Acute drug-induced hepatitis

Acute drug hepatitis develops only in a small proportion of patients taking drugs, and manifests itself approximately 1 week after the start of treatment. The probability of developing acute drug hepatitis is usually not predictable. It does not depend on the dose, but it increases with repeated use of the medicine.

[1], [2], [3], [4], [5]

Isoniazid

Heavy liver damage was reported in 19 of 2231 healthy employees, who received isoniazid because of a positive tuberculin test. Symptoms of the lesion appeared within 6 months after the start of the drug; jaundice developed in 13 patients, 2 patients died.

After acetylation, isoniazid is converted to hydrazine, from which a powerful acetylating agent is formed under the action of lysing enzymes, causing necrosis in the liver.

The toxic effect of isoniazid is enhanced when it is taken with enzyme inducers, for example with rifampicin, and also with alcohol, anesthetics and paracetamol. Significantly increased mortality with the combination of ioniazide with pyrazinamide. At the same time, PASK slows down the synthesis of enzymes and, perhaps, this explains the relative safety of the combination of PASK with isoniazid, previously used to treat tuberculosis.

In people belonging to "slow" acetylators, the activity of the enzyme N-acetyltransferase is reduced or absent. As the ability to acetylate on hepatotoxicity of isoniazid affects, it is unknown, it is nevertheless found that in Japanese "fast" acetylators are more sensitive to isoniazid.

Perhaps liver damage occurs with the participation of immune mechanisms. However, allergic manifestations are not observed, and the incidence of subclinical liver damage is very high - from 12 to 20%.

During the first 8 weeks of treatment, an increase in the activity of transaminases is often observed. Usually, it is asymptomatic, and even with continued use of isoniazid, their activity is further reduced. Nevertheless, the activity of transaminases should be determined before and after the start of treatment after 4 weeks. When it increases, the test is repeated at intervals of 1 week. With further increase in the activity of transaminases, the drug must be discontinued.

Clinical manifestations

Heavy hepatitis often develops in people older than 50 years, especially in women. After 2-3 months of treatment, nonspecific symptoms may appear: anorexia and weight loss. After 1-4 weeks, jaundice develops.

After discontinuation of the drug, hepatitis is usually resolved quickly, but if jaundice develops, the mortality rate reaches 10%.

The severity of hepatitis significantly increases if after the development of clinical manifestations or increased activity of transaminases, the drug is continued. If after the beginning of treatment more than 2 months have passed, hepatitis proceeds more severely. Malnutrition and alcoholism exacerbate liver damage.

When a liver biopsy reveals a picture of acute hepatitis. Continuation of taking the drug promotes the transition of acute hepatitis to chronic. The abolition of the drug, apparently, prevents further progression of the lesion.

[6], [7], [8], [9], [10],

Rifampicin

Rifampicin is usually used in combination with isoniazid. Rifampicin and itself can cause mild hepatitis, but it usually occurs as a manifestation of a general allergic reaction.

Methyldofa

In the treatment of methyldopa, an increase in the activity of transaminases, which usually disappears even against the background of continued use of the drug, is described in 5% of cases. Perhaps this increase is due to the metabolite, since in human microsomes, methyldopa can be converted into a powerful arylating substance.

In addition, immune mechanisms of the hepatotoxicity of the drug associated with the activation of metabolites and the production of specific antibodies are possible.

Lesion is more common in postmenopausal women who take methyldofu for more than 1-4 weeks. Usually hepatitis develops within the first 3 months of treatment. Hepatitis may be preceded by a short-term fever. In liver biopsy, bridges and multilobular necrosis are identified. In the acute stage, a lethal outcome is possible, but usually after the drug is discontinued the condition of the patients improves.

Other antihypertensive drugs

The metabolism of other antihypertensive drugs, like debrisoquine, is determined by the genetic polymorphism of cytochrome P450-II-D6. The hepatotoxicity of metoprolol, atenolol, labetalol, acebutolol and derivatives of hydralazine has been established.

Enalapril (an angiotensin-converting enzyme inhibitor) can cause hepatitis accompanied by eosinophilia. Verapamil is also capable of causing a reaction resembling acute hepatitis.

