Liver failure with cancer chemotherapy

There is no generally accepted definition of hepatic insufficiency (PN). Many clinicians under the PN understand the syndrome that develops in acute or chronic liver diseases, its main pathogenetic mechanism is liver-cell insufficiency and portal hypertension.

[1], [2], [3], [4], [5], [6], [7],

Epidemiology

Drug hepatitis of varying severity is developed in 2-10% of hospitalized patients with cancer.

[8], [9], [10]

Causes

In elderly patients, the hepatotoxic effect of drugs increases, which contributes to the development of liver failure, this is due to a decrease in the activity of enzymes involved in biotransformation of drugs, a decrease in liver volume and a decrease in hepatic blood flow.

[11],

How does hepatic insufficiency develop with cancer chemotherapy?

Metabolism of drugs in the liver can, although somewhat conditionally, be divided into phases:

• Phase 1 - metabolism involving the system of microsomal fraction of hepatocytes, monooxygenases, cytochrome-C reductase and cytochrome P450. A universal cofactor in these systems is the restored NADP.
• Phase 2 - the biotransformation to which drugs or their metabolites are exposed, the essence of the phase is the conjugation of metabolites with endogenous molecules. Enzyme systems providing conjugation are not specific for the liver, they are detected in a sufficiently high concentration.
• Phase 3 - active transport and excretion of biotransformed products with bile and urine.

There are several main mechanisms of drug damage to the liver:

• Violation of metabolic processes in hepatocytes (especially the acinus zone).
• Toxic destruction of subcellular structures.
• Induction of immune reactions.
• Carcinogenesis.
• Disturbance of blood supply of hepatocytes.
• Exacerbation of a previously existing hepatocellular lesion.

List of hepatotoxic drugs

Symptoms of hepatic failure in cancer chemotherapy

Clinico-morphological manifestations of medicinal liver lesions are classified into necrosis of hepatocytes of the III and I zones of the acini, mitochondrial cytopathies, steatohepatitis, liver fibrosis, vascular lesions, acute and chronic hepatitis, hypersensitivity reactions, acute and chronic cholestasis, cholangitis, biliary stasis.

Necrosis of hepatocytes of the III zone of the acini occurs with the use of paracetamol, salicylates, cocaine. Damage to hepatocytes in this type of drug damage to the liver is caused by active metabolites of drugs that have a high polarity. These intermediates have a pronounced alkylating or acetylating effect, which is accompanied by a decrease in intracellular detoxification and is characterized by a significant decrease in the content of glutathione (endogenous peptide), one of the most important intracellular detoxifying agents. The features of the clinical course include the defeat of other organs and systems, in particular the kidneys, which is expressed by a violation of their functions, up to the development of OPN.

Necrosis of hepatocytes of the 1st zone of the acini causes iron preparations and organophosphorus compounds when ingested in large doses. There are no obvious signs of involvement in the kidney process in the clinical picture, however, gastrointestinal (gastritis and enteritis) lesions are often observed.

Mitochondrial cytopathies are associated with the administration of tetracycline antibiotics (doxycycline) and nucleoside analogues for the treatment of viral infections (didanosine, zidovudine). The mechanism of toxic action is due to the blockade of respiratory chain enzymes in the mitochondria. Morphological features of the defeat of the hepatic parenchyma are characterized by necrosis of hepatocytes, mainly in zone III. From the clinical point of view, the development of hyperammonemia, lactate-acidosis, hypoglycemia, dyspeptic syndrome and polyneuropathies are observed.

Steatogepatitis is caused by the use of synthetic estrogens, antagonists of calcium ions and antimalarial drugs. Clinically, the lesion is represented very widely from an asymptomatic increase in the activity of transaminases to the development of fulminant liver failure (2-6% of cases of drug damage of this type), it is also possible to develop a cholestatic syndrome.

