent mitochondrial toxicity are the primary causes of acetaminophen toxicity. Nutritional status Drugs entering the small intestinal epithelium are partially metabolized by CYP3A, the so-called “drug-metabolism cascade”, which is the determining factor for the first-pass effect in the small intestine. Grapefruit, pomegranate, poppy seeds and grapefruit juice can inhibit CYP3A. Grapefruit juice inhibits CYP3A drug metabolism the most, and can increase the absorption of some oral drugs, inhibit the transport of some glycoprotein-bound drugs, enhance the effect on CYP3A. Cyclosporin A-induced cholestasis has been reported in one patient who used cyclosporin A and ingested sufficient grapefruit juice in an attempt to increase its absorption. Fasting lowers the threshold for acetaminophen toxicity in experimental animals and humans. Fasting depletes large amounts of hepatic glycogen, leading to loss of urinary nucleoside diphosphate glucose (UDPG) and also depletes glutathione. Underlying Diseases of the Liver Pharmacologic liver damage can lead to decompensation in patients with chronic liver disease. It has been shown that patients with underlying disease of the liver are at higher risk of abnormal liver function when using statins. Investigations of anti-tuberculosis treatment have shown that viral hepatitis and abnormal baseline liver tests are considered risk factors. OTHER DISEASES Compound sulfamethoxazole tablets cause liver injury in about 20% of patients with AIDS. It has been hypothesized that in such groups there is a deficiency in glutathione, which prevents the oxidation of hydroxylamine to the more toxic metabolite nitrososulfamethoxazole. It has also been suggested that there is an association with allergy induced by altered systemic immune function. At present, the more established risk factors for drug-induced liver injury are still not well defined, and there is still a considerable degree of difficulty in evaluating the risk factors for drug-induced liver disease. Genetic susceptibility to drug-induced liver disease Genetic and familial hereditary factors are the risk factors that face the greatest challenges in the field of drug-induced liver injury research, with the ultimate goal of guiding the use of medications in the majority of patients who are not at risk for liver injury and detecting the minority of patients at risk for liver injury. Most promising is the development of pharmacogenomics and metabolomics. One of the criteria for determining whether there is a genetic predisposition to a disease is by comparing the incidence of specific genetic variants in case and control groups. Currently, methods for detecting genetic polymorphisms in genetic association studies of drug-induced liver injury (DILI) are feasible, and the key is to have a sufficient number of definitively diagnosed DILI cases and matched controls. There are also limitations in current genetic studies of DILI. In most drug trials, discontinuation of therapy is usually required when serum ALT levels are found to exceed the upper limit of normal (ULN) by 3 to 5 times. However, this does not necessarily mean that these subjects will develop severe DILI if they continue to be treated with the drug, and in some cases a reversal of the ALT level may even occur if treatment with the drug is continued, a process known as “acclimatization”. For example, up to 15% of patients treated with isoniazid experience ALT levels exceeding 3 times ULN, and the majority of these patients continue to be treated with isoniazid, with less than 1% being forced to discontinue the drug due to the development of symptomatic hepatitis. It goes without saying that the occurrence of liver failure is a clear criterion for identifying progressive DILI (progressive liver injury from a drug). However, some trials fail to observe it because patient samples are too small, and even in clinical trials with relatively large sample sizes, drug therapy is often discontinued before jaundice develops in these individuals. Thus, the value of utilizing prospective clinical trial studies appears limited. Currently, the diagnosis of DILI is commonly made by exclusion, which makes it difficult to obtain a definitive diagnosis, and thus the definitive diagnosis of DILI is also an inherent difficulty in real-world studies. Clinical uncertainty exists regarding the classification of DILI, which can reduce the credibility of genetic association findings. In addition, for hepatocellular and cholestatic DILI, the mechanisms of liver injury differ, which will also have an impact on genetic association studies of DILI. Even if a definitive diagnosis can be made, determining which drug is the original culprit of DILI can be difficult, such as applying compounded preparations, or applying over-the-counter and herbal preparations, and it is difficult to identify the main drug that causes DILI, and the credibility of the study will be further undermined if other drugs are mistakenly taken as the drug that causes DILI. Most genetic studies of DILI are based on the “active metabolite” hypothesis. It is generally accepted that most DILIs are