List of hepatotoxic drugs

The consequences of induction and inhibition of enzymes

As a result of induction of enzymes in rats receiving phenobarbital, the assignment of carbon tetrachloride caused more pronounced necrosis of zone 3.

Drinking alcohol significantly increases the toxicity of paracetamol: significant damage to the liver is possible with only 4-8 g of the drug. Obviously, the reason for this is the induction of alcohol P450-3a (P450-II-E1), which plays an important role in the formation of toxic metabolites. In addition, it is involved in the oxidation of nitrosamines in the position of alpha. Theoretically, this can increase the risk of cancer in patients with alcoholism. Cimetidine, which inhibits the activity of oxidases of the P450 system, which have a mixed function, reduces the hepatotoxic effect of paracetamol. Similarly acts omeprazole. High doses of ranitidine also reduce the metabolism of paracetamol, while low doses increase its hepatotoxicity.

Taking drugs that induce microsomal enzymes, such as phenytoin, leads to an increase in serum GGTP.

Mushrooms of the genus Amanita

The use of various fungi of the genus  Amanita,  including  A. Phalloides  and  A. Vema,  can lead to acute hepatic insufficiency. During the disease, there are 3 stages.

• I stage begins 8-12 hours after the consumption of fungi and manifests itself with nausea, spastic pain in the abdomen and a loose stool in the form of rice broth. It lasts 3-4 days.
• II stage is characterized by an apparent improvement in the condition of patients.
• Stage III develops liver, kidney and central nervous system degeneration with massive cell destruction. In the liver, a marked necrosis of zone 3 is revealed in the absence of a significant inflammatory reaction. In cases with a fatal outcome, a fatty liver is observed. Despite severe liver damage, recovery is possible.

The toxin of fungoid fungi suppresses the polymerization of actin and causes cholestasis. Amanitin inhibits protein synthesis by inhibiting RNA.

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

Salicylates

In patients receiving salicylates for acute rheumatic fever, juvenile rheumatoid arthritis, rheumatoid arthritis in adults and systemic lupus erythematosus, acute liver damage and even chronic active hepatitis can develop. The defeat of the liver develops even with a low level of salicylates in the serum (below 25 mg%).

Cocaine

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

When histological examination of the liver, necrosis of zones 1, 2 or combination with shallow drop obesity of zone 1 is revealed.

The hepatotoxic metabolite is the norkokaine nitroxide, which is formed during N-methylation of cocaine with the participation of cytochrome P450. Highly reactive metabolites damage the liver by LPO, formation of free radicals and covalent binding to liver proteins. The hepatotoxicity of cocaine is enhanced by the intake of inducers of enzymes, for example phenobarbital.

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

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 small droplet fatty infiltration, blood stasis, cholestasis (sometimes protocol), hemosiderosis and infiltration of sinusoids by primitive cells. In cases with fatal outcome, dilatation of the venule of the portal system is expressed. In a biochemical study, an increase in the level of bilirubin, transaminase activity and a decrease in prothrombin and serum albumin levels can be noted. Damage develops due to hypoxia and direct action of elevated temperature. Some changes may be associated with endotoxemia. Obesity increases the risk of liver damage.

Heat stroke during physical exertion is characterized by collapse, convulsions, arterial hypertension and hyperpyrexia. It can be complicated by rhabdomyolysis and damage to the neurons of the cerebellum. For the purpose of treatment, hypothermia and rehydration are performed. There may be a need for liver transplantation.

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

Hypothermia

Although in experimental animals hypothermia reveals pronounced changes in the liver, in humans they are insignificant. The likelihood of serious damage to the liver with the action of low temperatures is low.

Burns

Within 36-48 hours after a burn in the liver, changes that resemble a picture when poisoned with carbon tetrachloride develop. They are accompanied by insignificant shifts in the biochemical parameters of liver function.

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

Necrosis of hepatocytes of zone 1

Morphological changes resemble the picture in the event of damage to zone 3, but are limited mainly by zone 1 (periportal).

Ferrous Sulphate

Accidental administration of large doses of ferrous sulfate leads to coagulation necrosis of hepatocytes of zone 1 with nucleopic disease, karyorexis in the absence or weak manifestation of inflammation.

[10], [11], [12], [13], [14], [15], [16]

Phosphorus

Red phosphorus is relatively non-toxic, but yellow phosphorus is extremely toxic - even 60 mg can be lethal. Powder of yellow phosphorus, used for the destruction of rats or for the manufacture of firecrackers, is taken accidentally or with a suicidal purpose.

Poisoning causes acute irritation of the stomach. In washing waters, it is possible to detect phosphorus. Exhaled air has a characteristic smell of garlic, and feces often phosphoresce. Jaundice develops on the 3rd-4th day. Poisoning can occur fulminantly with the development of coma and fatal outcome within 24 hours, or more often, during the first 4 days.

