Hepatotoxic effect. Effective treatment of drug-induced hepatitis Hepatotoxic drugs

General information

The liver plays a major role in the biotransformation and clearance (removal from the body) of many chemicals, and is therefore sensitive to the toxic effects of drugs, xenobiotics and oxidative stress. The liver is also an organ highly sensitive to oxygen deprivation and may suffer when taking medications that reduce hepatic blood flow. Some drugs, when taken in overdose and sometimes even when taken in therapeutic doses, can have a damaging effect on the liver. Other chemicals, such as solvents and various reagents used in laboratories and industry, natural chemicals (such as microcystins) and herbal preparations, even some components of dietary supplements can also cause liver damage.

Substances that cause liver damage are called hepatotoxic (hepatotoxic) substances ( hepatotoxins).

Mechanisms of hepatotoxicity

There are many different mechanisms for the implementation of the hepatotoxic effect.

Direct hepatotoxicity

Drugs or toxins that exhibit true direct hepatotoxicity are those chemicals that have predictable dose-effect curve (higher doses or concentrations of a substance cause a greater hepatotoxic effect, more severe liver damage) and have well-known and studied mechanisms of hepatotoxic action, such as direct damage to hepatocytes or blockade of certain metabolic processes in the liver.

A typical example of true direct hepatotoxicity is the hepatotoxicity of acetaminophen (paracetamol) in overdose, associated with the saturation of its normal metabolic pathway, which has limited capacity, and the inclusion of an alternative pathway for the biotransformation of acetaminophen, which produces a toxic, highly reactive nucleophilic metabolite. At the same time, the inclusion of an alternative pathway of acetaminophen biotransformation in itself does not lead to liver damage. Direct damage to hepatocytes results from the accumulation of the toxic metabolite acetaminophen in such quantities that it cannot be effectively neutralized by binding to glutathione. At the same time, glutathione reserves in the liver are depleted, after which the reactive metabolite begins to bind to proteins and other structural elements of the cell, which leads to its damage and death.

Direct hepatotoxicity usually occurs shortly after a certain “threshold” level of toxic substance concentration in the blood or a certain duration of toxic exposure has been reached.

Metabolism of drugs in the liver

Many common drugs are metabolized in the liver. This metabolism can vary significantly between individuals due to genetic differences in the activity of drug biotransformation enzymes.

Hepatotoxic substances

Cytotoxic drugs

Organic solvents

Links

Wikimedia Foundation. 2010.

See what “Hepatotoxicity” is in other dictionaries:

Noun, number of synonyms: 1 toxicity (6) ASIS Dictionary of Synonyms. V.N. Trishin. 2013… Synonym dictionary

Active ingredient ›› Trastuzumab* (Trastuzumab*) Latin name Herceptin ATX: ›› L01XC03 Trastuzumab Pharmacological group: Antitumor agents - monoclonal antibodies Nosological classification (ICD 10) ›› C50... ...

Herbalife, Ltd. Type... Wikipedia

Active ingredient ›› Protionamide* (Protionamide*) Latin name Protionamid Akri ATX: ›› J04AD01 Protionamide Pharmacological group: Other synthetic antibacterial agents Nosological classification (ICD 10) ›› A15 A19… … Dictionary of medicines- I Antifungal agents As P. s. In medical practice, antibiotics with antifungal activity (so-called antifungal antibiotics) and some synthetic drugs are used. Among the antifungal... ... Medical encyclopedia

Active ingredient ›› Pyrazinamide* (Pyrazinamide*) Latin name Pyrazinamide ATX: ›› J04AK01 Pyrazinamide Pharmacological group: Other synthetic antibacterial agents Nosological classification (ICD 10) ›› A15 A19 Tuberculosis ... Dictionary of medicines

Latin name Aminoplasmal 10% SE ATX: ›› B05BA01 Amino acids Pharmacological group: Agents for enteral and parenteral nutrition Nosological classification (ICD 10) ›› E46 Protein-energy deficiency, unspecified... ... Dictionary of medicines

For quotation: Topchiy N.V., Toporkov A.S. Hepatotoxicity - the most likely causes and possibilities for optimal correction with Heptral // Breast Cancer. 2013. No. 5. P. 249

