I. Overview
The liver is the most important target organ for drugs or toxins, so liver damage caused by drugs and toxins is more common. Drug-related liver damage is a disease caused by toxic damage to the liver or allergic reaction to drugs during the application of therapeutic doses of drugs. If there are certain viral infections or underlying infections, liver damage is more likely to occur and can be life-threatening in severe cases. In the United States, drug-related hepatitis accounts for about 2-5% of hospitalized liver disease patients and 10% of adult liver disease patients, and 25% of fulminant liver failure is caused by drugs. Drug-related liver damage accounts for 10-15% of the overall adverse drug reactions. Due to the high incidence of viral hepatitis in China, the rate of drug-related hepatitis is lower than that of foreign countries, but the incidence is on the rise.
Second, the etiology
1, the toxic effect of the drug itself is also a direct effect and dose related
2, drug-induced allergy, i.e., metabolic reactions.
3.Anti-metabolic effect of certain drugs, such as drugs that cause abnormal lipid metabolism can cause hepatocyte steatosis.
4.Some drugs have immunosuppressive effects, leading to the replication of the original hepatophilic virus, fibrous stasis biliary hepatitis, also can activate the activity of potential viruses such as CMV.
Third, the pathogenesis
1, the drug is converted into active metabolites. The biochemical transformation process of drugs in the liver is accomplished by drug metabolizing enzymes in microsomes, such as cytochrome P450. Different drugs undergo oxidation, reduction or hydrolysis reactions in the liver, and finally combine with glucuronic acid and so on to become water-soluble substances, of which those with molecular weight <200 are excreted by the kidney; those >200 are excreted by the bile duct.
2.Drugs interfere with the metabolic process of hepatocytes. For example, drugs interfere with the metabolism of bilirubin and affect the excretion of bile; the effect of drugs on fat metabolism; the toxic effect on the main structures of hepatocytes; inducing immune metamorphosis-mediated liver damage.
Fourth, the common drugs that cause drug-related liver damage
1, carbon tetrachloride, halothane, chloroform, paracetamol, antimony, arsenic and organophosphorus and other chemical toxins certain antibiotics such as tetracycline, erythromycin, isoniazid, rifampin, etc.
2.Anti-psychotic drugs
3.Anti-metabolic drugs
4.Anti-tumor and other chemotherapy drugs
5.Chinese medicine, especially tonics
V. Factors of drug-related liver damage
Whether a drug causes liver disease depends on two factors, namely, the toxicity of the drug to the liver and the body’s reaction to the drug. Drugs that are toxic to the liver are called liver-damaging drugs, of which there are direct liver-damaging drugs and indirect liver-damaging drugs.
Six, drug-related liver damage factors
1, the drug itself: some drugs have their own liver toxicity, can directly or indirectly cause liver damage. Methotrexate, 6-mercaptopurine, etc. selectively interfere with a link in the metabolism of liver parenchymal cells, affecting the synthesis of liver proteins.
2, individual factors: hereditary idiosyncratic physique or genetic factors of the variation can make some people to some drugs increased sensitivity. Usually patients with allergies or a history of drug allergies are more likely to develop drug hepatitis.
3, the impact of the original disease on the occurrence of drug hepatitis: the original chronic liver disease, renal insufficiency, malnutrition of patients can increase the susceptibility of the body to drug toxicity.
4, the impact of gender and age on the occurrence of drug-related hepatitis: drug-related liver damage is more often seen in women. The elderly are also prone to drug-related liver damage, the reason may be related to the reduction of microsomal enzyme system activity, liver and kidney function itself is reduced.
5, the course of treatment and the impact of the dose on the occurrence of drug-related hepatitis: generally have a direct toxicity to the liver cells of the drug and the application of dose related. The higher the dose, the longer the course of treatment, and the more severe the liver damage.
Seven, clinical manifestations
The “incubation period” of drug-related liver damage varies in length. Among them, the onset of the drug within 2 weeks accounted for 50-70%; within 8 weeks of the onset of 80-90%; more than 3 months onset of the disease is rare. Chlorpromazine, methyltestosterone, INH and PAS are mostly used in about one month. Symptoms of liver disease have been reported with the use of methotrexate for more than 1 to 3 years for the treatment of skin disease, and with the use of the light laxative diacetin for 6 months to more than 2 years for the onset of liver disease. Usually the shorter the incubation period, the more severe the disease.
