List of hepatotoxic drugs

Consequences of enzyme induction and inhibition

As a result of enzyme induction in rats treated with phenobarbital, administration of carbon tetrachloride caused more pronounced zone 3 necrosis.

Alcohol consumption significantly increases the toxicity of paracetamol: significant liver damage is possible with just 4-8 g of the drug. Apparently, this is due to the induction of P450-3a (P450-II-E1) by alcohol, which plays an important role in the formation of toxic metabolites. In addition, it is involved in the oxidation of nitrosamines in the alpha position. Theoretically, this may increase the risk of cancer in alcoholics. Cimetidine, which inhibits the activity of mixed-function P450 oxidases, reduces the hepatotoxic effect of paracetamol. Omeprazole has a similar effect. High doses of ranitidine also reduce the metabolization of paracetamol, while low doses increase its hepatotoxicity.

Administration of drugs that induce microsomal enzymes, such as phenytoin, results in increased serum GGT levels.

Mushrooms of the genus Amanita

Consumption of various mushrooms of the genus Amanita, including A. phalloides and A. vema, can lead to acute liver failure. The disease can be divided into 3 stages.

• Stage I begins 8-12 hours after eating mushrooms and is characterized by nausea, cramping abdominal pain, and loose stools in the form of rice broth. It lasts 3-4 days.
• Stage II is characterized by an apparent improvement in the condition of patients.
• Stage III involves liver, kidney and central nervous system dystrophy with massive cell destruction. In the liver, pronounced necrosis of zone 3 is detected in the absence of a significant inflammatory reaction. Fatty liver is observed in fatal cases. Despite severe liver damage, recovery is possible.

The mushroom toxin phalloidin inhibits actin polymerization and causes cholestasis. Amanitin inhibits protein synthesis by inhibiting RNA.

Treatment consists of supporting the function of vital organs by all possible means, including hemodialysis. There are reports of successful liver transplantation.

Salicylates

Acute liver injury and even chronic active hepatitis may develop in patients receiving salicylates for acute rheumatic fever, juvenile rheumatoid arthritis, adult rheumatoid arthritis, and systemic lupus erythematosus. Liver injury occurs even at low serum salicylate levels (below 25 mg%).

Cocaine

In acute cocaine intoxication and rhabdomyolysis, biochemical signs of liver damage appear in 59% of patients.

Histological examination of the liver reveals necrosis of zones 1, 2 or a combination with small-droplet obesity of zone 1.

The hepatotoxic metabolite is norcocaine nitroxide, which is formed by N-methylation of cocaine with the participation of cytochrome P450. Highly reactive metabolites damage the liver by lipid peroxidation, formation of free radicals and covalent binding to liver proteins. The hepatotoxicity of cocaine is enhanced by the use of enzyme inducers, such as phenobarbital.

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Hyperthermia

Heat stroke is accompanied by damage to hepatocytes, which in 10% of cases is severe and can lead to the death of the victim. Histological examination reveals pronounced fine-droplet fatty infiltration, blood stagnation, cholestasis (sometimes ductal), hemosiderosis and infiltration of sinusoids with primitive cells. In cases with a fatal outcome, dilation of the venules of the portal system is pronounced. Biochemical examination may note an increase in bilirubin, transaminase activity and a decrease in prothrombin and albumin levels in the serum. Damage develops as a result of hypoxia and the direct effect of elevated temperature. Some changes may be associated with endotoxemia. Obesity increases the risk of liver damage.

Heatstroke during physical exertion is characterized by collapse, convulsions, hypertension, and hyperpyrexia. It may be complicated by rhabdomyolysis and damage to cerebellar neurons. Treatment includes hypothermia and rehydration. Liver transplantation may be necessary.

3,4-Methylenedioxymethamphetamine (ecstasy) can cause malignant hyperthermia syndrome with hepatocyte necrosis resembling viral hepatitis. Liver transplantation may be required.

Hypothermia

Although significant changes in the liver are observed in experimental animals during hypothermia, in humans they are insignificant. The probability of serious liver damage from exposure to low temperatures is small.

Burns

Within 36-48 hours after the burn, changes develop in the liver that resemble the picture of carbon tetrachloride poisoning. They are accompanied by minor shifts in biochemical indicators of liver function.

