drug-induced liver disease
Introduction
Introduction to drug-induced liver disease Drug induced liver disease (drug induced liverdisease) is referred to as drug liver, which refers to liver damage caused by drugs or/and their metabolites. It can occur in healthy people who have no previous history of liver disease or those who have had serious diseases. The liver damage that occurs to a different extent after using a certain drug is called liver. At present, at least 600 kinds of drugs can cause liver medicine, and its performance is the same as that of various liver diseases in human beings, which can be manifested as hepatocyte necrosis, cholestasis, intracellular microlipid deposition or chronic hepatitis, cirrhosis and the like. basic knowledge The proportion of illness: the incidence rate is about 0.005%-0.008%, mostly related to long-term use of anti-tuberculosis drugs Susceptible people: no special people Mode of infection: non-infectious Complications: abdominal distension, jaundice, ascites, liver cirrhosis, hepatic encephalopathy
Cause
Cause of drug-induced liver disease
(1) Causes of the disease
There are hundreds of drugs that can cause different degrees of liver damage, among which drugs acting on the central nervous system such as chlorpromazine, diazepam, etc., chemotherapy drugs such as sulfonamides, isoniazid, rifampicin, p-aminosalicylic acid Etc., antibiotics such as tetracycline, erythromycin, etc., antipyretic analgesics such as indomethacin, phenylbutazone, acetaminophen, salicylic acid, etc., anticancer drugs such as methotrexate, 6-mercaptopurine 5-fluorouracil is more common; other such as testosterone, estrogen, some progesterone contraceptives, oral hypoglycemic agent tolbutamide, anti-thyroid drugs, and certain Chinese medicines such as yellow medicine, Xanthium, etc. Can cause drug-induced liver damage.
(two) pathogenesis
The drug is metabolized in the liver, and a series of drug-metabolizing enzymes (referred to as drug enzymes, including cytochrome P-450, monooxygenase, cytochrome C reductase, etc.) and cytosol in the microsomes on the smooth endoplasmic reticulum of the liver cells. Coenzyme II (reduced NADPH), which is oxidized or reduced or hydrolyzed to form the corresponding intermediate metabolite (phase I reaction), and then combined with glucuronic acid or other amino acids (phase II reaction, ie biotransformation of the drug) Forming a water-soluble final product that is excreted from the body. The biliary system with a molecular weight of more than 200 in the final metabolite is excreted from the intestine, and the rest is secreted by the kidney.
The mechanism of drug-induced liver injury may be: 1 the direct toxic effect of the drug and its intermediate metabolites on the liver, which can be predicted; 2 the body's allergic reaction to the drug or the drug-specific reaction (idiosyncracy) Allergic reactions to metabolites. It is the body's immune response to drugs and metabolites or complexes that covalently bind drugs and metabolites to macromolecules in the liver. This type of medicine is unpredictable.
The pathogenesis of the drug liver can inhibit the K+, Na+-ATPase on the cell membrane, interfere with the uptake process of the liver cells, and destroy the cytoskeletal function by changing the physical properties (viscosity) and chemical properties (cholesterol/phospholipidation) of the liver cell membrane. The formation of insoluble complexes in bile directly leads to liver damage, and can also selectively destroy cellular components, covalently bind to key molecules, interfere with specific metabolic pathways or structural processes, and indirectly cause liver damage.
Prevention
Drug-induced liver disease prevention
1. Master the indications for medication: clinicians should be familiar with the performance of the drugs used and liver toxicity, try to use less or no drugs that have toxic effects on the liver. It is contraindicated to abuse drugs and long-term use of drugs when the indications are unclear.
2. Understand the patient's medication history: ask the patient's medical history in detail before taking the medicine, especially liver disease, diet, exposure to industrial chemical poisons, kidney disease and allergy history. For patients with a history of drug-induced liver disease, avoid giving the same or similar chemical structure. drug.
3. Before taking the drug, you should also pay attention to the individual condition of the patient: taking into account the general condition, age, gender, physiological and pathological state, nutritional status, drug tolerance, mental and other factors, such as patients with liver and kidney disease, For newborns, pregnant patients, etc., the choice of use and dosage should be carefully considered.
4. Consider the impact of co-morbidity on the liver: patients with liver disease often have infections with pathogenic factors such as viruses, bacteria, fungi, and parasites. These factors and their metabolites can aggravate the burden on the liver. From an immunological point of view, these Infection often involves cellular immunity, and a large number of lymphokines can cause hepatocyte necrosis. For example, when combined with central nervous system, cardiovascular, digestive, endocrine and urinary system diseases, the complexity of medication is also increased.
5. Avoid the following situations when using medication: avoid taking drugs under fasting or starvation; avoid nutrient-poor drugs, avoid using drugs with hepatotoxicity; avoid heavy drinking during medication, or take medication after drinking; patients with middle-aged or older should have detoxification ability Close monitoring of liver function changes; the drugs used should be avoided with phenobarbital or chlorpromazine for a long time; anesthetics, sleeping pills, analgesics, sulfonamides should not be taken for a long time.