The liver provides the energy and plastic needs of the body, and also largely performs a detoxification function. Based on clinical, laboratory and morphological signs, the following types of liver damage are distinguished:
- mitochondrial lesions - the development of fibrosis, sometimes with pronounced proliferation of the bile ducts. Usually provoked by drugs, parenteral nutrition;
- fibrosis - develops in most drug-induced liver damage (DILI). Fibrous tissue deposits in the space of Disse and impairs blood flow in the sinusoids, causing noncirrhotic portal hypertension and impaired hepatocyte function;
- disturbance of protein synthesis - protein degeneration of hepatocytes with the ensuing functional, morphological and laboratory consequences. Develops as a result of significant toxic effects of the environment: food with toxic impurities, alcohol, drugs, viral, microbial, intoxicating effects;
- veno-occlusive disease - develops as a result of the toxic effect of certain plants (for example, valerian), which are part of food additives and products, medicinal teas, Chinese drugs, including restoratives, stress relievers, used for insomnia;
- hepatocanalicular cholestasis - develops under the influence of many toxic, toxic-allergic, toxic-immune influences: viral, alcoholic, medicinal, food, herbal, including those included in food additives, medicinal teas, etc.;
- liver damage associated with hypervitaminosis (in particular A). Morphologically, this is expressed in Ito cell hyperplasia with the subsequent development of fibrosis and portal hypertension. Drugs often act as provoking factors, for example a group of antihypertensive drugs that realize their effect through cytochrome P450-11D6, characterized by pronounced polymorphism. A special place in this group is occupied by angiotensin-converting enzyme inhibitors, which can cause hepatitis, often occurring with severe peripheral eosinophilia and eosinophilic infiltration of the portal tracts;
- indirect damaging effect of any toxic factors on the hepatocyte, mediated through edema, “inflammatory” infiltration, hypoxia, allergy, idiosyncrasy. At the same time, a biochemical blood test records an increase in the level of transaminases;
- induction and competitive inhibition of enzymes that trigger any of the listed mechanisms.
Alcohol is generally accepted as the most common cause of hepatotoxicity. Alcoholic liver disease (ALD) includes several types of parenchymal damage due to systematic alcohol abuse: steatosis, alcoholic hepatitis (AH) and liver cirrhosis (LC). The main factors predisposing to the development of ALD include the amount of alcohol consumed, gender, genetic polymorphism of enzymes involved in alcohol metabolism, and nutritional status. When drinking alcohol for several days, there is a risk of developing hepatic steatosis, a condition in which macrovesicular triglyceride inclusions accumulate in hepatocytes. As a rule, the disease does not manifest itself clinically and is often an accidental diagnostic finding. A much more severe form is hypertension, the manifestation of which usually occurs after another alcoholic excess. CP is the terminal stage of ALD.
Diagnosis of severe forms of ALD is based on clarifying anamnestic data indicating alcohol abuse, identifying clinical and laboratory signs of liver failure, and excluding other liver diseases. The dose of alcohol is calculated using the Widmark formula: vol.% × 0.8 = amount of alcohol in grams per 100 ml of drink. Alcohol doses of 40-80 g/day are considered hepatotoxic. in terms of pure ethanol. It has been proven that sensitivity to the toxic effects of ethanol and the severity of liver damage are influenced by factors such as the amount and duration of alcohol consumption, the type of alcoholic beverages consumed, gender, ethnicity and genetic polymorphisms of enzymes, especially alcohol dehydrogenase, acetaldehyde dehydrogenase and cytochrome P 450. Fatty infiltration of the liver develops in approximately 90% of individuals who consume about 60 g of ethanol per day. In addition, obesity, iron overload syndrome, and hepatitis virus infection are recognized as factors associated with more severe ALD. Studies have shown that even in the case of abstinence, in 5-15% of cases progression of fibrosis is observed, followed by transformation into cirrhosis. It was also found that if such patients continue to drink alcohol at a dose of more than 40 g/day. the risk of progression to cirrhosis increases to 30%. Often patients carefully hide the fact of alcohol abuse. In such a situation, many authors recommend using special questionnaires when collecting anamnesis, such as CAGE, MAST (Michigan Alcoholism Screening Test) and AUDIT (Alcohol Use Disorders Identification Test). In turn, the prevalence of hepatitis C in people suffering from alcohol dependence is quite high and amounts to more than 25%. .
An objective examination of a patient with ALD reveals the stigmas of long-term alcohol abuse: Dupuytren's contracture, enlarged parotid salivary glands, signs of feminization. In addition, a physical examination can detect dilation of the veins of the anterior abdominal wall, telangiectasia, edema, ascites, and an enlarged and often painful liver. Characteristic laboratory signs of hypertension include increased levels of serum transaminases. As a rule, the level of aspartate aminotransferase (AST) is more than 2 times higher than normal, but rarely >300 U/ml; the level of alanine aminotransferase (ALT) is slightly lower (de Ritis index >2); leukocytosis, hypocoagulation, hypoalbuminemia and hyperbilirubinemia occur. If necessary, the differential diagnosis includes: non-alcoholic steatohepatitis, LIPP, acute viral hepatitis, Wilson's disease, autoimmune liver diseases, α1-antitrypsin deficiency. To exclude these diseases, patients are advised to study viral markers, autoantibody levels and copper metabolism parameters. In some cases, when the results of laboratory tests are questionable, the question of performing a liver biopsy arises, which is associated with a high risk of complications in patients with hypocoagulation and ascites.
In the human body, ethanol is oxidized to acetaldehyde with the participation of the enzyme alcohol dehydrogenase and then with the participation of acetaldehyde dehydrogenase to acetate. In both reactions, nicotinamide dinucleotide (NAD) acts as a coenzyme, reducing it to NADH. A minority of ethanol is oxidized to acetaldehyde in smooth endoplasmic reticulum microsomes by the microsomal ethanol oxidation system (MEOS). Acetaldehyde promotes lipid peroxidation (LPO), disruption of the electron transport chain in mitochondria, suppression of DNA repair and stimulation of collagen synthesis. Increased lipid peroxidation leads to direct damage to plasma and intracellular membranes due to a decrease in the content of phosphatidylcholine in them. The consequence of this is an increase in membrane permeability and disruption of membrane transport and receptor functions.
Hepatotoxicity is often observed as a rather dangerous side effect of drug use. For a doctor, LIPP are a complex clinical problem due to a wide range of clinical and morphological options and the lack of clear treatment principles other than drug withdrawal. The estimated incidence of LIPP development is 6-3.9 per 100 thousand patients. According to world statistics, in the structure of acute and chronic liver diseases, LIPPs range from 0.7 to 20%. Currently, drug use is the leading cause of liver failure, requiring liver transplantation in developed countries. Despite the fact that, due to their damaging effect on the liver, many drugs have been withdrawn from use or have significant restrictions on their use, more than 1000 drugs that cause hepatotoxicity are described in modern literature.
The group of hepatotoxic drugs, the use of which leads to the development of LIPP in more than 40% of patients, includes antibiotics (for example, tetracyclines), antifungals, antituberculosis drugs, laxatives, amiodarone, metatrexate, steroids, estrogens, tamoxifen, non-steroidal anti-inflammatory drugs (acetylsalicylic acid, indomethacin, ibuprofen), anticonvulsants, anesthetics, psychotropic, antidepressants. Hepatotoxicity is a characteristic complication of highly active antiretroviral therapy using human immunodeficiency virus protease inhibitors. Its risk increases with simultaneous infection with hepatitis B and C viruses. Many antitumor drugs also have high hepatotoxicity. Hepatotoxic effects are one of the main reasons for dose reduction of chemotherapy drugs and delayed chemotherapy cycles, both of which worsen treatment outcomes.
It is known that only the liver removes all lipophilic substances from the body, including drugs, by biotransforming them into water-soluble ones, which are excreted by various excretory organs. The pharmacokinetics of a drug includes four stages: binding of the drug to plasma proteins, transport through the bloodstream to the liver, its absorption by hepatocytes (hepatic clearance) and excretion of the drug or its metabolites in the urine or bile. In the smooth endoplasmic reticulum of the hepatocyte, with the participation of monooxygenases, cytochrome C reductase and the cytochrome P450 enzyme system, hydroxylation or oxidation of drugs occurs with the formation of toxic metabolites (phase I). Next, the mechanisms of biotransformation of metabolites are turned on, namely, their conjugation with many endogenous molecules - glutathione, glucuronides, sulfates, etc., aimed at reducing their toxicity (phase II). The next stage is active transcytosolic transport and excretion of formed substances from the liver cell with the participation of carrier proteins, enzymes and pumps localized in the cytoplasm, at the basolateral and canalicular pole of the hepatocyte (phase III). Violation of the kinetics of a drug at any stage of its metabolism can lead to the development of organ damage, primarily the liver. During the metabolism of drugs, hepatotoxic substances are formed, both inherent to the drug and of the idiosyncratic type. Depending on the effect of these toxins on the hepatocyte, two groups of pathological processes are distinguished:
1) immune-independent toxic, caused by the damaging effects of medicinal metabolites, which are predictable, dose-dependent and occur within a few days from the start of therapy;
2) immune-mediated idiosyncratic, which develop unpredictably at various times (from a week to a year or more) from the start of taking drugs in usual therapeutic doses.
Most drugs cause idiosyncratic effects. Predisposing factors for the development of LIPP include: the presence of liver diseases with signs of hepatocellular failure, decreased hepatic blood flow, female gender, polypharmacy (simultaneous use of three or more drugs, including alternative medicine), old age, weight loss, pregnancy, strict vegetarianism , parenteral nutrition, environmental pollution with heavy metals and dioxins, as well as uncontrolled use of household chemicals. Thus, hepatotoxicity may be much more common than expected by physicians, especially in primary care.
It has been established that liver cells are damaged predominantly not so much by the drug itself, but by its metabolites, the formation and spectrum of which are genetically determined. Genetic variability of cytochrome P450 enzymes and polymorphism in the composition and activity of hepatocyte conjugation systems acquired as a result of environmental factors underlie individual susceptibility to toxic and idiosyncratic reactions and explain the fact that a certain drug can cause different LIPP in different patients. With LIPP, the pathological process usually involves hepatocytes, cholangiocytes, stellate (Ito cells) and endothelial cells, which causes the formation of a wide variety of clinical and morphological variants of liver lesions. In LIPP, the pathology of hepatocytes manifests itself in three pathomorphological variants: necrosis, fatty degeneration and dysfunction of the liver cell in the absence of its structural disorders. Hepatocyte necrosis may be associated with direct toxic or immune-mediated effects of drugs. Direct toxic damage to hepatocytes is caused by the formation, with the participation of the cytochrome P450 enzymatic system, of a large number of toxic substances and highly reactive molecules that enhance LPO in membranes, accompanied by an increase in their permeability, an imbalance of cellular ions, a decrease in ATP levels, disruption of vital functions and the development of cell necrosis. This mechanism of hepatocyte cytolysis underlies most acute and chronic drug-induced hepatitis, including steatohepatitis (SH).
Immune-induced hepatotoxicity is due to the ability of medicinal metabolites to acquire the properties of haptens, bind to hepatocyte proteins and act as neo-autoantigens with further activation on the outer cell membranes of T cells and the production of autoantibodies. The latter bind to autoantigens fixed on the cell membranes of hepatocytes, and the formed immune complexes are a trigger for autoantibody-dependent cytolytic and inflammatory reactions. Immune-mediated acute hepatitis is rare, but it often transforms into chronic hepatitis and cirrhosis. Drugs and their metabolites can inhibit mitochondrial β-oxidation and/or respiratory chains with the development of oxidative stress and the transfer of cell metabolic processes to the anaerobic pathway. At the same time, under conditions of lactic acidosis and an excessive amount of free radicals, the synthesis of very low density lipoproteins (VLDL) is disrupted and triglycerides (TG) accumulate in the cell. Clinically, patients develop non-alcoholic fatty liver disease (NAFLD) with the presence of steatosis (liver function tests are not changed) or FH (increased levels of aminotransferases, other abnormalities are possible). Drugs and their metabolites are capable of disrupting the functions of enzymes and transport proteins without significant organic damage to the hepatocyte. As a result, a picture of hepatocellular dysfunction is formed in the absence of necrosis. Typical manifestations of this pathology are competitive unconjugated hyperbilirubinemia or isolated conjugated hyperbilirubinemia, as well as an increase in the level of gamma-glutamyl transpeptidase (GGTP), caused by the induction of cytochrome P450 enzymes, in the absence of other changes in liver function tests. The formation of cholestasis is based on the blockade of enzymes involved in the excretion of bile components, damage to the biliary pole of the hepatocyte, as well as cholangiocytes of the intra- and extra-lobular bile ducts by drug metabolites. Intrahepatic cholestasis is divided into intralobular (hepatocellular and/or canalicular) and extralobular with damage to the epithelium of the bile ducts of the portal tracts. Drug-induced cholestasis can be an independent process or one of the syndromes of other LIPPs. As a result of irritation of stellate cells by drugs and their metabolites or due to necrosis of hepatocytes, which is accompanied by the accumulation of connective tissue components in the spaces of Disse and capillarization of sinusoids, septal fibrosis and cirrhosis are formed. Other LIPPs, including liver vascular lesions, granulomatous hepatitis, and benign tumors, are rare, and the mechanisms of their development are not well understood.
The diagnosis of LIPP is made if there is a history of indications for taking any drugs or alternative drugs, with the exclusion of other causes, and primarily viral hepatitis (hepatitis A, B, C, cytomegalovirus, Epstein-Barr, etc.), autoimmune hepatitis, metabolic and cholestatic diseases of the liver and biliary system. To confirm the etiological role of drugs in liver damage, the following parameters are taken into account:
1. The time interval between taking the drug and the development of hepatotoxicity ranges from 5 to 90 days (presumably), 90 or more days (definitely).
2. The rate of decline in impaired functions after drug withdrawal by 50% within 8 days (very suggestive), if elevated levels of liver enzymes decrease within 30 days for hepatocellular and 180 days for cholestatic liver damage (presumably).
3. Exclusion of other causes of liver disease.
4. Development of similar liver damage (increase in enzyme levels by at least 2 times) with repeated administration of drugs, if this is permissible.
The development of pathological changes in the liver is considered associated with taking drugs if the first three criteria or two of the first three and the fourth criterion are present. Clinical manifestations of LIPP are usually nonspecific and can range from the absence or presence of mild dyspepsia (nausea, loss of appetite, abdominal discomfort) with minor changes in laboratory test results to severe cytolytic and cholestatic syndromes with jaundice and, in some cases, the development of acute liver failure with liver failure. coma and death. A number of patients may develop systemic immune-mediated hypersensitive reactions with the appearance of rash, lymphadenopathy, and eosinophilia. When using hepatotoxic dose-dependent drugs, pathological effects develop within several days or weeks from the start of their use and depend on the mechanism of action of the drug on the liver. In turn, the duration of latent time when using drugs that have immune-mediated effects is several weeks or months.
A significant role in diagnosing the type of LIPP belongs to the assessment of biochemical liver tests with the identification of syndromes of cytolysis, cholestasis, immune inflammation and hepatocellular failure. A marker of hepatocyte cytolysis (process activity) is an increase in the level of ALT, AST and total bilirubin with a predominance of conjugated fractions. In this case, the following are distinguished: low activity with an increase in the level of ALT, AST to 2 norms and normal serum bilirubin; moderate - with ALT and AST levels up to 5 norms and normal serum bilirubin; high activity - with an ALT, AST content above 5 norms with an increased or normal level of serum bilirubin. More than 30 years ago, H. Zimmerman showed that the development of jaundice in drug-induced hepatocellular damage is an extremely dangerous sign, increasing the likelihood of death by 10%. Since that time, the term “Hey's Rule” or “Hey's law” was introduced as an indicator of severe drug-induced liver damage, which is used to designate a situation when, when using drugs, there is a more than threefold increase in the level of ALT in combination with a twofold or more increase in the level of total bilirubin in the absence of biliary obstruction (cholestasis) or Gilbert's syndrome. Depending on the leading mechanism of hepatocyte necrosis, it is advisable to distinguish the following pathogenetic variants of cytolytic syndrome, which are taken into account when choosing treatment tactics for LIPP:
- necrosis of hepatocytes without cholestasis and autoimmune disorders, caused by increased lipid peroxidation. Biochemical markers: increased blood serum ALT, AST with normal levels of alkaline phosphatase (ALP), GGTP, gamma globulins;
- necrosis of hepatocytes with intralobular cholestasis. Biochemical markers: increased levels of ALT, AS, GGTP, possibly alkaline phosphatase, but not more than two norms;
- necrosis of hepatocytes with extralobular (ductular) cholestasis. Biochemical markers: increased levels of ALT, AST, GGTP, and alkaline phosphatase by two or more times;
- necrosis of hepatocytes of autoimmune origin. Biochemical markers: increase in the level of ALT, AST, gamma globulins by one and a half times or more, circulating immune complexes (CIC), immunoglobulins.
Biochemical markers of cholestasis syndrome are an increase in serum GGTP, alkaline phosphatase and, in some cases, total bilirubin with a predominance of conjugated bilirubin. With intralobular cholestasis, there is either an isolated increase in the level of GGTP (hepatocellular cholestasis), or an increase in the level of GGTP in combination with an increase not exceeding a twofold level of alkaline phosphatase (canalicular cholestasis). Extralobular (ductular) cholestasis is characterized by an increase in the level of GGTP and the content of alkaline phosphatase, which exceeds the norm by two or more times. Immune inflammation syndrome is characterized, along with an increase in the level of ALT and AST, by an increase in the content of gamma globulins by one and a half times or more, as well as CEC and immunoglobulins.
In the presence of hepatocellular failure syndrome, there is a decrease in the prothrombin index or an increase in the prothrombin time and often the level of albumin. General criteria for hepatotoxicity are presented in Table 1. Table 2 presents factors predisposing to drug-induced hepatotoxicity.
Elimination of the toxic factor is an important point in eliminating hepatotoxicity. Abstinence is a priority and one of the main therapeutic measures for any form of ALD. Treatment of LIPP comes down to the abolition of all drugs except those that are needed for health reasons. Hepatoprotectors are used as pathogenetic therapy for hepatotoxicity, the selection of which is made taking into account the leading mechanism of disease development. Pathological processes in the liver in which hepatoprotectors are used: necrosis and fatty infiltration of hepatocytes, intra- and extralobular cholestasis, fibrosis. The main hepatoprotectors used in the treatment of both ALD and LIPP: ursodeoxycholic acid, essential phospholipids, silymarin, components of hepatocellular metabolic cycles: α-lipoic acid, ademetionine. In the presence of a high degree of hepatitis activity, as well as immune-mediated reactions, glucocorticosteroids are used.
According to the results of a number of studies, from the point of view of evidence-based medicine, adenosylmethionine (S-adenosyl-L-methionine) is among the most effective drugs for the correction of hepatotoxicity. Adenosylmethionine is a natural substance, endogenously synthesized from methionine and adenosine under the influence of the enzyme methionine adenosyltransferase. It is a natural antioxidant and antidepressant produced in the liver in amounts up to 8 g/day. and present in all tissues and fluids of the body, in greatest concentration - in places of formation and consumption, i.e. in the liver and brain. A decrease in the biosynthesis of hepatic adenosylmethionine is characteristic of all forms of chronic liver damage. It was first described in Italy by G.L. Cantoni in 1952. Adenosylmethionine first appeared on the Russian pharmaceutical market under the name Heptral.
Numerous experimental and clinical studies have proven the effectiveness of adenosylmethionine (Heptral) as a hepatoprotector, which doctors are well aware of and therefore use it in this capacity. There are 7 effects of adenosylmethionine: detoxification, antioxidant, choleretic, cholekinetic, antidepressant, neuroprotective, regenerating. Most liver diseases are accompanied by a decrease in the activity of this enzyme, which naturally entails disturbances in the production of adenosylmethionine and the course of biological reactions. In the liver, adenosylmethionine acts as a necessary structural element in three important biochemical processes: transmethylation, transsulfuration and aminopropylation. F. Hirata et al. demonstrated the importance of methylation in promoting hepatocyte membrane function and integrity. Adenosylmethionine (Heptral) is the main endogenous methyl group donor in biological transmethylation reactions. It is involved in the synthesis of nucleic acids and proteins, plays a major role in the synthesis of polyamines and is a source of cysteine ​​necessary for the formation of glutathione, the main endogenous hepatoprotector.
Glutathione has a number of essential functions, including neutralization of oxygen free radicals, thiosulfide metabolism, storage and transport of cysteine, conjugation and neutralization of reactive metabolites in the biotransformation of xenobiotics. Insufficient glutathione levels lead to increased susceptibility to oxidative stress. In liver cells, its deficiency also causes inactivation of ademetionine synthetase, which causes further depletion of glutathione in the liver. In addition, adenosylmethionine serves as a precursor to other thiol compounds, such as cysteine, taurine, coenzyme A. Along with glutathione, taurine plays an important role in the detoxifying function of the liver. Experimental studies have demonstrated the effectiveness of using adenosylmethionine (Heptral) in the treatment of liver damage caused by carbon tetrachloride, D-galactosamine, acetaminophen, alcohol, etc. In clinical studies, the use of adenosylmethionine (Heptral) made it possible to postpone liver transplantation and increase survival in patients with alcoholic liver damage. In addition, Heptral has a beneficial effect on intrahepatic cholestasis that develops in pregnant women and chronic non-alcoholic liver damage. It has been established that adenosylmethionine also affects the metabolism of nitric oxide, reducing the production of inducible NO synthase, and the cytokine balance, shifting it towards anti-inflammatory cytokines. As an additional positive effect, the antidepressant effect of adenosylmethionine (Heptral) can be noted.
The effectiveness of adenosylmethionine (Heptral) in the treatment of 220 patients with biopsy-proven liver disease was proven in a double-blind, placebo-controlled study. Inclusion criteria were at least a twofold increase in the levels of total and conjugated bilirubin, and serum alkaline phosphatase activity. The effectiveness of Heptral at a dose of 1600 mg has been proven against clinical and laboratory manifestations of cholestasis compared to placebo. The ability of adenosylmethionine (Heptral) has also been demonstrated to reduce the lithogenic properties of bile according to the assessment of the bile cholesterol saturation index. A randomized, double-blind, placebo-controlled, multicenter study was also conducted, which included 123 patients with alcoholic cirrhosis, divided into 2 groups, taking 1200 mg of adenosylmethionine (Heptral) or placebo for 2 years. Mortality and the need for liver transplantation by the end of treatment in the main group was 16% versus 30% in the placebo group (p=0.077), and in patients with severe cirrhosis class C according to Child-Pugh (Child-Pugh) the rate was 12% versus 29 % (p=0.025) .
A number of studies have shown the high effectiveness of adenosylmethionine (Heptral) in the treatment and prevention of drug-induced hepatotoxicity. Moreover, work on the correction of LIPP in the treatment of cancer patients is of particular importance, when the withdrawal of a drug that has caused drug-induced hepatotoxicity significantly worsens the effectiveness of treatment of the underlying disease and, as a consequence, the prognosis of life. In a domestic open clinical and biochemical study conducted at the Russian Cancer Research Center named after. N.N. Blokhin of the Russian Academy of Medical Sciences, 44 patients with hemoblastosis with hepatic cell failure as a result of drug hepatotoxicity were observed. The treatment regimen included adenosylmethionine (Heptral) at a dose of 400-800 mg intravenously or intramuscularly or 400-800 mg orally 2 times a day. until stable normalization of the functional state of the liver. The duration of the course of treatment was at least 30 days with an extension of the course if necessary. For patients with risk factors for hepatotoxicity, Heptral was prescribed for the entire period of chemotherapy. During the period of hematopoiesis recovery in the absence of complications, there was a tendency towards a decrease in the levels of markers of cholestasis and cytolysis syndromes (ALT, AST, ALP, GGTP, bilirubin), normalization of the level of malondialdehyde to initial values. The clinical condition of the patients began to improve by the 8-14th day of treatment and was characterized by normalization of sleep rhythm or a significant decrease in daytime sleepiness, improvement of memory, general well-being, weakening of asthenic syndrome and signs of depression, and increased anti-dyspeptic effect. In 50% of patients, the indicators of psychometric tests normalized, in the remaining patients they improved. It was noted that the protective effect of adenosylmethionine (Heptral) can reduce the number of forced changes in polychemotherapy protocols (PCT) associated with liver damage in the majority of patients.
The obtained effect allowed this team of authors to continue the study in a group of 60 patients with an increase in the dose of Heptral to 800-1600 mg intravenously or intramuscularly or orally in a daily dose of 800/1200-1600 mg. The administration of adenosylmethionine (Heptral) contributed to the normalization of redox status with a decrease in the levels of nitric oxide, superoxide dismutase, malondialdehyde and an increase in the values ​​of glutathione and glutathione-S-transferase. Against this background, a significant decrease in the levels of markers of cytolysis and cholestasis was noted. In continuation of the study of the effectiveness of Heptral for the prevention and treatment of hepatotoxicity in cancer patients at the State Institution Russian Cancer Research Center named after. N.N. Blokhin Russian Academy of Medical Sciences conducted a clinical observation of the use of the drug in a group of 19 patients with various malignant tumors and normal initial levels of transaminases in the treatment of chemotherapy-induced hepatotoxicity. Use of Heptral in a dosage of 400 mg 2 times a day. within 4 weeks. in patients with grade I hepatotoxicity against the background of PCT allowed to completely eliminate the manifestations of cytolysis in 83.3% of patients without changing PCT regimens. Extension of the course of therapy for another 2 weeks. ensured normalization of serum transaminases in 100% of patients in this group. Use of Heptral at a dose of 400 mg 2 times a day. stabilized the level of ALT and AST in patients with stage II hepatotoxicity, keeping the level of transaminases at the lower limit in this group. This allowed patients to receive PCT in full and on schedule. To normalize serum transaminases in patients with stage II hepatotoxicity, the course of therapy with Heptral was extended to 2-4 months. without deviations from the PCT regime. Heptral when taken orally, 400 mg 2 times a day. did not cause adverse reactions and was well tolerated by patients. Thus, Heptral was recommended as an accompanying therapy in the treatment of hepatotoxicity that arose during cytostatic PCT.
A series of studies conducted by Italian researchers on the prevention and correction of drug hepatotoxicity in cancer patients is also evidence-based. D. Santini et al. in 2003, published the results of an open study that was conducted among an oncology population of elderly patients (median age was 63 years). The study included patients with malignant tumors and hepatotoxicity that developed for the first time due to PCT; An increase in transaminases within 2.5-4 norms was considered as a criterion for hepatotoxicity. Patients were prescribed adenosylmethionine at a dose of 400 mg 2 times a day. during and in the interval between chemotherapy courses. The study revealed a decrease in the activity of transaminases and cholestasis enzymes by more than 30% in each of the patients, regardless of the presence or absence of metastatic liver disease. As a result of treatment, only one patient required a reduction in the dose of chemotherapy, and only three patients required a delay in subsequent courses. However, no side effects of adenosylmethionine were noted during treatment. The protective effect persisted throughout subsequent courses of chemotherapy, significantly reducing the incidence of course rescheduling or dose reduction of chemotherapy drugs due to elevated transaminase levels.
In another randomized, controlled, double-blind study, S. Nei et al. evaluated the effectiveness of Heptral for the prevention of drug-induced hepatitis induced by the immunosuppressant cyclosporine. The study included patients with severe exudative psoriasis, who were divided into two equal groups. Patients of the first group, in addition to the main treatment with cyclosporine, received adenosylmethionine (Heptral) at a dose of 400 mg 1 time/day; Patients in the second (control) group did not receive metabolic therapy. During the study, half of the patients in the control group showed an increase in transaminases and alkaline phosphatase, while in the patients in the main group there was no increase in liver enzymes in any case, which allowed them to successfully complete the course of treatment with cyclosporine.
In 2011, the results of a retrospective study of the role of adenosylmethionine in the prevention of hepatotoxicity in 105 patients with colorectal cancer who received adjuvant therapy with FOLFOX (fluorouracil + calcium folinate + oxaliplatin) were published. Patients were randomized into 2 groups: in the comparison group they received only PCT; in the main group, 60 patients also received adenosylmethionine (Heptral) 400 mg 2 times a day during the entire course of chemotherapy. intravenously. Hepatotoxicity was recorded significantly and significantly less frequently in the group receiving adenosylmethionine (Heptral), and its severity was significantly lower than in the comparison group. Accordingly, in the first group, course changes, dose reductions, or treatment discontinuations occurred in 71% of patients, while in the group receiving adenosylmethionine (Heptral), violations of the treatment protocol were noted only in 14% of cases. By the end of treatment with adenosylmethionine (Heptral), a significant decrease in such markers of cytolysis and cholestasis as AST and ALT, GGTP, and total bilirubin was revealed. ALP and LDH levels also tended to decrease.
A similar study design was used to monitor 78 patients with metastatic colorectal cancer. Patients were randomized into 2 groups: 46 patients received bevacizumab + XELOX regimen (oxaliplatin + capecitabine) for 3 weeks, and 32 patients, in addition to antitumor treatment, received intravenous adenosylmethionine (Heptral) 400 mg 2 times a day. The medians of all hepatotoxicity markers, except ALP, in the second group were significantly lower than in the first. As in the authors' study, hepatotoxicity was recorded significantly less often in the group receiving adenosylmethionine (Heptral), and its severity was significantly lower than in the comparison group. Changes in the treatment protocol in the form of rescheduling the course, reducing the dose, or canceling chemotherapy in the first group were recorded in all 100% of patients versus 37.5% in the second group.
The effectiveness of Heptral was also demonstrated in a domestic retrospective multicenter case-control study using a model of combined and complex treatment of breast cancer (BC). An analysis of more than 4,200 archival case histories and 2,900 outpatient records of breast cancer patients in 4 clinics in Moscow and Samara from 1993 to 2003 was carried out. The study included 1,643 patients treated/consulted in accordance with the medical and economic standards of breast cancer. In total, acute hepatotoxicity in accordance with the criteria of the National American Cancer Institute during mandatory visits was detected in 439 (26.7%) patients. Only in 158 (36.0%) of these patients, due to hepatotoxicity detected during routine visits, measures were taken to correct it. The data obtained allowed us to conclude that there was a high incidence of drug-induced hepatotoxicity during PCT in cancer patients, which required corrective prescription of hepatoprotectors. During the study, a large evidence base was obtained indicating the high effectiveness of the use of Heptral for these patients. The feasibility of prescribing the drug to patients with risk factors for hepatotoxicity has been confirmed. The authors determined that the most effective is a two-stage administration of Heptral: first, intravenous administration followed by a transition to long-term oral administration.
It is known that in ALD there is a decrease in the activity of phosphatidylethanolamine methyltransferase. Normally, phosphatidylcholine is formed from phosphatidylethanolamine by methylation with the participation of adenosylmethionine. In addition, in patients with ALD, the content of adenosylmethionine in the liver is reduced already at the stage of steatosis, while the activity of S-adenosylmethionine synthetase remains normal. Decreases in adenosylmethionine correlate with indicators of oxidative stress, such as increased levels of 4-HNE (one of the toxic aldehydes) and decreased glutathione levels, which are associated with mitochondrial damage. In the body, adenosylmethionine is formed during the conversion of methionine with the participation of ATP and the enzyme S-adenosylmethionine synthetase into homocysteine ​​and the antioxidants cysteine ​​and glutathione. As a result of these effects, the elimination of free radicals and other toxic metabolites from hepatocytes increases. On the other hand, translocation of lipopolysaccharides through the intestinal wall plays an important role in the pathogenesis of hypertension. Lipopolysaccharide in complex with lipopolysaccharide-binding protein interacts with CD14 on the Kupffer cell membrane.
Based on the results of experimental and clinical studies, the famous J.M. study was designed. Mato to evaluate the effectiveness of treatment with adenosylmethionine (1.2 g/day) in 123 patients with alcoholic cirrhosis in a double-blind, randomized, placebo-controlled, multicenter study over 24 months. In 84% of patients the diagnosis was confirmed histologically. When assessing the severity of cirrhosis, 75 patients were assigned to Child-Pugh class A, 40 to class B and 8 to class C. The effectiveness of treatment was assessed based on survival rates or liver transplantation for a period of less than 2 years. Overall mortality at the end of the study was 16% in the adenosylmethionine group and 30% in the placebo group, although the difference was not statistically significant. When patients with advanced cirrhosis (class C) were excluded from the group receiving adenosylmethionine, the indicator “overall mortality - liver transplant” became significantly higher in the placebo group compared to those treated with adenosylmethionine (p = 0.046). These results confirm that long-term use of adenosylmethionine may improve survival or prolong the timing of liver transplantation in patients with alcoholic cirrhosis, especially in the compensated and subcompensated stages. Thus, the use of ademetionine in patients with ALD reduces liver damage by preventing a decrease in the level of endogenous adenosylmethionine and glutathione. It is optimal to prescribe adenosylmethionine to patients with compensated and subcompensated cirrhosis and milder forms of ALD.
Treatment is recommended for a long time - from several months to a year or more. With long-term use, adenosylmethionine improves the life prognosis of patients with ALD. Clinical studies indicate that the use of Heptral in the treatment of ALD increases the level of glutathione in liver tissue, and also has a positive effect on the survival of these patients (especially in severe forms of the disease). In patients with alcoholic cirrhosis of classes A and B (according to the Child-Pugh classification), the use of Heptral leads to a reduction in mortality from 29 to 12%.
Therapeutic tactics for mild to moderate hypertension were determined as follows. Patients with mild to moderate hypertension and DF<32, без признаков печеночной энцефалопатии, а также те, у которых отмечена тенденция к нормализации показателей сывороточного билирубина и снижению индекса Маддрея в течение первой недели госпитализации, нуждаются в тщательном наблюдении, абстиненции и нутритивной поддержке. Применение глюкокортикостероидов в данном случае не оправдано. Пациентам с ЦП классов А и В по Чайлд-Пью и более легкими формами АБП целесообразно назначение аденозилметионина (Гептрала) в дозе 1200 мг/сут., предпочтительно на период не менее 1 года. При длительном применении никаких серьезных побочных действий препарата не зарегистрировано. Кроме того, в ряде работ отмечена хорошая приверженность пациентов к лечению на фоне приема Гептрала .
An important aspect of the use of Heptral is its antidepressant effect, because emotional problems arise in almost every alcohol-abusing patient with symptoms of general depression and affective disorders. Depression can lead to increased alcohol abuse, creating a vicious cycle. Depression often accompanies diseases that require the use of PCT and a number of other long-term medications, which is associated both with the underlying disease and with the side effects of certain drugs. According to statistics from the World Health Organization, 4-5% of the world's population suffers from depression, while the risk of developing a major depressive episode is 15-20%. According to various authors, from 60 to 85% of chronic diseases of the digestive system are accompanied by emotional disorders of varying severity. A special place in the structure of depression in the group of patients under consideration is occupied by masked (somatized) depression, in the clinical picture of which somatic symptoms come to the fore, and psychopathological manifestations remain in the shadows, i.e., depressive affect is hidden behind a variety of bodily sensations. Depressive states - both obvious and masked - are widespread in gastroenterology, where their frequent combination with functional gastrointestinal pathology and chronic diffuse liver diseases significantly complicates treatment and reduces the quality of life of patients. The basis of treatment for depression is adequate duration of use of antidepressants.
In this case, antidepressants themselves can have a hepatotoxic effect. According to the severity of this effect, drugs can be divided into three groups: with a low risk of hepatotoxicity (paroxetine, citalopram, mianserin, tianeptine - these drugs can be prescribed to patients with concomitant severe liver pathology in normal doses); with moderate risk (amitriptyline, trazodone, fluoxetine, moclobemide - they can be prescribed to patients with severe liver pathology in reduced daily doses); with a high risk of hepatotoxicity (sertraline).
Heptral combines the properties of a hepatoprotector and has pronounced antidepressant activity; moreover, it is considered an atypical stimulant antidepressant. The antidepressant activity of adenosylmethionine (Heptral) has been known for more than 20 years, but a general concept that would explain the mechanism of the antidepressant action of this compound has not yet been developed. Obviously, it differs from the mechanism of action of antidepressants of all chemical groups known today. Adenosylmethionine (Heptral) is usually classified as an atypical antidepressant, and its neuropharmacological properties are associated with stimulating the formation of neurotransmitters.
The first observations confirming the effectiveness of adenosylmethionine for depression were published in the 1970s. Clinical studies were carried out in Germany, Italy, Great Britain and the USA. The results confirmed that when administered intravenously or intramuscularly, Heptral is significantly more effective than placebo. Some studies have found that oral adenosylmethionine at a daily dose of 1600 mg is effective in patients with depression. Currently, Heptral is used in psychiatric practice precisely as an antidepressant for the treatment of depression, alcoholism, drug addiction and affective disorders.
A meta-analysis of the results of 19 comparative clinical studies involving 498 patients suffering from depression of varying severity confirmed the statistically significant superiority of Heptral therapy compared to placebo (38-60%). Heptral was statistically significantly more effective than placebo in recurrent endogenous and neurotic depression resistant to amitriptyline, differing from the latter in its ability to interrupt relapses and the absence of side effects. Almost all researchers noted a more rapid development and stabilization of the antidepressant effect of Heptral (1st and 2nd weeks, respectively) compared to traditional antidepressants, especially when administered parenterally.
In an open multicenter clinical trial in 195 patients with depression, remission occurred after 7-15 days of parenteral administration of the drug at a dose of 400 mg/day. The most clearly positive effect of therapy was manifested in somatized depression. Clinical signs of improvement were noted from the 2nd week. treatment, which was expressed by a reduction in somatization disorders and hypothymia itself. Subjectively, the effect of Heptral is characterized by normalization of muscle tone, increased activity, improved tolerance to physical activity, and restoration of the ability to experience pleasure. The drug is recommended for use in the treatment of non-psychotic depression, in particular asthenic depression. Therefore, adenosylmethionine (Heptral), especially taking into account its somatotropic effect, is one of the drugs preferred for use in general medical practice. The drug is recommended for the treatment of depression in daily doses of 400-1600 mg, but in some cases a daily dose of over 3000 mg is required to achieve an antidepressant effect. Antidepressant properties give Heptral particular importance in persons suffering from alcohol dependence and in connection with dysphoric states and other affective disorders that complicate symptoms of psychoactive substance withdrawal.
Thus, the problem of hepatotoxicity is quite relevant. The main method of treating this pathology is the elimination of hepatotoxic agents. To quickly restore the structure and functions of the liver, hepatoprotective agents are used, the selection of which is based on taking into account the main pathogenetic mechanisms of development and the nature of morphological changes in the liver. In many cases, the doctor is faced with the problem of the impossibility of discontinuing the main drug that caused drug-induced liver damage. Heptral can be recommended as an accompanying therapy in the treatment of hepatotoxicity of any etiology.