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Hepatocyte necrosis zone 1

Morphological changes resemble the picture with damage to zone 3, but are limited mainly to zone 1 (periportal).

Ferrous sulfate

Accidental ingestion of large doses of iron sulfate results in coagulative necrosis of zone 1 hepatocytes with nucleopycnosis, karyorrhexis, and absence or mild inflammation.

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Phosphorus

Red phosphorus is relatively non-toxic, but yellow phosphorus is extremely poisonous - even 60 mg can be fatal. Yellow phosphorus powder, used to kill rats or make firecrackers, is taken accidentally or for suicidal purposes.

The poisoning causes acute irritation of the stomach. Phosphorus can be detected in the rinsing waters. The air exhaled by the patient has a characteristic smell of garlic, and the feces are often phosphorescent. Jaundice develops on the 3rd-4th day. The poisoning can proceed fulminantly with the development of coma and death within 24 hours or, more often, within the first 4 days.

Liver biopsy reveals zone 1 necrosis with large- and medium-sized fatty infiltration. Inflammation is minimal.

About half of cases end in recovery with full restoration of liver function. There is no specific treatment.

Mitochondrial cytopathies

The toxic effect of some drugs affects mainly the mitochondria and consists, in particular, in the suppression of the activity of the respiratory chain enzymes. Clinically, this is manifested by vomiting and lethargy of the patient. Lactic acidosis, hypoglycemia and metabolic acidosis develop. Beta-oxidation of fatty acids in the mitochondria is accompanied by the development of fine-droplet fatty infiltration. Electron microscopy reveals damage to the mitochondria. Toxic damage affects many organ systems.

Sodium valproate

Approximately 11% of patients receiving sodium valproate have asymptomatic increases in transaminase activity, which decrease when the dose is reduced or the drug is discontinued. However, more severe liver reactions may develop, including death. Mostly children and young people are affected - from 2.5 months to 34 years old, in 69% of cases the age of patients does not exceed 10 years. Men are more often affected. The first symptoms appear within 1-2 months after the start of taking the drug and do not occur after 6-12 months of treatment. The first manifestations include vomiting and impaired consciousness, accompanied by hypoglycemia and blood clotting disorders. In addition, other signs characteristic of the droplet obesity syndrome can be identified.

Biopsy reveals small droplet obesity, mainly in zone 1. In zone 3, hepatocyte necrosis of varying degrees of severity is noted. Electron microscopy reveals mitochondrial damage.

Mitochondrial dysfunction, particularly fatty acid beta-oxidation, is caused by sodium valproate itself or its metabolites, especially 2-propylpentanoic acid. Polypharmacy, presumably through enzyme induction, increases the risk of fatal toxic liver injury in young children. The observed increase in blood ammonia indicates suppression of urea cycle enzymes in the mitochondria. Sodium valproate suppresses urea synthesis even in healthy individuals, causing hyperammonemia. Severe reactions to the drug may be due to congenital deficiencies of urea cycle enzymes, which, however, has not been proven. However, there is a report of a patient with congenital carbamoyltransferase deficiency who died after taking sodium valproate.

Tetracyclines

Tetracyclines suppress the production of transport proteins that ensure the removal of phospholipids from the hepatocyte, which leads to the development of fatty liver.

There have been cases of pregnant women dying from hepatorenal failure that developed after high doses of tetracycline were administered intravenously to treat pyelonephritis. In addition, acute fatty liver of pregnancy has been associated with tetracycline use. Although liver damage probably only occurs with high doses of tetracyclines administered intravenously, these drugs should be avoided in pregnant women.

Nucleoside analogues with antiviral activity

Clinical trials of FIAU (a fluorinated pyridine nucleoside derivative originally proposed for the treatment of AIDS) in patients with chronic hepatitis B yielded disappointing results. After 8-12 weeks, volunteers developed liver failure, lactic acidosis, hypoglycemia, coagulopathy, neuropathy, and renal failure. Of these, 3 patients died of multiple organ failure, and 4 patients required liver transplantation, during which 2 died. Liver biopsy revealed microvascular obesity and mitochondrial damage. The mechanism of damage probably consists of FIAU being incorporated into the mitochondrial genome instead of thymidine.