6. Monitoring the medication process: Strengthen the monitoring during the medication, pay attention to monitoring various toxic reactions and adverse reactions, and regularly detect blood, urine, bilirubin, transaminase, ALP, etc., especially during the trial period of new drugs.
7. In the past, there was a new drug for chemical synthesis of patients with a history of drug allergy or allergies. Even if no cases of poisoning were reported, there was a risk of allergic liver damage. Allergic liver damage may occur in biological preparations containing the same or different proteins. Anyone who takes a large dose or a long time will have an increased chance of developing allergies; those who are at high tide of bacterial infection or shortly after resection of the tumor are prone to drug allergic reactions.
8. Use or avoid drug interactions to prevent adverse reactions: corticosteroids can be used to prevent or alleviate most drug-induced liver damage; biphenyl diester and anti-tumor drugs can prevent drug-induced liver damage; p-aminosalicylic acid It can block the acetylation of isoniazid and reduce its liver damage; cysteine can restore the glutathione reserve, can reduce the toxicity of acetaminophen; due to the decomposition of barbital in the liver, some drugs Hepatic damage can be aggravated when combined with barbiturates; it should be avoided; those with abnormal liver function, such as morphine, barbiturates, methionine, ammonia, anesthetics, and strong diuretics are easy to induce hepatic encephalopathy. Should be banned; long-term use of tetracycline and corticosteroids, easy to cause fatty liver.
9. Stop the drug: Once liver damage occurs, stop the drug immediately.
10. Precautions for medication for patients with liver disease When liver function is impaired, the half-life of the drug is prolonged, which may cause accumulation of the drug in the body and increase toxicity. Therefore, the dosage regimen should be adjusted to reduce the dose or prolong the interval of administration, especially for those who are eliminated from the liver. And drugs with more adverse reactions should pay attention to, such as the use of chloramphenicol in patients with liver dysfunction, the incidence of aplastic anemia increased, patients with liver disease with cardiac insufficiency, rapid digital supraventricular arrhythmia when using digitalis treatment, Use digoxin mainly excreted by the kidney, and not use digoxigenin mainly excreted by the liver to avoid accumulation of poisoning. When patients with liver disease are infected with tuberculosis, consider using ethambutol, cycloserine, capreomycin, etc. Anti-tuberculosis drugs with little effect on liver damage, and try to avoid the use of isoniazid, rifampicin, pyrazinamide and other drugs with more obvious hepatotoxicity.
Hepatic encephalopathy and its pre-patients are very sensitive to sedatives and anesthetics, such as diazepam, morphine, barbiturates, etc., which are prone to dangerous central nervous system depression. The main reason is not the drug detoxification effect, but the drug effect is enhanced. Is due to increased sensitivity of central nervous receptors, such as GABA receptors with the severity of liver disease, drugs and endogenous, exogenous central neurotransmitters or pseudo-neurotransmitters compete for changes, in addition, can increase blood Treatment methods for ammonia concentration such as blood transfusion, plasma transfusion, protein delivery and other nitrogen-containing drugs (such as methionine), or drugs that can reduce the metabolism of metabolism (such as monoamine oxidase inhibitors) may also induce hepatic encephalopathy, which is severely affected by liver function. Damage to patients with acetazolamide, thiazide diuretics, because it can reduce the excretion of H + in the urine, and reduce the excretion of NH4:, increase the accumulation of ammonia in the body, induce hepatic encephalopathy, and reduce blood potassium during diuresis can also induce Hepatic encephalopathy.
In the case of liver dysfunction, the use of oral anticoagulants such as coumarins, the inhibition of coagulation function is more obvious, recovery after the withdrawal is also late, which may be due to the liver's ability to use vitamins to synthesize thrombin and other coagulation factors On the other hand, it may also be related to an increase in free drug type and an increase in action.
When cirrhotic portal hypertension is used for portal vein anastomosis, the drug can be bypassed by the liver after oral administration, and the bioavailability is increased, and the effect is enhanced, such as propranolol, verapamil, etc., while some drugs need to undergo liver metabolism. Activated into an effective drug, the drug is reduced in liver dysfunction. For example, prednisone needs to be converted into prednisolone by 11-hydroxydehydrogenase in the liver to achieve therapeutic effect. Among patients with acute and chronic liver disease, some The level of prednisolone in plasma after oral administration of prednisone was significantly lower than normal. In the clinical recovery of liver disease, the level of prednisolone in the blood was significantly increased after taking prednisone. Therefore, patients with liver disease should use prednisolone instead. Prednisone, in addition, the immunosuppressive drug azathioprine, anti-tumor drug cyclophosphamide, etc. need to be activated in the liver to be effective, liver disease patients should pay attention to the application, in short, patients with liver disease must be careful to use drugs, drugs are rarely used Proper, the dose should not be too large, can not be combined with a variety of drugs at the same time, so as not to increase the burden on the liver and various adverse reactions.