The clinical manifestations of drug-related liver damage vary, often with jaundice as the first symptom, often with symptoms similar to those of acute viral hepatitis and/or obstructive jaundice, such as fever, malaise and other systemic symptoms, as well as digestive manifestations such as poor appetite, nausea, vomiting, abdominal distention, pain in the liver area, and jaundice. There is the presence of bile depression in the course of the disease, some of which is transient, while others are severe enough to require the application of anti-yellowness medication or, in severe cases, artificial liver support. The severity of the disease is often related to the type of liver-damaging drugs and the mechanism by which they cause liver disease. Patients may have varying degrees of hepatomegaly, elevated serum bilirubin and transaminases, and in severe cases, acute or subacute signs of hepatic necrosis such as progressive jaundice, bleeding tendency and hepatic encephalopathy, and death from liver failure within a short period of time, similar to heavy viral hepatitis. In contrast, drug-induced liver disease with intrahepatic biliousness as the main manifestation has a milder onset, with symptoms such as weakness, poor appetite, and discomfort in the liver area being less pronounced than jaundice, but skin itching, lighter fecal color, and increased serum ALP and GGT are more prominent. Although serum bilirubin was increased to varying degrees, blood transaminases remained normal or rose slightly, resembling obstructive jaundice. Physical examination: yellow staining of skin and sclera, enlargement of liver, in severe cases, shrinkage of liver, shrinkage of hepatic turbinate, percussion pain in the liver area, distension in the abdomen, bulging sound on percussion, implying hepatocyte necrosis Petechiae and petechiae on the skin and mucous membranes.
VIII. Laboratory tests
1.Blood count White blood cell count Eosinophil increase means the presence of allergic reaction or allergic reaction
2. Liver function is characterized by elevated serum transaminase and alkaline phosphatase. This is followed by an increase in serum bilirubin, γ-glutamate transpeptidase, lactate dehydrogenase and serum bile acid concentration, a decrease in plasma albumin, and urinary triple bile (+).
3. Pathogenetic examination Mainly HBV, HCV, CMV
IX. Clinical typing
1. Acute drug-related liver damage
According to the nature of the main lesions are divided into three types of acute hepatocellular necrosis, biliary hepatitis or mixed liver disease.
(1) hepatocellular type (ALT rises to more than 2 times the upper limit of normal, ALT/ALP ≥ 5) according to different conditions can be manifested as ① no obvious conscious symptoms, only an increase in liver enzyme levels; ② similar to non-jaundiced hepatitis, with weakness, poor performance, epigastric discomfort, nausea, vomiting, etc.; ③ similar to jaundiced hepatitis, with conscious symptoms heavier than those without jaundice, and jaundice; ④ similar to fulminant hepatitis. The symptoms are heavy, the disease progresses quickly, and there may be coagulation disorders and hepatic encephalopathy and other diseases.
(2) Silicotic liver damage (ALT/ALP) ≤2 often presents with fever, chills, nausea, abdominal distension, malaise, followed by jaundice and pruritus, and the main biochemical changes are increased serum bilirubin and bile acids, ALP can be more than 3 times the normal value, and γ-GT is also increased.
(3) Mixed liver damage Clinical manifestations have the characteristics of both types, i.e., ALT and ALP are elevated, and ALT/ALP is between 2 and 5, which is mixed liver damage.
2.Chronic drug-related liver disease
(1) Chronic drug-related hepatitis. After weeks or months after the onset of the disease, clinical and biochemical abnormalities persist or worsen, indicating that the disease has become chronic, often due to the continued use of disease-causing drugs after the onset of the disease.
(2) Cirrhosis of the liver. The clinical presentation is similar to that of cirrhosis due to other causes, but drug-induced cases may have immune dysfunction. Autoantibodies and nonspecific antibodies are present in the serum.
(3) Chronic biliary sludge. Jaundice persists for more than 6 weeks after discontinuation of the causative agent, or biochemical abnormalities for up to 1 year due to drug-induced acute hepatitis, and also includes patients with jaundice free biliousness with increased ALP and γ-GT.
(4) Fatty liver
(5) Liver tumor
(6) Hepatic vascular lesions
X. Diagnosis
Preliminary diagnosis can be made based on the history of drug use, screening and comparison of the most likely causative agents, search or exclusion of other etiologies, combined with clinical manifestations, laboratory indicators, etc.