Literature
1. Abdurakhmanov D.T., Moiseev S.V. Drug-induced liver damage // Farmateka. - 2011.- No. 17.- P. 67-73.
2. Bueverov A.O. Oxidative stress and its role in liver damage // Ros. magazine gastroenterol. hepatol. coloproctol. - 2002. - T. 12, No. 4. - P. 21-25.
3. Bueverov A.O., Maevskaya M.V., Ivashkin V.T. Alcoholic liver disease. - RMZH. - 2001. - T. 9, No. 2. - P. 61-64.
4. Bueverov A.O. Ademetionine: biological functions and therapeutic effects // Klin. prospects for gastroenterol., hepatol. - 2001.-№3.
5. Butorova L.I., Kalinin A.V., Loginov A.F. Drug-induced liver damage. Educational and methodological manual. - M.: Institute for Advanced Medical Studies. Federal State Institution NMHC named after. N.I. Pirogov", 2010. - 64 p.
6. Vybornykh D.E., Kikta S.V. Treatment of depression in gastroenterological practice // Klin. perspectives of gastroenterol., hepatol.- 2010.- No. 6.- P. 21-28.
7. Ivashkin V.T., Mayevskaya M.V. Alcohol-viral liver diseases. - M.: Littera, 2007. - P. 85-118.
8. Ignatova T.M. Drug-induced liver damage // Klin. pharmacology and therapy (adj. Hepatology forum). - 2008.- No. 2. - P. 2-8.
9. Ilchenko L.Yu., Vinnitskaya E.V. Pathways of metabolism and use of Heptral in chronic liver diseases // Experiment. and wedge. gastroenterology. - 2002. - No. 2. - P. 62-65.
10. Kazyulin A.N. and others. Drug hepatotoxicity during antitumor chemotherapy of oncological diseases and the possibility of its correction // Farmateka. - 2012. - No. 8.- P. 1-7.
11. Kovtun A.V. et al. Drug-induced liver damage. Diagnosis and treatment // Attending physician. Gastroenterology. - 2011. - No. 2. - P. 2-7.
12. Larionova V. B. et al. Possibilities for correcting hepatic metabolic disorders during chemotherapy for hematologic cancer patients // Klin. perspectives of gastroenterology, hepatology. - 2008. - No. 5. - P. 1-7.
13. Larionova V.B., Gorozhanskaya E.G. Prospects for the use of heptral in hemoblastoses // Farmateka. - 2012. - No. 20 (253). - special issue “Oncology”.
14. Minushkin O.N. Some hepatoprotectors in the treatment of liver diseases // Attending physician. - 2008.- No. 3.
15. Moiseev S.V. Drug hepatotoxicity // Klin. pharmacology and therapy. - 2005. - T. 14, No. 1. - P. 10-14.
16. Podymova S.D. Ademetionine: pharmacological effects and clinical use of the drug // Breast Cancer. - 2010.- T.18, No. 13.- P. 800-804.
17. Sivolap Yu.P. Hepatoprotectors in drug treatment practice // Journal of neurology and psychiatry. - 2012. - Issue 2, No. 5. - P. 49-50.
18. Snegovoy A.V., Manzyuk L.V. Efficacy of Heptral in the treatment of liver toxicity caused by cytostatic chemotherapy // Farmateka. - 2010.- No. 6.- P. 1-5.
19. Toporkov A.S. Algorithm for diagnosis and treatment of toxic and alcoholic liver damage // RMZh.- 2004.- T.12, No. 7 (207). - P. 445-446.
20. Khobeish M.M. Heptral in the treatment of psoriasis // Bulletin of Dermatology and Venereology. - 2009.- No. 3.
21. Sherlock S., Dooley J. Diseases of the liver and biliary tract: Pract. hand: Per. from English / Ed. Z.T.Aprosina, N.A.Mukhina. -M: Geotar Medicine, 1999.- P. 864.
22. Bjornsson E., Olsson R. Outcome and prognostic markers in severs drug-induced liver disease // Hepatology. 2005. Vol. 42. P. 481-489.
23. Cabrero C., Duce A.M., Ortiz P. et al. Specific loss of the high-molecularweight form of S-adenosyl-L-methionine synthetase in human liver cirrhosis // Hepatol. 1988. Vol. 8. P. 1530-1534.
24. Chalasani N., Fontana R.J., Bonkovsky H.L. et al. For the DILIN Study Group. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States // Gastroenterology. 2008. Vol. 135. P. 1924-1934.
25. Christoffersen P., Nielsen K. Histological changes in human liver biopsies from chronic alcoholics // Acta Pathol. Microbiol. Scand. A. 1972. Vol. 80. P. 557-565.
26. Dunne J.B., Davenport M., Williams R., Tredger J.M. Evidence that S-adenosylmethionine and N-acetylcysteine ​​reduce injury from sequential cold and warm ischemia in the isolated perfused rat liver // Transplantation. 1994. Vol. 57. P. 1161-1168.
27. Floyd J., Mirza I., Sachs B. et al. Hepatotoxicity of chemotherapy // Semin. Oncol. 2006. Vol. 33(1). P. 50-67.
28. Frezza M., Surrenti C., Manzillo G. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study // Gastroenterol. 1990. Vol. 99(1). P. 211-215.
29. Frezza M., Terpin M. The use of S-adenosyl-L-methionine in the treatment of cholestatic disorders. A meta-analysis of clinical trials // Drug Invest. 1992. Vol. 4(4). P. 101-108.
30. Giudici G.A., Le Grazie S., Di Padova C. The use of ademethionine (SAMe) in the treatmen of cholestatic liver disorders: meta-analysis of clinical trials / Mato J.M., Lieber C., Kaplowitz N., Caballero A. , ed. Methionine Metabolism: Molecular Mechanism and Clinical Implications. - Madrid CSIC Press, 1992. P. 67-69.
31. Hirata F., Viveros O.H., Diliberto E.J.Jr., Axelrod J. Identification and properties of two methyltransferases in the conversion of phosphatidylethanolamine to phosphatidylcholine // Proc. Natl. Acad. Sci USA. 1978. Vol. 75. P. 1718-1721.
32. Ibanez L., Perez E., Vidal X., Laporte J.R. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs // J. Hepatol. 2002. Vol. 37. P. 592-600.
33. Kim W., Biggins S., Kremers W. et al. Hyponatremia and Mortality among Patients on the Liver-Transplant Waiting List // NEJM. 2008. Vol. 359, No. 10. P. 1018-1026.
34. Kretzschmar M., Klinger W. The hepatic glutathione system influences of xenobiotics // Exp. Pathol. 1990. Vol. 38. P.145-164.
35. Lieber Ch. Alcoholic liver disease: new symptoms in pathogenesis leading to new treatment // J. Hepatol. 2000. Vol. 32 (suppl. 1). P. 113-128.
36. Lucey M., Mathurin Ph., Morgan T. Alcoholic Hepatitis // N. Engl. J. Med. 2009. Vol. 360. P. 2758-2769.
37. Mato J.M., Camara J., Fernandez de Paz J. et al. S-Adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial // J. Hepatol. 1999. Vol. 30. P. 1081-1089.
38. Mischoulon D., Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence // Am. J. Clin. Nutr. 2002. Vol. 76, No. 5. P. 1158-1161.
39. Mendenhall C.L. Anabolic steroid therapy as an adjunct to diet in alcoholic hepatic steatosis // Am. J.Dig. Dis. 1968. Vol. 13. P. 783-791.
40. Mendenhall C.L. Alcoholic hepatitis // Clin. Gastroenterol. 1981. Vol. 10. P. 417-441.
41. Rambaldi A., Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases // Cochrane Database Syst. Rev. 2006. Vol. 19, No. 2. CD002235.
42. Rosenbaum J.F., Fava M., Falk W.E. et al. The antidepressant potential of oral S-adenosyl-l-methionine // Acta Psychiatr. Scand. 1990. Vol. 81, N 5. P. 432-436.
43.O`Shea R.S., Dasarathy S., McCullough A.J. et al. Alcoholic liver disease. AASLD practice guidelines // Hepatol. 2010. Vol. 51, N 1. P. 307-328.
44.Russo M.W., Galanko J.A., Shrestha R. et al. Liver transplantation for acute liver failure from drug-induced liver injury in the United States // Liver Transplantation. 2004. Vol. 10. P. 1018-1233.
45. Santini D., Vincenzi B., Massacesi C. et al. 5-adenosylmethionine (heptral) in the treatment of liver damage caused by chemotherapy // Farmateka. - 2007. Oncology ASCO. - P. 1-5.
46. ​​Savolainen V.T., Liesto K., Mannikko A. et al. Alcohol consumption and alcoholic liver disease: evidence of a threshold level of effects of ethanol // Alcohol. Clin. Exp. Res. 1993. Vol. 17. P. 1112-1117.
47. Sgro C., Clinard F., Ouazir K. et al. Incidence of drug-induced hepatic injuries: a French population-based study // Hepatol. 2002. Vol. 36. P. 451-455.
48. Sorensen T.I., Orholm M., Bentsen K.D. et al. Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis // Lancet. 1984. Vol. 2. P. 241-244.
49. Vincenzi B., Santini D., Frezza A.M. et al. The role of S-adenosyl methionine in preventing FOLFOX-induced liver toxicity: a retrospective analysis in patients affected by resected colorectal cancer treated with adjuvant FOLFOX regimen // Exp. Opin. Drug Saf. 2011. Vol. 10(3). P. 345-349.
50. Vincenzi B., Daniele S., Frezza A.M. The role of S-adenosylmethionine in preventing oxaliplatin-induced liver toxicity: a retrospective analysis in metastatic colorectal cancer patients treated with bevacizumab plus oxaliplatinbased regimen // Supp. Care Cancer. 2012. Vol. 20(1). P. 135-139.
51. Vuppalanchi R., Liangpunsakul S., Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States // Am. J. Gastroenterol. 2007. Vol. 102. P. 558-562.
52. Weinstein W.M., Hawkey C.J., Bosch J. // Clin. Gastroenterol. and Hepatol. Elsevie, 2005. 1191 p.

