Use potentially dangerous hepatotoxic agents. Hepatotoxic reactions and hepatoprotective therapy in phthisiology

Hepatotoxic action is the ability of chemical compounds to negatively affect the function and anatomical structure of liver tissues. In the outside world, there are a huge number of substances that in one way or another affect the hepatic parenchyma.

However, only those compounds are considered hepatotoxic, the threshold of sensitivity of hepatocytes to which is lower than to other substances. Aliphates, halogens, cyanides, metals and their salts, bacterial and viral toxins, and some drugs have the strongest effect on the body.

For example, the hepatotoxicity of statins is still the cause of controversy regarding the need for their use in clinical practice. So, what is the hepatotoxic effect of chemicals? What is it and what does it lead to?

The liver is one of the organs involved in the transformation and excretion of the toxicant.

The transformation of chemicals consists of two stages:

• formation of an intermediate product;
• formation of a conjugate suitable for excretion.

During the first stage of metabolism, hepatotoxic drugs and substances attach a polar functional group to themselves, which makes them more water-soluble. Next, the resulting compounds are conjugated with endogenous molecules, after which the resulting polar compounds are captured by hepatocytes and excreted into the bile with the help of multifunctional transport proteins. After that, the toxicant enters the intestines and is excreted in the stool.

In the process of conversion, the toxicity of xenobiotics may change. Some substances are neutralized and become harmless, the dangerous properties of others only increase. In some cases, active metabolites become the initiators of the pathological process or change the type of negative impact.

Hepatotoxic substances most strongly affect the liver tissue. In the process of their transformation, hepatocytes are exposed to extremely negative effects. In this case, the function of both the cells of the organ themselves (impact at the cellular level) and the mechanisms of bile secretion (functional disorders) can be disrupted.

Main impacts

Toxic hepatopathy can manifest itself in a cytotoxic or cholestatic form.

Cytotoxic effects can have the following manifestations:

1. Steatosis (toxic hepatosis) - fatty degeneration of hepatocytes, accumulation of excess lipids in them. One of the first manifestations of the toxic effects of chemicals. As a rule, it develops with regular intake of ethyl alcohol, steroid hormones, tetracycline. The cause of steatosis is a violation of lipid metabolism in the cells of the organ, as well as increased intake of fatty acids in the liver.
2. Necrosis is the death of liver cells. It develops under the influence of acetaminophen, carbon tetrachloride. May be focal or total. In the first case, a limited area of ​​\u200b\u200bthe organ is affected, in the second - all or almost all of its volume.
3. Fibrosis is the formation of collagen strands in the liver instead of healthy tissues. This disrupts the hepatic blood flow, the process of bile separation. One of the substances that cause fibrosis is trichloroethane.
4. Toxic hepatitis is an inflammation of the liver tissues, which is the result of the irritating action of poisons.
5. Cirrhosis is structural and functional changes in the liver caused by exposure to a toxicant and accompanied by the formation of fibrous septa, regeneration nodes, and restructuring of the vascular system.
6. Carcinogenesis - malignancy of hepatocytes with the formation of a malignant tumor. It develops against the background of cirrhosis with regular use of ethyl alcohol, methotrexate, arsenic (see), thorium dioxide.

Cholestatic effects of hepatotoxic substances are manifested in the following forms:

1. Violation of bile secretion by blocking the mechanisms of its formation.
2. Violation of the outflow of bile due to blockage of the bile ducts, a decrease in their tone or dysfunction of the microvilli.

Unlike cytotoxic effects, hepatotoxic reactions of the cholestatic type are usually reversible. The function of the liver, gallbladder and biliary tract is restored some time after the end of the action of the toxicant.

Interesting to know: a hepatotoxic effect also develops with some allergic reactions. In this case, the formation of an eosinophilic infiltrate in the liver tissues occurs. Pathology occurs 1-5 weeks after repeated contact with the allergen.

Clinical manifestations of hepatotoxic processes

The clinical picture in toxic lesions of hepatocytes depends on the specific type of pathological process and the severity of its course. In addition, the degree of damage to the organ and the duration of the disease are important.

Steatosis

Steatosis is one of the safest forms of liver damage. It is distinguished by a stable course and the absence of a pronounced clinical picture. In patients suffering from toxic hepatosis, the doctor notes heaviness in the area of ​​\u200b\u200bthe diseased organ, weak pulling pain after physical exertion and heavy meals, increased fatigue, nausea, and weakness.

An objective examination of patients reveals mild hepatomegaly, the brightness of the liver tissue due to its fatty diffuse infiltration. The clinic intensifies with the development of steatohepatitis (inflammatory process) and fibrotic changes. With continued entry of the toxicant into the liver, the transition of steatosis to cirrhosis is possible.

Necrosis

The primary symptoms of developing hepatic tissue necrosis and focal necrosis are:

• nausea;
• vomit;
• bitterness in the mouth;
• pain in the hypochondrium on the right;
• jaundice.

As the process develops, the symptoms of the disease also increase. Hepatotoxic drugs that cause liver necrosis are the cause of acute liver failure, hepatic encephalopathy, coma and death of the patient.

Until the moment of falling into a coma, the patient has inadequate behavior, tremor of the limbs, pain intensifies and begins to radiate to the lower back. Swelling of the liver develops, the organ increases in size and begins to compress the surrounding tissues. Due to the accumulation of toxic metabolic products in the body, brain tissue is irritated, which leads to its edema.

Fibrosis

At the initial stage of the formation of collagen strands, the patient has increased fatigue, an inability to endure high psychological and physical stress, and a general deterioration in well-being. Further, the clinic progresses.

The patient's immune defense level decreases, spider veins form on the skin, and anemia develops. There are violations of the digestive processes.

The diagnosis is made on the basis of ultrasound data, gastroscopy, coprogram. Ultrasound examination reveals the presence of strands. With gastroscopy, dilated veins of the esophagus become visible. These coprograms indicate a decrease in the quality of food processing and the presence of its undigested residues in the feces.

Toxic hepatitis

Develops suddenly. The onset of the disease is characterized by an increase in body temperature up to 38 ° C and above, signs of intoxication, severe pain in the right hypochondrium. Further, the patient has vascular disorders, the appearance of pinpoint hemorrhages on the skin, and blood clotting disorders. There may be bleeding from the nose, gums, unhealed skin defects.

In severe cases, the patient develops jaundice. The stool becomes light in color, the urine resembles dark beer in color. Development of the phenomena of toxic encephalopathy is possible.

Such patients are not aware of the surrounding reality, are not aware of their actions, are aggressive and inadequate. Instructions for assistance require soft fixation of patients with toxic encephalopathy to the bed.

cirrhosis

Patients with cirrhosis of the liver, who have been using hepatotoxic substances for a long time, note increased fatigue and nervousness. Objectively, they revealed the presence of spider veins, palmar erythema. The sclera are icteric, there is jaundice, itching of the skin, nosebleeds periodically occur.

According to ultrasound data, the liver of such patients is enlarged and protrudes beyond the edge of the costal arch by 1-2 centimeters. There is also an enlargement of the spleen. Body temperature may be normal or elevated to subfebrile values. In some cases, hepatosplenomegaly does not develop.

Crayfish

The first stage of the disease is asymptomatic. However, the cancer progresses rapidly, therefore, after 3-4 weeks from the onset of the disease, the patient's liver increases in size, the first symptoms of its damage appear:

• bitterness in the mouth;
• pain in the right hypochondrium;
• jaundice;
• bleeding;
• nervousness;
• tremor of the limbs;
• vascular network on the skin;
• indigestion.

As the tumor develops, the symptoms also increase. Ascites, obstruction of the biliary tract, signs of impaired blood supply to the liver join the existing signs. The patient is emaciated, rapidly losing weight, refuses to eat.

If you compare photos of such people before and after the onset of the disease, it becomes noticeable how much they lost weight in a short period of time. In the presence of metastases, signs of damage to other organs and systems join the existing clinical picture.

On a note: liver cancer is an almost incurable pathology, which leads to the death of the patient in a short time. Modern methods of cytostatic therapy can somewhat prolong human life, but the five-year survival threshold is reached by no more than 60% of such patients.

Principles of treatment

The basis of the therapy of pathology is the termination of the action of the toxicant. This measure alone can improve the prognosis for the disease.

For example, according to the second volume of the monograph "Internal Diseases" authored by Professor and Academician of the Russian Academy of Sciences N.A. Mukhina, the five-year survival rate of patients with alcoholic cirrhosis is 30% if they continue to drink alcohol, and 70% if they refuse alcoholic beverages.

In addition to alcohol, you should stop taking hepatotoxic antibiotics, which include:

• amoxiclav;
• oxacillin;
• rifampicin.

If it is necessary to carry out antibiotic therapy, the patient should be prescribed non-hepatotoxic antibiotics, the metabolism of which occurs without the participation of the liver:

• cefdinir;
• cefuroxime;
• cephalexin.

In addition to avoiding the use of liver toxins, diet matters. In liver diseases, high-calorie nutrition (up to 3000 kcal / day) is recommended.

At the same time, the amount of protein and vitamins in food should be increased, fats should be reduced. It is permissible to use high-protein enteral mixtures such as Nutrison protison or Nutrison energy, but their price is quite high (about 800 rubles per 1 liter of product).

Drug therapy depends on the type of pathology. The main treatment regimens are shown in the following table:

Forecasts

Forecasts for toxic hepatopathy directly depend on the severity of the course of the disease, the type of exposure, the presence or absence of the ongoing action of the toxicant. Fibrosis and steatosis are reversible processes. The prognosis for them is favorable if the patient follows the recommendations for treatment and diet. The situation is similar with toxic hepatitis.

Cirrhosis and liver cancer have extremely unfavorable prognoses. A huge number of patients suffering from these diseases die after 2-3 years from the start of the process. The rapid variant of the course can kill the patient in a few weeks or months.

A liver transplant can save the life of a cirrhotic patient. However, it is impossible to perform this operation for everyone who needs it due to the lack of donor organs and the high cost of such treatment.

With cancer in the stage of metastasis, transplantation does not make sense. Cytostatic therapy allows to somewhat slow down the growth of the tumor and prolong the life of the patient. However, it is only palliative in nature. You can learn more about what toxic liver damage is and how it manifests itself from the video in this article.

It is known that many pharmacological drugs have a so-called dual action. On the one hand, they effectively cope with the disease, on the other hand, they negatively affect the work of many organs, in particular, the liver. Thus, after prolonged or unreasonable use, for example, cytostatics, antibiotics or certain other drugs increased risk of drug-induced hepatitis. Diagnosis and effective treatment of drug-induced hepatitis require a careful approach.

Without appropriate treatment, long-term drug-induced liver injury can lead to liver fibrosis, liver tumors, or liver failure. Treatment of drug-induced hepatitis is carried out by specialists of the multidisciplinary medical clinic EXCLUSIVE on the basis of their own day hospital or, at the request of the patient, on an outpatient basis. In the course of therapy, safe for the patient and most effective methods of treatment and appropriate medications, which provides a positive result in the shortest possible time.