related to the accumulation of active metabolites of the parent drug in hepatocytes, and that when the accumulation exceeds a critical “threshold”, a cascade of events leading to apoptosis of the hepatocyte is triggered (see Fig. Many researchers have also often focused their susceptibility studies on enzyme genetic signatures of dysfunction in the detoxification or elimination of the drug. enzyme genetic signs. Fig. Active metabolites can trigger hepatocyte stress. Defects in drug enzyme activity or transporter function, resulting in drug shunting to bioactivation pathways, increase susceptibility to DILI. NAT: N-acetyltransferase; UGT: urinary nucleoside diphosphate glucuronosyltransferase; HLA: human leukocyte antigen; IL: interleukin; CYP: cytochrome P450 Relatively large sample sizes are imperative in the study of the genetic association of DILI. A single nucleotide polymorphism (SNP) is said to occur when the frequency of the phenotype determined by a pair of alleles is greater than 1% in the population with the disease and in the cumulative number of people with the disease, whereas usually the number of patients with idiosyncratic DILI is not that high, and therefore, the genetic susceptibility to DILI may not be caused exclusively by single gene polymorphisms. Only a small percentage of patients with progressive DILI have susceptibility associated with SNPs. Non-genetic factors may also be important in some cases. There are two possibilities for genetic susceptibility to DILI, one favoring a single gene variant, which has an incidence of less than 1% in the population, and the other involving multiple gene polymorphisms, where strongly susceptible individuals may be due to altered function in several different genes with polymorphisms. For example, in patients with DILI caused by the delisted insulin sensitizer troglitazone, a 46% allelic variant of the phase I metabolizing enzyme CYP2C19*2 was reported, and it was later found that there were genetic polymorphisms in the phase II metabolizing enzyme glutathione S-transferase (GST), and that defects in the GSTT1 and GSTM1 genes were strongly associated with elevated ALT and aspartate aminotransferase (AST) in these patients ( generation of the active intermediate quinone epoxide). Two independent studies have demonstrated a correlation between HLA type II genotype and susceptibility to amoxicillin/clavulanate-induced liver damage. Both studies found an association with the HLADRB1*1501 allele. Polymorphisms in drug transporter proteins should also be noted. Some drugs and their metabolites enter and exit hepatocytes via specific transporters. Typical sinusoidal transporters include the organic anion transporter (OAT) and organic anion-transporting polypeptide (OATP) families; transporters diverted into the bile include the transporter multiresistance-associated protein 2 (MRP2), the antimammary carcinoma protein and multidrug-resistant glycoprotein 1 (MDR-1), and the bile salt efflux pump (BSEP). Several polymorphisms in drug transporter proteins have been identified. Genetic factors influence the ability to generate an immune response to a new antigen. the HLA genes are highly polymorphic gene clusters and there have been many studies that have attempted to apply a DNA approach to HLA typing. In studies of genetic susceptibility to DILI, techniques for detecting gene polymorphisms are mandatory, and the most difficult problem is screening a sufficient number of susceptible patients and matched controls. The Drug-Induced Liver Disease Network (DILIN) studies have enabled various disciplinary fields to obtain detailed clinical and experimental data on cases through rigorous causality arguments, while providing the patient’s genetic DNA, serum, and immortalized lymphocytes in a registry for supervised retention for 20 yr. The establishment of the DILIN has also allowed for a number of subordination studies, including lineage analyses and phenotypic determinations along with the determination of genotype . The selection of an independent laboratory to perform genotyping of all subjects and to finalize gene sequencing facilitates quality control and ensures the internal consistency of the experiment as well as the integrity of the DNA samples and donor profiles. Principles of treatment of drug-induced liver disease The mainstay of treatment is the immediate discontinuation of the drug in question and the suspected drug, supportive therapy and monitoring, and prevention of hepatic failure. Most cases of mild drug-induced liver disease recover within a short period of time. For those with severe liver function damage or liver failure, they should be treated actively according to liver failure. N-acetylcysteine can be used as a nonspecific detoxifying agent, glucocorticoids can be used with caution in allergy-specific and intrahepatic cholestasis, ursodeoxycholic acid can be used in cholestatic type, and antioxidants and membrane protectors such as polyene phosphatidylcholine can be used in metabolic specificity. Liver transplantation should be considered if hepatic encephalopathy and coagulation disorders develop.