For general drugs, the plasma concentration of the drug caused by liver dysfunction often does not exceed 2 to 3 times. In the absence of changes in receptor sensitivity, the clinical significance of this change in blood drug concentration is It is not very important, because there may be such individual differences among normal people, but some drugs may have an adverse reaction when liver dysfunction, and should be noted.
Complication
Drug-induced liver disease complications Complications, abdominal distension, jaundice, ascites, cirrhosis, hepatic encephalopathy
Patients with cholestatic inflammatory disease may have fever, chills, fatigue, nausea, abdominal distension, followed by jaundice and itching. Those with severe disease may have ascites, coagulopathy and hemorrhage, cirrhosis, and hepatic encephalopathy.
Symptom
Symptoms of drug-induced liver disease Common symptoms Liver lesions diffuse nausea Upper abdominal discomfort Liver congestion Appetite loss Skin itching nose Hair burning Liver vein disease Liver cholestatic
Symptoms and signs
There is a history of receiving drugs, generally there are loss of appetite, upper abdominal discomfort, nausea and other gastrointestinal symptoms, hepatitis-like clinical manifestations like viral hepatitis, with or without jaundice, patients with intrahepatic cholestatic type, in addition to gastrointestinal symptoms, All have jaundice, itchy skin, dark yellow urine, light color of manure or terracotta color, liver damage caused by allergic reactions caused by drugs, jaundice appeared 2 to 4 weeks after administration, but it can also occur in 1-3 days Repeated medication can cause immediate reaction. In addition to jaundice, the patient may be accompanied by fever, rash, joint pain, muscle pain, etc. The liver may be swollen and tender, and the spleen may be swollen.
Examine
Examination of drug-induced liver disease
Laboratory inspection
(1) Serum markers of various viral hepatitis are negative.
(2) serum bilirubin, transaminase, alkaline phosphatase, total bile acid, serum cholesterol, etc. can be increased to varying degrees, plasma albumin can be reduced, prolonged prothrombin time, activity decreased, blood ammonia Increased, decreased blood glucose, etc., the total number of white blood cells increased (about 21%), normal or decreased.
(3) Patients with allergic reactions have increased eosinophilia in peripheral blood (>3% of 6%), and the positive rate of drug-induced lymphocyte transformation test can reach more than 50%.
Film degree exam
1. B-mode ultrasound: whether it is selected, depending on the condition, it is helpful for the diagnosis of fatty liver, cirrhosis, liver tumor and hepatic vascular disease.
2. CT examination: the indication and its significance are similar to B-ultrasound.
3. Liver biopsy: The pathological type of liver damage can be determined, but it is not possible to determine whether it is caused by drugs.
Diagnosis
Diagnosis and identification of drug-induced liver disease
diagnosis
The diagnosis of drug-induced liver disease can be based on the history of medication, clinical manifestations, blood, liver function tests, liver biopsy and the effects of drug withdrawal. The diagnostic criteria for drug-induced liver disease are summarized as follows:
1. The liver damage appears within 1 to 4 weeks after administration, but it can also appear after several months of taking the drug. A few incubation periods can be longer.
2. The initial symptoms may have fever, rash, itching and so on.
3. Peripheral blood eosinophils > 0.6.
4. Pathological and clinical manifestations of intrahepatic cholestasis or hepatic parenchymal cell damage.
5. Positive for macrophage or lymphoblastic transformation test.
6. Serological markers of various viral hepatitis are negative.
7. Liver damage occurs again after accidental administration of the same drug.
With the above article 1, plus any two of the 2 to 7, can be considered as drug-induced liver disease.
Differential diagnosis
The disease needs to be differentiated from acute viral hepatitis and drug-induced liver damage.
Acute viral hepatitis
The basis for the identification of ischemic hepatitis and viral hepatitis is:
(1) The serum markers of various hepatitis viruses are all negative. However, there is a certain difficulty in the differential diagnosis of ischemic hepatitis in hepatitis virus carriers.
(2) The dynamic changes of serum enzymes in ischemic hepatitis, and the abnormalities of ALT and AST caused by viral hepatitis will not decrease rapidly in a short period of time.
(3) Serum LDH is significantly elevated in ischemic hepatitis, while viral hepatitis is only slightly elevated or not elevated.
2. Drug-induced liver injury The identification of ischemic hepatitis and drug-induced liver injury is mainly based on the dynamic changes of serum enzymes, lacking other specific indicators, and drug-induced liver damage caused by ischemic hepatitis and acetaminophen. Identification, by calculating the ALT/LDH ratio, the latter's ALT/LDH ratio often exceeds 11.25.