Major hepatotoxic drugs and hepatotropic poisons

medicinal product	The mechanism of the damaging effect of the drug	Type of damage and notes
Azathioprine	Predominantly the 3rd zone of the hepatic acinus, cholangiocytes of the intrahepatic bile ducts, endotheliocytes of the terminal (central) hepatic venules of the 3rd zone of the hepatic acinus and interlobular hepatic veins. Leads to disruption of the process of transporting bilirubin from hepatocytes (parenchymal-tubular cholestasis) and difficulty in venous outflow from the liver	Obliterating endophlebitis of the hepatic veins. Peliosis and perisinusoidal fibrosis. Veno-occlusive disease. Postsinusoidal portal hypertension. Budd-Chiari Syndrome
Azithromycin	Has a direct toxic effect on hepatocytes
Aztreonam	Leads to disruption of the process of transporting bilirubin from hepatocytes (parenchymal-tubular cholestasis)	Mixed (raising levels activity of ALT, AST, alkaline phosphatase and total bilirubin)
Allopurinol	Causes macrophage and lymphoid infiltration of the hepatic lobules
Amiodarone	It has a direct toxic effect on hepatocytes, in some cases - on cholangiocytes of the intrahepatic bile ducts. Causes fatty liver disease	Hepatocellular (rise in the levels of ALT and AST activity), in some cases -. Steatohepatitis (phospholipidosis)
Amitriptyline	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, leads to disruption of the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis)
Amoxicillin with clavulonic acid (amoxiclav)	It causes immune-mediated (immunoglobulin E) damage to cholangiocytes of the intrahepatic bile ducts (the cytotoxic response is directed to the components of the cholangiocyte membrane). It leads to disruption of the process of transporting bilirubin from hepatocytes	Cholestatic (rise in levels of alkaline phosphatase and total bilirubin). Fever, skin rash, eosinophilia
Ampicillin	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Amphetamine	Causes dystonia of intrahepatic vessels, leading to ischemic damage to hepatocytes of the 3rd zone of the hepatic acinus and cholangiocytes of the interlobular bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Amphotericin B	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Anabolic steroids	On cholangiocytes of the intrahepatic bile ducts, they lead to a disruption in the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis). They cause focal expansion of the sinusoids of the 1st zone of the hepatic acinus. They have an oncogenic effect, increase the risk of developing hepatocellular cancer, adenoma and angiosarcoma of the liver	Cholestatic (rise in levels of alkaline phosphatase and total bilirubin). Peliosis and perisinusoidal fibrosis. With prolonged (more than 12 months) administration, sinusoidal portal hypertension may develop.
Androgens	They have a direct toxic effect on the cholangiocytes of the intrahepatic bile ducts, lead to disruption of the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis). They have an oncogenic effect, accelerate the formation of various liver tumors	cholestatic (rise activity levels of alkaline phosphatase and total bilirubin). Peliosis and perisinusoidal fibrosis (sinusoidal portal hypertension)
Acetaminophen (paracetamol)	At high doses (>140 mg/kg) causes accumulation of a toxic metabolite N-acetyl- p-benzoquinone, which affects hepatocytes and leads to necrosis of the 3rd zone of the hepatic acinus. Causes fatty liver disease	Hepatocellular (rise in the levels of ALT and AST activity). Macrovesicular steatosis
Acetylsalicylic acid (aspirin)	In combination with macrophage-lymphoid infiltration of the hepatic lobules	microvesicular steatosis. Liver granulomatosis
Baclofen	Has a direct toxic effect on the membranes of hepatocytes and intracellular organelles	Hepatocellular (transient rise in ALT and AST activity levels)
Valproic	It has a direct toxic effect on hepatocytes. Violates the process of mitochondrial cellular respiration in hepatocytes (mitochondrial cytopathy), beta-oxygenation leads to lactic acidosis and intracellular accumulation of triglycerides. Causes fatty degeneration of the liver (small-drop obesity of hepatocytes of the 1st zone and necrosis of hepatocytes of the 3rd zone of the hepatic acinus)
Verapamil	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, disrupts the process of transporting bilirubin from the hepatocyte	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Acute drug-induced hepatitis
Vincristine
Vitamin A	With prolonged (many months) intake, it causes hyperplasia of fat-storing Ito cells. Activates arrow-shaped cells, accelerates fibrogenesis	Fibrosis of the liver. Presinusoidal and sinusoidal portal hypertension
	Up to bridge-like necrosis of the 3rd zone of the hepatic acinus. With repeated use (especially in overweight women), it can lead to the development of massive liver necrosis and fulminant liver failure.	Hepatocellular (rise in the levels of ALT and AST activity). Acute toxic hepatitis. Fever, skin rash, eosinophilia
Glucocorticosteroids	May lead to hepatic steatosis	Macrovesicular steatosis
genus Amanita	They have a direct toxic effect on hepatocytes of the 3rd zone of the hepatic acinus (pronounced focal or confluent necrosis and fatty degeneration of hepatocytes)	Hepatocellular (rise in the levels of ALT and AST activity). Acute toxic hepatitis
Griseofulvin	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Josamycin	Has a direct toxic effect on hepatocytes	Hepatocellular (rise in ALT and AST activity levels)
Diazepam	Causes macrophage and lymphoid infiltration of the hepatic lobules	Liver granulomatosis
diclofenac (voltaren)	Hepatotoxic effect is realized by the type of idiosyncrasy or allergy (mainly in women)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Serum can detect antinuclear antibodies
Diltiazem	It has a direct toxic effect on the membranes of hepatocytes and intracellular organelles. Causes macrophage and lymphoid infiltration of the hepatic lobules	Hepatocellular (rise in the levels of ALT and AST activity). Liver granulomatosis
Doxycycline	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, can lead to disruption of the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Doxorubicin	It has a direct toxic effect on endotheliocytes of terminal hepatic venules and interlobular veins, hinders venous outflow from the liver	Obliterating endophlebitis of the hepatic veins, veno-occlusive disease. Postsinusoidal portal hypertension
Zidovudine	Violates the process of mitochondrial cellular respiration in hepatocytes (mitochondrial cytopathy), beta-oxygenation leads to lactic acidosis and intracellular accumulation of triglycerides. Causes fatty liver disease	Microvesicular steatosis
ibuprofen	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Isoniazid	In the liver, it undergoes the process of acetylation, resulting in the formation of a powerful metabolite (acetylating substance), which has a direct toxic effect on hepatocytes, up to bridge-like necrosis. Possible development of massive liver necrosis and fulminant hepatic insufficiency. Metabolite accumulation causes macrophage and lymphoid infiltration of baked lobules	Hepatocellular (rise in the levels of ALT and AST activity). Acute drug-induced hepatitis. With prolonged use - chronic active drug-induced hepatitis. Liver granulomatosis
Isoflurane	Causes immune-mediated (immunoglobulin E) damage to hepatocytes (cytotoxic response is directed to hepatocyte membrane components)
Captopril	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, leads to disruption of the process of transporting bilirubin from hepatocytes (“inflammatory” cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Carbamazepine	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, leads to necrosis of hepatocytes with the formation of granulomas, disrupts the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Liver granulomatosis
Caspofungin	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, disrupts the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Ketoconazole (nizoral)	With prolonged use (for more than 10 days), an idiosyncratic reaction develops, hepatocytes are affected mainly in the 3rd zone of the hepatic acinus (up to bridging necrosis). Possible development of massive liver necrosis and fulminant liver failure	Hepatocellular (rise in ALT and AST activity levels)
Ketoprofen	Violates the process of mitochondrial cellular respiration in hepatocytes (mitochondrial cytopathy), beta-oxygenation leads to lactic acidosis and intracellular accumulation of triglycerides. Causes fatty liver disease	Microvesicular steatosis
Clarithromycin
Clindamycin	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
	It undergoes the process of N-methylation with the participation of cytochrome P450, resulting in the formation of a hepatotoxic metabolite of norcocaine nitroxide, leading to necrosis of hepatocytes of the 1st and 2nd zones of the hepatic acinus. It causes dystonia of intrahepatic blood vessels, leading to ischemic damage to hepatocytes of the 3rd zone of the hepatic acinus and cholangiocytes of the interlobular bile ducts. Leads to small-drop obesity of hepatocytes of the 1st zone of the hepatic acinus	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Microvesicular steatosis
Levofloxacin	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles). May disrupt the process of removing bilirubin from hepatocytes	Mixed (rise in activity levels of ALT, AST and total bilirubin). Does not cause morphological changes
Linezolid	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, which can lead to disruption of the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Lincosamides (lincomycin, clindamycin)	They have a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, which can lead to disruption of the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Losartan	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles)	Hepatocellular (rise in the levels of ALT and AST activity). Does not cause morphological changes
6-Mercaptopurine	It has a direct toxic effect on endotheliocytes of terminal hepatic venules and interlobular veins, hinders venous outflow from the liver	Obliterating endophlebitis of the hepatic veins, veno-occlusive disease. Postsinusoidal fibrosis and portal hypertension
Methyldopa (aldomet)	Predominantly in women causes immune-mediated (immunoglobulin E) damage to hepatocytes, up to bridging necrosis (cytotoxic response is directed to the components of the hepatocyte membrane), with the development of fulminant liver failure	Hepatocellular (rise in the levels of ALT and AST activity). Acute drug-induced hepatitis. With prolonged use - chronic active drug-induced hepatitis. Skin rash, eosinophilia
3,4-Methylenedioxymethamphetamine (ecstasy)	Has a direct toxic effect on hepatocytes	Hepatocellular (rise in ALT and AST activity levels)
Methoxyflurane	Causes immune-mediated (immunoglobulin E) damage to hepatocytes (cytotoxic response is directed to hepatocyte membrane components)	Hepatocellular (rise in the levels of ALT and AST activity). Fever, skin rash, eosinophilia
Methotrexate
Metronidazole (tinidazole)	Has a direct toxic effect on hepatocytes	Hepatocellular (transient rise in ALT and AST activity levels). Does not cause morphological changes
Moxifloxacin	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts, can lead to disruption of the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis) and inhibition of the synthetic function of the liver	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Decreased levels of prothrombin index and serum albumin
Nalidix	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Naproxen	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Nicotine	Causes dystonia of intrahepatic blood vessels, leading to ischemic damage to hepatocytes of the 3rd zone of the hepatic acinus
Nitrofurans	They cause immune-mediated (immunoglobulin E) damage to hepatocytes and cholangiocytes of the intrahepatic bile ducts (the cytotoxic response is directed to the components of the membranes of hepatocytes and cholangiocytes). Parenchymal tubular cholestasis develops. Cause macrophage and lymphoid infiltration of the hepatic lobules	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase). With prolonged use - chronic active drug-induced hepatitis. Fever, skin rash, eosinophilia, antinuclear antibodies. Liver granulomatosis
Nifedipine	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts. Causes the development of "pseudo-alcoholic" hepatic steatosis and the appearance of hyaline bodies of Mallory (Mallory)	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase). Pseudoalcoholic steatohepatitis
	Most NSAIDs have a hepatotoxic effect, which can be realized through direct toxic action, allergy or idiosyncrasy.	Most often - hepatocellular (rise in the activity levels of ALT, AST)
Oxacillin	Causes macrophage and lymphoid hepatic lobule infiltration	Liver granulomatosis
Omeprazole	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles)	Hepatocellular (rise in the levels of ALT and AST activity). Does not cause morphological changes
Penicillins	They can cause immune-mediated (immunoglobulin E) damage to hepatocytes and cholangiocytes of the intrahepatic bile ducts (the cytotoxic response is directed to the membrane components of hepatocytes and cholangiocytes). May cause macrophage and lymphoid infiltration of hepatic lobules	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase). Liver granulomatosis
Oral contraceptives	They cause focal expansion of the sinusoids of the 1st zone of the hepatic acinus. The endotheliocytes of the terminal (central) hepatic venules of the 3rd zone of the hepatic acinus are affected. They have an oncogenic effect, increase the risk of developing hepatocellular cancer and liver adenomas. Cause the development of thrombosis of the hepatic veins. Cause macrophage and lymphoid infiltration of the hepatic lobules	Cholestatic (rise in levels of alkaline phosphatase and total bilirubin). Veno-occlusive disease. Postsinusoidal portal hypertension. Granulomatosis of the liver. Peliosis and perisinusoidal fibrosis. Budd-Chiari Syndrome
Pefloxacin	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles). May interfere with the transport of bilirubin from hepatocytes	Mixed (transient rise in the activity levels of ALT, AST and total bilirubin). Does not cause morphological changes
Pyrazinamide	Has a direct toxic effect on hepatocytes	Hepatocellular (rise in activity levels of ALT, AST)
Preparations for parenteral nutrition	Cause fatty liver disease	Steatohepatitis (phospholipidosis)
Ranitidine	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles) and cholangiocytes of the intrahepatic bile ducts (parenchymal tubular cholestasis). Reduces the activity of microsomal liver enzymes	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Rifampicin	It has a direct toxic effect on hepatocytes (mainly in women). It hinders the process of capture of bilirubin by hepatocytes and intracellular transport of bilirubin. Potentiates isoniazid hepatotoxicity	Hepatocellular (rise in activity levels of ALT, AST). Acute drug-induced hepatitis. Unconjugated hyperbilirubinemia
Roxithromycin	Has a direct toxic effect on hepatocytes, can lead to disruption of the process of transporting bilirubin from hepatocytes (parenchymal cholestasis)	Mixed (rise in activity levels of ALT, AST and total bilirubin)
Salicylates	Have a direct toxic effect on hepatocytes	Hepatocellular (rise in activity levels of ALT, AST)
	Have a direct toxic effect on hepatocytes	Hepatocellular (rise in activity levels of ALT, AST)
Sulfamethoxazole	Causes immune-mediated (immunoglobulin E) damage to hepatocytes and cholangiocytes of the intrahepatic bile ducts (the cytotoxic response is directed to the components of the membranes of hepatocytes and cholangiocytes)	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase). Skin rash, eosinophilia
Sulfonamides	They cause immune-mediated (immunoglobulin E) damage to hepatocytes and cholangiocytes of the intrahepatic bile ducts, which leads to the development of parenchymal tubular cholestasis (the cytotoxic response is directed to the components of the membranes of hepatocytes and cholangiocytes). Cause macrophage and lymphoid infiltration of the hepatic lobules	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Fever, skin rash, eosinophilia. Liver granulomatosis
Terbinafine	It has a direct toxic effect on the cholangiocytes of the intrahepatic bile ducts, which leads to a disruption in the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis)	Cholestatic (elevated levels of alkaline phosphatase and total bilirubin)
Tetracyclines (tetracycline, metacycline)	They have a direct toxic effect on hepatocytes, as a rule, when administered parenterally and mainly in women. Violate the process of mitochondrial cellular respiration in hepatocytes (mitochondrial cytopathy), beta-oxygenation leads to lactic acidosis and intracellular accumulation of triglycerides. Cause fatty liver disease	Hepatocellular (rise in the levels of ALT and AST activity). Microvesicular steatosis
Trimethoprim-sulfamethoxazole	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts. Causes fatty liver disease	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase). Steatohepatitis (phospholipidosis)
1,1,1-Trichloroethane	Has a direct toxic effect on hepatocytes of the 3rd zone of the hepatic acinus - causes necrosis, ballooning and fatty degeneration of hepatocytes	Hepatocellular (rise in ALT and AST activity levels)
Tricyclic antidepressants	They have a direct toxic effect on cholangiocytes of the intrahepatic bile ducts and lead to a disruption in the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis)	Cholestatic (elevated levels of alkaline phosphatase and total bilirubin)
Phenytoin	Causes immune-mediated (immunoglobulin E) damage to hepatocytes and cholangiocytes of the intrahepatic bile ducts, which leads to disruption of the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis). Causes the development of "allergic" hepatitis, granulomatous liver disease and fulminant liver failure
Phenothiazides	They have a direct toxic effect on cholangiocytes of the intrahepatic bile ducts, lead to a disruption in the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis)	Cholestatic (elevated levels of alkaline phosphatase and total bilirubin)
Fluconazole		Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin). Eosinophilia. Liver granulomatosis
Ftivazid	Has a direct toxic effect on hepatocytes	Hepatocellular (rise in activity levels of ALT, AST)
	It causes immune-mediated (immunoglobulin E) damage to hepatocytes and cholangiocytes of the intrahepatic bile ducts (the cytotoxic response is directed to the components of the membranes of hepatocytes and cholangiocytes). Causes macrophage and lymphoid infiltration of the hepatic lobules	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase). Granulomatosis of the liver. Fever, skin rash, eosinophilia
Chloramphenicol (levomycetin)	Chloramphenicol metabolites affect hepatocytes and cholangiocytes of the intrahepatic bile ducts, which leads to disruption of the process of transporting bilirubin from hepatocytes (parenchymal tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Chlorpromazine	Metabolites of chlorpromazine affect hepatocytes and cholangiocytes of the intrahepatic bile ducts, which leads to ductopenia and disruption of the process of transporting bilirubin from hepatocytes (parenchymal and "congestive" tubular cholestasis). Toxic metabolites reduce the activity of intrahepatic bile duct cells and reduce bile flow. Cause macrophage-lymphoid infiltration of the hepatic lobules, mononuclear and eosinophilic infiltration of the portal tracts	Cholestatic (rise in levels of alkaline phosphatase and total bilirubin). Liver granulomatosis
Cefazolin	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles)
Cefoperazone (cefoperazone - sulbactam)	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles)	Hepatocellular (rise in activity levels of ALT, AST). Does not cause morphological changes
Cefotaxime	It has a direct toxic effect on hepatocytes (increases the permeability of hepatocyte membranes and intracellular organelles)	Hepatocellular (rise in the levels of ALT and AST activity). Does not cause morphological changes
Ceftazidime	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Ceftriaxone	Causes thickening (sludge) and stagnation of bile in the lumen of the intrahepatic lobular and interlobular bile ducts ("congestive" tubular cholestasis)	Cholestatic (rise in levels of activity of alkaline phosphatase and OB)
Cefuroxime	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Cyclosporine	Has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts	Mixed (rise in activity levels of ALT, AST and alkaline phosphatase)
Cyclophosphamide	It has a direct toxic effect on hepatocytes, causes necrosis of hepatocytes, mainly in the 3rd zone of the hepatic acinus. Activates arrow-shaped cells, accelerates fibrogenesis and leads to collagenization of the space of Disse. Causes fatty liver disease	Hepatocellular (rise in the levels of ALT and AST activity). Fibrosis of the liver (cirrhosis of the liver). sinusoidal portal hypertension. Macrovesicular steatosis
Cimetidine		Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Tetrachloride carbon (CCl 4)	It has a direct toxic effect on hepatocytes of the 3rd zone of the hepatic acinus, causing necrosis, ballooning and fatty degeneration of hepatocytes	Hepatocellular (rise in ALT and AST activity levels)
Enalapril	It has a direct toxic effect on hepatocytes and cholangiocytes of the intrahepatic bile ducts (parenchymal tubular cholestasis)	Mixed (rise in activity levels of ALT, AST, alkaline phosphatase and total bilirubin)
Enfluran	Causes immune-mediated (immunoglobulin E) damage to hepatocytes (cytotoxic response is directed to hepatocyte membrane components)	Hepatocellular (rise in the levels of ALT and AST activity). Fever, skin rash, eosinophilia
Erythromycin, its derivatives and other macrolides	They have a direct toxic effect on cholangiocytes of the intrahepatic bile ducts and lead to a disruption in the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis)	Cholestatic (elevated levels of alkaline phosphatase and total bilirubin)
Estrogens	They have a direct toxic effect on the cholangiocytes of the intrahepatic bile ducts and lead to a disruption in the process of transporting bilirubin from hepatocytes (“congestive” tubular cholestasis). They have an oncogenic effect, increase the risk of developing various liver tumors	Cholestatic (elevated levels of alkaline phosphatase and total bilirubin)
	It has a direct toxic effect on hepatocytes, causes necrosis of the 3rd zone of the hepatic acinus	Hepatocellular (rise in activity levels of ALT, AST)

