The liver plays the role of a filter in the human body, taking on both the blows of external factors of aggression and the load on the synthesis-decay of biologically active substances. Stably intense rhythm of work with additional load on holidays, abundance of foreign agents and substances, the versatility of this body in themselves deplete hepatocytes. But sometimes we ourselves inevitably expose our liver to toxic substances, whose name is drugs. What medications have the strongest hepatotoxic effect and what their use leads to, MedAboutMe found out.
Of course, no one takes drugs specifically to cause liver damage. And even more so, doctors do not prescribe drugs for this purpose. Indications for the use of hepatotoxic drugs are usually strictly justified. It can be an infection, an autoimmune process, a pathology of the cardiovascular system, or a severe pain syndrome.
The feasibility of using drugs with a toxic effect on the liver is determined by the doctor after a detailed objective study, analysis of laboratory parameters and a thorough history taking. That is why it is so important to mention all concomitant and previous diseases, especially if the hepatobiliary system has already suffered before.
For the same reason, it is important to know which medications are most aggressive to the liver.
- Anti-tuberculosis drugs.
Isoniazid, rifampicin, streptomycin and ethambutol have a pronounced detrimental effect on the liver, and the appointment of several drugs at once, as required by the protocols for the treatment of tuberculosis, seriously worsens the condition of the "filter".
- Penicillins. Bright representatives of the group of drugs of the penicillin series, which have the most pronounced hepatotoxic effect, are oxacillin and amoxicillin. The harmful effect on the liver is prescribed in the instructions for oxacillin, however, it is worth noting that with strict adherence to the dosage, side effects rarely occur. The average daily dose of the drug is 3 g, and a direct hepatotoxic effect occurs at 5-6 g / day.
- Aztreonam, an antimicrobial drug of the monobactam group. Among his side effects refers to hepatitis.
- Tetracyclines. All drugs in this group have a negative effect on the liver. They can cause liver damage of varying severity, ranging from minor changes in the cells, ending with their necrosis.
- Macrolides. In comparison with the above groups of antimicrobial agents, macrolides rarely affect the liver, and yet, cholestatic hepatitis is classified as an adverse reaction of drugs in this group. A classic example of liver damage is toxic hepatitis while taking erythromycin.
This group includes a drug that is often and uncontrollably used in everyday life as a remedy for fever, headaches, or even as an additional ingredient in conservation. This is the well-known aspirin. Other drugs from the group of salicylates are used no less widely: Citramon and Askofen. According to studies, more than half of patients receiving 2 g of drugs from this group per day developed areas of necrosis in the liver. For your information: a standard citramone tablet contains about 250 mg of acetylsalicylic acid; Askofen tablet contains approximately 200 mg of salicylates, and aspirin is available in dosage forms of 100 and 500 mg.
- Non-steroidal anti-inflammatory drugs.
Despite the fact that salicylates also belong to anti-inflammatory drugs, the effect on the liver of diclofenac, nimesulide and coxibs (celecoxib, rofecoxib) is considered separately. The degree of liver damage varies from asymptomatic elevation of specific liver enzymes to fulminant (fulminant) liver failure. Paracetamol deserves special attention: half of the cases of the fulminant form of liver failure are provoked by taking this particular drug. For its development, 10-20 g of paracetamol is enough (one tablet contains from 200 to 500 mg of the active substance).
- anabolic drugs.
Oral preparations, that is, tablets, are especially dangerous. More often, taking anabolic drugs leads to cholestatic hepatitis, although there have been cases of necrotic changes in the liver.
- Antifungal medicines.
These include anti-thrush drugs well-known to women, as well as medications for the treatment of complications after taking antibiotics: fluconazole, ketoconazole, itraconazole, amphotericin B.
Again about women: both estrogen and progesterone, when taken orally, can cause cholestatic hepatitis.
- Cardiovascular drugs:
- Calcium blockers - nifedipine, verapamil.
- Angiotensin-converting enzyme inhibitors (enalapril, captopril).
- Antiarrhythmics - procainamide, amiodarone.
Drugs that affect the lipid profile, after 2-4 weeks from the start of administration, provoke an increase in the activity of specific liver enzymes.
If the regimen is not observed or the hepatobiliary system is compromised, these vitamins also have a toxic effect on the organ.
The onset of drug-induced hepatitis depends on the drug that caused the damage to the organ, the dosage of the drug, individual sensitivity and the initial state of the hepatobiliary system. On average, the first symptoms of toxic damage appear in the first week, with fulminant forms, the process develops in a short period of time. Long-term medication is required for the development of chronic forms. Thus, amiodarone causes changes in the liver years after the start of administration.
Acute drug-induced hepatitis is divided into cytolytic (in which liver cells are destroyed), cholestatic (in which bile outflow is disturbed) and mixed. All of them have similar symptoms, and differ in the laboratory by an increase in the activity of various enzymes.
Symptoms of liver damage include:
- Lack of appetite.
- Nausea not associated with eating and vomiting.
- Belching with bitterness.
- Weight loss.
- Stool disorders (diarrhea or constipation).
- Moderate pulling pains in the right hypochondrium.
- Enlargement of the liver.
- Pain on palpation of the right hypochondrium.
- Skin itching.
- Change in color of feces and urine.
These changes may be accompanied by fever and asthenic syndrome - weakness, headache, lethargy.
Drug-induced hepatitis rarely develops in people with a healthy hepatobiliary system who follow the prescribed medication regimen. On the contrary, the presence of risk factors not only doubles the chances of a toxic injury, but also exacerbates the severity of it.
Factors provocateurs of drug-induced hepatitis include a violation of the protein composition of the blood, age-related low functional activity of the liver (children and the elderly are more susceptible to hepatotoxic effects of drugs), pathology of the kidneys and liver. In addition, the pathology is more common in women.
Drinking alcohol doubles the hepatotoxicity of drugs. So, for the development of paracetamol liver failure for people who abuse alcohol, it is enough to take 5-10 g of the drug.
Every mother knows that aspirin can only be given to children over 12 years old, but not everyone knows why. The reason for this recommendation by WHO experts is that the brightest representative of salicylates is capable of causing the development of Reye's syndrome.
Reye's syndrome (white liver disease) is a severe condition characterized by combined brain damage and liver failure. World statistics say that 50% of cases of Reye's syndrome ended in death. At the same time, the vast majority (about 90%) of the cases were children under 15 years of age.
Symptoms of white liver disease include:
- nausea and repeated vomiting that does not bring relief;
- disturbances of consciousness of varying severity (from slight disorientation to coma);
- respiratory problems that often occur in young children;
How to protect yourself and your children from the effects of hepatotoxic drugs? Remember the three golden rules.