Fulminant hepatitis with severe lactic acidosis has been reported in patients with AIDS treated with didanosine. Some side effects of zidovudine and zalcitabine are probably related to the suppression of mitochondrial DNA synthesis. Lamivudine, a nucleoside analogue currently undergoing clinical trials in patients with hepatitis B, has no significant toxic effects and does not suppress mitochondrial DNA replication in intact cells.

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Steatohepatitis

The reaction, called nonalcoholic steatohepatitis, resembles acute alcoholic hepatitis histologically; electron microscopy sometimes reveals features of lysosomal phospholipidosis. Unlike true alcoholic hepatitis, hyaline Mallory bodies are found in zone 3.

Perhexyline maleate

Perhexiline maleate, an analgesic no longer used today, causes histological changes in the liver that resemble acute alcoholic hepatitis. The lesions are caused by the absence of a gene in patients that ensures the oxidation of debrisoquine. This defect results in a deficiency of the monooxidase reaction in liver microsomes.

Amiodarone

The antiarrhythmic drug amiodarone can cause toxic damage to the lungs, cornea, thyroid gland, peripheral nerves, and liver. Impaired biochemical liver function is observed in 15-50% of patients.

Toxic liver damage usually develops more than a year after the start of treatment, but can also be observed during the first month. The spectrum of clinical manifestations is wide: from isolated asymptomatic increase in transaminase activity to fulminant hepatitis with a fatal outcome. Hepatotoxic effect usually manifests itself as an increase in transaminase activity and, rarely, as jaundice. In the case of an asymptomatic course, liver damage is detected only during a routine biochemical blood test; the liver does not always enlarge. The development of severe cholestasis is possible. Amiodarone can lead to the development of liver cirrhosis with a fatal outcome. Its toxic effect can also manifest itself in children.

Amiodarone has a large volume of distribution and a long T _1/2, so its elevated blood level after discontinuation of administration may persist for many months. Amiodarone and its main metabolite N-desethylamiodarone can be detected in liver tissue for several months after discontinuation of administration. The likelihood of developing and the severity of side effects depend on the concentration of the drug in the serum. The daily dose of amiodarone should be maintained within 200-600 mg.

Amiodarone is iodinated, which results in increased tissue density on CT scans. However, this does not correspond to the degree of liver damage.

Histological changes resemble acute alcoholic hepatitis with fibrosis and sometimes with marked proliferation of small bile ducts. Severe liver cirrhosis may develop. Electron microscopy reveals lamellar bodies of lysosomes loaded with phospholipids and containing myelin figures. They are always detected during treatment with amiodarone and indicate only contact with the drug, not intoxication. Similar inclusions appeared in rat hepatocyte cultures exposed to amiodarone and deethylamiodarone. Enlarged zone 3 granular macrophages with lysosomal bodies, which apparently contain iodine, may serve as an early marker of the hepatotoxic effect of amiodarone. It is possible that the drug itself or its main metabolite suppresses lysosomal phospholipases, which ensure phospholipid catabolism.

Similar phospholipidosis can develop with parenteral nutrition and with treatment with trimethoprim/sulfamethoxazole (Septrin, Bactrim).

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Synthetic estrogens

Treatment of prostate cancer with high doses of synthetic estrogens can cause a picture resembling alcoholic hepatitis.

Calcium antagonists

Treatment with nifedipine and diltiazem may lead to the development of steatohepatitis, but there is insufficient data on this issue.

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Amodiaquine

Amodiaquine is an antimalarial drug that can cause a liver reaction of varying severity 4-15 weeks after the start of treatment. The degree of liver damage depends on the dose and duration of treatment. Amodiaquine is not currently used to prevent malaria. In mammalian cell cultures, the drug inhibits protein synthesis.

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Cyanamide

Cyanamide is an aldehyde dehydrogenase inhibitor used to produce an aversion to alcohol. In patients receiving this drug, in the absence of symptoms of liver damage, biopsy revealed ground-glass hepatocytes in zone 3 resembling HBsAg-containing cells. However, these hepatocytes did not stain with orcein and were PAS-positive. They were not detected after discontinuation of the drug.