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Hepatotoxicity is a property of chemicals, acting on the body non-mechanically

by causing structural and functional disorders of the liver.

A wide range of substances with hepatotoxicity is known. These include natural

compounds produced by plants, fungi, microorganisms, minerals, products of chemical and

pharmaceutical industry, waste from these types of production activities (table 1).

However, from among those presented, only a few, to the adverse effect of which the threshold

sensitivity of the liver is significantly lower than that of other organs and systems, which can conditionally be called

hepatotoxicants.

Table 1. Substances with hepatotoxicity

1. Industrial toxicants

Aliphatic hydrocarbons: heptane;

Alcohols: allyl alcohol, ethyl alcohol, ethylene chlorohydrin, heptyl alcohol, ethylene glycol and its

derivatives;

Esters and epoxy compounds: dioxane, epichlorohydrin, ethylene oxide, thiol ether;

Acetates: methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, amyl acetate,

ethyl salicylate;

Aliphatic halogenated hydrocarbons: carbon tetrachloride, chloroform,

dibromochloropropane, dichloroethane, dibromoethane, ethylene dibromide, ethylene dichloride, methyl bromide,

methyl chloride, propylene chloride, tetrachloroethane, tetrachlorethylene, trichloroethane, vinyl chloride;

Carboxylic acids and their anhydrides: phthalic anhydride;

Aliphatic amines: ethanolamine, ethylenediamine;

Cyanides and nitriles: acetonitrile, acrylonitrile;

Aromatic hydrocarbons: benzene, diphenyl, naphthalene, styrene, toluene, xylene;

Phenol and its derivatives: phenol, cresol;

Aromatic halogenated hydrocarbons: benzyl chloride, chlorinated biphenyls,

chlorinated benzene, chlorinated naphthalenes, polychlorinated biphenyls, polybrominated

biphenyls;

Aromatic amines: 2-acetaminofluorane, 3,3-dichlorobenzidine, 4-dimethylaminoazobenzene, 4,4-

methylenebis(2-chloroaniline);

Nitro compounds: dinitrobenzene, dinitrotoluene, dinitrophenol, nitrobenzene, nitroparaffins,

nitrophenol, picric acid, nitromethane, trinitrotoluene, 2-nitropropane;

Other nitro compounds: dimethylnitrosamine, dimethylformamide, ethylndiamine, hydrazine and its

derivatives, pyridine, dimethylacetamide;

Various organic compounds: - propiolactone, carbon disulfide, dimethyl sulfate, mercaptans,

tetramethylthiuram disulfide;

Halogens: bromine;

Metals: arsenic, beryllium, bismuth, boron, cadmium, chromium, copper, germanium, iron, nickel, phosphine,

phosphorus, pyrogallol, selenium, thallium, tin;

Pesticides: dipyridyls (paraquat, diquat), DDT.