1, acute drug-related liver disease has a clear history of drug exposure, the onset of time is relatively clear, a comprehensive diagnosis can be made based on the history of drug use, clinical symptoms, liver function tests and the effect of drug withdrawal, combined with liver biopsy histological examination can make the diagnosis more clear, especially can exclude the underlying disease caused by liver function damage, such as connective tissue disease, hematological disease, tumors, tuberculosis and other intrahepatic infiltration, it is not difficult to diagnose.
2, chronic drug-related liver damage clinical manifestations and laboratory tests are not specific, and it is not easy to distinguish from other causes of liver disease. For this reason, when diagnosing drug-related liver damage, it is appropriate to ask for a detailed history of drug exposure, including the history of taking drugs and hepatotoxic exposure, and then conduct a comprehensive analysis and make a comprehensive judgment.
3, the following items help the diagnosis of drug-related liver damage.
(1) a history of drug exposure and the incubation period consistent with it, the incubation period varies according to the type of drug hepatotoxicity, more than 1-5 weeks for immune-specific, short weeks, months for metabolism-specific, long more than 1 year.
(2) Liver damage or abnormal liver function due to other causes or diseases can be excluded.
(3) Once the diagnosis of drug-related liver disease is made, the serum ALT should start to decrease gradually after 8 d and stop increasing within 30 days after stopping the drug, and other liver function indexes also improve. If liver biopsy can be done, it will be more helpful for the diagnosis of this disease.
4, with drug allergic liver damage can refer to the following indicators.
(1) signs of liver function damage 1-4 weeks after drug administration.
(2) Relatively mild fever, rash, pruritus and jaundice, general malaise, and liver pain.
(3) Elevated eosinophils (>6%) or an increase in blood leukocytes.
(4) Positive drug allergy tests (skin tests, lymphocyte cultures, etc.).
(5) positive provocation test, where similar symptoms can occur with the same drug.
The key to early diagnosis of drug-related liver damage is a high degree of vigilance for this condition. Any patient with liver damage should first exclude drug-related liver damage, and should carefully inquire about the history of medication and drug allergy during consultation, paying special attention to the drug dose, route of administration, course of treatment and other drugs applied at the same time. If a suspicious drug is found, stop the drug in time and observe whether the liver damage has improved after stopping the drug. The severity of clinical symptoms of drug-related liver damage can vary greatly and have different clinical types depending on the specificity of the drug used and the individual patient.
Eleven, treatment
1, immediately discontinue the drugs related to liver damage or suspected, and pay attention to observe whether the patient’s condition improves within a few days, but there are some drugs can continue to worsen within a few weeks after discontinuation, and it takes several months to recover.
2. Patients should rest in bed and be given adequate heat and protein, vitamins and other systemic supportive therapy.
3.The treatment of most drug-related liver damage is the same as viral hepatitis, using liver-protective drugs, vitamin drugs, enzyme-lowering and anti-yellowing drugs. Oppose the application of bifenacoum for liver function abnormalities.
4.The treatment principle of acute liver failure is basically the same as that of fulminant hepatitis, giving preparations such as hepatocyte growth promoter and Mennen, intravenous supplementation of fresh plasma and albumin, applying artificial liver or dialysis treatment if available, and actively preventing and controlling complications such as hepatic coma and bleeding.
5. Those who have obvious cholestasis can use Eusebio.
12.Prevention
1, to maintain a high degree of vigilance to drug hepatitis, early detection of changes in liver function is very important to avoid the occurrence of drug hepatitis.
2, we should pay attention to ask the patient’s drug allergy history, where the allergic body, drug selection, dose, route of administration, should be doubly careful.
3, where the drug dose is large, the course of treatment is too long, the more chances of liver damage.
4, the simultaneous use of a variety of drugs, the more interactions in the metabolic process in the body, the more opportunities for the formation of new hepatotoxic substances, should try to avoid the repeated use of similar drugs.
5.Preparation for chemotherapy, in addition to routine and biochemical tests, certain common viral indicators such as HBV serological indicators, HBV DNA, anti-HCV, HCV RNA, CMV DNA and anti-CMV should also be checked.
6, monitoring during chemotherapy, changes in liver function, for some patients such as the original chronic HBV infection (carriers) it is necessary to carry out prophylactic antiviral therapy, but also prophylactic or targeted liver preservation therapy.