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Fibrosis

Fibrosis occurs in most drug-induced liver injury, but is the predominant feature in only a few. Fibrous tissue is deposited in the space of Disse and interferes with sinusoidal blood flow, causing noncirrhotic portal hypertension and hepatocyte dysfunction. The injury is caused by toxic drug metabolites and is usually localized in zone 3; the exception is methotrexate, which affects zone 1.

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Methotrexate

Liver damage during methotrexate treatment is caused by the formation of a toxic metabolite in the microsomes, which causes fibrosis and eventually leads to cirrhosis. Primary liver cancer may develop. Hepatotoxicity usually occurs during long-term therapy, such as for psoriasis, rheumatoid arthritis or leukemia. In rheumatoid arthritis, the risk of toxic liver damage is lower than in psoriasis. Liver damage is rarely clinically evident. Liver biopsy usually reveals reversible changes over time, although severe liver damage was noted in 3 of 45 patients with rheumatoid arthritis. The degree of fibrosis may range from minimal, of no clinical significance, to significant, including cirrhosis, at which point the drug must be discontinued.

The severity of fibrosis is determined by the dose and duration of treatment. Dosing at 5 mg at intervals of at least 12 hours three times a week (i.e. 15 mg/week) is considered safe. Liver biopsy before treatment should be performed only in high-risk patients who consume significant amounts of alcohol or have a history of liver disease. Transaminase activity is a poor indicator of liver disease but should be measured monthly; elevated transaminase activity is an indication for liver biopsy. Liver biopsy is also performed in all patients who have been taking methotrexate for 2 years or have received a cumulative dose of the drug exceeding 1.5 g.

Ultrasound examination (US) can detect fibrosis and determine indications for stopping methotrexate. There are reports of liver transplantation in patients with severe liver damage from methotrexate.

Other cytostatic drugs

The degree of hepatotoxicity of other cytostatic drugs varies. The liver is surprisingly resistant to damage by these drugs, possibly due to its low proliferative activity and high detoxifying capacity.

Cytostatic drugs in high doses cause an increase in the level of transaminases. Methotrexate, azathioprine and cyclophosphamide cause necrosis of hepatocytes of zone 3, fibrosis and cirrhosis. After treatment of leukemia with cytostatics, the development of moderate sclerosis of some portal zones was observed, which led to the emergence of a picture of idiopathic portal hypertension.

Veno-occlusive disease may be associated with treatment with cyclophosphamide, busulfan, or X-ray irradiation. When taking cytarabine, the development of cholestasis is noted, the severity of which depends on the dose of the drug. Treatment with azathioprine may be complicated by the development of hepato-canalicular cholestasis. When treating with sex or anabolic steroid hormones, sinusoid dilation, peliosis, and the development of liver tumors are observed. When combined, the toxic effect of drugs may be enhanced, for example, the effects of 6-mercaptopurine are enhanced by doxorubicin.

Long-term use of cytostatic drugs (patients after kidney transplantation or children with acute lymphocytic leukemia) leads to chronic hepatitis, fibrosis and portal hypertension.

Arsenic

Trivalent organic arsenic compounds are particularly toxic. Portal hypertension in the absence of cirrhosis has been reported in long-term treatment of psoriasis with 1% arsenic trioxide (Fowler's solution). Acute arsenic poisoning (probably homicidal) causes perisinusoidal fibrosis and veno-occlusive disease.

In India, arsenic in drinking water and folk remedies may be the cause of "idiopathic" portal hypertension. Fibrosis of the portal tracts and sclerosis of the portal vein branches are found in the liver. The development of angiosarcoma has been described.

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Vinyl chloride

Long-term industrial contact with vinyl chloride results in the development of a hepatotoxic reaction. Initially, sclerosis of the portal venules in zone 1 appears, clinically manifested by splenomegaly and portal hypertension. Subsequently, liver angiosarcoma and peliosis may develop. Early histological signs of contact with vinyl chloride include focal hyperplasia of hepatocytes and focal mixed hyperplasia of hepatocytes and sinusoid cells. These changes are followed by the development of subcapsular portal and perisinusoidal fibrosis.