2. Natural compounds:

Plant origin: albitocin, cycasin, icterogenin, safrole, tannic acid;

Mycotoxins: aflatoxins, ochratoxins, rubratoxins, sterigmatocystins, amanitin, phalloidin and

Bacterial toxins: exotoxins of the clostridium group, hemolytic streptococcus, ethionins.

3. Medications:

Antibiotics: chloramphenicol, rifampicin, tetracycline, nitrofurans, sulfonamides

drugs, etc.;

Fungicides: griseofulvin, amphotericin, 5-fluorocytosine, etc.;

Protozoocides: emetine, metronidazole, etc.;

Anti-tuberculosis drugs: cycloserine, isoniazid, rifampicin, p-aminosalicylic

Antiviral agents: cytrabin, vidarabine;

Endocrine drugs: antithyroid drugs, steroid drugs;

Anesthetics: halothane, methoxyflurane, ethers, chloroform, cyclopropane;

Psychotropic drugs: phenothiazines, thioxanthenes, butyrophenones, benzodiazepines, inhibitors

MAO, tricyclic antidepressants;

Anticonvulsants: phenytoin, phenobarbital, methadion;

Analgesics and non-steroidal anti-inflammatory drugs: acetaminophen, salicylates,

indomethacin, phenylbutazone, ibuprofen, phenylbutazone;

Cardiovascular agents: anticoagulants, quinidine, procainamide, verapamil, nifedipine,

methyldopa, captopril, diuretics, antianginal agents, etc.;

Anticancer drugs.

Miscellaneous: colchicine, allopurinol, cimetidine, disulfiram, vitamin A, BAL, penicillamine, etc.

The high sensitivity of the liver to chemical compounds is determined by several

circumstances. First, substances that enter the body through the gastrointestinal tract,

first of all, they enter the liver; thus, it is the first organ that stands in the way of a xenobiotic,

resorbed into the internal environment of the body. Secondly, the liver is the main organ responsible

for the metabolism of foreign substances. Since this is often associated with the formation of highly reactive

capable intermediates and the initiation of free radical processes (see sections

"Metabolism of xenobiotics", "Mechanism of cytotoxic action"), in the course of metabolism is very

likely organ damage.

At present, thanks to the implementation of hygienic measures and significant improvement

working conditions in the workplace, cases of acute toxic liver damage are rare. However, it is not uncommon

cases of subacute and chronic hepatotoxicity. Changes on the part of the body, in persons,

exposed to a toxicant can be difficult to diagnose. routine methods

studies are sometimes not sensitive enough to detect an adverse effect

from prolonged use of the drug or the action of an industrial toxicant. Such

cases, pathology can be detected only with the help of special diagnostic methods. That's why

often, the hepatotoxic effect can develop gradually over several months, and even

years, while remaining unrecognized.

1. Anatomical and physiological features of the liver

Due to its structure and functions, the liver is extremely sensitive to the action of toxicants.

The functional unit of the liver is the acinus. The area around the portal triad (hepatic

artery, portal vein, bile duct) is called the periportal zone (zone 1). Areas surrounding

terminal (central) vein, are referred to as the centrilobular or peripheral zone (111

zone). Between 1 and 111 zones there is an intermediate (11) zone. Such a zonal description of the acinus

based on the microphysiological characteristics of the organ.

Zone 1 is the main functional area of ​​the liver. In the blood flowing to this section of the acinus,

highest concentration of oxygen, nutrients, hormones and xenobiotics metabolized

liver. Here, a high intensity of the processes of protein and glycogen synthesis is determined. In cages 1

zone contains the largest number of mitochondria, and hence the enzymes of the Krebs cycle.

The centrilobular (111) zone is characterized by low activity of protein- and glycogen-synthesizing

processes. However, in the hepatocytes of this zone, the highest content of enzymes in the body,

metabolizing xenobiotics. In high concentration in hepatocytes of 111 zones, such

enzymatic associations, such as the NADPH-cytochrome reductase complex. The mentioned enzymes

enzyme complexes are localized on the membranes of the smooth endoplasmic reticulum of the hepatic

cells. Metabolism inducers of xenobiotics simultaneously increase the mass of smooth

endoplasmic reticulum and hepatocytes of the 111 zone. In the cells of this section of the liver, mainly

fats are synthesized and glycogen is deposited.

Metabolism of xenobiotics in hepatocytes was considered earlier (see above).

2. Pathological conditions formed under the action of hepatotoxicants

Pathological conditions of the liver of chemical etiology can be attributed to one of two classes:

cytotoxic and cholestatic. Regardless of the acting factor, a limited

the number of pathological reactions, among which the most important are: steatosis, necrosis, cholestasis, fibrosis (cirrhosis),

carcinogenesis. Cytotoxic liver damage is manifested by necrosis, steatosis, carcinogenesis.

Cholestatic - a violation of the secretion of bile, the development of jaundice. As a rule, toxic hepatopathy

are of a mixed nature.

2.1. Steatosis

Steatosis, or fatty degeneration of the liver, is a condition characterized by excessive

accumulation of fat in hepatocytes. At the same time, there is a decrease in the content of lipids in the blood plasma

and lipoproteins. Steatosis is often the earliest manifestation of toxic organ damage.

The mechanism of initiation of steatosis during intoxication with various hepatotoxicants is different. Accumulation

fat may be the result of either a violation of the processes of lipid catabolism, or excessive

the entry of free fatty acids into the liver, or damage to the mechanisms for the release of triglycerides

into blood plasma. Triglycerides are secreted into the blood in protein-bound form - lipoproteins.

(low density lipoproteins - LDL). There are several main mechanisms of damaging

effects of toxicants on lipid metabolism in hepatocytes:

Violation of protein synthesis in liver cells;

Violation of the processes of conjugation of triglycerides with proteins and the formation of lipoproteins (LDL);

Damage to the mechanisms of transport of lipoproteins across cell membranes;

Inhibition of the synthesis of phospholipids;

Violation of processes - oxidation of fatty acids in mitochondria;

Violation of the processes of bioenergetics in cells necessary for the implementation of protein synthesis and

phospholipids.

Often, several mechanisms underlie the action of toxicants on the process. Fact value

accumulation of fat in hepatocytes for the development of subsequent liver pathology is not yet clear.

2.2 Necrosis

Necrosis is a degenerative process leading to cell death. necrotic changes,

developing under the influence of toxicants, can affect only certain parts of the liver (focal

necrosis) or the entire mass of the organ (total necrosis). Cell death is accompanied by damage

plasma membranes; it is preceded by a number of morphological changes in hepatocytes: swelling of the cytoplasm,

dilatation of the cytoplasmic reticulum, swelling of mitochondria with rupture of cristae, degradation

polysomes, destruction of organelles and the cell nucleus, steatosis.

Biochemical changes preceding cell death include: initiation of free-

radical processes, binding of toxicants or their metabolites to proteins, nucleic acids

and unsaturated fatty acids of cell membranes, violation of plastic and bioenergetic

processes, a sharp increase in the content of free calcium in the cell.

It is believed that a fatal, irreversible stage in the development of hepatocellular necrosis is

violation of homeostasis of intracellular Ca + 2. Increasing the concentration of calcium in the cytoplasm of the cell

secondary __________ leads to damage to cell membranes and organelles (mitochondria, endoplasmic

reticulum, lysosomes), denaturation of structural proteins, enzyme inactivation. intimate mechanism,

leading to disruption of the cellular metabolism of Ca + 2 is not completely clear (see the section "Mechanisms

cytotoxicity").

Cell death may be a consequence of the implementation of regulated biological mechanisms

(controlled cell death - apoptosis) - a physiological "counterweight" to the process of continuous

cell division. Although apoptosis is a normal process, it can be greatly enhanced by the action of

a number of exogenous factors, such as oxidative stress, anoxia, ionizing radiation, toxicants.

There are morphological criteria (light and electron microscopy) to distinguish

necrosis from apoptosis. However, in the action of toxicants, as a rule, it is practically impossible to clearly

determine which of the processes, necrosis or activated apoptosis, underlies cell death. By

For the most part, with intoxications, signs of both processes are traced.

Inhibition of apoptosis can lead to the accumulation of constantly multiplying cells in the organ.

For example, clonal expansion of malignant cells and subsequent tumor growth may be

a consequence of inhibition of apoptosis.

The most studied toxicants causing steatosis and necrosis of hepatocytes are

carbon tetrachloride, chloroform, bromobenzene, phosphorus, aflatoxins, dimethylnitrosamine,

puromycin, pyrrolizidine alkaloids, beryllium.

2.3. cholestasis

Cholestasis is manifested by a violation of the process of bile excretion, increased permeability of the wall

bile ducts, dysfunction of the microvilli of the epithelium of the bile ducts, providing current

bile. Inflammation or blockage of the bile ducts also leads to bile retention in the liver, which in turn

turn is accompanied by the development of jaundice.

Among the substances that cause cholestasis are well-known drugs: thioridazine,

amitriptyline, diazepam, estradiol, sulfonamides, as well as industrial toxicants: 4,4-

diaminodiphenylmethane, aniline, etc.

2.4. Fibrosis (cirrhosis)

Fibrosis is the end result of chronically occurring pathological processes that develop in

liver when exposed to toxicants. Collagen strands appear in the damaged organ,

destroying the normal structure of the organ, disrupting intrahepatic blood flow, bile secretion.

Clinically, this is manifested by portal hypertension syndrome. The mechanism of the phenomenon is not clear. Most

often cirrhosis develops with alcoholism and chronic intoxication with halogenated

hydrocarbons (CCl4, trichlorethylene, 1,1,1-trichloroethane, etc.).

2.5. Carcinogenesis

Carcinogenesis is observed under the action of a number of natural and industrial toxicants. For

most substances, the mechanism of carcinogenic action has not been established (see section "Chemical

carcinogenesis"). Many hepatotoxicants act as initiators of tumor growth, causing

structural damage to DNA molecules. The list of hepatocarcinogens is presented in Table 2.