- Do not self-medicate.
The unjustified self-administration of antibacterial drugs has been discussed more than once, but the uncontrolled use of the “harmless” blood-thinning aspirin remains without attention. Any chemotherapeutic drug should be prescribed by a doctor, taking into account concomitant pathology.
- Provide the doctor with the most complete information about past and chronic diseases during the collection of anamnesis, as well as about the drugs used.
Detailing the state of health is extremely important, because a comprehensive examination of the body before prescribing a specific medication is not advisable. At the same time, information about the previous disease can tell the doctor in which direction to conduct research. The same applies to combinations of drugs: the combination of several drugs can lead to an increase or decrease in their effects.
- Strictly observe the prescribed dosage regimen of medications.
The dosage of drugs takes into account age characteristics and some concomitant diseases. Unauthorized excess of a single or daily dose will inevitably lead to negative consequences.
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 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.
Toxic hepatopathy can manifest itself in a cytotoxic or cholestatic form.
Cytotoxic effects can have the following manifestations:
- 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.
- 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.
- 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.
- Toxic hepatitis is an inflammation of the liver tissues, which is the result of the irritating action of poisons.
- 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.
- 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:
- Violation of bile secretion by blocking the mechanisms of its formation.
- 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 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.
The primary symptoms of developing hepatic tissue necrosis and focal necrosis are:
- bitterness in the mouth;
- pain in the hypochondrium on the right;
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.
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.
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.
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.
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;
- tremor of the limbs;
- vascular network on the skin;
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. Mukhin, 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:
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:
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 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.
Paracetamol has a dose-dependent effect on the liver. With the use of large amounts of paracetamol, either accidentally or with suicidal intent, massive centrilobular necrosis occurs in the liver. Signs of liver damage appear with a single dose of 10-15 g of the drug, and sometimes less. Ingestion of 25 g or more of paracetamol usually (though not always) causes fatal acute liver necrosis. The degree of liver damage depends on the concentration of paracetamol in plasma: a severe lesion develops if the concentration of the drug 4 hours after administration exceeds 300 mcg / ml; liver damage at drug concentrations below 150 mcg / ml is extremely unlikely. 4-12 hours after taking the drug, nausea, vomiting, diarrhea, abdominal pain and shock occur. After 24-48 hours, these symptoms disappear, but signs of liver damage appear. Often, pronounced manifestations of intoxication occur only on the 4-6th day after taking the drug. The activity of aminotransferases can reach 10,000 IU/l. Possible kidney damage and myocardial damage.
The active metabolite of paracetamol, which is formed during its microsomal oxidation, has a hepatotoxic effect. Glutathione binds to this substance and neutralizes it. However, with the formation of a large amount of metabolite, glutathione reserves in the liver are depleted, the active substance covalently binds to hepatocyte proteins and causes their necrosis. The exact mechanism of this process is unknown.
The hepatotoxic effect of paracetamol is enhanced under the influence of alcohol and other substances that cause the induction of microsomal liver enzymes, as well as with a decrease in glutathione reserves, for example, during starvation. In alcoholism, the toxic dose of paracetamol can be reduced to 2 g. Cimetidine inhibits microsomal enzymes and thus reduces the formation of a toxic metabolite.
TREATMENT. Begin with gastric lavage, then prescribe symptomatic therapy. Absorption of drug residues is prevented by taking activated charcoal or cholestyramine orally. These activities must be carried out no later than 30 minutes after taking paracetamol. If after 4 hours the content of paracetamol in plasma exceeds 200 μg / ml, and after 8 hours - 100 μg / ml, mercaptamine, cysteine or acetylcysteine are prescribed. They help prevent hepatocyte necrosis, as they contain sulfhydryl groups necessary for the binding of a toxic metabolite and the synthesis and reduction of glutathione. It is best to prescribe them no later than 8 hours after taking paracetamol, but they can also help after 24-36 hours. With a later appointment, the effectiveness of drugs containing sulfhydryl groups is significantly reduced.
For citation: Topchiy N.V., Toporkov A.S. Hepatotoxicity - the most likely causes and possibilities for optimal correction with Heptral // BC. 2013. No. 5. S. 249
The liver provides the energy and plastic needs of the body, and also largely performs a detoxification function. Based on clinical, laboratory and morphological features, the following types of liver damage are distinguished:
- mitochondrial lesions - the development of fibrosis, sometimes with severe proliferation of the bile ducts. Usually provoked by drugs (PM), parenteral nutrition;
- fibrosis - develops in most drug-induced liver injuries (LIPP). Fibrous tissue is deposited in the space of Disse and impairs blood flow in the sinusoids, causing non-cirrhotic portal hypertension and hepatocyte dysfunction;
- violation of protein synthesis - protein degeneration of hepatocytes with the resulting functional, morphological and laboratory consequences. It develops as a result of a significant toxic effect of the environment: food with toxic impurities, alcohol, drugs, viral, microbial, intoxication effects;
- veno-occlusive disease - develops as a result of the toxic effect of certain plants (for example, valerian), which are part of food supplements and products, medicinal teas, Chinese drugs, including restorative, stress-relieving, used for insomnia;
- hepatocanalicular cholestasis - develops under the influence of many toxic, toxic-allergic, toxic-immune effects: viral, alcoholic, medicinal, food, vegetable, including those included in food supplements, medicinal teas, etc .;
- liver damage associated with hypervitaminosis (particularly A). Morphologically, this is expressed in Ito cell hyperplasia with subsequent development of fibrosis and portal hypertension. Drugs often act as provoking factors, for example, a group of antihypertensive drugs that realize their effect through cytochrome P450-11D6, characterized by pronounced polymorphism. A special place in this group is occupied by angiotensin-converting enzyme inhibitors that can cause hepatitis, often occurring with severe peripheral eosinophilia and eosinophilic infiltration of the portal tracts;
- indirect damaging effect of any toxic factors on the hepatocyte, mediated through edema, "inflammatory" infiltration, hypoxia, allergies, idiosyncrasy. At the same time, a biochemical blood test fixes an increase in the level of transaminases;
- induction and competitive inhibition of enzymes that trigger any of the listed mechanisms.