Vitamin A

Vitamin A is increasingly used in dermatology, for cancer prevention, hypogonadism, and by people with eating disorders. Signs of intoxication appear when taken at a dose of 25,000 IU/day for 6 years or 50,000 IU/day for 2 years. Alcohol abuse increases the severity of intoxication.

Manifestations of intoxication include nausea, vomiting, hepatomegaly, changes in biochemical tests, and portal hypertension. Ascites may develop due to accumulation of exudate or transudate. Histologically, hyperplasia of fat-storing cells (Ito cells) containing vacuoles that fluoresce in UV light is detected. Fibrosis and cirrhosis may develop.

Vitamin A stores are metabolized slowly, so it can be detected in the liver for many months after treatment is stopped.

Retinoids

Retinoids are derivatives of vitamin A, which are widely used in dermatology. Severe liver damage can be caused by etretinate, which has a structure similar to retinol. Its metabolites acitretin and isotretinoin also have a hepatotoxic effect.

Vascular damage

Contraceptive use or anabolic steroid therapy may be complicated by focal dilation of zone 1 sinusoids. Hepatomegaly and abdominal pain occur, and serum enzyme activity increases. Hepatic arteriography reveals dilated, thinned branches of the hepatic artery and uneven parenchymal contrast.

Stopping hormone therapy leads to a reversal of these changes.

A similar picture is observed when taking azathioprine after kidney transplantation. After 1-3 years, patients may develop liver fibrosis and cirrhosis.

Peliosis

This complication results in the formation of large blood-filled cavities, often lined with sinusoidal cells. They are distributed unevenly and have a diameter of 1 mm to several centimeters. The formation of cavities may be based on the passage of red blood cells through the endothelial barrier of the sinusoids, revealed by electron microscopy, with the subsequent development of perisinusoidal fibrosis.

Peliosis is observed with oral contraceptives, with tamoxifen treatment of breast cancer, and in men with androgens and anabolic steroids. Peliosis has been described after kidney transplantation. It can also develop with danazol treatment.

Veno-occlusive disease

The small hepatic veins of zone 3 are particularly sensitive to toxic damage, developing subendothelial edema and later collagenization. The disease was first described in Jamaica as toxic damage to the smallest hepatic veins by pyrrolizidine alkaloids contained in the leaves of groundsel, which were part of some varieties of medicinal tea. It was subsequently identified in India, Israel, Egypt and even Arizona. Its development is associated with the consumption of wheat contaminated with heliotrope.

In the acute stage, the disease manifests itself as an enlarged and painful liver, ascites, and mild jaundice. Subsequently, complete recovery, death, or transition to a subacute stage with hepatomegaly and recurrent ascites are possible. In the chronic stage, cirrhosis develops, which does not have any distinctive features. The disease is diagnosed using a liver biopsy.

Azathioprine causes endotheliitis. Long-term use of azathioprine after kidney or liver transplantation is associated with sinusoidal dilation, peliosis, VOD, and nodular regenerative hyperplasia of the liver.

Treatment with cytostatic drugs, especially cyclophosphamide, azathioprine, busulfan, etoposide, as well as total irradiation at a dose of more than 12 Gy are accompanied by the development of VOD. VOD can also develop with high-dose cytostatic therapy after bone marrow transplantation. Morphologically, it is characterized by extensive damage to zone 3, covering hepatocytes, sinusoids and especially small hepatic venules. Clinically, VOD is manifested by jaundice, enlargement and pain of the liver, and an increase in body weight (ascites). In 25% of patients, it is severe and leads to death within 100 days.

Liver irradiation. The liver is quite sensitive to X-ray therapy. Radiation hepatitis develops when the total dose of radiation to the liver reaches or exceeds 35 Gy (10 Gy per week). Signs of VOD appear 1-3 months after the end of therapy. They can be transient, but in severe cases lead to death from liver failure. Histological examination reveals hemorrhages in zone 3, fibrosis and obliteration of the hepatic venules.

Hepatic vein occlusion (Budd-Chiari syndrome) has been described after oral contraceptive use and during azathioprine treatment after kidney transplantation.