Table 2. Hepatocarcinogens

A. Human hepatocarcinogens

proven alleged

Vinyl chloride

Thorium dioxide

carbon tetrachloride

Chloroform

Dieldrin

Heptachlor

Polyhalogenated biphenyls

Trichlorethylene

B. Animal hepatocarcinogens

SUBSTANCE TYPE OF ANIMAL

1. Azo dye and their precursors:

Aminoazobenzene

4-dimethylaminoazobenzene

O-aminoazotoluele

rats, mice

2. 2-acetaminofluorene rats, mice, hamsters, rabbits, dogs, cats

3. Nitroaromatic compounds:

Aromatic hydroxylamines

4-nitroquinolone-1-oxide

4. Rat Nitrosamines

5. Rat dialkyl- and arylalkylhydrazines

6. Mouse ethyl carbamates

7. Thio compounds:

thiourea

Thioacetamide

8. Alkyl halogens:

carbon tetrachloride

Chloroform

mice, rats, hamsters

Iodoform

Benzyl chloride

9. Aromatic compounds:

1,1,1-trichloro-2,2-bis

(p-chlorophenyl)ethane

1,1-dichloro-2,2-bis

(p-chlorophenyl)ethane

10. Toxins:

Aflatoxins

3. Morphological forms of toxic liver damage

The main forms of toxic liver damage are presented in Table 3. Damage can

be acute and chronic. As mentioned earlier, they manifest themselves as cytotoxic and

cholestatic effects. Cytotoxic damage is usually manifested by steatosis and

necrosis of hepatic cells. Cholestatic damage is accompanied by hepatocanalicular or

canalicular jaundice. Chronic forms of liver damage are manifested by chronic active

hepatitis, steatosis, phospholipidosis, cirrhosis, veno-acclusive condition, neoplasm.

Table 3. Morphological types of liver diseases caused by chemicals

TYPE EXAMPLE

Focal necrosis acetaminophen, carbon tetrachloride

Nonspecific hepatitis aspirin, oxacillin

Virus-like damage

hepatitis

isoniazid, methyldopa

Chronic active hepatitis

methyldopa, propylthiouracil,

sulfonamides, papverine,

clomethacin

Cholestasis:

Hepatocanalicular

Canalicular

erythromycin, organic arsenic compounds,

estrogens, anabolic hormones

Fatty degeneration

ethanol, corticosteroids, carbon tetrachloride

tetracycline

Vascular damage:

Thrombosis of the hepatic veins

Non-cirrhotic portal

hypertension

oral contraceptives

vinyl chloride

cirrhosis ethanol, methotrexate

Neoplasms:

focal nodular hyperplasia

Carcinoma

Angiosarcoma

contraceptives, androgens

contraceptives

contraceptives, vinyl chloride, anabolic

steroids

vinyl chloride, arsenic, copper sulfate

4. Brief description of hepatotoxicants

Zimmerman in 1978 proposed to classify substances that cause liver damage to one of two

groups: (1) obligate hepatotoxicants and (2) organ damaging only in sensitive individuals

(idiosyncratic).

Obligate hepatotoxicants cause a dose-dependent effect, usually reproducible in

experiments on experimental animals. Idiosyncratic hepatopathy develops in individuals with special

sensitivity to certain substances. This type of pathology is not reproduced in the experiment and

is not dose dependent.

The direct cytotoxic effect of substances of both groups on the liver is based on the following

mechanisms:

Damage to the mechanisms of transport of substances through the membranes of hepatocytes and cell organelles;

Damage to the mechanisms of bioenergetics in liver cells;

Disaggregation of ribosomes and endoplasmic reticulum;

Violation of nucleic metabolism in the nuclei of cells;

Block or delay in the release of natural metabolites from hepatocytes.

Mechanisms of mediated action of toxicants on the liver are extremely rare. As an example

the effects of some metals can be cited, which initially damage the kidneys, leading to

accumulation in the blood of substances such as urea, ammonia, etc. These substances, acting on the liver,

cause damage to it.

The least studied mechanism of hepatotoxicity is the stimulation of autoimmune processes,

developing as a result of the interaction of the toxicant with native macromolecules of liver cells

(mainly proteins). One example of this mechanism is liver damage.

ethanol in chronic alcoholism.

4.1. Obligate hepatotoxicants

Liver damage may result from the action of toxicants or their products on the organ.

metabolism.

Some toxicants in the process of metabolism initiate the generation of free hepatocytes in hepatocytes.

radicals, reactive oxygen species. These products cause lipid peroxidation, physical

chemical destruction of proteins, nucleic acids, disrupt intracellular calcium homeostasis. V

as a result - functional disorders, manifested by steatosis, necrosis of liver cells. Among the substances

realizing the toxic effect in this way, include, in particular, carbon tetrachloride,

other halogenated hydrocarbons, paraquat.

Under experimental conditions, it was shown that carbon disulfide causes fatty degeneration of hepatocytes,

hemorrhages in the tissue of the organ in laboratory animals. There is also an increase in the liver, oppression

activity of enzymes involved in the metabolism of xenobiotics. most studied

hepatotoxicants today are carbon tetrachloride and chloroform. Consequence

lesions by these substances are steatosis and necrosis of liver cells in the 111 zone of the acinus

(centrolobular necrosis). Some other chlorinated compounds have a similar effect on the organ.

hydrocarbons: trichlorethylene, 1,1,1-trichloroethane, etc. When studying liver biopsies of poisoned

eosinophilic infiltration of the periportal sections of the liver, cholestasis are detected. With electronic

microscopy of affected hepatocytes reveals proliferation of peroxisomes, smooth

endoplasmic reticulum. With repeated exposure to these substances in high doses

possible development of cirrhosis. Contact with small amounts of toxicants does not cause damage

Most hepatotoxicants cause liver damage through direct interaction with

cell structures. The action is based on the formation of chemical bonds between the toxicant or

products of its metabolism with macromolecules, accompanied by a violation of their physiological

properties. The nature of the bonds formed can be different. Substances such as acetaminophen,

bromobenzene, etc., form covalent bonds with the substrate, phalloidin, amanitin bind

non-covalently. Liver damage caused by these substances is manifested by cytotoxic

(steatosis, necrosis) and cholestatic (jaundice) effects.

Ethanol can be considered as a direct hepatotoxicant. Chronic alcohol intoxication

accompanied by fatty degeneration of the liver, a violation of metabolic processes in the body.

The substance can also cause necrosis of hepatocytes, either due to the action of the resulting

metabolism of acetaldehyde, or - energy deficit due to a sharp increase in consumption

oxygen liver cells. Ethanol, being an inducer of microsomal enzymes, with prolonged

when taken, it potentiates the hepatotoxic effect of toxicants undergoing bioactivation in the liver,

enhancing the process of their metabolism, for example, chlorinated hydrocarbons, acetaminophen, etc.

Cholestatic hepatotoxicants, damaging the bile ducts, selectively disrupting the mechanisms

excretion of bile, inhibit the capture by hepatocytes from the blood plasma of substances to be excreted.

4,4-diaminodiphenylmethane (plastic hardener), accidentally getting into flour, became the cause, in its

time, in England, a whole epidemic of cholestatic jaundice. Similar lesions were noted in Spain.

They were caused by aniline contaminating rapeseed oil. Damage to the bile ducts causes

paraquat. In an experiment on laboratory animals, the ability of some mycotoxins,

eg spirodesmin, cause damage to the bile ducts. Sensitivity to these substances

different people varies widely, but the effect is dose-dependent.

The mechanism of action of cholestatics is practically unknown.

4.2. Idiosyncratic hepatotoxicants

In a small part of people, substances that do not exhibit the properties of hepatotoxicants in the experiment, the

also cause liver damage. The phenomenon is based on genetically determined

features of xenobiotics metabolism and other causes of increased sensitivity of the organism to

substance, such as allergy.

Allergic hepatopathy develops several (1 - 5) weeks after exposure and

re-contact with the substance. As a rule, they are accompanied by other signs of an allergic process,

both functional (fever, rash, eosinophilia) and morphological (inflammatory

eosinophilic infiltrate in the liver). The diagnostic sign of allergic hepatopathy is

the development of a process in response to the introduction of minimal doses of a substance or its metabolites. If the process is not

develops, they conclude that the basis of idiosyncrasy is an aberration of metabolic transformations

xenobiotics. Thus, it has been shown that the hypersensitivity of individuals to phenytoin is based on a defect

an enzymatic system that converts its active metabolite (arenoxide) into an inactive one

dihydrodiol form. Altered xenobiotic metabolism can lead to the formation

intermediate products with direct hepatotoxicity or hapten properties (secondary

allergization).

It should be noted that far from always, allergic hepatopathy develops against the background of

distinct systemic manifestations, Thus, systemic reactions are not characteristic of the defeat of such

substances such as chlorpromazine, erythromycin, halothane, isoniazid, valproic acid. Conversely, far from

any systemic hyperergic reaction is accompanied by liver damage (penicillin,

procainamide).

Idiosyncratic liver injury may occur in individuals who work in chemical and

pharmaceutical industries.

5. Conditions for exposure to hepatotoxicants.

Substances that have the properties of hepatotoxicants can act on a person, both in everyday life and

and in production conditions. In everyday life, the most common causes of intoxication are drugs

household chemicals (chlorinated hydrocarbons, copper salts, yellow phosphorus), vegetable poisons

(mycotoxins), common drugs, overdose of which, or increased

sensitivity, can lead to organ damage (acetaminophen, salicylates, etc.). Poisoning

poisonous mushrooms are still a common cause of acute toxic liver damage. Aflatoxins, infecting

food products can cause both acute hepatopathy and provoke the development of neoplasm.

The poisons contained in the pale grebe (amanitin and

phalloidin). Food poisoning from this mushroom is usually fatal.

due to acute liver failure. Among the alkaloids found in foods,

substances from the pyrrolizidine group have the greatest hepatotoxicity.

A number of widely used insecticides from the group of chlorinated aromatic

hydrocarbons in high doses cause liver damage. Pathology may develop due to

eating food contaminated with insecticides, accidental or intentional household intoxication.

Cases of liver damage by DDT (the victim took 6 g of the substance), paraquat (taken about

20 g of substance). Intoxication ended in death. Autopsy revealed centrilobular

liver necrosis, destruction of intrahepatic bile ducts, cholestasis. Some substances mentioned

groups (DDT) after exposure are stored in the body for a long time, causing a sluggish pathology.

The most common causes of acute hepatopathy in the workplace are

intoxication with carbon disulfide (CS2), chloroform, trichloroethane, dichloroethane, toluene,

other organic solvents. In general, it should be noted that thanks to the activities

controlling services, the number of acute industrial hepatopathy is steadily decreasing.

In a survey of printing workers who had long-term exposure to toluene, a large

group of individuals revealed liver pathology, manifested by the phenomena of moderate steatosis and increased

activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in blood plasma.

Prolonged exposure to solvent mixtures can cause liver damage in industrial

conditions. The surveyed workers in contact with dyes, varnishes and other products, in

whose composition includes organic solvents (a mixture of aromatic and aliphatic hydrocarbons -

white spirit, xylene, petroleum ether, toluene, methyl ethyl ketone), a moderate increase was detected

ALT and AST activities in blood plasma. Selective biopsy revealed moderate steatosis,

foci of necrotic changes, expansion of portal passages, fibrosis.

6. Factors affecting hepatotoxicity

Various factors affect hepatotoxicity, mainly by modifying the ability of the liver

metabolize xenobiotics. The result of this modification is determined by two circumstances. In-

First, whether toxic products are formed during the biotransformation of the xenobiotic. Secondly, it enhances

or inhibits the factor under consideration the intensity of metabolism. In particular inductors

microsomal enzymes, activating cytochrome P450-dependent oxidases (and other oxidases of mixed

functions), can contribute to increased formation of toxic products of bioactivation

hepatotoxic xenobiotics. The most famous inductor, among those constantly used by man,

Ethanol. Industrial and ecotoxicants have the same properties: 1,1,1-trichloroethane,

synthetic steroids, polyhalogenated aromatic hydrocarbons (including DDT),

polyhalogenated biphenyls, TCDD, aldrin, hexachlorobenzene, lindane, chlordane, etc.