NSAIDs as potentially hepatotoxic drugs

As can be seen from the data in Table 2, most drugs with a high potential for developing hepatotoxicity are used for life-saving indications in specialized hospitals, which means it is possible to monitor liver function over time. Of the total mass of drugs, some NSAIDs stand out in particular. They are prescribed quite widely. Moreover, most drugs from this group can be purchased at pharmacies without a prescription. As a result, patients can resort to the drug they “like” as often as they see fit, even in the absence of compelling reasons. Many patients recommend them to their friends and family, putting the effectiveness of the drug at the forefront, not its safety. Treating physicians should be especially careful in selecting NSAIDs in the following situations:

• rheumatological and neurological patients (the risk increases in parallel with the duration of use);


• orthopedic and dental practice (high pain intensity, combination or high-dose therapy);
• patients who abuse alcohol (an increased risk of developing liver failure is expected);
• multimorbid patients (risk of drug interactions);
• history of cardiovascular diseases (it is necessary to take into account the parallel use of aspirin in small doses; limited use of drugs from the coxib class2 due to an increased risk of myocardial infarction).

In this review, we will consider drugs from the NSAID group available on the domestic market3, which are characterized by the highest potential for the development of hepatotoxic reactions (Table 3). Sulindac (Clinoril). It is used quite rarely in modern clinical practice, largely due to the high risk of hepatotoxic reactions. Sulindac competitively inhibits the canalicular transport of bile salts, which serves as the basis for the development of cholestatic liver damage.

Paracetamol (Acetaminophen). According to statistics, this drug is one of the leaders in the number of cases of hepatotoxicity and nephrotoxicity. In the United States alone, paracetamol use is associated with 1,600 episodes of acute liver failure per year. Most of them are associated with overdoses, prolonged uncontrolled use and interaction with alcohol, and in the latter case, cases of fulminant liver failure are not uncommon when used in doses of less than 4 g per day.

It should be noted that paracetamol is most dangerous when used in persons with alcoholism due to the high activity of the cytochrome P450 system and nucleophilic proteins of hepatocytes, which lead to the formation of toxic metabolites. At the same time, when used in children, the drug is practically safe, due to preferential metabolism by glucuronidation, which does not lead to the formation of toxic metabolites.

Nimesulide (Nise, Nimulid, Nimesil). This drug, which belongs to the group of preferential cyclooxygenase-2 (COX-2) inhibitors, requires special coverage. At one time, great hopes were placed on drugs from the class of COX-2 inhibitors, the action of which should be limited to the site of inflammation, which were largely justified. The use of selective NSAIDs actually reduced the risk of side effects, primarily undesirable effects on the gastrointestinal tract. But soon, in many clinical studies, it was discovered that highly selective COX-2 inhibitors (coxibs) can cause serious cardiovascular complications, after which most of them were hastily withdrawn from the market (rofecoxib, valdecoxib, lumiracoxib), and for the remaining, certain clinical suspicion (eg Arcoxia). After the high-profile story with the “hard” coxibs, the interest of doctors and patients switched to “soft” COX-2 inhibitors - nimesulide and oxicams (Movalis), which have proven themselves well in terms of cardiac safety.

Nimesulide has pronounced anti-inflammatory and analgesic activity, which is determined not only by inhibition of COX, but also by a decrease in the production of cytokines. The antipyretic effect of nimesulide differs from that of other COX inhibitors. It is determined not only by a decrease in prostaglandin synthesis, but also by inhibition of neutrophil activation, including that caused by their adhesion. In addition, nimesulide reduces the production of free radicals and the activation of lysosomal enzymes.

Developed in the USA, but never registered as a medicine there, nimesulide gained great popularity in Europe. This circumstance is explained by its high effectiveness in controlling pain even in complex patients, including those who have suffered trauma, with severe osteoarthritis and toothache. At the same time, the risk of developing erosive and ulcerative lesions of the gastrointestinal mucosa while taking nimesulide seemed even lower than when using such highly selective COX-2 inhibitors as celecoxib and rofecoxib. Due to the fact that many doctors (especially orthopedists, surgeons and dentists) in Italy and Portugal began to prescribe nimesulide to almost all patients with severe pain, at the beginning of the 21st century in these countries nimesulide came out on top in sales among NSAIDs.

However, gradually the attitude towards nimesulide in European countries began to change, and the reason for this was reports of the development of hepatotoxic reactions, including fulminant liver failure, against the background of its use. At the same time, hepatotoxic reactions associated with taking nimesulide are particularly severe and in some cases are fatal, even when treated using extremely effective methods, such as the molecular adsorption and recirculation system (MARS).

Apparently, of all the NSAIDs present on the domestic market, nimesulide is the most hepatotoxic drug. According to a study conducted in Finland, side effects with nimesulide occurred one hundred times more often than with other NSAIDs. In Spain, approximately ten cases of hepatotoxicity have been reported for every million nimesulide sachets sold. Liver damage when using nimesulide usually develops 1–4 months after the start of administration, however, hepatotoxic reactions delayed up to 8–14 months also occur. Acute liver failure may be accompanied by severe hemolytic anemia, as well as renal failure.

To date, the mechanism of liver damage caused by the use of nimesulide is not entirely clear. The main factors associated with the development of hepatotoxic reactions are the age of the patients, as well as gender (female). Morphologically, nimesulide-induced liver damage manifests itself in the form of bridging and centrilobular necrosis; in some cases, cholestatic liver damage can also be observed.

formation takes a long time, in some cases up to 16 months. Often, the only effective treatment for nimesulide-induced fulminant liver failure is liver transplantation. It was due to the high risk of hepatotoxic reactions that the registration of nimesulide was canceled in Finland (2002) and in Spain, and a special investigation was initiated by supervisory authorities.

In September 2007, the European Medicines Agency (EMEA) issued a special regulation regarding the hepatotoxicity of nimesulide, which emphasized that the period of use of nimesulide cannot exceed 15 days, and all packs of nimesulide containing more than 30 doses of the drug should be withdrawn from the market due to with a high risk of liver damage. In the USA, thanks to the active position of the FDA, as mentioned above, the drug was never registered. This example was followed by regulators in a number of other countries (Canada, Australia, Great Britain, New Zealand).

In addition, questions were raised regarding the safety of nimesulide for the gastrointestinal tract. There have been reports that with its long-term use, multiple perforations of the small and large intestine may develop. A possible explanation may be the topical effect of nimesulide on the intestinal wall due to its insufficient solubility.

which the authors believe that inhibition of COX-2 by nimesulide in the damaged intestinal mucosa may slow down the healing of erosions and subsequently potentiate perforation and penetration of ulcers. Other side effects of nimesulide were severe skin reactions (including acute exanthematous pustular eruptions, erythematous squamous elements), as well as eosinophilic infiltrates in the lungs).

umedp.ru

Hepatocyte necrosis

Acute necrosis of hepatocytes with high transaminase activity in the blood can be caused by many drugs, the most famous of which is paracetamol. Inflammation is not always present, but usually accompanies necrosis in lesions caused by diclofenac (NSAID) and isoniazid (an antituberculosis drug). With liver damage caused by allopurinol, the formation of granulomas is possible. Acute necrosis of hepatocytes has also been described with the use of certain herbal remedies, including dubrovnik, comfrey, and jin bu huan. In addition, some drugs, such as cocaine and ecstasy, can cause severe acute hepatitis.

Drug-induced hepatocyte necrosis is clinically indistinguishable from necrosis caused by other causes, such as viral infection or ischemia. Therefore, in such cases, it is important to obtain a complete drug history, paying particular attention to allergic reactions such as rash or eosinophilia.

Diagnosis usually established by drug history, after other possible causes (viral infections, ischemia) have been excluded using serological and other studies.

The severity of the lesion can vary - from minimal changes to acute liver necrosis. Drugs, especially paracetamol, are responsible for 20-50% of cases of acute liver necrosis.

Laboratory research. The activity of AST and ALT is usually increased by 2-30 times. These enzymes enter the blood from the cytoplasm of damaged or dying hepatocytes.

Early percutaneous liver biopsy can help determine the type and severity of liver damage.

• Carbon tetrachloride and drugs such as paracetamol and halothane cause centrilobular necrosis.
• Aspirin and other NSAIDs, thiazide diuretics, nicotinic acid, clofibrate, gemfibrozil, oxacillin, drugs containing a sulfonamide group, rifampicin, ketoconazole, fluorocytosine, zidovudine, isoniazid, tacrine, trazodone, calcium antagonists, beta-blockers and methyldopa cause diffuse damage to the liver parenchyma , as with viral hepatitis.
• cValproic acid, amiodarone, tetracycline (with intravenous administration) can cause fine-droplet deposition of fats in hepatocytes and lead to liver failure.

Treatment. Immediately discontinue the drug that caused liver damage and begin symptomatic treatment. Most patients recover within a few weeks or months. However, in acute liver necrosis, mortality remains high.

Steatosis

Fine-droplet accumulations of fats in hepatocytes, caused by a direct violation of β-oxidation in mitochondria, can develop when using tetracyclines and valproic acid. Large droplet accumulations of fat in hepatocytes have been described when taking tamoxifen and amiodarone. Vascular/sinusoidal lesions Some drugs, such as alkylating agents used in oncology, can damage the vascular endothelium with the development of obstruction of venous outflow from the liver. Long-term intake of vitamin A in excessive doses is sometimes accompanied by sinusoid damage and local fibrosis, which can lead to portal hypertension.

Liver fibrosis

Liver damage caused by most drugs is reversible. Fibrosis develops very rarely. However, methotrexate, in addition to its ability to cause acute liver damage in the initial stages of therapy, can lead to cirrhosis when used. Factors that increase the risk of developing drug-induced liver fibrosis include pre-existing liver disease and alcohol abuse.