The most commonly recognized cause of hepatotoxicity is alcohol. Alcoholic liver disease (ALD) includes several variants of parenchymal damage due to systematic alcohol abuse: steatosis, alcoholic hepatitis (AH) and cirrhosis of the liver (LC). The main factors predisposing to the development of ALD include the amount of alcohol consumed, gender, genetic polymorphism of enzymes involved in alcohol metabolism, nutritional status. When drinking alcohol for several days, there is a possibility of developing hepatic steatosis, a condition in which macrovesicular inclusions of triglycerides accumulate in hepatocytes. As a rule, the disease does not manifest itself clinically, it is often an accidental diagnostic finding. A much more severe form is hypertension, the manifestation of which usually occurs after another alcoholic excess. The CPU is the terminal stage of the BPA.
Diagnosis of severe forms of ALD is based on the clarification of anamnestic data indicating alcohol abuse, the identification of clinical and laboratory signs of liver failure, and the exclusion of other liver diseases. The dose of alcohol is calculated using the Widmark formula: vol.% × 0.8 = amount of alcohol in grams per 100 ml of drink. Hepatotoxic doses of alcohol are considered to be 40-80 g/day. in terms of pure ethanol. Sensitivity to the toxic effects of ethanol and the severity of liver damage have been proven to be influenced by factors such as the amount and duration of alcohol consumption, the type of alcoholic beverages consumed, gender, ethnicity and genetic polymorphism of enzymes, especially alcohol dehydrogenase, acetaldehyde dehydrogenase and cytochrome P 450. Fatty liver develops in approximately 90% of individuals who use about 60 g of ethanol per day. In addition, obesity, iron overload syndrome, infection with hepatitis viruses are recognized as factors associated with a more severe course of ALD. Studies have shown that even in the case of compliance with abstinence in 5-15% of cases, progression of fibrosis is observed, followed by transformation into cirrhosis. It was also found that if such patients continue to take alcohol at a dose of more than 40 g / day. the risk of progression in the CP increases to 30%. Often, patients carefully hide the fact of alcohol abuse. In such a situation, many authors recommend using special questionnaires, such as CAGE, MAST (Michigan Alcoholism Screening Test) and AUDIT (Alcohol Use Disorders Identification Test) when collecting an anamnesis. In turn, the prevalence of hepatitis C in people suffering from alcohol dependence is quite high and amounts to more than 25%. .
An objective examination of a patient with ALD reveals stigmas of prolonged alcohol abuse: Dupuytren's contracture, enlargement of the parotid salivary glands, signs of feminization. In addition, a physical examination reveals the expansion of the veins of the anterior abdominal wall, telangiectasia, edema, ascites, an enlarged and often painful liver on palpation. The characteristic laboratory signs of hypertension include an increase in the level of serum transaminases. As a rule, the level of aspartate aminotransferase (AST) is more than 2 times higher than normal, but rarely > 300 U / ml, the level of alanine aminotransferase (ALT) is slightly lower (de Ritis index> 2); leukocytosis, hypocoagulation, hypoalbuminemia, and hyperbilirubinemia occur. If necessary, the range of differential diagnosis includes: non-alcoholic steatohepatitis, LIPP, acute viral hepatitis, Wilson's disease, autoimmune liver diseases, α1-antitrypsin deficiency. To exclude these diseases, patients are shown a study of viral markers, the level of autoantibodies and indicators of copper metabolism. In some cases, when the results of laboratory tests are doubtful, the question arises of performing a liver biopsy, which is associated with a high risk of complications in patients with hypocoagulation and ascites.
In the human body, ethanol is oxidized to acetaldehyde with the participation of the enzyme alcohol dehydrogenase and further with the participation of acetaldehyde dehydrogenase to acetate. In both reactions, nicotinamide dinucleotide (NAD) acts as a coenzyme, reducing to NADH. A minority of ethanol is oxidized to acetaldehyde in microsomes of the smooth endoplasmic reticulum by the microsomal ethanol oxidation system (MEOS). Acetaldehyde contributes to lipid peroxidation (LPO), disruption of the electron transport chain in mitochondria, suppression of DNA repair and stimulation of collagen synthesis. Enhanced lipid peroxidation leads to direct damage to plasma and intracellular membranes due to a decrease in the content of phosphatidylcholine in them. The consequence of this is an increase in membrane permeability and a violation of membrane transport and receptor functions.
Hepatotoxicity is often observed as a rather dangerous side effect of the use of drugs. For a doctor, LIPP is a complex clinical problem due to a wide range of clinical and morphological options and the lack of developed clear principles of therapy other than drug withdrawal. Presumably, the incidence of LIPP is 6-3.9 per 100,000 patients. According to world statistics, in the structure of acute and chronic liver diseases, LIPP range from 0.7 to 20%. Currently, drug use is the leading cause of liver failure requiring liver transplantation in developed countries. Despite the fact that due to the damaging effect on the liver, many drugs have been withdrawn from use or have significant restrictions on their use, more than 1000 drugs that cause hepatotoxicity are described in modern literature.
The group of hepatotoxic drugs, the use of which leads to the development of LIPP in more than 40% of patients, includes antibiotics (for example, tetracyclines), antifungals, anti-tuberculosis drugs, laxatives, amiodarone, metatrexate, steroids, estrogens, tamoxifen, nonsteroidal anti-inflammatory drugs (acetylsalicylic acid, indomethacin, ibuprofen), anticonvulsants, anesthetics, psychotropics, antidepressants. Hepatotoxicity is a characteristic complication of highly active antiretroviral therapy using human immunodeficiency virus protease inhibitors. The risk of it increases with simultaneous infection with hepatitis B and C viruses. Many antitumor agents also have high hepatotoxicity. Hepatotoxic effects are one of the main reasons for lower doses of chemotherapy drugs and delayed cycles of chemotherapy, both of which impair treatment outcomes.
It is known that only the liver removes from the body all lipophilic substances, including drugs, by biotransforming them into water-soluble substances, which are excreted by various excretory organs. Pharmacokinetics of drugs includes four stages: binding of the drug to plasma proteins, transport with blood flow to the liver, absorption by hepatocytes (hepatic clearance) and excretion of the drug or its metabolites in the urine or bile. In the smooth endoplasmic reticulum of the hepatocyte, with the participation of monooxygenases, cytochrome C-reductase and the cytochrome P450 enzyme system, hydroxylation or oxidation of drugs occurs with the formation of toxic metabolites (phase I). Further, the mechanisms of biotransformation of metabolites are switched on, namely, their conjugation with many endogenous molecules - glutathione, glucuronides, sulfates, etc., aimed at reducing their toxicity (phase II). The next step is active transcytosolic transport and excretion of formed substances from the liver cell with the participation of carrier proteins, enzymes and pumps localized in the cytoplasm, at the basolateral and canalicular pole of the hepatocyte (phase III). Violation of the kinetics of drugs at any stage of its metabolism can lead to the development of organ lesions, primarily the liver. During the metabolism of drugs, hepatotoxic substances are formed, both inherent in this drug and idiosyncratic type. Depending on the action of these toxins on the hepatocyte, two groups of pathological processes are distinguished:
1) immune-independent toxic, caused by the damaging effects of drug metabolites, which are predictable, dose-dependent and occur within a few days from the start of therapy;
2) immune-mediated idiosyncratic, which develop unpredictably at different times (from a week to a year or more) from the start of taking drugs in usual therapeutic doses.