Halothane

The defeat of the liver caused by halothane is very rare. It proceeds either gently, manifested only by an increase in the activity of transaminases, or fulminantly (usually in patients already exposed to halothane).

Mechanism

Hepatotoxicity of products of reducing reactions is enhanced by hypoxemia. The products of oxidative reactions are also active. Active metabolites cause LPO and inactivation of enzymes that ensure the metabolism of the drug.

Halothane accumulates in adipose tissue and is secreted slowly; Halothane hepatitis often develops against the background of obesity.

Given the development of halothane hepatitis, as a rule, with repeated administration of the drug, as well as the nature of fever and the development in some cases of eosinophilia and skin rashes, it is possible to assume the participation of immune mechanisms. In the case of halothane hepatitis, specific antibodies to microsomal liver proteins with which halothane metabolites bind are detected in the serum.

Patients and their families are diagnosed with increased cytotoxicity of lymphocytes. The extreme rarity of fulminant hepatitis testifies to the possibility for predisposed individuals of biotransformation of the drug according to the unusual mechanism and / or pathological reaction of tissues to polar halothane metabolites.

Clinical manifestations

In patients with halotoxic anesthesia performed repeatedly, halothane hepatitis develops significantly more often. Especially high risk in obese elderly women. Possible liver damage in children.

If the toxic reaction develops with the first administration of halothane, then fever, usually with chills, accompanied by malaise, nonspecific dyspeptic phenomena and pain in the right upper quadrant of the abdomen, appears no earlier than 7 days (from 8 to 13 days) after surgery . In the case of multiple halothane anesthesia, an increase in temperature is observed on the 1-11th day after the operation. Soon after the fever, usually 10-28 days after the first administration of halothane and after 3-17 days in the case of repeated halotane anesthesia, jaundice develops. The time interval between fever and the appearance of jaundice, approximately equal to 1 week, has a diagnostic value and allows excluding other causes of postoperative jaundice.

The number of leukocytes in the blood is usually normal, sometimes eosinophilia is possible. The serum bilirubin level can be very high, especially in cases of death, but 40% of patients do not exceed 170 μmol / l (10 mg%). Halothane hepatitis can also occur without jaundice. The activity of transaminases corresponds to the values characteristic of viral hepatitis. Sometimes there is a significant increase in serum alkaline phosphatase activity. With the development of jaundice, lethality significantly increases. According to one study, 139 (46%) of 310 patients with halothane hepatitis died. With the development of coma and a significant increase in IIb, there is practically no chance of recovery.

[11], [12], [13]

Changes in the liver

Changes in the liver can not differ in anything from those peculiar to acute viral hepatitis. Drug etiology can be suspected on the basis of leukocyte infiltration of sinusoids, the presence of granulomas and fat changes. Necrosis can be submissive and draining or massive.

In addition, at week 1, the picture of liver damage may correspond to direct damage by metabolites with massive hepatocyte necrosis of zone 3, covering two-thirds of each acinus and more.

At the slightest suspicion, even a mild reaction after the first halotane anesthesia, repeated administration of halothane is unacceptable. Before the introduction of any other anesthetic should carefully analyze the history of the disease.

Repeated anesthesia with halothane can be performed no earlier than 6 months after the first. If there is a need for surgery before the expiry of this period, another anesthetic should be used.

Enflurane and isoflurane are metabolized to a much lesser degree than halothane, and poor solubility in the blood causes their rapid release with exhaled air. Consequently, less toxic metabolites are formed. Nevertheless, repeated use of isoflurane marked the development of FPN. Although cases of liver damage after enflurane administration have been described, they are extremely rare. Despite the high cost, these drugs are more preferable than halothane, but do not use them at short intervals. After halothane hepatitis, antibodies remain that can "recognize" the metabolites of enflurane. Therefore, the replacement of halothane with enflurane in repeated anesthesia will not reduce the risk of liver damage in patients with a predisposition.

[14], [15], [16], [17], [18], [19], [20],

Ketoconazole (Nizoral)

Clinically significant liver reactions in the treatment of ketoconazole develop very rarely. Nevertheless, 5-10% of patients taking this drug have a reversible increase in transaminase activity.