With liver biopsy, necrosis of zone 1 with large and medium droplet fat infiltration is revealed. Inflammation is expressed minimally.

About half of cases end in recovery with complete restoration of liver function. Specific treatment is not.

Mitochondrial cytopathies

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

Valproate sodium

Approximately 11% of patients receiving sodium valproate have an asymptomatic increase in transaminase activity, which decreases with decreasing dose or drug withdrawal. However, more severe hepatic reactions can occur even up to a lethal outcome. Suffer mainly children and young people - from 2.5 months to 34 years, in 69% of cases, the age of patients does not exceed 10 years. Men are more often amazed. The appearance of the first symptoms is observed within 1 -2 months after the beginning of taking the drug and does 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, it is possible to identify other signs characteristic of the syndrome of small-boned obesity.

When biopsy revealed small droplet obesity, mainly in zone 1. In zone 3 there is necrosis of hepatocytes of varying severity. In electron microscopy, damage to the mitochondria is detected.

Malfunction of mitochondria, in particular beta-oxidation of fatty acids, is caused by sodium valproate itself or its metabolites, especially 2-propylpentanoic acid. Polypharmacy, presumably by induction of enzymes, increases the likelihood of fatal toxic damage to the liver in young children. The increase in the level of ammonia in the blood indicates that the urea cycle enzymes are suppressed in the mitochondria. Valproate sodium suppresses the synthesis of urea even in healthy people, causing hyperammonemia. Severe reactions to the drug may be due to congenital insufficiency of enzymes in the urea cycle, which, however, has not been proven. Nevertheless, there is a report of a patient with congenital insufficiency of carbamoyltransferase, who died after taking sodium valproate.

Tetracyclines

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

Cases of death of pregnant women from liver-kidney failure, which developed after intravenous injection of large doses of tetracycline with the purpose of treating pyelonephritis, are described. In addition, the development of acute fatty liver of pregnant women is associated with tetracycline. Although liver damage probably develops only after intravenous administration of large doses of tetracyclines, the use of these drugs by pregnant women should be avoided.

Analogues of nucleosides with antiviral action

In clinical trials of the preparation FIAU (fluorinated derivative of pyridine nucleosides, originally proposed for the treatment of AIDS) in patients with chronic hepatitis B, the results were sad. After 8-12 weeks, volunteers developed liver failure, lactic acidosis, hypoglycemia, coagulopathy, neuropathy, and renal insufficiency. Of these, 3 patients died from multiple organ failure, 4 patients required liver transplantation, in which 2 of them died. With liver biopsy, small-droplet obesity and mitochondrial damage were identified. The mechanism of the lesion is probably to incorporate FIAU instead of thymidine into the mitochondrial genome.

In the treatment of AIDS patients  didanosine  described the development of fulminant hepatitis with severe lactic acidosis. Some side effects of  zidovudine  and  zalcitabine are  probably related to the suppression of DNA synthesis in the mitochondria. Lamivudine,  an analogue of nucleosides, currently undergoing clinical trials in patients with hepatitis B, is devoid of serious toxic effects and does not inhibit the replication of mitochondrial DNA in intact cells.

[17], [18], [19], [20], [21], [22], [23], [24], [25], [26]

Steatohepatitis

The reaction, called  non-alcoholic steatohepatitis,  histologically resembles acute alcoholic hepatitis; Sometimes, electron microscopy reveals signs of phospholipidosis with lysosomes. Unlike true alcoholic hepatitis, Mallory's calves are found in zone 3.

Perhexylene maleate

Perhexylin maleate, not currently used as an analgesic, causes histological changes in the liver resembling acute alcoholic hepatitis. The lesion is caused by the absence in the patients of the gene, which provides the oxidation of debrisoquine. This defect leads to a failure of a monooxidase reaction in liver microsomes.

Amiodarone

Antiarrhythmic drug amiodarone can cause toxic damage to the lungs, cornea, thyroid, peripheral nerves and liver. Violation of biochemical parameters of liver function is noted in 15-50% of patients.

Toxic liver damage usually develops more than a year after the initiation of treatment, but may also occur within the first month. The spectrum of clinical manifestations is wide: from an isolated asymptomatic increase in the activity of transaminases to fulminant hepatitis with a lethal outcome. Hepatotoxic effect is usually manifested by increased activity of transaminases and rarely by jaundice. In the case of asymptomatic disease, liver damage is detected only with a planned biochemical blood test; the liver does not always increase. Perhaps the development of severe cholestasis. Amiodarone can lead to the development of cirrhosis of the liver with a fatal outcome. Its toxic effect can manifest itself in children.