Chronic alcohol intake increases the toxicity of carbon tetrachloride, trichlorethylene,

methylene chloride, vinyl chloride, xylene, styrene, carbon disulfide, magnesium, mercury, a number of other substances like

humans and experimental animals. However, the simultaneous appointment of ethanol in high

doses and trichlorethylene or methylene chloride is accompanied by a decrease in their toxicity. This is due

the fact that enzyme systems, metabolizing methanol, are switched off from the process of biotransformation

toxicants, during which their toxic metabolites are formed. Simultaneous

the appointment of ethanol with xylene, styrene, toluene increases the content of the latter in the blood. Some

substances, similar to disulfiram, inhibit the rate of ethanol metabolism (inhibitors

aldehyde dehydrogenase). As a result, acetaldehyde accumulates in the body, causing severe

headache, tachycardia, redness of the skin, sometimes collapse. alcohol dehydrogenase

inhibited by fatty acid amides, dithiocarbamates, carbamates, cyanamide, nitroglycols,

oximes, carbon disulfide, dimethylformamide. Technical fluids interfere with metabolism,

significantly changing the toxicokinetic and toxicodynamic characteristics of each other (see section

"Coergism"). Since the results of interaction are largely determined by the conditions

(dose ratio, time factor), the consequences of intoxication with mixtures of substances in each

specific case will be different.

Along with chemical, hepatotoxicity is modified by other factors. Among these

relate:

1. Nutritional status: calcium, copper, iron, zinc, magnesium - necessary for the implementation of functions

OSF. Their deficiency significantly inhibits the activity of microsomal enzymes. The same way

there is a deficiency of vitamins (ascorbic acid, tocopherol, vitamins of the B complex), starvation.

A diet low in protein increases the toxicity of many xenobiotics.

2. Age: in the tissues of newborns, the metabolism of xenobiotics is less intense,

than in adult tissue. The increase in toxicity of many substances in the elderly is not associated with

metabolic rate. Phenomena such as speed reduction play a decisive role here.

blood flow, violation of the mechanisms of excretion of xenobiotics, etc.

3. Genetic factors: OSF and other enzymes involved in the metabolism of foreign substances

exist in several isoforms, their ratio is determined genetically. Hence significant

differences in the sensitivity of individuals to xenobiotics (see above).

4. Physical activity, various habits (smoking) affect the activity of the OSF.

5. Biological species: patterns identified in one species of experimental animals,

far from always fair to a person.

7. Brief toxicological characteristics of individual hepatotoxicants

7.1. Pale toadstool toxins

Representatives of the group Amanita phalloides (pale toadstool) are the cause of more than 50% of cases

mushroom poisoning. 95% of poisonings are fatal. More than 40 years ago Wielands, and

later Faulstich (1978) established the structure of the toxins responsible for the development of a severe lesion. Imi

turned out to be. at least seven heptapeptides (phallotoxins) and eight cyclic octapeptides

(Amatoxins) (Figure 1). The latter are among the most toxic known natural poisons.

Figure 1. Structure of α-amanitin

Amatoxins are inhibitors of nuclear RNA polymerase B. Inhibiting the activity of the enzyme,

toxins disrupt protein synthesis in cells at the transcription stage. This in turn causes

numerous biochemical disturbances in the affected cells (see above), termination of the process

cell division and cell necrosis. Actively dividing cells are especially affected.

massive exposure to toxins. These primarily include epithelial cells of the gastrointestinal tract.

intestinal tract, liver and, to a lesser extent, kidneys. Pathological diseases developing during intoxication

changes include necrosis of the intestinal mucosa, centrilobular liver necrosis of the "acute

yellow atrophy", necrosis of the epithelium of the proximal tubules of the kidneys. Signs of poisoning, such as

usually develop 6 to 24 hours after mushroom consumption. In the latent period,

the penetration of the toxin into the cells, its interaction with the enzyme and blocking the synthesis of messenger RNA.

The first symptoms are nausea, vomiting and profuse cholera-like diarrhea,

lasting up to a day. If the doctor ensures the maintenance of water and electrolyte balance (introduction

up to 9 liters of fluid per day) temporary improvement is possible. Then comes jaundice

signs of acute liver (and sometimes kidney) failure, coma develops and death for 4 - 7

day. In the case of non-fatal lesions, recovery stretches for three or more weeks. Treatment

affected symptomatic. Recently, a positive effect on the course has been shown

-lipoic acid intoxication (thiooctanoic acid).

7.2. Dichloroethane

Dichloroethane (ethylene chloride, ClCH2-CH2Cl) is used as a solvent for varnishes, paints, etc.

It is a colorless, practically insoluble in water, fairly volatile liquid (temperature

boiling 83.70) with a peculiar smell. Vapors of dichloroethane (ECE) are approximately 3.5 times heavier than air.

Poisoning can occur when DCE enters through the respiratory tract, gastrointestinal

tract and skin. A picture of severe intoxication develops when taking per os 20 ml or more

substances, or with a 30-minute inhalation of dichloroethane vapor at a concentration of 200 g / m3. Ultimately

permissible content of DCE in the air is 1 10-2 g/m3.

Once in the internal environment of the body, DCE quickly disappears from the blood, accumulating in

liver and lipid-rich tissues. However, the substance is not deposited here and for several days

completely disappears from the body. In the liver, kidneys, lungs and some other organs, dichloroethane

undergoes metabolic transformations with the participation mainly of cytochrome P-450-dependent oxidases,

and glutathione-S-transferases. Intermediate products of the metabolism of a substance have a high

reactivity. With their action on target molecules and activation of free-radical

processes link the mechanism of action of DCE on parenchymal organs (see above). Main

the final metabolites of the toxicant are thiodiacetic acid, thionyl diacetic acid,

combination of chloroacetic acid with cysteine.

The duration of the latent period for inhalation lesions is 1-12 hours. At

ingestion of the substance inside the poisoning develops rapidly. Abdominal pains appear quickly and indomitable

vomiting with an admixture of blood, signs of a narcotic (non-electrolytic) effect of a substance (up to a coma).

After 2 to 3 days, symptoms appear that indicate damage to the liver and kidneys: jaundice, in the blood

increased content of bilirubin, increased activity of aminotransferases, in the urine - protein,

erythrocytes, cylinders.

In the study in the affected hepatocytes, damage to cell organelles is noted:

rough endoplasmic reticulum (violation of protein synthesis), smooth endoplasmic

reticulum (violation of the detoxifying function of the liver), mitochondria (violation of cellular respiration),

lysosomes (activation of autolysis processes).

There are no specific antidotes for DCE. In addition to general therapeutic measures used in

acute intoxications in general, and toxic hepatopathy in particular, it is recommended to use

antioxidants (retinyl palmitate - 400,000 IU daily for 4 days; levamisole - 10 - 50 mg / kg;

tocopherol) and substances that bind intermediate products of DCE metabolism (unithiol - 5 ml 5%

solution 2 - 4 times a day, intramuscularly; acetylcysteine ​​- 5% solution, up to 400 ml per day).

8. Study of hepatotoxicity of xenobiotics

The hepatotoxicity of a substance is established in the course of classical acute, subacute and chronic

toxicological experiments. The tests used in this case are no different from those

used in the diagnosis of liver diseases in humans, but should take into account the features

toxic effect of the studied compound.

At the same time, it must be borne in mind that the pathogenesis of acute and chronic liver damage by one and

the same toxicant can be different. Therefore, the selection of tests should not be based on

solely from the concept of the mechanism of acute toxic action of xenobiotics.

Improving methods for detecting hepatotoxicity is also carried out in the experiment.

Most often, as a model substance, to determine the suitability of a new test, use

vinyl chloride. This substance, having a flat hepatotoxicity curve, acting in minimal doses

causes isolated liver damage.

8.1. Determination of enzyme activity in blood plasma.

Increased plasma activity of enzymes such as alanine aminotransferase (ALT),

aspartate aminotransferase (AST), gamma-glutamic acid transferase (TGGC), lactate dehydrogenase

(LDH) indicates a violation of the integrity of hepatocytes and is a reliable indicator of acute

liver damage. ALT and AST activity to a greater extent reflect the state of membrane permeability

hepatocytes than the functional state of the organ. An increase in the level of enzymes in the blood, usually

indicates hepatic necrosis. In addition, the level of activity of these enzymes

determined by a number of additional conditions, in particular, the nature of nutrition, the presence

infectious process. The activity of both enzymes can increase with pathology of the heart,

muscle tissue, lungs. A more reliable indicator of hepatic pathology is a change

relationship ALT/AST. An increase in the coefficient above 1.6 is found, in particular, when

centrilobular fatty degeneration of the liver, observed during intoxication with many substances

(toluene, dichloroethane, alcohol, etc.)

THGC is a liver-specific enzyme and a sensitive indicator of liver status. Raise

THGC activity is also noted in case of poisoning with a variety of toxicants. However, in practice

a high percentage of false-positive reactions is detected.

The level of LDH, although reflecting the state of the liver, is not a specific sign of it.

lesions, since an increase in activity is noted in diseases of the heart, muscles, lungs, etc.

In subacute and chronic intoxications, the activity of enzymes can increase only transiently.

In addition, a gradually developing decrease in the volume of the hepatic parenchyma may not

accompanied by changes in enzyme activity. So, in the terminal period of liver disease

mass death of hepatocytes, accompanied by a deterioration in the condition of the experimental animal,

may occur against the background of a decrease in the activity of enzymes in the blood plasma. Specified circumstances

cause caution in interpreting the results obtained.

Among the most common tests that reveal the cholestatic effect of substances,

include the determination of the activity of alkaline phosphatase and bilirubin in blood plasma (direct and

indirect). However, both tests are not specific indicators of organ toxicity.

Thus, the activity of alkaline phosphatase also increases in the pathology of the skeletal system. Raise

bilirubin often accompanies acute infectious liver disease. specific indicator

damage to the biliary tract is the activity of 5-nucleotidase. However, this test is not specific to

chemical pathology.

8.2. Functional trials

8.2.1. Assessment of the metabolic activity of the liver

Reliable methods are direct measurement of the activity of enzymes involved in

metabolism of xenobiotics, in the organ homogenate of laboratory animals, at various times after

administration of the test substance.