Fibrosis of the liver is associated with the use of cytostatics, retinoids, arsenic compounds. Fibrosis of one or another degree of severity as a morphological process develops with damage to the hepatic parenchyma of almost any type. However, in some variants of drug damage of the liver, this morphological sign is the main one, while the fibrous tissue is formed mainly in perisinusoidal spaces, causing a disturbance of blood flow in the sinusoids and to a much lesser extent a violation of the function of hepatocytes. The clinical manifestation is noncyrrotic portal hypertension.

Vascular damage is represented by peliosis, veno-occlusive disease and sinusoids. When the patient is examined, hepatic enlargement, ascites, marked cytolysis and minor jaundice in the initial stage are revealed.

• The expansion of sinusoids is mainly localized in the I zone of the acinus, the process is observed when using contraceptives, anabolic steroids and azathioprine.
• Pelion is a morphological variant of drug damage of the liver, in which large cavities filled with blood are formed. Such liver damage is caused by the use of contraceptives, androgens, anabolic steroids, antiestrogen drugs (tamoxifen), antigonadotropic drugs.
• Venokoklyuzionnaya disease is most often associated with the use of cytostatics (cyclophosphamide, urea derivatives) and is characterized by damage to small hepatic veins of the III zone of the acinus, which are particularly sensitive to toxic agents.

Acute hepatitis is described with the use of anti-tuberculosis agents (isoniazid), aminoglycosides, antifungal drugs (ketoconazole, fluconazole), androgens (flutamide), it is impossible to predict the development of acute hepatitis. Defeat of the liver is detected approximately 5-8 days after the start of drug use. The pre-egg period is characterized by nonspecific symptoms of anorexia, dyspepsia, adynamia. In icteric period, achiolia, darkening of urine, hepatomegaly, correlating with an increase in the activity of transaminases are observed. With the withdrawal of the drug, presumably caused the disease, the regression of clinical symptoms is rapid, but the development of fulminant liver failure is possible. Clinically and morphologically distinguish liver damage of this type from acute viral hepatitis is not possible the severity of inflammatory infiltration is different, necroses often develop.

Chronic hepatitis, by its characteristics, resembles autoimmune hepatitis, there are no markers of a viral infection, in some cases it is possible to detect autoantibodies. Chronic drug-induced hepatitis is often detected by chance, without a previously diagnosed episode of acute hepatitis. The morphological pattern is characterized mainly by acinar and periportal localization of lesions, the content of a large number of plasma cells in the infiltrate, sometimes expressed by fibrosis. Of drugs that can cause liver damage of this type, you can note isoniazid, nitrofurans, antibiotics.

Hypersensitivity reactions cause sulfonamides, NSAIDs, antithyroid and anticonvulsants. Morphological picture of "variegated" necrosis, involvement in the process of the gall ducts, significant eosinophilic infiltration of the hepatic parenchyma, formation of granulomas. The clinical picture of liver damage is diverse from manifestations of ordinary acute hepatitis with moderate activity to highly active forms with severe jaundice, arthritis, cutaneous vasculitis, eosinophilia and hemolysis.

Tubular cholestasis develops with the intake of hormonal drugs (androgens, estrogens) containing the cyclopentane perhydrophenanthrene ring. In addition, this pathology of the liver is caused by anabolic steroids, cyclosporin A. The pathophysiology of the process is based on a decrease in the bile flow, which does not depend on bile acids, a decrease in the fluidity of the sinusoids membranes and the contractility of the near-tubular microfilaments, a violation of the density of cell-cell contacts. The morphological sign is the preserved liver architectonics, the cholestatic component affects mainly the III zone of the acinus with the development of a weakly expressed cellular reaction. The main clinical manifestations include pruritus with an insignificant level of bilirubin, a transient increase in the activity of transaminases, while an increase in the activity of alkaline phosphatase (APF) is not always recorded, often it remains within the normal range.

In parenchymal-tubular cholestasis, more significant damage to hepatocytes is noted. The main drugs that cause this type of liver damage are sulfonamides, penicillins, macrolides (erythromycin). The morphological picture is represented by the cholestatic component, mostly in the III and I zones of the acinus, with a pronounced cellular reaction localized mainly in the portal, while in the infiltrate eosinophils are detected in large numbers, possibly also granuloma formation. A clinically distinctive feature is a prolonged cholestatic syndrome (several months or years, despite the withdrawal of the drug).