Drug-induced cholestasis

Isolated cholestasis (i.e., impaired outflow of bile in the absence of liver damage) can be caused by estrogens [which was often observed earlier when high doses of estrogens (50 mg/day) were used for contraception]. Modern drugs for oral contraception and hormone replacement therapy can be used for chronic liver pathology.

Drugs such as chlorpromazine and some antibiotics can cause cholestatic hepatitis, characterized by inflammation and damage to the bile capillaries. Among antibiotics, changes in FPP are often caused by amoxiclav. Anabolic steroids used by bodybuilders can also cause cholestatic hepatitis. Some drugs, such as NSAIDs and COX-2 inhibitors, can cause cholestasis in combination with acute damage to the liver parenchyma.

Drug-induced cholestasis develops when the secretion of bile by hepatocytes is impaired. This may be based on changes in the physical and chemical properties of hepatocyte membranes, for example, under the influence of estrogens and C17 alkylated testosterone derivatives. In addition, drugs or their metabolites can cause cholestasis through effects on the cytoskeleton of hepatocytes, inhibition of N + ,K + -ATPase in cell membranes, or immune reactions with damage to hepatocytes or small bile ducts. Cholestasis is most often caused by phenothiazines, tricyclic antidepressants, erythromycin, carbamazepine, cyproheptadine, tolbutamide, captopril, phenytoin, TMP/SMX, sulfasalazine and lipid-lowering drugs.

Diagnosis. Clinical and laboratory features of drug-induced cholestasis may resemble intra- and extrahepatic bile duct obstruction, septic cholangitis, or acute cholecystitis.

1. Clinical picture. Characterized by fever, pain, tenderness on palpation of the upper abdomen (especially in the right hypochondrium), jaundice and itching. The level of direct bilirubin may increase significantly (up to 34-513 µmol/l). Rash and other manifestations of allergic reactions are also possible.
2. Diagnostics. Most patients undergo ultrasound to rule out bile duct obstruction. In difficult cases, endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, or CT may be required.
3. Liver biopsy. The indication for it is the inability to make a diagnosis using the methods described above. Cholestasis is usually detected, sometimes with signs of inflammation. Inflammation of the small bile ducts, inflammatory infiltration of the portal tracts, and minor necrosis of hepatocytes may be present.

Treatment is symptomatic. It is important to immediately discontinue the hepatotoxic drug.

Mixed liver damage

In patients, the activity of serum aminotransferases and alkaline phosphatase, as well as the level of bilirubin, are moderately increased. For the most part, these are manifestations of hypersensitivity to drugs, occurring only in a few individuals predisposed to them.

Phenytoin. The clinical picture of liver damage resembles infectious mononucleosis. The temperature rises, the lymph nodes enlarge, the liver is painful on palpation. Liver biopsy reveals lymphocytic infiltration of the portal tracts and focal necrosis of hepatocytes.

Quinidig, allopurinol, nitrofurantoin, diltiazem and many other drugs cause granulomatous inflammation with partial necrosis of hepatocytes.

Detailed list hepatotoxic drugs and a description of their effects on the liver can be found in Lewis's article.

Amiodarone

Three drugs used to treat cardiovascular disease—amiodarone, perhexiline, and diethyphen—have recently been found to cause liver damage resembling alcoholic hepatitis.

Pathogenesis. In 20-40% of patients, amiodarone causes deposits in the skin and cornea, thyrotoxicosis or hypothyroidism, pulmonary infiltrates and interstitial pneumosclerosis, neuropathy, hepatomegaly with increased activity of serum aminotransferases. On liver biopsy, the histological picture resembles alcoholic hepatitis. Possible proliferation of bile ducts, fibrosis and cirrhosis of the liver. Electron microscopy reveals phospholipids within secondary lysosomes. It has been shown that amiodarone accumulates in lysosomes containing acidic enzymes, where it acts as a competitive inhibitor of lysosomal phospholipases. As a result, phospholipids are not destroyed, but accumulate in the lysosomes of hepatocytes. The relationship between phospholipidosis and the development of conditions resembling alcoholic hepatitis and cirrhosis is not yet clear.

Amiodarone is slowly eliminated from the body and has a large volume of distribution. Even several months after discontinuation, the drug is found in the liver and its blood level remains elevated. Amiodarone hepatotoxicity is usually not clinically apparent. As a rule, it develops after a year of taking the drug, but sometimes it can appear within a month.

Diagnosis. Liver damage is indicated by hepatomegaly, mild increases in serum aminotransferases, and sometimes elevated bilirubin levels. A final diagnosis may require a liver biopsy with histological examination and electron microscopy of the material.

Course of the disease and treatment. Amiodarone is discontinued and symptomatic treatment is prescribed. Hepatomegaly resolves over time, but liver damage can progress, leading to cirrhosis and its complications.

Aspirin

It has been shown that aspirin and other salicylates can cause liver damage in people with rheumatic diseases and CTD, including rheumatoid arthritis and juvenile rheumatoid arthritis, rheumatism, and SLE. Sometimes healthy people suffer, as well as patients with non-rheumatic diseases, such as orthopedic disorders.

Pathogenesis. An important role appears to be played by the level of the drug in the blood (more than 5 mg%) and the duration of administration (from 6 days to several weeks). Apparently, liver damage is cumulative in nature, since it appears only after many days of taking aspirin in large therapeutic doses. A single overdose of aspirin almost never leads to liver damage.

Rheumatic diseases and CTD may increase the sensitivity of the liver to the toxic effects of aspirin. The cause may be hypoalbuminemia, which results in higher levels of unbound aspirin in the blood than in healthy people; pre-existing liver dysfunction; and possibly impaired salicylate metabolism. The basis of liver damage in this case is the toxicity of the salicylates themselves rather than the individual intolerance of them by patients. Choline salicylate and sodium salicylate also have hepatotoxicity. Liver damage is usually mild, acute, and reversible. To make it go away, it is enough to reduce the dose of aspirin without stopping the drug completely. There is good reason to believe that aspirin may cause Reye's syndrome in children with a viral infection.

Clinical picture. Symptoms of liver damage are mild. In most patients, it is generally asymptomatic, although some complain of loss of appetite, nausea, and abdominal discomfort. Jaundice, as a rule, does not occur.

Liver damage is usually mild, but cases of encephalopathy, severe coagulopathy, and fatal acute liver necrosis have been reported. There is no evidence that aspirin causes chronic liver damage.

Diagnostics. The activity of serum aminotransferases is usually moderately increased. Alkaline phosphatase activity is usually normal or only slightly increased. Serum bilirubin levels increased in only 3% of reported cases.

Treatment is symptomatic. In most cases, it is not necessary to discontinue the drug - it is enough to reduce the dose so that the serum level of aspirin does not exceed 15 mg%.

Paracetamol

Paracetamol has analgesic and antipyretic effects; at therapeutic doses, its side effects are usually minor. But in large doses it is hepatotoxic and can cause liver necrosis.

As a rule, liver damage is caused by a single overdose of paracetamol (more than 10 g) for the purpose of suicide. However, repeated use of small doses of the drug for medicinal purposes can lead to the total dose being large enough to cause liver damage. In alcoholism, smaller doses of paracetamol have a hepatotoxic effect - a single dose of 3 g or taken in therapeutic doses of 4-8 g/day for 2-7 days. In addition, repeated use of paracetamol in therapeutic doses can cause hepatotoxicity in pre-existing liver disease, malnutrition, and severe exhaustion.

Pathogenesis. About 5-10% of the drug is oxidized to catecholamine derivatives, as well as β-hydroxy- and β-methoxyparacetamol. Another 5-10% is hydroxylated by liver microsomal enzymes to form the highly active toxic metabolite N-acetyl-p-benzoquinoneimine. Normally, it binds to the cysteine ​​residue of glutathione in the cytosol of hepatocytes and is excreted in the urine in the form of thioesters.

The risk of liver damage when taking a large dose of paracetamol depends on:

• age of the patient;
• the total amount of the drug taken;
• achieved serum concentration of paracetamol;
• the rate of its destruction;
• glutathione reserves in the liver.

Patient's age. In young children, the risk of liver damage from an overdose of paracetamol is significantly lower than in adults.

The total amount of the drug taken. A toxic single dose of paracetamol, as a rule, exceeds 15 g, but in some cases a dose of 3-6 g may be toxic.

Glutathione reserves in the liver. The toxicity of paracetamol largely depends on the amount of glutathione in the liver. Hepatocyte necrosis begins when more than 70% of glutathione is consumed or when glutathione reserves are reduced after fasting, exhaustion, or after drinking alcohol.

Hepatotoxicity of paracetamol in alcoholism. Against the background of alcoholism, liver damage can develop even with therapeutic doses of paracetamol. The reason is that long-term alcohol intake induces microsomal liver enzymes, and the exhaustion accompanying alcoholism reduces the body's ability to bind the toxic metabolites of paracetamol due to the reduced amount of glutathione.

Localization of liver damage. Damage to the liver parenchyma is usually centrilobular, which corresponds to the location of the enzymes involved in the metabolism of paracetamol. Sinusoids are often filled with blood and expanded towards the center. Characterized by extensive hemorrhagic necrosis of hepatocytes with minor inflammatory infiltration and without fatty degeneration.

Diagnosis

1. Clinical picture. A few hours after taking a large dose (more than 10 g) of paracetamol, the patient usually experiences nausea and vomiting. If tranquilizers are taken simultaneously with paracetamol, stunning is possible. Within 24 hours, nausea and vomiting disappear, and the victim appears healthy.
2. Diagnostics. The activity of ALT and AST is usually greatly increased, the activity of ALP does not increase so significantly. In most cases, severe coagulation disorders develop rapidly, which are manifested by prolongation of PT. Prolongation of PT by more than twice the normal value indicates an unfavorable prognosis. Bilirubin levels are usually only slightly elevated.
3. The severity of liver damage can vary. 4-18 days after paracetamol enters the body, toxic liver dystrophy may develop with a fatal outcome.
4. Damage to other organs...
5. Recovery. If the patient experiences an acute period, then within 3 months the structure of the liver is completely restored.

Treatment

Treatment for an overdose of paracetamol is aimed at reducing the absorption of the drug (prescribed activated carbon or cholestyramine) and accelerating its elimination (through hemodialysis and hemosorption). None of these methods guarantee success.

Acetylcysteine. Since glutathione is needed to neutralize the toxic metabolites of paracetamol, it is important to replenish its reserves in the liver. For this, patients are prescribed acetylcysteine, which provides the body with cysteine, a precursor to glutathione. Acetylcysteine ​​is effective when administered within the first 10 hours after an overdose of paracetamol. If more than 10 but less than 24 hours have passed since the poisoning, acetylcysteine ​​is still prescribed, but its effectiveness is noticeably lower. When taken orally, acetylcysteine ​​is well tolerated by most patients; it may cause slight nausea and sometimes vomiting. If oral administration is not possible, the drug is administered intravenously.

Treatment regimen. Treatment begins with establishing the fact of paracetamol poisoning, determining the amount of the drug that has entered the body and the time that has passed since that moment. If less than a day has passed, the stomach is washed through a large-diameter nasogastric tube. The patient is prescribed an initial dose of acetylcysteine ​​orally. The total duration of treatment is 72 hours. During treatment, the serum concentration of paracetamol is determined. If liver damage is likely at the existing serum concentration, a full course of treatment is necessary. If it is below toxic, treatment can be interrupted. If the patient does not tolerate acetylcysteine ​​well, an antiemetic is prescribed. In case of persistent vomiting after taking acetylcysteine, the drug is administered through a nasogastric or nasojejunal tube. You can also dilute acetylcysteine ​​with Coca-Cola, juice or water in a three to one ratio to make it easier to drink.

In case of serious condition of the patient carry out active symptomatic treatment as for severe viral hepatitis. Constantly monitor basic physiological indicators, diuresis, heart and kidney function, and blood count. Any disturbances in water-electrolyte balance and acid-correction hormones are immediately corrected.

For any questions regarding the treatment of acetaminophen poisoning, you can call the Denver Poison Center 24 hours a day at 800-525-6115.

Chronic drug-induced hepatitis

Chronic drug-induced hepatitis can be caused by drugs such as oxyphenizatin, methyldopa, nitrofurantoin, dantrolene, isoniazid, propylthiouracil, halothane, and sulfonamides. Each causes chronic hepatitis very rarely, and the total number of cases is small. However, if chronic hepatitis is suspected, a medical history must be collected.

Methyldopa very rarely causes chronic hepatitis; however, if not detected in time, the disease can progress and lead to chronic active hepatitis. Hepatitis develops after several weeks of treatment with methyldopa, suggesting a role for hypersensitivity reactions. If the disease is recognized in time, after discontinuation of the drug, the inflammation subsides.

Oxyphenizatin is a laxative that has been discontinued in the United States but is still used in Europe and South America, especially by women. Oxyphenizatin can cause acute and chronic hepatitis, resembling chronic autoimmune (“lupoid”) hepatitis. If you do not stop taking the drug, cirrhosis may develop over time. After discontinuation of oxyphenizatine, progression of the disease usually stops, and the condition of the liver may even improve.

Isoniazid. In 20% of patients, in the first 2-3 months of treatment with isoniazid, the activity of serum aminotransferases increases and mild asymptomatic liver damage occurs. But in approximately 1% of cases, liver damage is severe, up to toxic liver degeneration with a fatal outcome.

Pathogenesis. Drug-induced hepatitis is believed to be caused by hepatotoxic intermediate metabolites of isoniazid. The drug is first acetylated and then converted to acetylphenylhydrazine, which is highly hepatotoxic. There is evidence that those with high acetylating enzyme activity (for example, most East Asians) are more likely to suffer from isoniazid-induced hepatitis.

Clinical picture. Symptoms of hepatitis caused by taking isoniazid are nonspecific and resemble viral hepatitis. Characterized by fatigue, malaise, loss of appetite. Jaundice is observed in 10% of patients. Allergic reactions, rash, swollen lymph nodes, arthralgia and arthritis are rare. The susceptibility to hepatitis caused by isoniazid is higher in the elderly, especially women. Under the age of 20, such hepatitis is rare. At the age of 20-35 years, the risk increases to 0.5%, 35-50 years - up to 1.5%, over 50 years - up to 3%. Drinking alcohol and taking drugs that induce liver microsomal enzymes, such as rifampicin, increase the risk of isoniazid-induced hepatitis. Continuing to take the drug after the onset of hepatitis symptoms aggravates liver damage, so it is extremely important to discontinue the drug in the first 1-2 weeks after the onset of symptoms.

Treatment. There is no specific treatment for hepatitis caused by isoniazid. The main thing is to stop taking the drug, after which symptomatic treatment is carried out. Glucocorticoids are ineffective in this case.

Medicines contraindicated in liver cirrhosis

In case of liver cirrhosis, most analgesics should be used with caution, as they can provoke the development of complications. NSAIDs should not be used as they have hepatotoxic effects and may worsen hepatic renal failure. For chronic diseases, paracetamol should not be prescribed in doses exceeding 3 g/day.

www.sweli.ru

7.2.1. State of the world, in other words

Sasha. Preferences 2 points in the context of the legal system assorted signals ó 2 /ç ïasöèítov. The big ones in the world in the world Yelp and yuras. In this case, in this case, in the Russian Federation, in other words, in the Russian Federation. about this, this is the world.

Tavern. More information about the world in the Russian Federation, in the Russian Federation the case between the world and the other Forms of information and terms of reference ålåïàtov. This is the meaning of the world. In other words, in this case 2 on the other side and 1 on the other side.