Most drugs cause idiosyncratic effects. Predisposing factors for the development of LIPP include: the presence of liver diseases with signs of hepatocellular insufficiency, decreased hepatic blood flow, female sex, polypharmacy (concurrent use of three or more drugs, including alternative medicine), old age, weight loss, pregnancy, strict vegetarianism , parenteral nutrition, environmental pollution with heavy metals and dioxins, as well as uncontrolled use of household chemicals. Thus, hepatotoxicity may be much more common than expected by the physician, especially in the primary care setting.
It has been established that liver cells are damaged mainly not so much by the drug itself, but by its metabolites, the formation and spectrum of which are genetically determined. The genetic variability of cytochrome P450 enzymes and the polymorphism of the composition and activity of hepatocyte conjugation systems acquired as a result of environmental factors underlie individual susceptibility to toxic and idiosyncratic reactions and explain the fact that certain drugs in different patients can cause different LIPP. In LIPP, the pathological process usually involves hepatocytes, cholangiocytes, stellate (Ito cells) and endothelial cells, which leads to the formation of a wide variety of clinical and morphological variants of liver lesions. In LIPP, the pathology of hepatocytes manifests itself in three pathomorphological variants: necrosis, fatty degeneration, and dysfunction of the liver cell in the absence of its structural disorders. Hepatocyte necrosis may be associated with direct toxic or immune-mediated effects of drugs. Direct toxic damage to hepatocytes is caused by the formation, with the participation of the cytochrome P450 enzymatic system, of a large number of toxic substances and highly reactive molecules that enhance LPO in membranes, accompanied by an increase in their permeability, an imbalance of cellular ions, a decrease in ATP levels, a violation of vital functions and the development of cell necrosis. This mechanism of hepatocyte cytolysis underlies most acute and chronic drug-induced hepatitis, including steatohepatitis (SH).
Immune-induced hepatotoxicity is due to the ability of drug metabolites to acquire the properties of haptens, bind to hepatocyte proteins and act as neo-autoantigens with further activation on the outer cell membranes of T-cells and the production of autoantibodies. The latter bind to autoantigens fixed on the cell membranes of hepatocytes, and the formed immune complexes are the trigger mechanism for autoantibody-dependent cytolytic and inflammatory reactions. Immune-mediated acute hepatitis is rare, but it often transforms into chronic hepatitis and cirrhosis. Drugs and their metabolites can inhibit mitochondrial β-oxidation and / or respiratory chains with the development of oxidative stress and the transfer of cell metabolism to the anaerobic pathway. At the same time, under conditions of lactic acidosis and an excess of free radicals, the synthesis of very low density lipoproteins (VLDL) is disrupted and triglycerides (TG) accumulate in the cell. Clinically, patients develop non-alcoholic fatty liver disease (NAFLD) with the presence of steatosis (liver function tests are not changed) or FH (increased levels of aminotransferases, other deviations are possible). Drugs and their metabolites are capable of disrupting the functions of enzymes and transport proteins without significant organic damage to the hepatocyte. As a result, a picture of hepatocellular dysfunction is formed in the absence of necrosis. Typical manifestations of this pathology are competitive unconjugated hyperbilirubinemia or isolated conjugated hyperbilirubinemia, as well as an increase in the level of gamma-glutamyl transpeptidase (GGTP) due to the induction of cytochrome P450 enzymes, in the absence of other changes in liver function tests. The formation of cholestasis is based on the blockade of enzymes involved in the excretion of bile components, damage to the biliary pole of the hepatocyte, as well as cholangiocytes of the intra- and extralobular bile ducts by drug metabolites. Intrahepatic cholestasis is subdivided into intralobular (hepatocellular and / or canalicular) and extralobular with damage to the epithelium of the bile ducts of the portal tracts. Drug-induced cholestasis can be an independent process or one of the syndromes of other LIPP. As a result of irritation of stellate cells by drugs and their metabolites or due to necrosis of hepatocytes, which is accompanied by the accumulation of connective tissue components in the spaces of Disse and capillarization of sinusoids, septal fibrosis and cirrhosis are formed. Other LIPPs, including hepatic vascular disease, granulomatous hepatitis, and benign tumors, are rare and their mechanisms of development are not well understood.
The diagnosis of LIPP is made if there is a history of indications for taking any drugs or alternative drugs, with the exclusion of other causes, and primarily viral hepatitis (hepatitis A, B, C, cytomegalovirus, Epstein-Barr, etc.), autoimmune hepatitis, metabolic and cholestatic diseases of the liver and biliary system. To confirm the etiological role of drugs in liver damage, the following parameters are taken into account:
1. The time interval between taking the drug and the development of hepatotoxicity is from 5 to 90 days (presumably), 90 or more days (definitely).
2. The rate of decline in impaired functions after drug withdrawal by 50% within 8 days (very likely), if elevated liver enzymes decrease within 30 days for hepatocellular and 180 days for cholestatic liver damage (presumably).
3. Exclusion of other causes of liver disease.
4. The development of similar liver lesions (increased levels of enzymes at least 2 times) with repeated administration of drugs, if allowed.
The development of pathological changes in the liver is considered associated with the use of drugs in the presence of the first three criteria or two of the first three and fourth criteria. Clinical manifestations of LIPP are usually non-specific and can range from the absence or presence of mild dyspepsia (nausea, anorexia, abdominal discomfort) with slight changes in laboratory tests to severe cytolytic and cholestatic syndromes with jaundice and, in some cases, the development of acute liver failure with liver failure. coma and death. A number of patients may develop systemic immune-mediated hypersensitivity reactions with the appearance of a rash, lymphadenopathy, eosinophilia. When using hepatotoxic dose-dependent drugs, pathological effects develop within a few days or weeks from the start of their administration and depend on the mechanism of the effect of drugs on the liver. In turn, the duration of the latent time when using drugs that have immune-mediated effects is several weeks or months.