Intra-flow cholestasis. The ducts and tubules are filled with clots containing bilirubin and concentrated bile, without an inflammatory reaction in the surrounding tissues. This drug damage to the liver is very rare (described a similar reaction when taking only benoxiprofen, whose treatment is currently prohibited).

Bile sludge characterizes the violation of bile passage through the extrahepatic ducts. This phenomenon is caused by a violation of the transport of bile acids in the liver and the excretion of lipids with bile. The change in physicochemical properties of bile is combined with an increase in the content of calcium salts of medicinal preparations. The main drugs, the use of which is associated with the development of the sludge syndrome, are the antibiotics of the cephalosporin group (ceftriaxone, ceftazidime). Clinically, slaj often is asymptomatic, but some patients develop biliary colic.

Sclerosing cholangitis develops when antitumor agents are prescribed (5-fluorouracil, cisplatin) directly into the hepatic artery, X-ray therapy with irradiation of the lower abdomen. The clinical picture is characterized by persistent and persistent cholestasis. The main sign that this complication can be distinguished from the primary sclerosing cholangitis is the intactness of pancreatic ducts.

Diagnostics

[12], [13], [14], [15]

Laboratory research

Clinical and biochemical studies of cell integrity, excretory capacity and cholestasis, liver function, mesenchymal activity and immune response are used to assess hepatocyte damage.

Cell Integrity Study

Clinical symptoms are expressed by intoxication and jaundice of varying severity. Enzyme tests are highly sensitive indicators of cytolysis of hepatocytes, which determines their role in the primary diagnosis of acute hepatitis of different etiologies. Calculate the coefficient of ACT / ALT, normally close to 1. Its decrease of less than 0.7 additionally confirms hepatic, and a rise of more than 1.3 - non-hepatic genesis of hyperfermentemia. A particularly significant decrease in the coefficient is considered as an indicator of severe liver damage. To assess the nature of hyperfermentemia, its hepatogenic dependence, studies of the activity of so-called liver-specific enzymes - sorbitol dehydrogenase (SDG), fructose-1-phosphataldolase, urokinase and some others are used. Heavier damage to the hepatic cell arises from the destruction of mitochondria and is accompanied by an increase in the level of glutamate dehydrogenase (GldgH).

[16], [17], [18], [19], [20], [21]

Study of excretory capacity and cholestasis

Bilirubin exchange rates significantly supplement the clinical assessment of jaundice and determine the degree of damage to the liver parenchyma. More informative are the results of a separate quantitative determination of the free and bound fraction of bilirubin in the blood. The bilirubin ratio characterizes the ratio of the bound fraction to its total content in viral hepatitis and reaches 50-60%, while in physiological conditions the bound fraction is absent or its content does not exceed 20-25%. Clarification of the nature of jaundice (the predominance of cytolysis or cholestasis) is important for the rationale for the patient's treatment plan, the choice of the most rational therapeutic agents. Cholestasis is a functional concept, characterizing the violation of the outflow of bile. Accordingly, not only bile pigments (bilirubinglucuronides) accumulate in the liver and in the blood, as in jaundice of the cytolytic nature, but also other components of bile, bile acids, cholesterol, excretory enzymes, ie alkaline phosphatase, leucine aminopeptidase (LAP), y- glutamintranspeptidase COGT), and with prolonged cholestasis and copper. The appearance of jaundice in itself does not yet indicate the development of cholestasis. Significantly less often, signs of a violation of bile flow are detected with anicteric forms of liver failure. The criterion of cholestasis in this case is the data of ultrasound of the liver, the detection of dilated bile ducts.

Liver function tests

With extensive damage to the liver parenchyma, or fulminant PN, the synthesis of almost all plasma proteins is reduced. Decrease in the level of albumin, cholinesterase (CE) and coagulation factors in plasma accompanies chronic liver diseases.