Alterations. Another version of the system, called 6-phase e, m, ur, k èçâñòíî, ïrðèvîäèò k èççìåíåíèþ ázèmè÷ the meaning of the word - the meaning of the word "the world" This is the case between the two countries and the world around the world the world in the center . In this case, this is the case between the world and the world. ågåïàtovî, âîñïàëèòåëüíàÿ èíofèëütðàöèñ ñ ôèáðîîçîîïîðòàëüíòò raskova systoriya magistro-storovka i 6-motorika; this is the case with the syllables. Introducing the Russian Federation in the Russian Federation rasa, this is 3 years ago; in this regard This is the case.

www.rusmedserver.ru

The article covers the issues of diagnosis and treatment of drug-induced liver damage.

In recent years, the importance of drug-induced liver injury (DILI) has increased significantly; doctors of all specialties are faced with this problem. The difficulty of diagnosing DILI lies in the fact that clinical and laboratory manifestations and histological signs can “simulate” other liver diseases or overlap with existing viral and/or alcoholic liver damage. At the same time, DILI needs to be diagnosed at an earlier stage, since continued use of medications can greatly increase the severity of clinical manifestations and significantly affect the outcome of the disease as a whole.
According to A.O. Bueverova, “the true prevalence of drug-induced liver damage remains and, apparently, will remain unknown, however, it can be stated that in clinical practice this diagnosis is formulated unreasonably rarely. This is due to several factors, among which the most important are:
1) the patient’s reluctance to report taking certain medications (antidepressants, antipsychotics, etc.);
2) reluctance of doctors to document iatrogenic diseases.
General factors predisposing to the development of DILI are as follows:
1) prescribing medications in high doses;
2) dosing of the drug without taking into account the individual characteristics of the patient;
3) long-term treatment;
4) polypharmacy;
5) liver diseases of any etiology;
6) background systemic diseases (especially kidney diseases).
Zimmerman in 1978 proposed classifying substances that cause liver damage into one of 2 groups: 1) obligate hepatotoxicants and 2) damaging the organ only in sensitive individuals (idiosyncratic).
Obligate hepatotoxicants cause a predictable dose-dependent effect, usually reproducible in experiments on experimental animals.
In a small proportion of people, medicinal substances that do not exhibit hepatotoxicant properties in experiments nevertheless cause liver damage. The phenomenon is based on genetically determined characteristics of the metabolism of xenobiotics and other reasons for the body’s increased susceptibility to the drug. This type of pathology is not reproduced experimentally and is not dose-dependent. The criteria for distinguishing between these forms are presented in Table 1. But in practice, it is not always possible to clearly distinguish between direct hepatotoxicity and idiosyncrasy. Moreover, in susceptible patients, some drug compounds that were previously classified as allergens appear to directly damage hepatocyte membranes through intermediate toxic metabolites.

A toxic substance can directly affect the structure of the hepatocyte (metabolite of paracetamol - N-acetyl-p-benzoquinone) and/or have an indirect effect on specific metabolic reactions (for example, inhibition of protein synthesis when using cytostatic antibiotics). Most direct hepatotoxicants cause dose-dependent liver necrosis, often in the presence of effects on other organs (kidneys). The classic drug with an obligate hepatotoxic effect is paracetamol.
The basis of the toxic effect of drugs on the liver is damage to hepatocytes. The mechanisms underlying the hepatocytotoxic effect of drugs (Table 2) are closely interconnected and often aggravate each other’s effects in a “vicious circle” manner.

The spectrum of clinical manifestations of drug-induced liver disease can be extremely varied, but the most common are acute lesions of the hepatitis type (in approximately 80% of cases). Chronic DILI can be an independent disease (for example, with long-term use of methyldopa), but usually develops as the outcome of an acute pathological process (with long-term use of drugs or their combination).
The severity of drug-induced liver diseases varies from an asymptomatic increase in transaminase levels to the development of fulminant liver failure (FLF).
In addition to symptoms characteristic of liver diseases (jaundice, skin itching, “liver signs”, bleeding, liver enlargement and pain on palpation), general manifestations are often observed (nausea, abdominal discomfort, loss of appetite, general weakness, decreased ability to work). Although the development of acute liver failure is possible, in most cases drug reactions are transient and resolve spontaneously.
The latent period when using hepatotoxic dose-dependent drugs is usually short (pathological manifestations develop within 48 hours from the start of administration). Depending on the degree of increase in the levels of alanine aminotransferase (ALT) and alkaline phosphatase (ALP), acute liver damage is classified as hepatocellular (cytolytic), cholestatic, or mixed, combining signs of cholestasis and cytolysis (Table 3).

More often, in 2/3 of cases, the hepatocellular type of damage occurs. An increase in ALT activity up to 5 times the upper limit of normal is considered moderate hyperenzymemia; 6–10 times – as moderate hyperenzymemia, more than 10 times – as high. In drug-induced liver diseases, elevated ALT levels are the most sensitive early diagnostic test. In mitochondrial hepatocytopathies, the activity of aspartate aminotransferase (AST) increases significantly. Depending on the underlying type of liver damage, clinical symptoms and changes in biochemical parameters can vary widely.
Acute drug-induced hepatitis of varying severity , is perhaps the most common drug-induced liver injury. As a rule, it is caused by idiosyncratic reactions; the risk of developing drug-induced hepatitis increases with prolonged and repeated use of the drug. The clinical picture in the prodromal period is dominated by dyspeptic disorders, asthenic and allergic syndromes. With the development of the icteric period, darkening of the urine and lightening of the feces are noted, and enlargement and tenderness of the liver are detected. An increase in aminotransferase activity and alkaline phosphatase level is directly dependent on cytolysis and the spread of liver necrosis. The level of γ-globulins in the serum increases. When the drug is discontinued, regression of clinical symptoms occurs quite quickly. In some cases, drug-induced hepatitis carries the risk of FPN, the mortality rate of which can reach 70%. Acute drug-induced hepatitis has been described with the prescription of antituberculosis agents (especially isoniazid), aminoglycosides (streptomycin, amikacin, rifampicin), antihypertensive drugs (methyldopa, atenolol, metoprolol, labetolol, acebutolol, enalapril, verapamil), antifungals (ketoconazole, fluconazole), antiandrogenic drugs drugs (flutamide), tacrine (a reversible cholinesterase inhibitor used for Alzheimer's disease), clonazepam (an anticonvulsant).
Steatohepatitis . Corticosteroids, tamoxifen, and estrogens may act as triggers for steatohepatitis in predisposed individuals, such as those with diabetes, central obesity, or hypertriglyceridemia. Drug-induced steatohepatitis usually develops during long-term pharmacotherapy (more than 6 months) and is apparently associated with the accumulation of drugs. Acute fatty liver changes can be caused by tetracyclines, NSAIDs, as well as corticosteroids, valproic acid and anticancer drugs. A feature of steatohepatitis caused by some drugs is its continued progression after discontinuation of the drug.
Chronic drug-induced hepatitis may also cause repeated prescriptions of nitrofurans for recurrent urinary infections, clometacin, fenofibrate (a lipid-lowering agent), isoniazid (a tuberculostatic), papaverine, minocycline (a tetracycline antibiotic) and dantrolene (a muscle relaxant, used to eliminate muscle spasms in cerebral palsy, multiple sclerosis and spinal cord injuries). Chronic drug-induced hepatitis often develops in people who chronically drink alcohol.
Acute cholestasis described with the use of drugs from various pharmacological groups, including estrogens, anabolic steroids, tamoxifen, neuroleptics (chlorpromazine), statins, antibiotics (erythromycin, oxypenicillins, fluoroquinolones, amoxicillin/clavulanate), antiplatelet agents (ticlopidine), antihistamines (terfenadine) and antifungal agents (terbinafine), NSAIDs (nimesulide, ibuprofen), antihypertensive (irbersartan) and antiarrhythmic drugs (propafenone), etc.
Isolated hepatocellular cholestasis is more often observed with the use of sex hormones and anabolic steroids. Drug-induced cholangiopathy (cholestasis in small or interlobar ducts) can be acute and self-resolving after drug withdrawal or, on the contrary, take a protracted course, leading to ductopenia and sometimes biliary cirrhosis.

Diagnosis of drug-induced liver damage
Early diagnosis of DILI is of particular importance due to the high risk of disease progression without drug discontinuation. The possibility of lesions of this kind is taken into account when liver function is impaired in patients taking various drugs and alternative medicine.
Due to the large number of asymptomatic drug-associated liver diseases in patients receiving hepatotoxic drugs and with polypharmacy, it is advisable to regularly (at least 1 time/2 weeks, and with long-term therapy - 1 time/month) determine the activity of aminotransferases , ALP and serum bilirubin levels. If transaminase activity is increased more than 3 times, the drug is discontinued. An alternative to discontinuing the drug, as well as if it is necessary to continue treatment with a hepatotoxic drug, is to reduce the dose of the hepatotoxicant and take an oral hepatoprotector. The drug of choice in this situation is drugs based on silymarin (Legalon). Indications for immediate discontinuation of the drug are the appearance of fever, rash or itching in the patient.
The basis for diagnosing DILI is a carefully collected history of the medications used, assessing the duration and dose of the drugs received, and determining the possibility of taking them in the past. It is imperative to clarify your immediate medical history and find out whether you have taken biologically active food additives. They are not formally drugs, but are usually positioned as treatments for a wide range of diseases, including liver diseases, while the substances included in such drugs often have pronounced hepatotoxic properties (Table 4).

The diagnosis of drug-associated liver injury is in most cases a diagnosis of exclusion. A variant of the diagnostic algorithm is presented in Table 5.

With the help of biochemical and immunological studies, ultrasonography (and in some cases, other radiation diagnostic methods), liver diseases of a different etiology are established. But it should be remembered that DILI can overlap with “classical” liver disease and change its course. An attempt to re-expose the drug is unacceptable for ethical reasons. The diagnosis is confirmed if clinical symptoms, changes in biochemical parameters and histological signs of liver damage disappear or decrease after stopping the medication. Liver biopsy may be indicated if preexisting liver pathology is suspected or if biochemical parameters do not normalize after discontinuation of the drug. There are no specific histological changes for DILI. Granulomas, a significant admixture of eosinophils in the inflammatory infiltrate, and a clear zone of demarcation between the area of ​​necrosis and unaffected parenchyma are often found. When making clinical and morphological comparisons, attention is drawn to the discrepancy between the severity and volume of morphological changes with the general relatively satisfactory condition of the patient and moderate changes in liver test parameters.

Treatment of drug-induced liver damage
The first step in the treatment of drug-associated liver disease should be discontinuation of the drug. In most cases, discontinuation of the “culprit” drug quickly leads to a significant improvement in clinical and laboratory data.
But in practical work, this is sometimes a very difficult task for a doctor, for example, when conducting chemotherapy in cancer patients, complex anti-tuberculosis treatment or treatment of neuropsychiatric diseases, diseases of the joints, heart, etc. In addition, multicomponent therapy, which is a complex potentially hepatotoxic substances, often does not allow us to specify the substance that caused the pathological reaction.
If a doctor prescribes a drug with a known hepatotoxic effect (paracetamol, chemotherapeutic agents) or re-prescribes a course of drug treatment in which negative biochemical changes in liver tests were previously noted, hepatoprotective agents (milk thistle flavonoids) are included in the therapy from the first day of treatment (Table 6 ).
In some cases, DILI can be prevented by adjusting the doses of medications used. For example, in people who chronically drink alcohol, the dose of paracetamol should not exceed 2 g/day. In case of hypersensitivity reactions, drugs that can cause cross-allergic reactions should be avoided, i.e. representatives of the same chemical group, for example, phenothiazines, tricyclic antidepressants, halogenated anesthetics, etc.
The results of numerous experimental and clinical studies demonstrate the therapeutic effect of some drugs from the group of hepatoprotectors in drug-associated liver diseases.
The very concept of “hepatoprotectors” is, by definition, not strict and is interpreted quite arbitrarily by different specialists. In the most common understanding, this is a class of drugs that, regardless of the mechanism of action, increase the functional ability of liver cells to synthesize, detoxify and excrete various biological products, and support the resistance of hepatocytes to various pathogenic influences. The goals of prescribing hepatoprotectors for drug-induced liver diseases are to restore and/or maintain liver cell homeostasis.
In clinical practice in previous years, a variety of drugs were used as hepatoprotectors, many of which turned out to be ineffective and fell out of use. Currently, the drugs presented in Table 6 are predominantly used for drug-associated liver diseases.
The basic requirements for an “ideal” hepatoprotector were formulated by R. Preisig:
– fairly complete absorption;
– the presence of a first-pass effect through the liver;
– pronounced ability to bind or prevent the formation of highly active damaging compounds;
– the ability to reduce excessive inflammation;
– suppression of fibrogenesis;
– stimulation of liver regeneration;
– natural metabolism in liver pathology;
– extensive enterohepatic circulation;
– lack of toxicity.
In the practice of a therapist who often deals with manifestations of moderate hepatotoxicity of medications, it is advisable to use not infusion, but oral forms of hepatoprotectors, which do not require patients to stay even in a day hospital. This condition is best met by the original preparation based on milk thistle, containing the maximum amount of silymarin. Silymarin is the common name for chemically related flavonolignan isomers from milk thistle fruit. The main bioflavonoids in silymarin are: silibinin, silydianin, silicristin, isosilibinin, among which silibinin has the greatest biological activity. The full range of actions of silymarin, using the example of the original drug Legalon, is reflected in Table 8. Numerous studies have proven that silibinin contributes to a significant increase in the content of reduced glutathione in the liver, thereby increasing the organ’s protection from oxidative stress, maintaining normal detoxification function of the liver. The hepatoprotective properties of silymarin (silibinin) are associated not only with the restoration of the liver’s own antioxidant systems. Silymarin itself is an antioxidant due to the presence of a phenolic structure in the molecule. Silibinin binds free radicals in hepatocytes and converts them into less aggressive compounds. Thus, the process of lipid peroxidation (LPO) is interrupted and further destruction of cellular structures does not occur. At the same time, it inhibits both the formation of malondialdehyde, a marker of oxidative stress, and prevents the effect of TNF-α on the activation of reactive oxygen species, which also leads to the interruption of the LPO process. The antioxidant effect of silymarin and inhibition of lipid peroxidation reactions have been clearly demonstrated in vitro. Milk thistle flavonoids exhibit 10 times higher antioxidant activity than tocopherol.
The mechanism of the anti-inflammatory effect of silibinin is associated with its ability to inhibit the lipoxygenase pathway of arachidonic acid metabolism with suppression of the synthesis of active inflammatory mediators, especially leukotrienes B-4 in Kupffer cells. A large number of experiments have demonstrated the ability of silymarin to suppress the activation of NF-kB in cell cultures. NF-kB is a key regulator of inflammatory and immune responses, which binds to DNA and induces gene expression.
An important aspect of the metabolic action of milk thistle flavonoids is the ability to activate the synthesis of proteins and phospholipids and support the process of hepatocyte regeneration. Silibinin stimulates the activity of nuclear RNA polymerase A in hepatocytes, accelerates transcription and the rate of RNA synthesis, which, in turn, leads to an increase in the number of ribosomes and activation of the biosynthesis of structural and functional proteins.
Comparative characteristics of silymarin-containing drugs are presented in Table 7.
Hepatoprotector Legalon, obtained from milk thistle fruits, includes the maximum amount of silymarin and silibinin thanks to a patented production technology that increases the concentration of silibinin in the medicinal substrate. This makes it possible to achieve higher bioavailability compared to similar drugs, i.e., it satisfies most of the requirements for hepatoprotectors.
When taken orally, the drug Legalon quickly dissolves and enters the intestines. After absorption in the intestine through the portal vein system, 85% of silibinin enters the liver after 45 minutes and is selectively distributed in hepatocytes. In the liver, silymarin is metabolized by conjugation and does not form active metabolites. 80% of the active substance during the first passage through the liver is excreted in the bile in combination with glucuronides and sulfates. Due to deconjugation in the intestine, up to 40% of silymarin excreted in the bile is reabsorbed and enters the enterohepatic circulation. The maximum concentration in bile is 100 times higher than in plasma. The concentration of silibinin stabilizes after repeated doses, and the drug does not accumulate in the body.
The regenerative mechanism of action of Legalon is due to the possibility of forming a complex with steroid cytoplasmic receptors and is transported into the cell nucleus, where it activates RNA polymerase A. At the same time, silibinin does not affect the rate of reduplication and transcription in altered cells with a maximum level of DNA synthesis, which excludes the possibility of its proliferative actions.
FDA 1 and EMEA 2 experts approved the use of the drug Legalon as a hepatoprotective agent with a proven ability to restore the detoxification function of the liver (Table 8).