Using non-invasive research methods, information about the state of metabolic activity

liver can be obtained by staging clearance tests. These tests detect acute and

subacute liver damage. The clearance of indocyanine green, antipyrine, caffeine,

phenacetin, ionic dyes, bile pigments. In case of damage by vinyl chloride, the definition

clearance of indocyanine green and bile acids allow to detect liver dysfunction at the earliest

process steps. The experiment shows the dose dependence between the amount of administered

vinyl chloride and a decrease in the rate of excretion of indocyanine green from the body. Very useful

to establish the prognosis of the outcome of intoxication in the terminal stage of liver failure

is an aminopyrine breath test. With the participation of mixed-function oxidases (OSF) aminopyrine

dealkylated, and then the cleaved radical is oxidized. Introducing into the body of an animal

carbon-labeled aminopyrine, and then, measuring the amount of 14CO2 in the exhaled breath for 2 hours

air, it is possible in dynamics, to re-quantify the state of the metabolizing function

Other methods for assessing the state of the metabolizing properties of the liver are also possible. For example, with this

the goal is to determine the rate of elimination of endogenous substances, such as d-galactose, 6-hydroxycortisol.

Determination of the level of bile acids in the blood plasma does not require an assessment of excretory functions

introduction of exogenous substances. The result of the measurement of conjugates of cholic acid and choliglycin can

considered as an indicator of the excretory function of the liver. The sensitivity of the method is close to the method

determining the activity of gamma-glutamic acid transaminase (TGGK).

specific tests of the functional state of the liver. They correlate well with others.

indicators of the state of the body. Thus, the level of bile acids in the blood plasma reacts sensitively to

liver damage caused by alcohols, vinyl chloride.

With chronic exposure to toxicants, chronic liver pathology is often accompanied by

proliferation of connective tissue (fibrosis). For this reason, the level of bilirubin and bile acids

quite well reflects the depth of subchronic and chronic liver lesions, while

plasma enzyme activity - acute lesions.

8.2.2. Assessment of the synthetic activity of the liver

The liver synthesizes many substances circulating in the blood. Their content is

an indirect indicator of the synthetic activity of an organ. Albumins are most often determined,

prothrombin, cholesterol, transport protein molecules, for example, transferrin. It should be noted that

the liver has a huge reserve of synthetic functions and, as a result, only with a very significant

a deficit in the mass of the parenchyma of the organ, a change in indicators should be expected.

8.3. Structural studies

Functional studies are highly specific, but usually not very sensitive to

detection of liver pathology in the early stages of its development. Methods for studying the morphology of an organ are deprived of

these shortcomings. However, it should be borne in mind that the results of morphological studies also do not

always easy to interpret, because in the organ, in response to the action of various etiological

factors, a relatively small number of typical pathological changes develop.

9. Principles for the detection of toxic hepatopathy in humans

Establishing the fact of acute liver injury by a xenobiotic is usually not difficult.

task. Identification of latent forms of liver pathology associated with subacute and chronic effects

hepatotoxicants at times proves to be extremely difficult.

Using the tests used, it is sometimes difficult to distinguish liver lesions with asymptotic

flow from the norm. In a number of cases, the minimum deviations detected are the result of

a defeat that happened once, violations in the diet, alcohol intake, etc.

9.1. Acute hepatopathy of chemical etiology.

In acute attack by some well-known hepatotoxicants (tetrachloric

carbon, yellow phosphorus, pale toadstool toxins, acetaminophen) three

the period of the course of intoxication: acute gastrointestinal and neurological manifestations; imaginary

well-being; severe liver damage, often accompanied by kidney damage. However, in

in most cases, clearly defined stages in the course of the process are not detected.

The basis for the diagnosis of hepatopathy of chemical etiology is a carefully collected anamnesis. V

during the conversation, the features of the professional activity of the subject are clarified, which

he uses medicines, what chemicals he comes into contact with in everyday life, does not

whether he abuses alcohol. It should be found out if there were any previous liver diseases, whether

the patient or his relatives have allergies, is there any hypersensitivity to any factors

environment. When solving expert questions, it should be borne in mind that more often the reasons

liver damage are factors of non-chemical nature (viral, bacterial, fungal,

taking an anamnesis and identifying a chemical factor as the cause of pathology requires special attention,

since the profile of detected biochemical changes, as a rule, reflects only a picture

morphological processes taking place in the body. Hepatocellular disorders associated with

tissue necrosis, resemble viral hepatitis, both in clinical and laboratory diagnostic

respect. This type of organ damage is manifested by malaise, nausea, vomiting, jaundice.

Biochemical methods reveal an increase in the activity of aminotransferases in the blood plasma (AST,

ALT), a decrease in the blood level of plasma coagulation factors. Important diagnostic

tests are the determination of the content of bilirubin in the blood plasma and prothrombin time.

Diffuse parenchymal degeneration of the organ with minimal hepatocyte necrosis,

observed, for example, during intoxication with salicylates, is accompanied by a syndrome resembling

anicteric forms of hepatitis.

Cholestatic lesions of the liver are clinically manifested by jaundice, pruritus. In blood

a moderate increase in the activity of aminotransferases, alkaline phosphatase, and cholesterol is determined.

Hepatocanalicular and canalicular forms of cholestatic jaundice differ in morphology

pathological process and biochemical manifestations. With hepatocanalicular form

(caused, for example, by chlorpromazine) the level of alkaline phosphatase in blood plasma may increase

more than three times, significantly increases the content of cholesterol in the blood. Canalicular

jaundice is not accompanied by pronounced changes in the biochemical parameters of the blood.

Fever, rash, eosinophilia are commonly associated with liver disease developing

due to hypersensitivity to a toxicant (idiosyncrasy). Typical hypersensitivity reaction

to xenobiotics (phenytoin, sulfonamides, aminosalicylic acid, etc.) is accompanied

manifestations resembling serum sickness: fever, rash, lymphadenopathy,

lymphocytosis with the appearance in the blood of "atypical" forms of lymphocytes.

9.2. Subacute and chronic toxic hepatopathies

Identification of liver dysfunctions developing as a result of long-term exposure to toxicants,

especially in the initial period of development of the pathological process, is a difficult task. Especially

it is difficult to detect toxicant-induced liver neoplasms. These tasks can be successfully

resolved only in specialized institutions using modern diagnostic methods.

9.3. Identification of hepatotoxicity in a population of individuals in contact with hazardous chemicals

agents.

Programs designed to ensure the control of persons in contact with hepatotoxicants,

like all screening programs, should be built in accordance with certain principles.

Surveys should be carried out selectively, and under special control should be persons

belonging to the risk group. The survey methods used must be reliable,

informative and ensure the detection of organ damage before its distinct manifestation. Risk

for the health of the subject and the cost of the method according to his assessment should be commensurate. The most important

an element of the program is the permanence of observation. The main purpose of the survey is

identification of latent forms of organ pathology and prevention of its irreversible damage.

However, as already mentioned, an attempt to apply existing methods for studying the state

liver for mass screening of people is facing serious difficulties. So, in some

studies have shown that 30% of workers in chemical enterprises in the absence of symptoms

liver diseases during examination using biochemical methods, deviations from

norms. In this regard, some experts are not inclined to consider deviations as reliable if

the obtained values ​​are less than two times different from the average. Sometimes this approach

leads to ignoring the initial forms of the lesion. Other causes of diagnostic errors -

the use of insufficiently specific, giving a large percentage of false positive answers, or

insensitive tests that do not reveal pathology. At the same time, the importance of planned mass

surveys in production is growing from year to year. The cost of making a mistake also increases. Not

detection of pathology where it is, means continued exposure to the toxicant, and therefore,

potential disability first of the most sensitive, and then of other persons in contact with

occupationally harmful factor. On the contrary, overdiagnosis may be a reason for

unreasonable, useless, costly measures to rehabilitate production, remove from

the work of healthy individuals, the appointment of complex and sometimes unsafe methods of in-depth examination.

World practice formulates a number of requirements for the conduct of the events under consideration,

to reduce the chance of errors:

1. Before conducting an analysis, it is necessary, if possible, to strictly outline the concept of a norm for

the population under study. The size of the surveyed group should be at least 150 - 200 people.

2. To assess the condition of an organ, several tests must be used simultaneously. significant

3. Research should begin with highly specific samples. After

highly specific, highly sensitive assays must be performed in order to isolate

true positive results. The unsystematic application of a battery of tests that differ significantly

sensitivity and specificity increases the likelihood of false-positive results.

4. In order to further minimize false-positive results, in the distinguished group

further research may be possible.

it is advisable to evaluate the activity of THGC and the clearance value of indocyanine green. positive

the results at both stages of the work are the reason for an in-depth examination of persons by specialists,

using, if necessary, methods for studying biopsy specimens. Approximate plan for conducting

survey is presented in Table 4.

Table 4. Sample plan for conducting a survey of persons in contact with potential

hepatotoxicants.

A. Initial examination

Objective: To identify conditions that increase the risk of occupational organ damage

1. Obtaining information about previous liver diseases. Attitude towards alcohol intake.

2. Collection of professional anamnesis. Assessment of possible prior impacts

hepatotoxicants at work and at home.

3. Examination to identify manifest forms of chronic liver pathology.

4. Urinalysis for the content of urobilinogen and bile pigments.

5. Determination of the activity of AST and THGC in blood plasma.

6. Determination of alkaline phosphatase activity and bilirubin content in blood plasma.

7. An in-depth examination of persons with identified deviations from the norm.

B. Periodic examinations

Objectives: To identify liver damage associated with the action of toxicants

1. History taking

2. Determination of alkaline phosphatase activity and content of bile acids in blood plasma

3. Determination of THGC activity in blood plasma; assessment of the clearance of indocyanine green

4. Suspension from work associated with exposure to potential toxicants, persons with identified

deviations of the studied indicators from the norm

5. In-depth survey of persons suspended from work

10. Conclusion

Liver damage is still one of the most common consequences of acute,

subacute and chronic intoxications. The high sensitivity of the organ to toxicants is due to its

anatomical and physiological features. The liver is the main organ where metabolism takes place.

foreign compounds. The result of metabolism is the formation of substances that are easily released from

organism. However, during biotransformations, reactive intermediates are often formed,

which damage the liver tissue.

Depending on the structure of the toxicant, dose, frequency of administration, duration of exposure to the form

lesions are different. Acting at a high dose, xenobiotic can cause acute cytotoxic

liver damage. Intermittent, subacute, chronic action of the toxicant is accompanied by

the formation of a sluggish current process, often leading to fibrosis, cicatricial changes in the organ,

neoplasms.

Identification of acute forms of hepatotoxic action is possible with the help of widely used

research methods. In most cases, they are quite informative. Important

The challenge facing toxicology is the development of sensitive, specific tests that allow

identify initial and sluggish, non-manifesting forms of toxic hepatopathy. Only

the widespread introduction into practice of such methods and their correct use can ensure

prevention of diseases caused by professional contact with toxicants.