Study of mesenchymal activity

The study is carried out by determining the levels of y-globulins, immunoglobulins and procollagen-III peptide. Chronic liver diseases are accompanied by increased levels of y-globulins, IgA, IgG and IgM In addition, immunoglobulinemia indicates a pronounced autoimmune process.

Evaluation of the immune response

This method is used for differential diagnosis and evaluation of the course of liver diseases.

[22], [23], [24], [25], [26], [27], [28]

Instrumental research

To confirm the results of various clinical and biochemical studies, instrumental studies of CT, liver scintigraphy, ultrasound and laparoscopy are used.

Treatment of hepatic failure in cancer chemotherapy

The treatment program should be comprehensive and include two main areas (etiotropic and pathogenetic therapies). Etiotropic therapy is aimed at correction of antitumor therapy, it is carried out according to WHO recommendations, which distinguishes five degrees of intensity of side effects of antitumor drugs and manifestations of hepatotoxicity from 0-absence of manifestations to 4-hepatic coma. In view of this, an adjustment of doses of cytostatics has been developed depending on the function of the liver. With the persistent deviation of laboratory indicators from the normal level, it is recommended to stop the antitumor therapy.

Reduction of the dose of anthracyclines by 50%, of other cytostatics by 25% with an increase in the level of total bilirubin by 1.26-2.5 times, transaminase 2-5 times.

Reduction of the dose of anthracyclines by 75%, other cytostatics by 50% with an increase in the level of total bilirubin by 2.6-5 times, transaminases by 5.1-10 times.

In the pathogenetic therapy program, basic and non-specific therapies are given.

Basic therapy is a complex of measures not related to the use of medicines and aimed at providing a protective regime and adequate therapeutic nutrition.

Nonspecific drug therapy includes normalization of amino acid and electrolyte homeostasis, achievement of a positive nitrogen balance, prevention and treatment of PE, as well as detoxification and metabolic therapy.

Medication

Drug therapy involves the use of targeted drugs for liver damage, drugs that reduce the absorption of ammonia formed in the large intestine, and drugs that improve the formation of ammonia in the liver.

Preparations that reduce the formation, absorption of ammonia and other toxins that form in the large intestine.

Lactulose 10-30 ml 3 times a day, lactitol 0.3-0.5 g / kg per day. The dose is selected individually, it is optimal, if the appointment achieves a soft stool 2-3 times a day.

Antibiotics (rifaximin, ciprofloxacin, metronidazole). The effectiveness of antibiotics is similar to that of lactulose. In addition, antibiotics quickly stop the symptoms of PE and are better tolerated than lactulose. A significant disadvantage of antibiotic treatment is the limited duration of their use (5-7 days).

Arsenal of targeted drugs with liver damage is small. Ademetionine, ursodeoxycholic acid (UDCA), essential phospholipids, flumecinol, and metadoxine can be classified.

Ademethionine is produced in vials with lyophilizate for injections and tablets in the enteric coating. The drug is initially administered parenterally for 5-10 ml (400-800 mg) intravenously or intramuscularly for 10-14 days, then 400-800 mg (1-2 tablets) 2 times a day. The duration of treatment is 30 days. If necessary, it is possible to extend or repeat the course. Patients at risk should constantly receive ademetionine throughout the chemotherapy Contraindications to the appointment of ademetionine is not established.

Indications for use:

• the appearance of jaundice and hyperfermentemia (an increase in transaminases 5 times or more) with toxic or viral hepatitis, with cholestasis,
• patients initially infected with hepatitis B and C viruses,
• prevention of hepatotoxicity in patients who had a history of liver damage in previous courses of polychemotherapy,
• reduction of already developed manifestations of hepatopathy,
• planned high-dose polychemotherapy,
• bone marrow transplantation.

UDCA - tertiary bile acid, formed in the hepatocytes and intestines, is hydrophilic and non-toxic. When prescribing drugs, the following mechanisms are considered: choleretic, immunomodulating, choleretic, antifibrotic, and cytoprotective effects, which are directed to hepatocytes and bile ducts. Assign 10-15 mg / kg per day to the resolution of cholestasis. Cholagogue agents help maintain bile secretion and prevent bile condensation. Recommended use of drugs only after the termination of complete achiolia, otherwise stimulation of bile secretion can provoke biliary hypertension and promote the progression of cholestasis.