Legalon should be accompanied by drug therapy from the first days of treatment, because, according to numerous studies, an earlier start of hepatoprotective protection significantly reduces the risk of chronic disease.
The drug is advisable to use in patients with DILI with clinical and biochemical signs of activity in preventive courses if long-term use of hepatotoxic drugs (for example, cytostatics, NSAIDs, antiarrhythmic drugs, antidepressants, contraceptives, etc.) is necessary, with forced polypharmacy (a special risk group is women after 40 years). Drug therapy for patients with a history of diffuse liver diseases of any etiology or suffering from alcohol and nicotine addiction should also be carried out in combination with taking Legalon. Prophylactic use of the drug is recommended for workers in hazardous chemical industries.
Directions for use:
1. For DILI with moderately severe cytolytic syndrome: 70 mg 3 times a day for 3–4 months.
2. For severe DILI: 140 mg 3 times a day for 3–4 weeks, with a transition to maintenance doses of 70 mg 3 times a day for 3–4 months.
3. For chronic liver intoxication (drugs, industrial, household hepatotoxic compounds): 70 mg 3 times a day in courses of 3–4 months. 2–3 rubles/year.
4. If drug therapy is necessary for patients with diffuse liver diseases of any etiology: 140 mg 3 times during treatment and then 70 mg for 3–4 months.
5. For the prevention of DILI for workers in hazardous industries: 70 mg for a long time.
Treatment of DILI remains a traditionally difficult problem for practitioners. Discontinuation of a hepatotoxic drug is often impossible without creating an immediate or delayed threat to the patient's life, or without significantly deteriorating the patient's quality of life. At the same time, widely known data on the ability of liver tissue to regenerate allow us to fairly optimistically assess the prospects and potential possibilities of pathogenetic therapy of drug-induced liver damage with hepatoprotectors.

Conclusion
The liver metabolizes most drugs. In case of liver diseases of any etiology, with long-term use of drugs, polypharmacy, its ability to metabolize drugs is impaired, therefore, when they are prescribed in normal dosages, unexpected toxic reactions may occur.
The possibility of toxic effects of drugs should always be taken into account in the differential diagnosis of liver failure, jaundice, and increased transaminase levels. An isolated increase in cytolysis markers while taking medications should be treated with great caution, since this may indicate the development of drug-induced liver pathology.
Detection of drug-induced hepatitis remains one of the most difficult challenges in medicine. The diagnosis is rarely made and, as a rule, at the stage of jaundice or hepatomegaly. The range of clinical manifestations of liver diseases caused by medicinal substances is extremely diverse, these manifestations often have similarities with the “classical” forms of liver diseases. The basis of diagnosis is a carefully collected anamnesis of the medications used.
It should be borne in mind (due to the large number of oligosymptomatic DILI) that in patients receiving potentially hepatotoxic drugs, it is advisable to regularly determine the activity of aminotransferases, alkaline phosphatase and the level of bilirubin in the blood serum.
Hepatoprotective agents are used to accelerate the restoration of liver structure and function. For outpatient clinics, it is advisable to use oral forms of medications based on silymarin from the first day of drug therapy. The drug of choice among silymarin-containing hepatoprotectors is the original hepatoprotector Legalon.

1 Food and Drug Administration
drugs (FDA, Food and Drug Administration) –
government agency subordinate to the Ministry of Health
US opinions.
2 European Medicines Agency (EMEA, European
Medicines Agency) is an agency for evaluating medicinal products.
products for their compliance with the requirements set out in the European
Pharmacopoeia.

www.rmj.ru

Of course, no one takes medications specifically to cause liver damage. And even more so, doctors do not prescribe drugs for this purpose. Indications for the use of hepatotoxic drugs are usually strictly justified. This could be an infection, an autoimmune process, a pathology of the cardiovascular system, or severe pain.

The advisability of using drugs with a toxic effect on the liver is determined by the doctor after a detailed objective examination, analysis of laboratory parameters and careful collection of anamnesis. This is why it is so important to mention all concomitant and previous diseases, especially if the hepatobiliary system has already suffered previously.

For the same reason, it is important to know which medications are most aggressive towards the liver.

• Anti-tuberculosis drugs.

Isoniazid, rifampicin, streptomycin and ethambutol have a pronounced detrimental effect on the liver, and the administration of several drugs at once, as required by tuberculosis treatment protocols, seriously worsens the condition of the “filter”.

• Antibiotics:

1. Penicillins. Prominent representatives of the group of penicillin drugs that have the most pronounced hepatotoxic effect are oxacillin and amoxicillin. The harmful effects on the liver are stated in the instructions for oxacillin, but it is worth noting that if the dosage is strictly followed, side effects rarely occur. The average daily dose of the drug is 3 g, and a direct hepatotoxic effect occurs at 5-6 g/day.
2. Aztreonam, an antimicrobial drug from the monobactam group. Its side effects include hepatitis.
3. Tetracyclines. All drugs in this group have a negative effect on the liver. They can cause liver damage of varying severity, ranging from minor changes in cells to their necrosis.
4. Macrolides. In comparison with the above groups of antimicrobial agents, macrolides rarely affect the liver, and yet cholestatic hepatitis is considered an adverse reaction of drugs in this group. A classic example of liver damage is toxic hepatitis caused by taking erythromycin.

• Salicylates.

This group includes a drug that is often and uncontrollably used in everyday life as a remedy for fever, headaches, or even as an additional ingredient in preservation. This is the well-known aspirin. Other drugs from the group of salicylates are used no less widely: citramon and askofen. According to studies, more than half of patients receiving 2 g of drugs from this group per day developed areas of necrosis in the liver. Please note: a standard citramone tablet contains about 250 mg of acetylsalicylic acid; Ascophen tablet contains approximately 200 mg of salicylates, and aspirin is available in dosage forms of 100 and 500 mg.

• Non-steroidal anti-inflammatory drugs.

Despite the fact that salicylates are also anti-inflammatory drugs, the effect on the liver of diclofenac, nimesulide and coxibs (celecoxib, rofecoxib) is considered separately. The degree of liver damage varies from asymptomatic elevation of specific liver enzymes to fulminant (fulminant) liver failure. Paracetamol deserves special attention: half of the cases of fulminant liver failure are caused by taking this particular drug. For its development, 10-20 g of paracetamol is sufficient (one tablet contains from 200 to 500 mg of active substance).

• Anabolic drugs.

Oral medications, that is, tablets, are especially dangerous. More often, taking anabolic drugs leads to cholestatic hepatitis, although there have also been cases of necrotic changes in the liver.

• Antifungal medications.

These include well-known drugs for women against thrush, as well as medications for the treatment of complications after taking antibiotics: fluconazole, ketoconazole, itraconazole, amphotericin B.

• Contraceptives.

Again about women: both estrogen and progesterone, when taken orally, can cause cholestatic hepatitis.

• Cardiovascular drugs:

1. Calcium blockers - nifedipine, verapamil.
2. Angiotensin-converting enzyme inhibitors (enalapril, captopril).
3. Antiarrhythmics - procainamide, amiodarone.

• Statins.

Drugs that affect the lipid profile provoke an increase in the activity of specific liver enzymes after 2-4 weeks from the start of administration.

• Vitamins A and B.

If the regimen is not followed or the hepatobiliary system is compromised, these vitamins also have a toxic effect on the organ.

The onset of drug-induced hepatitis depends on the drug that caused organ damage, the dosage of the drug, individual sensitivity and the initial state of the hepatobiliary system. On average, the first symptoms of toxic damage appear in the first week; with fulminant forms, the process develops in a short period of time. For the development of chronic forms, long-term medication is required. Thus, amiodarone causes changes in the liver years after the start of use.

Acute drug-induced hepatitis is divided into cytolytic (in which liver cells are destroyed), cholestatic (in which the outflow of bile is disrupted) and mixed. All of them have similar symptoms, and in the laboratory they differ in the increase in the activity of different enzymes.

Symptoms of liver damage include:

• Lack of appetite.
• Nausea not associated with food intake and vomiting.
• Belching with bitterness.
• Weight loss.
• Bowel disorders (diarrhea or constipation).
• Moderate nagging pain in the right hypochondrium.
• Increased liver size.
• Pain on palpation of the right hypochondrium.
• Jaundice.
• Skin itching.
• Change in color of stool and urine.

The listed changes may be accompanied by fever and asthenic syndrome - weakness, headache, lethargy.

Drug-induced hepatitis rarely develops in people with a healthy hepatobiliary system who follow the prescribed medication regimen. On the contrary, the presence of risk factors not only doubles the chances of toxic damage, but also aggravates its severity.

Factors provoking drug-induced hepatitis include a violation of the protein composition of the blood, age-related low functional activity of the liver (children and the elderly are more susceptible to the hepatotoxic effects of drugs), kidney and liver pathology. In addition, the pathology occurs more often in women.

Alcohol consumption doubles the hepatotoxicity of medications. Thus, for the development of paracetamol liver failure for persons who abuse alcohol, taking 5-10 g of the drug is sufficient.

Every mother knows that aspirin can only be given to children over 12 years old, but not everyone knows why. The reason for this recommendation by WHO experts is that the most prominent representative of salicylates can cause the development of Reye's syndrome.

Reye's syndrome (white liver disease) is a serious condition characterized by combined brain damage and liver failure. World statistics say that 50% of cases of Reye's syndrome are fatal. Moreover, the vast majority (about 90%) of the sick were children under 15 years of age.

Symptoms of white liver disease include:

• nausea and repeated vomiting that does not bring relief;
• disturbances of consciousness of varying severity (from slight disorientation to coma);
• breathing problems, which often occur in young children;
• hepatomegaly.

How to protect yourself and your children from the effects of hepatotoxic drugs? Remember the three golden rules.

• Do not self-medicate.

The unjustified self-prescription of antibacterial drugs has been discussed repeatedly, but the uncontrolled use of the “harmless” blood thinner aspirin remains unaddressed. Any chemotherapy drug must be prescribed by a doctor taking into account the concomitant pathology.

• Provide the doctor with the most complete information about past and chronic diseases during medical history collection, as well as about the medications used.

Detailing the state of health is extremely important, because a comprehensive examination of the body before prescribing a specific medication is not advisable. At the same time, information about a previous disease can tell the doctor in which direction to conduct research. The same applies to the combination of medications: the combination of several drugs can lead to an increase or decrease in their effects.

• Strictly follow the prescribed medication dosage regimen.

The dosage of medications takes into account age characteristics and some concomitant diseases. Unauthorized excess of a single or daily dose will inevitably lead to negative consequences.

General information

Mechanisms of hepatotoxicity

There are many different mechanisms for the implementation of the hepatotoxic effect.

Direct hepatotoxicity

Drugs or toxins that exhibit true direct hepatotoxicity are those chemicals that have predictable dose-effect curve (higher doses or concentrations of a substance cause a greater hepatotoxic effect, more severe liver damage) and have well-known and studied mechanisms of hepatotoxic action, such as direct damage to hepatocytes or blockade of certain metabolic processes in the liver.

A typical example of true direct hepatotoxicity is the hepatotoxicity of acetaminophen (paracetamol) in overdose, which is associated with the saturation of its normal metabolic pathway, which has limited capacity, and the inclusion of an alternative pathway for the biotransformation of acetaminophen, which produces a toxic, highly reactive nucleophilic metabolite. At the same time, the inclusion of an alternative pathway of acetaminophen biotransformation in itself does not lead to liver damage. Direct damage to hepatocytes results from the accumulation of the toxic metabolite acetaminophen in such quantities that it cannot be effectively neutralized by binding to glutathione. At the same time, glutathione reserves in the liver are depleted, after which the reactive metabolite begins to bind to proteins and other structural elements of the cell, which leads to its damage and death.

Direct hepatotoxicity usually occurs shortly after a certain “threshold” level of toxic substance concentration in the blood or a certain duration of toxic exposure has been reached.

Metabolism of drugs in the liver

Many common drugs are metabolized in the liver. This metabolism can vary significantly between individuals due to genetic differences in the activity of drug biotransformation enzymes.

UDC 616-099 BKK 52.8

HEPATOTOXIC EFFECTS OF ANTIRETROVIRAL THERAPY - MYTH OR

REALITY (REVIEW ARTICLE)

SITDIKOV I.I., MOSKALEVA A.V., VLASOVA T.I. Federal State Budgetary Educational Institution of Higher Education "MSU named after N.P. Ogarev", Saransk, Russia e-mail: vudi.95@,mail.ru

annotation

The problem of hepatotoxicity of antiretroviral therapy (HAART) in HIV-infected patients and patients with HIV/HBV (HCV) coinfection remains debated. It was found that HAART in patients with coinfection reduces the progression of liver fibrosis and the likelihood of developing liver failure in people with this pathology. To achieve the best treatment outcome, timely detection of HIV/HBV(HCV) coinfection and early initiation of HAART in accordance with recommended treatment regimens are necessary.

Key words: HIV infection, HIV/HBVHCV infection), hepatotoxicity, liver fibrosis, HAART.

Relevance. Despite significant progress in the field of science and medicine, the problem of HIV infection in the population today, unfortunately, remains extremely relevant. HIV remains a major global public health problem, having claimed more than 35 million lives to date. In 2016 alone, approximately 1.0 million people died from HIV-related causes worldwide. According to the World Organization

At the end of 2016, there were approximately 36.7 million people living with HIV worldwide, and 1.8 million people acquired HIV infection in 2016. In addition, it is worth noting that most patients have

concomitant pathology - viral hepatitis B and/or C, which is explained by their similar transmission routes. Moreover, the statistics on the incidence of viral hepatitis are even more impressive - according to new data from the World Health Organization, an estimated 325 million people in the world live with chronic infection caused by the hepatitis B virus (HBV) or hepatitis C virus (HCV). Co-infection with HIV/HBV or HIV/H^ represents a serious problem in terms of prognosis and survival of patients, which requires careful selection of tactics and treatment methods. The question remains open

hepatotoxicity of antiretroviral

drugs, especially in conditions of co-infection in the body.

Goal of the work. Based on an analysis of literature data, to assess the current state of the problem of hepatotoxicity of retroviral therapy in HIV-infected patients and patients with HIV/HBV (HCV) coinfection.

Research results. One of the problems in the modern course of co-infection with HIV/HIV and HIV/HIV is liver damage such as liver fibrosis, followed by liver failure, leading to death. Patients with coinfection experience more rapid progression of liver fibrosis, which is caused by both the hepatotoxicity of hepatitis C or B virus and the hepatotoxicity of the human immunodeficiency virus. HIV has been shown to significantly alter the course of viral hepatitis B and C, increasing viremia levels in these infections, especially during the period of seroconversion. A 2- to 8-fold increase in viremia levels significantly increases the risk of infection

vertically and during sexual intercourse. HIV infection aggravates the histological course of viral hepatitis, increasing the risk of developing and accelerating the course of cirrhosis, liver failure and

hepatocellular carcinoma. These phenomena are explained by earlier progression

fibrosis in persons with co-infection, which correlates with the number of CD4+ T-lymphocytes (less than 200 cells per 1 ml). Mechanisms of accelerated progression of chronic hepatitis C in HIV-infected individuals may include both direct effects of the virus and immunological disorders, in particular increased apoptosis or suppression of the specific T-cell response to HCV. In addition, HIV causes increased secretion of cytokines (interleukins 4, 5 and 13, transforming growth factor b), which increase liver inflammation and fibrosis. Causes of damage to liver tissue can also be increased apoptosis of hepatocytes or the accumulation of cytotoxic CD8 T lymphocytes in the liver and their release of tumor necrosis factor a, which causes liver fibrosis. Recently, it was shown that HIV is capable of replication in hepatocytes and hepatic stellate cells and causes increased collagen expression and the secretion of proinflammatory cytokines.