Amiodarone has a large volume of distribution and a prolonged T _1/2, so its elevated level in the blood after discontinuation can persist for many months. Amiodarone and its main metabolite N-desethylamiodarone can be found in liver tissue for several months after discontinuation. The likelihood of development 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, and this leads to an increase in tissue density on computer tomograms. However, it does not correspond to the degree of liver damage.

Histological changes resemble acute alcoholic hepatitis with fibrosis, and sometimes with pronounced proliferation of small bile ducts. Possible development of severe cirrhosis of the liver. Electron microscopy reveals lamellar bodies of lysosomes loaded with phospholipids and containing myelin patterns. In the treatment with amiodarone, they are always found and indicate only the contact with the drug, and not about intoxication. When amiodarone and deethylamiodarone were exposed to a culture of rat hepatocytes, similar inclusions appeared in them. Increased granular macrophages of zone 3 with lysosomal bodies, which apparently contain iodine, may serve as an early marker of the hepatotoxic effect of amiodarone. Perhaps, the drug itself or its main metabolite inhibits phospholipase by lysosomes, providing catabolism of phospholipids.

Similar phospholipidosis can develop with parenteral nutrition and with trimethoprim / sulfamethoxazole (septrin, bactrim).

[27], [28], [29], [30], [31], [32], [33]

Synthetic estrogens

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

Calcium antagonists

Treatment with nifedipine and diltiazem can lead to the development of steatohepatitis, but data on this issue is not enough.

[34], [35], [36], [37], [38],

Amodiaquine

Amodiaquine is an antimalarial drug that can cause a liver reaction of varying severity after 4-15 weeks after starting treatment. The degree of damage to the liver depends on the dose and duration of the drug. Currently, for the prevention of malaria, amodiaquine is not used. In the culture of mammalian cells, the drug suppresses protein synthesis.

[39], [40], [41], [42], [43], [44], [45],

Cyanamide

Cyanamide is an aldehyde dehydrogenase inhibitor, which is used to develop an aversion to alcohol. In patients receiving this drug, in the absence of symptoms of liver damage, biopsy revealed matt vitreous hepatocytes in zone 3 resembling cells containing HBsAg. However, these hepatocytes were not stained with orsein and were SHIC-positive. After discontinuation of the drug, they were not detected.

[46], [47], [48], [49]

Fibrosis

Fibrosis develops with the majority of medicinal lesions of the liver, but only with some it is the predominant symptom. Fibrous tissue is deposited in the Disse space and disrupts the blood flow in sinusoids, causing noncirrhotic portal hypertension and impaired hepatocyte function. Damage is caused by the action of toxic metabolites of drugs and is usually localized in zone 3; The exception is methotrexate, which affects zone 1.

[50], [51], [52], [53], [54], [55], [56], [57]

Methotrexate

The defeat of the liver in the treatment of methotrexate is due to the formation of a toxic metabolite in microsomes, which causes fibrosis and eventually leads to cirrhosis. Possible development of primary liver cancer. Hepatotoxicity usually occurs with prolonged therapy, for example, for psoriasis, rheumatoid arthritis or leukemia. With rheumatoid arthritis, the risk of toxic damage to the liver is lower than with psoriasis. The defeat of the liver rarely appears clinically. With liver biopsy, reversible changes are usually seen in the dynamics, although 3 of 45 patients with rheumatoid arthritis have severe liver damage. The degree of severity of fibrosis can range from a minimal, not having a clinical value, to a significant extent up to cirrhosis, at which the drug has to be canceled.

The severity of fibrosis is determined by the dose of the drug and the duration of treatment. Admission to 5 mg with an interval of at least 12 hours 3 times a week (15 mg / week) is considered safe. A liver biopsy before the start of treatment should be performed only by patients from high-risk groups who consume significant amounts of alcohol or who have a history of liver disease. The activity of transaminases weakly reflects the presence of liver disease, but it should be determined monthly; increased transaminase activity is an indication for liver biopsy. A liver biopsy is also performed for all patients who take methotrexate within 2 years or received a total dose of the drug exceeding 1.5 g.

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

Other cytotoxic drugs

The degree of hepatotoxicity of other cytotoxic drugs is different. The liver has surprisingly high resistance to damage by these drugs, possibly due to small proliferative activity and a high detoxification ability.

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 the treatment of leukemia with cytostatics, the development of moderate sclerosis of certain portal zones was observed, which led to the emergence of a picture of idiopathic portal hypertension.

The veno-occlusive disease  may be associated with treatment with cyclophosphamide, busulfan, or X-ray irradiation. When taking cytarabine, development of cholestasis is noted, the severity of which depends on the dose of the drug. Treatment with azathioprine can be complicated by the development of  hepato-cancular cholestasis. In the treatment of sexual or anabolic steroid hormones, there is an expansion of sinusoids, peliosis, the development of liver tumors. With the combined use of drugs, their toxic effects may increase, for example, the effects of 6-mercaptopurine are enhanced by doxorubicin.