A significant role in the diagnosis of LIPP type belongs to the assessment of biochemical liver samples with the release of syndromes of cytolysis, cholestasis, immune inflammation and hepatocellular insufficiency. A marker of hepatocyte cytolysis (activity of the process) is an increase in the level of ALT, AST and total bilirubin with a predominance of conjugated fractions. At the same time, there are: low activity with an increase in the level of ALT, AST up to 2 norms and normal serum bilirubin; moderate - with the level of ALT, AST up to 5 norms and normal serum bilirubin; high activity - with the content of ALT, AST over 5 norms with elevated or normal levels of serum bilirubin. More than 30 years ago, H. Zimmerman showed that the development of jaundice in drug-induced hepatocellular damage is an extremely dangerous sign that increases the likelihood of death by 10%. Since that time, the term "Hy's Rule" or "Hy's law" has been introduced as an indicator of severe drug-induced liver injury, which is used to refer to a situation when, with the use of drugs, there is more than a three-fold increase in ALT levels in combination with a two-fold or more increase in total bilirubin. in the absence of biliary obstruction (cholestasis) or Gilbert's syndrome. Depending on the leading mechanism of hepatocyte necrosis, it is advisable to distinguish the following pathogenetic variants of the cytolytic syndrome, which are taken into account when choosing the tactics of treating LIPP:
- necrosis of hepatocytes without cholestasis and autoimmune disorders, due to increased lipid peroxidation. Biochemical markers: increase in serum ALT, AST with a normal content of alkaline phosphatase (AP), GGTP, gamma globulins;
- Necrosis of hepatocytes with intralobular cholestasis. Biochemical markers: increased levels of ALT, AS, GGTP, possibly alkaline phosphatase, but not more than two norms;
- necrosis of hepatocytes with extralobular (ductular) cholestasis. Biochemical markers: increase in the level of ALT, AST, GGTP, as well as alkaline phosphatase two or more times;
- necrosis of hepatocytes of autoimmune genesis. Biochemical markers: an increase in the level of ALT, AST, gamma globulins by one and a half times or more, circulating immune complexes (CIC), immunoglobulins.
Biochemical markers of cholestasis syndrome are an increase in serum GGTP, alkaline phosphatase and, in some cases, total bilirubin with a predominance of conjugated bilirubin. With intralobular cholestasis, either an isolated increase in the level of GGTP (hepatocellular cholestasis) or an increase in the level of GGTP in combination with an increase not exceeding a twofold level of alkaline phosphatase (canalicular cholestasis) is noted. Extralobular (ductular) cholestasis is characterized by an increase in the level of GGTP and the content of alkaline phosphatase, which exceeds the norm by two or more times. For the syndrome of immune inflammation, along with an increase in the level of ALT and AST, an increase in the content of gamma globulins by one and a half times or more, as well as the CEC and immunoglobulins, is characteristic.
In the presence of a syndrome of hepatocellular insufficiency, a decrease in the prothrombin index or an increase in prothrombin time and, often, the level of albumin is noted. General criteria for hepatotoxicity are presented in Table 1. Table 2 lists factors predisposing to drug-induced hepatotoxicity.
Elimination of the toxic factor is an important point in the elimination of hepatotoxicity. Withdrawal is a primary and one of the main therapeutic measures in any form of ALD. Treatment of LIPP is reduced to the abolition of all drugs, with the exception of those needed for health reasons. As a pathogenetic therapy for hepatotoxicity, hepatoprotectors are used, the selection of which is made taking into account the leading mechanism of the development of the disease. Pathological processes in the liver, in which hepatoprotectors are used: necrosis and fatty infiltration of hepatocytes, intra- and extralobular cholestasis, fibrosis. The main hepatoprotectors used in the treatment of both ALD and LIPP: ursodeoxycholic acid, essential phospholipids, silymarin, components of hepatocellular metabolic cycles: α-lipoic acid, ademethionine. In the presence of a high degree of hepatitis activity, as well as immune-mediated reactions, glucocorticosteroids are used.
According to the results of a number of studies, from the point of view of evidence-based medicine, adenosylmethionine (S-adenosyl-L-methionine) is among the most effective drugs for correcting hepatotoxicity. Adenosylmethionine is a natural substance synthesized endogenously from methionine and adenosine under the influence of the enzyme methionine adenosyltransferase. It is a natural antioxidant and antidepressant, formed in the liver in an amount of up to 8 g / day. and present in all tissues and body fluids, in the highest concentration - in the places of formation and consumption, i.e. in the liver and brain. A decrease in the biosynthesis of hepatic adenosylmethionine is characteristic of all forms of chronic liver damage. It was first described in Italy by G.L. Cantoni in 1952. For the first time, adenosylmethionine appeared on the Russian pharmaceutical market under the name Heptral.
Numerous experimental and clinical studies have proven the effectiveness of adenosylmethionine (Heptral) as a hepatoprotector, which doctors are well aware of and therefore use it in this capacity. There are 7 effects of adenosylmethionine: detoxifying, antioxidant, choleretic, cholekinetic, antidepressant, neuroprotective, regenerating. Most liver diseases are accompanied by a decrease in the activity of this enzyme, which naturally leads to a violation of the production of adenosylmethionine and the course of biological reactions. In the liver, adenosylmethionine acts as a necessary structural element in three important biochemical processes: transmethylation, transsulfonation and aminopropylation. F. Hirata et al. demonstrated the importance of methylation in maintaining the function and integrity of hepatocyte membranes. Adenosylmethionine (Heptral) is the main endogenous methyl group donor in biological transmethylation reactions. It is involved in the synthesis of nucleic acids and protein, plays a major role in the synthesis of polyamines and is a source of cysteine, which is necessary for the formation of glutathione, the main endogenous hepatoprotector.
Glutathione performs a number of essential functions, including the neutralization of free oxygen radicals, the exchange of thiosulfide, the storage and transfer of cysteine, the conjugation and neutralization of reactive metabolites during the biotransformation of xenobiotics. Insufficient glutathione content leads to increased susceptibility to oxidative stress. In hepatic cells, its deficiency also causes inactivation of ademetionine synthetase, which causes further depletion of glutathione in the liver. In addition, adenosylmethionine serves as a precursor to other thiol compounds such as cysteine, taurine, coenzyme A. Along with glutathione, taurine plays an important role in the detoxifying function of the liver. Experimental studies have demonstrated the effectiveness of using adenosylmethionine (Heptral) in the treatment of liver damage caused by carbon tetrachloride, D-galactosamine, acetaminophen, alcohol, etc. . In clinical studies, the use of adenosylmethionine (Heptral) made it possible to postpone liver transplantation and increase survival in patients with alcoholic liver disease. In addition, Heptral gives a beneficial effect in intrahepatic cholestasis that develops in pregnant women and chronic non-alcoholic liver damage. It has been established that adenosylmethionine also has an effect on the exchange of nitric oxide, reducing the production of inducible NO-synthase, and on the cytokine balance, shifting it towards anti-inflammatory cytokines. As an additional positive effect, the antidepressant effect of adenosylmethionine (Heptral) can be noted.