It is worth noting that various literature sources provide evidence that antiretroviral therapy itself can lead to the progression of liver fibrosis and, as a consequence, liver failure in patients with HIV infection. For example, a number of foreign researchers highlight several

mechanisms of hepatotoxicity

antiretroviral drugs: (1) mitochondrial damage during treatment with nucleoside analogues; (2) hypersensitivity reactions (nevirapine,

efavirenz, abacavir); (3) direct hepatotoxic effect (ritonavir in full doses); (4) restoration of immune function in patients with severe immunosuppression. Nucleoside analogues may contribute to the development of hepatic steatosis, which is often observed in HIV-infected patients. Steatohepatitis accelerates the progression of liver fibrosis in patients with chronic HCV infection. The incidence of liver steatosis is higher in patients with genotype 3 of the virus, which is often found in HIV-infected drug addicts, which may be one of the explanations for the accelerated development of liver fibrosis and higher

frequency of hepatotoxicity of drugs.

With HIV/HBV coinfection, progressive liver fibrosis is also observed, which is caused both by the effect of the hepatitis B virus on hepatocytes mediated through the patient’s immune system, and by the effects of HIV and the hepatotoxicity of antiretroviral drugs.

Thus, taking into account the duration of necessary therapy (lifelong use of drugs) for HIV infection, as well as the proven hepatotoxicity of antiretroviral therapy and the deterioration of the general condition in patients with mixed infection, the problem of using antiretroviral drugs against the background of HIV/HCV and HIV/HBV co-infection in patients in need of this treatment.

Undoubtedly, to increase

To lengthen and improve the quality of life of patients, it is necessary to carry out combination rational therapy for both HIV infection and chronic viral hepatitis. However, given the side effects, in particular the hepatotoxicity of antiretroviral therapy, the question arises: how to prevent the occurrence of

undesirable effects of therapy and not harm the patient and, at the same time, provide him with the necessary full assistance.

Antiretroviral drugs have high hepatotoxicity, as evidenced by many domestic and foreign studies. It should be noted that hepatotoxicity of nucleoside reverse transcriptase inhibitors, which are the main first-line antiretroviral drugs and are part of the vast majority of combination highly active antiretroviral therapy, is quite rare. It has been reliably proven for zidovudine, didanosine and stavudine and manifests itself in the form of hepatomegaly, increased activity of liver enzymes (mainly ALT and AST) and/or lactic acidosis. Abacavir and lamivudine can also cause similar effects, but to a much lesser extent. The zidovudine + didanosine and stavudine + didanosine regimens should be avoided. Hepatotoxicity

Non-nucleoside reverse transcriptase inhibitors are associated in most cases with nevirapine. Risk of developing liver damage

When taking nevirapine, it differs between men and women. In addition, it is highly dependent on the level of CD4+ T-lymphocytes at the time of treatment. Nevirapine is not used in women if at the start of treatment the level of CD4+ T-lymphocytes is above 250 cells/μl, and is not used in men if at the start of treatment the number of CD4+ T-lymphocytes is more than 400 cells/μl. It is worth noting that if we are not talking about starting treatment, but about replacing some other drug with nevirapine, then the level of CD4+ T lymphocytes does not play an important role in terms of the risk of side effects, especially if the viral load is no longer detectable. There is also minimal risk if nevirapine is added as an additional drug to an existing regimen for any reason. However, there are also cases of death while taking nevirapine. Protease inhibitors have mild hepatotoxicity, but high doses of ritonavir (more than 1000 mg per day) may be more toxic than other protease inhibitors. It should also be noted that the hepatotoxic effect of protease inhibitors can manifest itself at any period of treatment, in contrast to non-nucleoside reverse transcriptase inhibitors, in which it manifests itself in the first weeks of treatment. However, despite the high incidence of hepatoxicity with highly active antiretroviral therapy, treatment does not cause severe liver damage in almost 90% of patients, regardless of the presence of liver damage. The development of hepatotoxicity to the listed drugs is based on various pathogenetic mechanisms, which is also reflected in the timing of its occurrence. Thus, the basis of the hepatotoxicity reaction to nucleoside reverse inhibitors is mitochondrial toxicity. The onset of this pathology reaches 6 months or more from the start of therapy. Histologically, signs of fatty liver are determined. Non-nucleoside reverse transcriptase inhibitors often cause hypersensitivity reactions in the first 12 weeks of treatment. Pathological reactions to atazanavir and indinavir are based on liver enzyme inhibition

glucuronyl transferase, which leads to an increase in serum bilirubin levels. This condition occurs almost

47% of patients receiving these drugs. Of these, less than 2% stop treatment. Hyperbilirubinemia is usually asymptomatic and clinically resembles Gilbert's syndrome. However, if hyperbilirubinemia manifests itself as clinically significant jaundice, it can cause difficulty communicating with other people and interfere with daily life. After discontinuation of the drug, bilirubin levels normalize.

However, scientific progress in the field of medicine, including in the field of treatment of HIV infection, does not stand still. According to the updated recommendations of the European AIDS Clinical Society (EACS) for the treatment of HIV infection from October 2017, drugs with a high

hepatotoxicity, namely zidovudine, stavudine, didanisine, nevirapine and some others, are currently excluded from the main regimens of highly active

antiretroviral therapy. Currently, it is advisable to use the following treatment regimens:

2 nucleoside reverse transcriptase inhibitors + integrase inhibitor:

Abacavir/lamivudine/dolutegravir

Tenofovir alafenamide (TAF)/emtricitabine or tenofovir disoproxil fumarate (TDF)/emtricitabine + dolutegravir

TAF/emtricitabine/elvitegravir/cobicistat or TDF/emtricitabine/elvitegravir/cobicistat

TAF/emtricitabine or TDF/emtricitabine + raltegravir

2 nucleoside reverse transcriptase inhibitors + non-nucleoside reverse transcriptase inhibitor:

TAF/ emtricitabine/ rilpivirine

TDF/ emtricitabine/ rilpivirine

2 nucleoside reverse transcriptase inhibitors + protease inhibitor:

TAF/emtricitabine or TDF/emtricitabine + darunavir/cobicistat or darunavir/ritonavir

The above treatment regimens include drugs that do not have reliably proven hepatotoxicity both in patients with isolated HIV infection and in patients with HIV/HBV and HIV/HCV coinfection. In addition, there is evidence that highly active antiretroviral therapy with these drugs in patients with mixed

infection, on the contrary, leads to a statistically significant decrease in mortality from progressive liver disease due to its inherent antifibrotic effect. Combination antiretroviral therapy has been shown to attenuate hepatic extracellular matrix remodeling in patients with HIV infection. Also, it should be noted that the drugs included in combination antiretroviral therapy can significantly reduce the severity of liver fibrosis in patients with HIV/HBV and HIV/HCV co-infection. For example, lamivudine, used in the main treatment regimens for HIV infection, is also one of the main drugs used to treat viral hepatitis B. It is able to suppress viral replication and significantly reduce the viral load, thereby slowing the progression of liver fibrosis, and with prolonged use of the drug - reduce the severity of pathological changes in the liver and lead to partial regression of liver fibrosis.

A successful response to antiretroviral therapy among HIV/HCV coinfected patients is associated with an increase in the cellular immune response to hepatitis C virus, a decrease in hepatitis C virus RNA levels, and elimination of this pathogen. In this regard, in case of coinfection, it is recommended to start antiretroviral therapy in the early stages of HIV infection. Initiating treatment for HIV infection before a significant drop in the number of CD4+ T lymphocytes allows one to maintain a specific immune response to the hepatitis C virus and prevent the progression of liver fibrosis. Application

antiretroviral therapy in

coinfected patients reduces the possibility of liver decompensation and death. It is worth noting that the progression of liver fibrosis in patients with HIV/HCV coinfection is largely determined by the order of infection of patients with these pathogens. It has been proven that liver fibrosis takes on a progressive nature much more often in cases where HIV enters the body earlier than the hepatitis C virus. This category of patients is classified as a high-risk group for the progression of liver fibrosis, while patients in whom the virus was the first pathogen

hepatitis C, constituted the lowest risk group. Thus, when assessing the risk factors for progressive liver fibrosis in patients co-infected with HIV/HCV, one should take into account the patient’s antiretroviral therapy, the combination of drugs for antiretroviral therapy, and, if possible, the order in which viral pathogens enter the patient’s body. There is evidence that the very fact of taking antiretroviral therapy significantly increases the likelihood of a regressive course of fibrotic changes in the liver, while the most favorable for the development of a fibrotic process in the liver is a treatment regimen in which reverse transcriptase inhibitors are combined with protease or integrase inhibitors. In the latter case, if infection with viral hepatitis C occurred earlier than HIV, progressive liver fibrosis is not observed at all. In the study by A.V. Kravchenko "Modern schemes

antiretroviral therapy" from 2016 also shows that the use of raltegravir in therapy for patients with HIV infection and chronic hepatitis C, which is also included in modern treatment regimens for HIV infection, has convincingly shown a decrease in the hepatotoxicity of the antiretroviral therapy regimen and an improvement in blood lipid parameters.

When choosing antiretroviral drugs in patients with chronic hepatitis B, two nucleoside reverse transcriptase inhibitors active against viral hepatitis B should be prescribed, primarily tenofovir in combination with lamivudine or emtricitabine. In patients with normal or slightly increased (less than 2.5 normal) ALT activity, it is recommended to combine them with efavirenz, and in patients with higher ALT activity - with protease inhibitors boosted with raltegravir. Among protease inhibitors, lopinavir or atazanavir are usually preferred.

Conclusions. Modern rational highly active antiretroviral therapy of patients with HIV/HCV and HIV/HBV co-infection not only does not increase the incidence of liver damage, but also significantly reduces the progression of liver fibrosis by reducing the viral load, and, therefore, reduces the likelihood of developing liver disease.

the future of liver failure in patients with this pathology. To achieve the best treatment outcome and improve the prognosis and quality of life of patients, timely detection of HIV/HCV co-infection and

HIV/HBV and immediate initiation of effective combination therapy

highly active antiretroviral therapy in accordance with recommended treatment regimens.

Bibliography

1. Abdurakhmanov D.T. Antiviral therapy and regression of liver fibrosis in chronic hepatitis B / D.T. Abdurakhmanov //Russian Journal of Gastroenterology, Hepatology, Coloproctology. - 2010. - T. 20., No. 1. - P. 1420.

2. Antiretroviral therapy and the risk of progression of liver fibrosis in patients coinfected with HIV/HCV / M.S. Aristanbekova [and others]//Medical news of Georgia. - 2017. - No. 5. - P. 58-63.

3. Antiretroviral therapy: the most common side effects /M. Dotsenko [and others] // Recipe. - 2007. - No. 4.

4. Viral hepatitis: Clinic, diagnosis, treatment / N.D. Yushchuk [and others]. - M.: GEOTAR - Media, 2012. -117 p.

5. HIV/AIDS/WHO Media Center //Information Bulletin. - 2017.

6. Kizhlo S.N. Combination of antiviral therapy for chronic viral hepatitis and HIV infection / S.N. Kizhlo, S.Yu. Romanova //HIV infection and immunosuppression. - 2011. - No. 3. - P. 88-93.

7. Kravchenko A.V. Modern regimens of antiretroviral therapy /A.V. Kravchenko //Medical Council. - 2016.

- No. 17. - pp. 84-89.

8. Moiseev S.V. Chronic hepatitis B in HIV-infected people / S.V. Moiseev, S.L. Maksimov, D.T. Abdurakhmanov //Clinical pharmacology and therapy. - 2014. - No. 23. - P. 5-12.

9. New data on hepatitis shows the need for urgent global action / WHO Media Center // WHO News Release. - 2017.

10. Features of liver damage in HIV infection / E.V. Kolesnikova // Suchasna gastroenterology. - 2008. -№5. - P. 100-104.

12. Antiretroviral therapy and sustained virological response to HCV therapy are associated with slower liver fibrosis progression in HIV-HCV-coinfected patients: study from the ANRS CO 13 HEPAVIH cohort / M.A. Loko//Antivir. Ther.

2012. - Vol. 17, no. 7. - P. 1335-1343.

13. Blackard J. HCV/ HIV co-infection: time to re-evaluate the role of HIV in the liver? / J. Blackard, K. Sherman // J. Viral Hepat. - 2008. - Vol. 15, No. 5. - R. 323-330.

14. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel / V. Soriano // J. AIDS. - 2007. - No. 21. - R. 1073-1089.

15. Clavel F. HIV Drug Resistance / F. Clavel, A.J. Hance // NEJM. - 2004. - Vol. 350, No. 10. - P. 1023-1035

16. Combined antiretroviral therapy attenuates hepatic extracellular matrix remodeling in HIV patients assessed by novel protein fingerprint markers / J. Diana et al.] // J. AIDS. - 2014. - Vol. 28, No. 14. - R. 2081-2090.

17. HIV-specific T-cells accumulate in the liver in HCV/HIV co-infection /B. Vali //PLoS One. - 2008. - Vol. 3, No. 10.

18. Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for thepathogenesis of HIV/hepatitis C virus-induced liver fibrosis / A. Tuyama //Hepatology. - 2010. - Vol. 52, No. 2. - R. 612-622.

19. Influence of genotype 3 hepatitis C coinfection on liver enzyme elevation in HIV-1-positive patients after commencement of a new highly active antiretroviral regimen: results from the EPOKA-MASTER cohort / C. Torti et al.] // J. AIDS . - 2006. -№41. - R. 180-185.

20. Kim A. Coinfection with HIV-1 and HCV - a one-two punch / A. Kim, R. Chung // Gastroenterology. - 2009. - Vol.137, No. 3. - R. 795-814.

21. Liver fibrosis in HIV-infected individuals on long-term antiretroviral therapy: associated with immune activation, immunodeficiency and prior use of didanosine / W. Katherine [et al.] // J. AIDS. - 2016. - Vol. 30, no. 11. - R. 17711780. " "

22. Operskalski E. HIV/HCV m-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies / E. Operskalski, A. Kovacs // Curr. HIV/AIDS Rep. - 2011. - No. 8. - R. 12-22.

23. Piroth L. Liver steatosis in HIV-infected patients / L. Piroth //AIDS Rev. - 2005. - No. 7. - R. 197-209

24. Roe B. Cellular and molecular interactions in coinfection with hepatitis C virus and human immunodeficiency virus / B. Roe, W. Hall //Expert Rev. Mol. Med. - 2008. - No. 10. - P. 30."

HEPATOTOXIC EFFECTS OF ANTIRETROVIRAL THERAPY - MYTH OR REALITY

(REVIEW ARTICLE)

SITDIKOV I.I., MOSKALEVA A.V., VLASOVA T.I. MRSU, Saransk, Russia e-mail: [email protected]

The problem of hepatotoxicity of ART in patients with HIV and HIV /HBV(HCV) co-infection remains controversial. HAART has been shown to reduce the risk of progression of liver fibrosis and development of hepatic impairment. To improve the prognosis and quality of life of patients is necessary the timely identification of HIV / HBV(HCV) co-infection and early initiation of HAART should be made in accordance with recommended treatment regimens.

Keywords: HIV infection, coinfection of HIV / HBV (HCV), hepatotoxicity, liver fibrosis, HAART.