The lesion is observed mainly in elderly patients (mean age 57.9 years), more often in women, usually with a duration of treatment more than 4 weeks; Taking the drug for less than 10 days does not cause a toxic reaction. Histological examination often reveals cholestasis, which can cause death.

The reaction refers to idiosyncrasy, but is not immune, since it rarely shows fever, rash, eosinophilia, or granulomatosis. Two cases of death from massive liver necrosis, mainly of the 3 acini zone, are described.

Hepatotoxicity may be characteristic of more modern antifungal agents - fluconazole and itraconazole.

Cytotoxic drugs

Hepatotoxicity of these drugs and BEP have already been discussed above.

Flutamide, an antiandrogenic drug used to treat prostate cancer, can cause both hepatitis and cholestatic jaundice.

Acute hepatitis can cause cyproterone and etoposide.

[21], [22], [23], [24]

Means that affect the nervous system

Tacrin, a drug used to treat Alzheimer's disease, causes hepatitis in almost 13% of patients. An increase in the activity of transaminases, usually during the first 3 months of treatment, is noted in half of the patients. Clinical manifestations are rare.

With the withdrawal of the drug, the activity of transaminases decreases, with the resumption of reception usually does not exceed the norm, which suggests the possibility of adapting the liver to tacrine. Cases of death from the hepatotoxic effect of the drug is not described, however, during the first 3 months of treatment with tacrine, the activity of transaminases should be monitored.

Pemoline, a central nervous system stimulant used in children, causes acute hepatitis (probably caused by a metabolite), which can lead to the death of patients.

Disulfiram, used to treat chronic alcoholism, causes acute hepatitis, sometimes fatal.

Glafenin. The liver reaction to this analgesic develops within 2 weeks - 4 months after the start of the procedure. Clinically, it resembles a reaction to zinhoven. Of 12 patients with a toxic reaction to glaphenin 5 killed.

Clozapine. This drug for the treatment of schizophrenia can cause FPN.

Drugs of long-acting nicotinic acid (niacin)

Drugs of long-acting nicotinic acid (in contrast to crystalline forms) can have a hepatotoxic effect.

The toxic reaction develops 1-4 weeks after the start of treatment at a dose of 2-4 mg / day, manifests itself as a psychosis and can be fatal.

[25], [26], [27], [28], [29]

Symptoms of acute drug hepatitis

In the pre-zheltushnom period there are nonspecific symptoms of lesions of the gastrointestinal tract, observed in acute hepatitis. After this, jaundice develops, accompanied by discolored stool and darkening of the urine, as well as an increase and painfulness of the liver. A biochemical study reveals an increase in the activity of liver enzymes, indicating the presence of cytolysis of hepatocytes. The level of y-globulins in the serum increases.

In convalescing patients, the serum bilirubin level begins to decrease from the 2-3 rd week. If the flow is unfavorable, the liver decreases and the patient dies of liver failure. Mortality among those with established diagnosis is higher - higher than among patients with sporadic viral hepatitis. With the development of hepatic precoma or coma, the mortality rate reaches 70%.

Histological changes in the liver may not differ in any way from the pattern observed in acute viral hepatitis. With moderate activity, the necrotic motes are revealed, the zone of which expands and can diffusely cover the entire liver with the development of its collapse. Bridge necrosis often develops; Inflammatory infiltration is expressed in different degrees. Sometimes later develops chronic hepatitis.

The mechanism of such liver damage may be either in the direct damaging effect of toxic metabolites of drugs or in their indirect effects when these metabolites, acting as haptens, bind to cell proteins and cause immune damage to the liver.

Medicinal hepatitis can cause many drugs. Sometimes this property of the drug is detected after it goes on sale. Information about individual products can be obtained in special manuals. The toxic reactions to isoniazid, methyldofu and halothane are described in detail, although they may occur with the use of other drugs. Each individual drug can cause several kinds of reactions, and the manifestations of acute hepatitis, cholestasis and allergic reaction can be combined.

Reactions usually take place very hard, especially if you do not stop taking the medication. In case of development of FPN, liver transplantation may be required. The effectiveness of corticosteroids has not been proven.

Acute drug-induced hepatitis particularly often develops in older women, while in children it is rare.