The effectiveness of adenosylmethionine (Heptral) in the treatment of 220 patients with biopsy-proven liver disease was proven in a double-blind, placebo-controlled study. Inclusion criteria were at least a twofold increase in the levels of total and conjugated bilirubin, serum ALP activity. The effectiveness of Heptral at a dose of 1600 mg in relation to clinical and laboratory manifestations of cholestasis was proven compared to placebo. The ability of adenosylmethionine (Heptral) to reduce the lithogenic properties of bile was also demonstrated according to the assessment of the index of saturation of bile with cholesterol. A randomized, double-blind, placebo-controlled, multicenter study was also conducted, which included 123 patients with alcoholic cirrhosis, divided into 2 groups, taking 1200 mg of adenosylmethionine (Heptral) or placebo for 2 years. Mortality and the need for liver transplantation at the end of treatment in the main group was 16% vs. 30% in the placebo group (p = 0.077), and in patients with severe cirrhosis of class C according to Child-Pugh (Child-Pugh), the rate was 12% vs. 29 % (p=0.025) .
A number of studies have shown the high efficiency of adenosylmethionine (Heptral) in the treatment and prevention of drug-induced hepatotoxicity. Moreover, work on the correction of LIPP in the treatment of cancer patients is of particular importance, when the abolition of the drug that caused drug hepatotoxicity significantly worsens the effectiveness of the treatment of the underlying disease and, as a result, the prognosis of life. In a domestic open clinical and biochemical study conducted at the State Institution of Russian Cancer Research Center named after N.I. N.N. Blokhin of the Russian Academy of Medical Sciences, 44 patients with hemoblastoses with hepatocellular insufficiency as a result of drug hepatotoxicity were observed. The treatment regimen included adenosylmethionine (Heptral) at a dose of 400-800 mg intravenously or intramuscularly or 400-800 mg orally 2 times a day. until stable normalization of the functional state of the liver. The duration of the course of treatment was at least 30 days with an extension of the course if necessary. Patients with risk factors for hepatotoxicity were prescribed Heptral for the entire period of chemotherapy. During the recovery period of hematopoiesis in the absence of complications, there was a trend towards a decrease in the levels of markers of cholestasis and cytolysis syndromes (ALT, AST, alkaline phosphatase, GGTP, bilirubin), normalization of the level of malondialdehyde to the initial values. The clinical condition of the patients began to improve by the 8-14th day of treatment and was characterized by normalization of the sleep rhythm or a significant decrease in daytime sleepiness, improved memory, general well-being, weakening of asthenic syndrome and signs of depression, and an increase in the antidyspeptic effect. In 50% of patients, the indicators of psychometric tests normalized, in the rest of the patients they improved. It was noted that the protective effect of adenosylmethionine (Heptral) reduces the number of forced changes in polychemotherapy protocols (PCT) associated with liver damage in most patients.
The obtained effect allowed this team of authors to continue the study in a group of 60 patients with an increase in the dose of Heptral to 800-1600 mg intravenously or intramuscularly or orally at a daily dose of 800/1200-1600 mg. Appointment of adenosylmethionine (Geptral) contributed to the normalization of the redox status with a decrease in the levels of nitric oxide, superoxide dismutase, malondialdehyde and an increase in the values of glutathione and glutathione-S-transferase. Against this background, there was a significant decrease in the levels of markers of cytolysis and cholestasis. In continuation of the study of the effectiveness of the use of Heptral for the prevention and treatment of hepatotoxicity in cancer patients, N.N. Blokhin RAMS conducted a clinical observation on the use of the drug in a group of 19 patients with various malignant tumors and normal initial levels of transaminases in the treatment of hepatotoxicity induced by chemotherapy. The use of Heptral at a dosage of 400 mg 2 times / day. within 4 weeks. in patients with I degree of hepatotoxicity on the background of PCT allowed to completely eliminate the manifestations of cytolysis in 83.3% of patients without changing the PCT regimens. Extension of the course of therapy for another 2 weeks. ensured the normalization of serum transaminases in 100% of patients in this group. The use of Heptral at a dose of 400 mg 2 times / day. stabilized the level of ALT and AST in patients with II degree of hepatotoxicity, keeping the level of transaminases at the lower limit in this group. This allowed patients to receive PCT in full and on schedule. To normalize serum transaminases in patients with grade II hepatotoxicity, the course of therapy with Heptral was extended to 2-4 months. without deviations from the PCT regimen. Heptral when administered orally 400 mg 2 times / day. did not cause adverse reactions and was well tolerated by patients. Thus, Heptral was recommended as an accompanying therapy in the treatment of hepatotoxicity that occurred during cytostatic PCT.
Evidence is also a series of studies conducted by Italian researchers on the prevention and correction of drug-induced hepatotoxicity in cancer patients. D. Santini et al. in 2003 published the results of an open study, which was conducted among the oncological population of elderly patients (median age was 63 years). The study included patients with malignant tumors and hepatotoxicity that first developed on the background of chemotherapy; as a criterion for hepatotoxicity, an increase in transaminases in the range of 2.5-4 norms was considered. Patients were prescribed adenosylmethionine at a dose of 400 mg 2 times a day. during and in the interval between courses of chemotherapy. The study revealed a decrease in the activity of transaminases and cholestasis enzymes by more than 30% in each of the patients, regardless of the presence or absence of liver metastases. As a result of the treatment, only one patient needed to reduce the dose of chemotherapy, and only three patients needed to delay subsequent courses. At the same time, there were no side effects of adenosylmethionine during treatment. The protective effect was maintained throughout subsequent courses of chemotherapy, significantly reducing the frequency of transferring courses or reducing the dose of chemotherapeutic drugs due to elevated levels of transaminases.
In another randomized, controlled, double-blind study, S. Nei et al. evaluated the effectiveness of Heptral for the prevention of drug-induced hepatitis induced by the immunosuppressant cyclosporine. The study included patients with severe exudative psoriasis, who were divided into two equal groups. Patients of the first group, in addition to the main treatment with cyclosporine, received adenosylmethionine (Heptral) at a dose of 400 mg 1 time / day; patients of the second (control) group did not receive metabolic therapy. During the study, half of the patients in the control group showed an increase in transaminases and alkaline phosphatase, while patients in the main group did not have an increase in liver enzymes in any case, which allowed them to successfully complete the course of treatment with cyclosporine.