UDC 616-099 BKK 52.8

HEPATOTOXIC EFFECTS OF ANTIRETROVIRAL THERAPY - MYTH OR

REALITY (REVIEW)

I. I. Sitdikov, A. V. Moskaleva, and T. I. Vlasova N.P. Ogarev Moscow State University, Saransk, Russia e-mail: [email protected] mail.ru

annotation

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

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 of the population today, unfortunately, remains extremely relevant. HIV remains a major global public health problem, with more than 35 million deaths to date. In 2016 alone, about 1.0 million people died from HIV-related causes worldwide. According to the World Organization

At the end of 2016, there were an estimated 36.7 million people living with HIV worldwide, and 1.8 million people acquired HIV infection in 2016. In addition, it should be noted that the majority of 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 is 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 hepatitis B virus (HBV) or hepatitis C virus (HCV). Co-infection with HIV/HBV or HIV/HBV is a serious problem in terms of prognosis and survival of patients, which leads to careful selection of tactics and methods of treatment. The question remains open

hepatotoxicity of antiretroviral

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

Objective. Based on the analysis of literature data, to evaluate 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 of the current course of co-infection with HIV/HCV and HIV/HVU is liver damage in the form of liver fibrosis, followed by liver failure, leading to death. Patients with co-infection have a more rapid progression of liver fibrosis, which is due to both the hepatotoxic effect of viral hepatitis C or B, and the hepatotoxicity of the human immunodeficiency virus. It has been shown that HIV significantly alters the course of viral hepatitis B and C, increasing the levels of viremia 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 development and accelerating the course of cirrhosis, liver failure and

hepatocellular cancer. These phenomena are explained by earlier progression

fibrosis in individuals with co-infection, which correlates with the number of CD4+ T-lymphocytes (less than 200 cells per 1 ml). Mechanisms for the accelerated progression of chronic hepatitis C in HIV-infected individuals may include both direct effects of the virus and immunological disturbances, in particular increased apoptosis or suppression of the specific T-cell response against HCV. In addition, HIV causes an increase in the secretion of cytokines (interleukins 4, 5 and 13, transforming growth factor b), which increase liver inflammation and fibrosis. The causes of damage to the liver tissue can also be increased apoptosis of hepatocytes or the accumulation in the liver of cytotoxic CD8 T-lymphocytes and their release of tumor necrosis factor a, which causes liver fibrosis. More recently, HIV has been shown to be able to replicate in hepatocytes and hepatic stellate cells and cause an increase in collagen expression and the secretion of pro-inflammatory cytokines.

It should be noted that various literature sources provide evidence that antiretroviral therapy itself can lead to the progression of liver fibrosis and, as a result, to liver failure in patients with HIV infection. For example, a number of foreign researchers identify several

mechanisms of hepatotoxicity

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

ifavirenz, abacavir); (3) direct hepatotoxicity (ritonavir at 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 people. 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 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 drug hepatotoxicity.

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 exposure to HIV and 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, there is a problem with the use of antiretroviral drugs against the background of co-infection with HIV/HCV and HIV/HBV in patients in need of this treatment.

Undoubtedly, to increase

the duration and improvement of the quality of life of patients, it is necessary to conduct a combined 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 highly active antiretroviral combination therapy, is quite rare. It has been reliably proven with zidovudine, didanosine and stavudine and manifests itself in the form of hepatomegaly, increased activity of liver enzymes (mainly ALT and ASAT) and / or lactic acidosis. Abacavir and lamivudine are also capable of causing similar effects, but to a much lesser extent. 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 differs in men and women. In addition, it is highly dependent on the level of CD4+ T-lymphocytes at the time of treatment initiation. Nevirapine is not used in women if the CD4+ T-lymphocyte count is above 250 cells/µL at the time of treatment initiation, and it is not used in men if CD4+ T-lymphocyte count is more than 400 cells/µL at the start of treatment. It should be noted 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 already undetectable. The risk is also minimal if nevirapine is added as an additional drug to an already taken regimen for any reason. However, there are also cases of death while taking nevirapine. Protease inhibitors have mild hepatotoxicity, but high doses of ritonavir (greater than 1000 mg daily) 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 administration. However, despite the high incidence of hepatoxic effects of highly active antiretroviral therapy, in almost 90% of patients, regardless of the presence of liver damage, the treatment does not cause severe 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 reaction of hepatotoxicity to nucleoside reverse inhibitors is based on mitochondrial toxicity. The onset of this pathology reaches 6 months or more from the start of therapy. Histologically, signs of fatty degeneration of the 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 hepatic enzyme inhibition.

glucuronyltransferase, 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 is manifested by clinically pronounced jaundice, this can cause difficulties in communicating with other people and interfere with daily life. After discontinuation of the drug, bilirubin levels return to normal.

However, scientific progress in the field of medicine, including the 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 that have a high

hepatotoxicity, namely zidovudine, stavudine, didanizine, 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 in both 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 proven to attenuate remodeling of the extracellular matrix of the liver in patients with HIV infection. Also, it should be noted that the drugs that are part of combination antiretroviral therapy can significantly reduce the severity of liver fibrosis in patients with HIV/HBV and HIV/HCV coinfection. For example, lamivudine, which is used in the main regimens for the treatment of 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 down the progression of liver fibrosis, and with prolonged the use of the drug - to reduce the severity of pathological changes in the liver and lead to a partial regression of liver fibrosis.

Successful response to antiretroviral therapy among HIV/HCV coinfected patients is associated with an increase in the cellular immune response to viral hepatitis C, a decrease in the level of viral hepatitis C RNA, and the elimination of this pathogen. In this regard, it is recommended to start antiretroviral therapy already in the early stages of HIV infection in case of coinfection. Starting HIV treatment before a significant drop in the number of CD4+ T-lymphocytes allows you 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 should be noted 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 character much more often in cases where HIV enters the body earlier than the hepatitis C virus.

hepatitis C were the lowest risk group. Thus, when assessing the risk factors for progressive liver fibrosis in patients coinfected 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 of A.V. Kravchenko "Modern schemes

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

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 elevated (less than 2.5 norms) ALT activity, it is recommended to combine them with ifavirenz, and in patients with higher ALT activity - with protease inhibitors boosted by raltegravir. Among protease inhibitors, preference is usually given to lopinavir or atazanavir.

Conclusions. Modern rational highly active antiretroviral therapy in patients with HIV / HCV and HIV / HBV coinfection not only does not increase the incidence of liver damage, but also significantly reduces the progression of liver fibrosis due to a decrease in viral load, and, therefore, reduces the likelihood of developing

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 an effective combination

highly active antiretroviral therapy in accordance with recommended treatment regimens.

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HEPATOTOXIC EFFECTS OF ANTIRETROVIRAL THERAPY - MYTH OR REALITY

(REVIEW ARTICLE)

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

The problem of hepatotoxicity of ART in patients with HIV and HIV/HBV(HCV) co-infection remains controversial. HAART was 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.

The potential therapeutic effect of herbal preparations on liver disease must be fully explored. However, the growing popularity of complementary and alternative therapies in developed countries is leading to more and more cases of herbal liver toxicity being reported. Many herbal preparations have been used for centuries, due in part to their complete safety, so reports of their hepatotoxicity came as a surprise. The explanation lies in non-compliance with the recommended doses and the parallel use of other drugs, including traditional ones. Toxic effects may appear with the use of new, more biologically active compounds. For example, a 78-year-old woman developed acute hepatitis after consuming a ready-made Lingzhi fungus extract powder, despite taking the drug for a year without toxic effects.

The only difference was that the previously used drug was prepared in and, apparently, it was not as concentrated as the purchased one, which caused adverse reactions. An important point that determines the toxicity of medicinal herbs may be individual sensitivity. Kava kava, a fairly safe and widely used anxiolytic, rarely causes liver toxicity; found to be more likely to cause acute hepatitis in Caucasians with low expression of CYP 2D6 enzymes. The same phenotype was noted in patients with toxic damage to the hay liver; found a violation of pharmacokinetics with a prolongation of the half-life and high. Compared to these drugs, others have significant hepatotoxic potential.

Some herbal preparations can trigger the immunoallergic mechanism of liver damage. Others can exacerbate liver disease, these herbs can exacerbate autoimmune hepatitis. Rarely, herbal preparations can trigger latent autoimmune hepatitis. This relationship between herbal medicines and existing liver disease is poorly understood, but is of great importance, as many patients with viral hepatitis use herbal medicines and are not always recognized as such.

The main problems in reports of herbal hepatotoxicity are late diagnosis, contamination of foods, or confusion of herbs. The last two problems can be avoided when using products prepared according to industrial recipes: in some countries, appropriate legislation for the sale of herbal preparations is well developed, but the international availability of herbal preparations via the Internet cancels out positive results. It is necessary that doctors and the public be more aware of the possible hepatotoxic effects of herbal preparations, as this will allow timely diagnosis; the consequences of continued use of hepatotoxic substances after the onset of signs of liver damage are the same for both conventional drugs and herbal preparations. Natural remedies are often considered safe and may be overlooked by both patients and physicians. It is difficult to determine the true causal relationship with liver damage when using skin cream, natural soothing drugs, drinking herbal tea, tonics.

Some herbal remedies can complicate the treatment of patients with chronic lung disease, as they increase bleeding or suppress the antimineralocorticoid spironolactone. Herbs with immunostimulatory effects may interfere with the effect of immunosuppressive therapy and provoke graft rejection reactions.

The toxic effect of herbal preparations on the liver is manifested by acute hepatitis, steatosis, fibrosis, hepatic vein obstruction syndrome, submassive and massive liver necrosis.

CHAPARAL

Chaparral is sold as tablets, capsules, and herbal teas. It is used as an "energy" food supplement, as well as for the treatment of various diseases: from chicken pox to cancer. The toxic effect on the liver is manifested mainly by cholestatic hepatitis, but there have been cases of acute hepatitis, subacute liver necrosis and acute liver failure. The toxic effect on the liver is, at least in part, dependent on the dose, in some severe cases the recommended dose has been exceeded. In any case, three patients in the terminal stage of the disease needed a liver transplant.

DUBROVNIK

Dubrovnik has been used for centuries and became popular in the 1980s, especially in France and Italy, as a weight loss remedy. More than 30 cases of toxic liver damage have been registered, mainly in middle-aged women. Acute hepatitis developed eight weeks after taking dubrovnik capsules or herbal tea. Rarely, antinuclear antibodies, anti-smooth muscle antibodies, and transient antimitochondrial M2 antibodies have been found. Although in most cases there was a recovery. Several deaths from acute liver failure have been reported. Some patients developed chronic hepatitis or cirrhosis. In the study of other cases, it was clear that adverse outcomes are often associated with continued or repeated use of the drug after the onset of signs of liver damage. The rapid appearance of disturbances in liver function parameters after repeated use of the drug indicates immunoallergic idiosyncrasy. This assumption confirms the appearance of microsomal autantibodies after Dubrovnik application. On the other hand, in favor of liver damage by toxic metabolites, the fact that the main dubrovnik diterpenoids are metabolized by CYP 3A enzymes with the formation of epoxides that deplete glutathione stores and initiate oxidative and apoptosis testifies in favor of liver damage.

Herbal preparations derived from the related plants Teucrium polirnn L, and Teucrium capitatum I also cause acute liver failure and acute hepatitis with bridging necrosis, respectively.

With this Chinese remedy, the first symptoms appear on average after 20 weeks. Focal necrosis of the liver with many eosinophils, mild lobular hepatitis with microvesicular steatosis, and bridging necrosis have been described. Recovery occurred after 8 weeks. after discontinuation of the drug, but it is known that chronic hepatitis can develop with prolonged use. The active ingredient, L-tetrahydropalmatine, structurally resembles the hepaugoxic alkaloids of pyrrolysine. Although the drug has been banned in the US and Canada since 1994, there are new cases of toxic reactions, so vigilance regarding this drug should be maintained.