Choleretic zhelchesoderzhashchie drugs bile (used after eating), vegetable flowers immortelle, corn stigmas, choleretic collections, flakumin, tanatshehol, rosehips rosehip extract, fat-soluble vitamins retinol + vitamin E, vitamin E, retinol.

Phospholipids, or phosphoglycerides are classified as a class of highly specialized lipids, they are esters of glycerophosphoric acid. Their main function is the formation of a double lipid layer in the cell membranes. The recommended mode of taking phospholipids + multivitamins is 2 capsules 2-4 times a day for at least 2-3 months, phospholipids - 2-4 ampoules of 5 ml for 4-6 weeks (1 ampoule contains 250 mg of essential phospholipids), capsules prescribe 3 once a day, 4-6 weeks (before meals). When prescribing drugs of this group, it is possible to achieve clinically significant effects:

• decrease in the level of indicator hepatic enzymes in blood plasma,
• weakening of lipid peroxidation,
• reduction of the degree of membrane damage,
• acceleration of hepatocyte regeneration,
• improve metabolic processes that occur in the liver.

Flumecinol is classified as a group of phenobarbital-type inducers. When it is administered, a significant increase in the total content of the key enzyme of the cytochrome P450 monooxygenase system is noted, and the activity of the microsomal liver enzyme glutathione-B transferase is increased. Flumecinol administration is indicated for patients initially infected with hepatitis B and C viruses, and in patients with a history of significant liver reactions to prior therapy. The recommended regimen for flumecinol is 10 mg / kg body weight (but not more than 800 mg) once a week. To reduce the already developed manifestations of hepatopathy - 1-2 medications, to prevent manifestations of hepatotoxicity, you need a constant intake of the drug throughout the chemotherapy.

Metadoxine is an ion pair of pyridoxine and pyrrolidone of carboxylic acid. The drug is prescribed firstly inside 5-10 ml (300-600 mg) intravenously or intramuscularly for 10-14 days, and then 500-1000 mg (1-2 tablets) 2 times a day. With intravenous administration, the required dose of the drug is diluted in 500 ml of isotonic sodium chloride solution or in 5% glucose solution and injected for 1.5 hours. The course duration is 30 days. If necessary, it is possible to extend or repeat the course. The use of metadoxine can improve the subjective state of patients, reduce signs of depression. The purpose of metadoxine is shown:

• patients who had an anamnesis of alcoholic liver damage,
• patients with anamnesis who have information about toxic liver reactions in previous courses of polychemotherapy,
• with the planned high-dose polychemotherapy,
• when bone marrow transplantation.

A drug that improves the formation of ammonia in the liver - ornithine aspartate affects certain parts of impaired hepatic metabolism and the pathogenesis of PE. The granulate is dissolved in 200 ml of liquid and taken after meals, the infusion solution concentrate is dissolved in 500 ml of the infusion solution. Patients with chronic hepatic insufficiency in the period of remission are recommended to take oral doses of ornithine at 9-18 g per day.

Scheme of application of ornithine

Granulate	Concentrate for infusion
Chronic hepatitis of various genesis (including viral, alcoholic toxic), fatty degeneration	Chronic hepatitis of various genesis (in viral, alcoholic toxic), fatty degeneration
With severe symptoms, 3 times 2 packets of granulate per day	At the expressed neurologic symptomatology (high dosage) to 4 ampoules a day
With medium-sized symptoms 2-3 times per 1 packet of granulate per day	Cirrhosis of the liver with a mild symptomatology of 1-4 ampoules a day
Cirrhosis of the liver with severe symptomatology of PE 3 times per 1-2 packets of granulate per day, depending on the severity of the disease	Cirrhosis of the liver with severe PE symptoms with mental disorders (precoma) or a coma up to 8 ampoules a day