In 2011, the results of a retrospective study of the role of adenosylmethionine in the prevention of hepatotoxicity in 105 patients with colorectal cancer who received adjuvant therapy with FOLFOX (fluorouracil + calcium folinate + oxaliplatin) were published. The patients were randomized into 2 groups: in the comparison group they received only PCT, in the main group 60 patients also received adenosylmethionine (Heptral) 400 mg 2 times a day during the entire course of chemotherapy. intravenously. Hepatotoxicity was recorded significantly and significantly less frequently in the group treated with adenosylmethionine (Heptral), and its severity was significantly lower than in the comparison group. Accordingly, in the first group, the course transfer, dose reduction or treatment withdrawal occurred in 71% of patients, while in the group receiving adenosylmethionine (Heptral), treatment protocol violations were noted only in 14% of cases. By the end of treatment with adenosylmethionine (Heptral), a significant decrease in such markers of cytolysis and cholestasis as AST and ALT, GGTP, and total bilirubin was revealed. ALP and LDH levels also tended to decrease.
A similar study design was used in the observation of 78 patients with metastatic colorectal cancer. Patients were randomized into 2 groups: 46 patients received bevacizumab + XELOX regimen (oxaliplatin + capecitabine) for 3 weeks, and 32 patients received intravenous adenosylmethionine (Heptral) 400 mg 2 times a day in addition to antitumor treatment. The medians of all markers of hepatotoxicity, except for ALP, in the second group were significantly lower than in the first. As in the authors' study, hepatotoxicity was recorded significantly less frequently in the group treated with adenosylmethionine (Heptral), and its severity was significantly lower than in the comparison group. A change in the treatment protocol in the form of course transfer, dose reduction, chemotherapy cancellation in the first group was recorded in all 100% of patients against 37.5% in the second group.
The effectiveness of Heptral was also demonstrated in a domestic retrospective multicenter case-control study on a model of combined and complex treatment of breast cancer (BC). More than 4200 archival case histories and 2900 outpatient records of patients with breast cancer were analyzed in 4 clinics in Moscow and Samara from 1993 to 2003. The study included 1643 patients treated/consulted in accordance with the medical and economic standards of breast cancer. In total, acute hepatotoxicity in accordance with the criteria of the National American Institute for Research on Cancer during mandatory visits was detected in 439 (26.7%) patients. Only in 158 (36.0%) of their number of patients, due to the hepatotoxicity detected during scheduled visits, measures were taken to correct it. The data obtained allowed us to conclude that there was a high frequency of drug-induced hepatotoxicity during PCT in cancer patients, which required the corrective prescription of hepatoprotectors. During the study, a large evidence base was obtained, indicating the high effectiveness of the use of Heptral for these patients. The expediency of prescribing the drug to patients with risk factors for hepatotoxicity was confirmed. The authors determined the most effective two-stage administration of Heptral: first, intravenous administration, followed by a transition to oral long-term administration.
It is known that in ALD there is a decrease in the activity of phosphatidylethanolamine methyltransferase. Normally, phosphatidylcholine is formed from phosphatidylethanolamine by methylation with the participation of adenosylmethionine. In addition, in patients with ALD, the content of adenosylmethionine in the liver is reduced already at the stage of steatosis, while the activity of S-adenosylmethionine synthetase remains normal. A decrease in adenosylmethionine correlates with indicators of oxidative stress, such as an increase in the level of 4-HNE (one of the toxic aldehydes) and a decrease in the level of glutathione, which is associated with damage to mitochondria. In the body, adenosylmethionine is formed during the conversion of methionine with the participation of ATP and the enzyme S-adenosylmethionine synthetase into homocysteine and the antioxidants cysteine and glutathione. As a result of these effects, the elimination of free radicals and other toxic metabolites from hepatocytes increases. On the other hand, translocation of lipopolysaccharides through the intestinal wall plays an important role in the pathogenesis of AH. Lipopolysaccharide in complex with lipopolysaccharide-binding protein interacts with CD14 on the Kupffer cell membrane.
Based on the results of experimental and clinical studies, the famous J.M. Mato to evaluate the effectiveness of treatment with adenosylmethionine (1.2 g/day) in 123 patients with alcoholic cirrhosis in a double-blind, randomized, placebo-controlled, multicenter study over 24 months. In 84% of patients, the diagnosis was confirmed histologically. In assessing the severity of cirrhosis, 75 patients were classified as Child-Pugh A, 40 as class B, and 8 as class C. The effectiveness of treatment was assessed based on survival rates or liver transplantation for a period of less than 2 years. Overall mortality at the end of the studies was 16% in the adenosylmethionine group and 30% in the placebo group, although the difference was not statistically significant. When patients with advanced cirrhosis (class C) were excluded from the group receiving adenosylmethionine, the indicator "total mortality - liver transplantation" became significantly higher in the placebo group compared with those treated with adenosylmethionine (p = 0.046). These results confirm that long-term use of adenosylmethionine may improve survival or prolong liver transplantation in patients with alcoholic cirrhosis, especially those with compensated and subcompensated stages. Thus, the use of ademetionine in patients with ALD reduces liver damage by preventing a decrease in the level of endogenous adenosylmethionine and glutathione. It is optimal to prescribe adenosylmethionine to patients with compensated and subcompensated cirrhosis and milder forms of ALD.
Treatment is recommended for a long time - from several months to a year or more. With long-term use, adenosylmethionine improves the life expectancy of patients with ALD. Clinical studies indicate that the use of Heptral in the treatment of ALD increases the level of glutathione in the liver tissue, and also positively affects the survival of these patients (especially in severe forms of the disease). In patients with alcoholic cirrhosis of classes A and B (Child-Pugh classification), the use of Heptral leads to a decrease in mortality from 29 to 12%.
Therapeutic tactics for mild to moderate hypertension was determined as follows. Patients with mild to moderate hypertension with DF<32, без признаков печеночной энцефалопатии, а также те, у которых отмечена тенденция к нормализации показателей сывороточного билирубина и снижению индекса Маддрея в течение первой недели госпитализации, нуждаются в тщательном наблюдении, абстиненции и нутритивной поддержке. Применение глюкокортикостероидов в данном случае не оправдано. Пациентам с ЦП классов А и В по Чайлд-Пью и более легкими формами АБП целесообразно назначение аденозилметионина (Гептрала) в дозе 1200 мг/сут., предпочтительно на период не менее 1 года. При длительном применении никаких серьезных побочных действий препарата не зарегистрировано. Кроме того, в ряде работ отмечена хорошая приверженность пациентов к лечению на фоне приема Гептрала .