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

Arsenic

Particularly toxic are trivalent organic compounds of arsenic. Long-term treatment of psoriasis with a 1% solution of arsenic trioxide (Fowler's solution) described the development of portal hypertension in the absence of cirrhosis. Acute arsenic poisoning (probably for the purpose of killing) causes perisinusoidal fibrosis and veno-occlusive disease.

In India, arsenic, found in drinking water and alternative medicine, can be the cause of "idiopathic" portal hypertension. In the liver, fibrosis of the portal tracts and sclerosis of the portal vein branches are revealed. The development of angiosarcoma is described.

[58], [59], [60], [61]

Vinyl chloride

With many years of industrial contact with vinyl chloride, a hepatotoxic reaction develops. First, there is sclerosis of portal venules in zone 1, which is clinically manifested by splenomegaly and portal hypertension. Subsequently, the development of angiosarcoma of the liver and peliosis is possible. Early histological signs of contact with vinyl chloride are focal hyperplasia of hepatocytes and focal mixed hyperplasia of hepatocytes and sinusoid cells. Following these changes, subcapsular portal and perisinusoidal fibrosis develops.

Vitamin A

Vitamin A is increasingly used in dermatology, for the prevention of cancer, hypogonadism, as well as people with disrupted eating behavior. Signs of intoxication appear when taking in a dose of 25,000 IU / day for 6 years or 50,000 IU / day for 2 years. Alcohol abuse increases the intensity of intoxication.

Manifestations of intoxication are nausea, vomiting, hepatomegaly, changes in biochemical samples and portal hypertension. Ascites may develop as a result of accumulation of exudate or transudate. Histologically, hyperplasia of fat-containing cells (Ito cells) containing vacuoles that fluoresce in UV light is detected. Possible development of fibrosis and cirrhosis.

Stocks of vitamin A are metabolized slowly, so after discontinuation of treatment it can be found in the liver for many more months.

Retinoids

Retinoids are derivatives of vitamin A, which are widely used in dermatology. Severe liver damage can cause etretinate, which has a similar structure to retinol. Hepatotoxic effect also gives its metabolites acitretin and isotretinoin.

Vascular injury

Reception of contraceptives or treatment with anabolic steroids can be complicated by focal expansion of sinusoids of zone 1. Hepatomegaly and abdominal pain appear, the activity of serum enzymes increases. Hepatic arteriography reveals dilated, thinned branches of the hepatic artery and uneven contrasting of the parenchyma.

Stopping hormone intake leads to the reverse development of these changes.

A similar pattern is observed with the use of azathioprine after kidney transplantation. After 1-3 years, patients may develop fibrosis and cirrhosis of the liver.

Pelion

With this complication large, blood-filled cavities are formed, often lined with sinusoidal cells. They are distributed unevenly, have a diameter of 1 mm to several centimeters. The formation of cavities can be based on the passage of erythrocytes detected through electron microscopy through the endothelial barrier of sinusoids, followed by the development of perisinusoidal fibrosis.

Pelion is observed with oral contraceptives, with tamoxifen treatment of breast cancer, and in men - with androgens and anabolic steroids. Pelion is described after kidney transplantation. In addition, it can develop when treated with danazol.

Veno-occlusive disease

The small hepatic veins of Zone 3 are particularly sensitive to toxic damage, they develop subendothelial edema, and later - collagenization. For the first time, the disease was described in Jamaica as a toxic damage to the smallest hepatic veins by pyrrolisidine alkaloids contained in the leaves of the shamrock, which were part of some varieties of medicinal tea. Subsequently, it was discovered in India, Israel, Egypt and even in Arizona. Its development is associated with the consumption of wheat, clogged with heliotrope.

In the acute stage, the disease manifests itself as an increase and pain in the liver, ascites and mild jaundice. Subsequently, complete recovery, death or transition to a subacute stage with hepatomegaly and recurrent ascites is possible. In a chronic stage, cirrhosis develops without any distinctive features. The disease is diagnosed with a liver biopsy.

Azathioprine  causes endotheliitis. Prolonged administration of azathioprine after kidney or liver transplantation is accompanied by an expansion of sinusoids, peliosis, VOB 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, is accompanied by the development of PSA. PSA can also develop with high-dose cytostatic therapy after bone marrow transplantation. Morphologically it is characterized by extensive damage zone 3, covering hepatocytes, sinusoids and especially small hepatic venules. Clinically, VOB is manifested by jaundice, an increase and pain in the liver, an increase in body weight (ascites). In 25% of patients it is severe and within 100 days leads to death.

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

Occlusion of the hepatic veins  (Badd-Chiari syndrome) is described after taking oral contraceptives, as well as in the treatment of azathioprine after kidney transplantation.