An important aspect of the use of Heptral is its antidepressant effect, tk. emotional problems occur in almost every alcohol abuse patient with symptoms of general depression and affective disorders. Depression can lead to increased alcohol abuse, creating a vicious cycle. Often, depression accompanies diseases that require the use of PCT and a number of other long-term medications, which is associated with both the underlying disease and the side effects of certain drugs. According to statistics from the World Health Organization, 4-5% of the world's population suffers from depression, while the risk of developing a major depressive episode is 15-20%. According to various authors, from 60 to 85% of chronic diseases of the digestive system are accompanied by emotional disorders of varying severity. A special place in the structure of depression in the group of patients under consideration is occupied by masked (somatized) depressions, in the clinical picture of which somatic symptoms come to the fore, and psychopathological manifestations remain in the shadows, i.e. the depressive affect is hidden behind a variety of bodily sensations. Depressive states - both overt and masked - are widespread in gastroenterology, where their frequent combination with functional gastrointestinal pathology and chronic diffuse liver diseases significantly complicates treatment and reduces the quality of life of patients. The mainstay of treatment for depression is adequate duration of antidepressants.
At the same time, antidepressants themselves can have a hepatotoxic effect. According to the severity of this effect, drugs can be divided into three groups: with a low risk of hepatotoxic effects (paroxetine, citalopram, mianserin, tianeptine - these drugs can be prescribed to patients with concomitant severe liver pathology in normal doses); with moderate risk (amitriptyline, trazodone, fluoxetine, moclobemide - they can be prescribed to patients with severe liver pathology in reduced daily doses); with a high risk of hepatotoxicity (sertraline).
Heptral combines the properties of a hepatoprotector and has a pronounced antidepressant activity; moreover, it is regarded as an atypical stimulant antidepressant. The antidepressant activity of adenosylmethionine (Heptral) has been known for more than 20 years, but a general concept that would explain the mechanism of the antidepressant action of this compound has not yet been developed. Obviously, it differs from the mechanism of action of antidepressants of all currently known chemical groups. Adenosylmethionine (Heptral) is usually referred to as atypical antidepressants, and its neuropharmacological properties are associated with stimulating the formation of neurotransmitters.
The first observations confirming the effectiveness of adenosylmethionine in depression were published in the 1970s. Clinical studies have been performed in Germany, Italy, UK and USA. The results confirmed that when administered intravenously or intramuscularly, Heptral is significantly more effective than placebo. Some studies have found that oral adenosylmethionine at a daily dose of 1600 mg is effective in patients with depression. Currently, Heptral is used in psychiatric practice precisely as an antidepressant for the treatment of depression, alcoholism, drug addiction and affective disorders.
A meta-analysis of the results of 19 comparative clinical studies involving 498 patients suffering from depression of varying severity confirmed a statistically significant superiority of Heptral therapy compared to placebo (by 38-60%). Heptral was statistically significantly more effective than placebo in recurrent endogenous and neurotic depression resistant to amitriptyline, differing from the latter in the ability to interrupt relapses and the absence of side effects. Almost all researchers noted a faster development and stabilization of the antidepressant effect of Heptral (1st and 2nd weeks, respectively) compared with traditional antidepressants, especially when used parenterally.
In an open multicenter clinical study in 195 patients with depression, remission occurred after 7-15 days of parenteral administration of the drug at a dose of 400 mg / day. The positive effect of therapy was most clearly manifested in somatized depression. Clinical signs of improvement were noted from the 2nd week. treatment, which was expressed by the reduction of somatized disorders and hypothymia itself. Subjectively, the action of Heptral is characterized by the normalization of muscle tone, increased activity, improved exercise tolerance, and restoration of the ability to experience pleasure. The drug is recommended for use in the treatment of non-psychotic depression, in particular asthenic. Therefore, adenosylmethionine (Heptral), especially in view of its somatotropic action, is one of the preferred agents for use in general medical practice. The drug is recommended for the treatment of depression in daily doses of 400-1600 mg, however, in some cases, a daily dose of more than 3000 mg is required to achieve an antidepressant effect. The antidepressant properties make Heptral of particular importance in people suffering from alcohol dependence and in connection with dysphoric conditions and other affective disorders that complicate the symptoms of psychoactive substance withdrawal.
Thus, the problem of hepatotoxicity is quite relevant. The main method of treatment of this pathology is the elimination of hepatotoxic agents. To quickly restore the structure and functions of the liver, hepatoprotective agents are used, the selection of which is based on taking into account the main pathogenetic mechanisms of development and the nature of morphological changes in the liver. In many cases, the doctor is faced with the problem of the impossibility of canceling the main drug that caused drug-induced liver damage. Heptral can be recommended as an accompanying therapy in the treatment of hepatotoxicity of any etiology.
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Mechanisms of hepatotoxicity
There are many different mechanisms for the implementation of the hepatotoxic effect.
Drugs or toxins that have true direct hepatotoxicity are those chemicals that have predictable dose-response curve (higher doses or concentrations of a substance cause a greater hepatotoxic effect, more severe liver damage) and have well-known and studied mechanisms of hepatotoxic action, such as direct damage to hepatocytes or blockade of certain metabolic processes in the liver.
A typical example of true direct hepatotoxicity is the hepatotoxicity of acetaminophen (paracetamol) in overdose, associated with the saturation of its usual pathway of metabolism, which has a limited capacity, and the inclusion of an alternative pathway for the biotransformation of acetaminophen, which produces a toxic highly reactive nucleophilic metabolite. At the same time, in itself, the inclusion of an alternative pathway for the biotransformation of acetaminophen does not yet lead to liver damage. Direct damage to hepatocytes results from the accumulation of the toxic metabolite of acetaminophen in such quantities that it cannot be effectively neutralized by binding to glutathione. At the same time, the reserves of glutathione in the liver are depleted, after which the reactive metabolite begins to bind to proteins and other structural elements of the cell, which leads to its damage and death.
Direct hepatotoxicity usually occurs shortly after a certain "threshold" level of the concentration of a toxic substance in the blood or a certain duration of toxic exposure has been reached.
Metabolism of drugs in the liver
Many conventional drugs are metabolized in the liver. This metabolism can vary significantly from person to person, due to genetic differences in the activity of drug biotransformation enzymes.