Liver failure with cancer chemotherapy

There is no generally accepted definition of liver failure (LF). Many clinicians understand LF as a syndrome that develops in acute or chronic liver diseases, its main pathogenetic mechanism is hepatocellular failure and portal hypertension.

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Epidemiology

Drug-induced hepatitis of varying severity develops in 2-10% of hospitalized cancer patients.

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Reasons

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 the biotransformation of drugs, a decrease in liver volume and a decrease in hepatic blood flow.

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How does liver failure develop during cancer chemotherapy?

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

• Phase 1 - metabolism involving the microsomal fraction of hepatocytes, monooxygenases, cytochrome C reductase and cytochrome P450. The universal cofactor in these systems is reduced NADP.
• Phase 2 - biotransformation, which drugs or their metabolites undergo, the essence of the phase is the conjugation of metabolites with endogenous molecules. Enzyme systems that provide conjugation are not specific to the liver, they are found in fairly high concentrations.
• Phase 3 - active transport and excretion of biotransformed products with bile and urine.

There are several main mechanisms of drug-induced liver damage:

• Disruption of metabolic processes in hepatocytes (especially the acinus zone).
• Toxic destruction of subcellular structures.
• Induction of immune responses.
• Carcinogenesis.
• Disruption of blood supply to hepatocytes.
• Exacerbation of pre-existing hepatocellular damage.

List of hepatotoxic drugs

Symptoms of Liver Failure During Cancer Chemotherapy

Clinical and morphological manifestations of drug-induced liver damage are classified into necrosis of hepatocytes of zones III and I of the acini, mitochondrial cytopathies, steatohepatitis, liver fibrosis, vascular damage, acute and chronic hepatitis, hypersensitivity reactions, acute and chronic cholestasis, cholangitis, bile stasis.

Hepatocyte necrosis of the III acinus zone occurs when using paracetamol, salicylates, and cocaine. Hepatocyte damage in this type of drug-induced liver injury is caused by active drug metabolites that have 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 clinical course includes damage to other organs and systems, in particular the kidneys, which is expressed by a violation of their functions, up to the development of acute renal failure.

Necrosis of hepatocytes of the first zone of the acinus is caused by iron preparations and organophosphorus compounds when taken orally in large doses. In the clinical picture, there are no pronounced signs of kidney involvement in the process, but damage to the gastrointestinal tract (gastritis and enteritis) is often observed.

Mitochondrial cytopathies are associated with the use 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 mitochondria. Morphological features of liver parenchyma damage are characterized by hepatocyte necrosis, mainly in zone III. From a clinical point of view, hyperammonemia, lactic acidosis, hypoglycemia, dyspeptic syndrome and polyneuropathies are observed.

Steatohepatitis is caused by the use of synthetic estrogens, calcium ion antagonists and antimalarial drugs. Clinically, the lesion is presented very widely from asymptomatic increase in transaminase activity to the development of fulminant liver failure (2-6% of cases of drug-induced damage of this type), and the development of cholestatic syndrome is also possible.

Liver fibrosis is associated with the use of cytostatics, retinoids, and arsenic compounds. Fibrosis of varying degrees of severity as a morphological process develops with damage to the liver parenchyma of virtually any type. However, in some variants of drug-induced liver damage, this morphological feature is the main one, with fibrous tissue forming primarily in the perisinusoidal spaces, causing impaired blood flow in the sinusoids and, to a much lesser extent, impaired hepatocyte function. Clinical manifestation - non-cirrhotic portal hypertension.

Vascular lesions are represented by peliosis, veno-occlusive disease and dilation of sinusoids. Examination of the patient reveals an enlarged liver, ascites, pronounced cytolysis and slight jaundice in the initial stage.

• The expansion of the sinusoids is mainly localized in zone I of the acinus; the process is observed with the use of contraceptives, anabolic steroids and azathioprine.
• Peliosis is a morphological variant of drug-induced liver damage, in which large cavities filled with blood are formed. This liver damage is caused by the use of contraceptives, androgens, anabolic steroids, anti-estrogen drugs (tamoxifen), and antigonadotropic drugs.
• Veno-occlusive disease is most often associated with the use of cytostatics (cyclophosphamide, urea derivatives) and is characterized by damage to the small hepatic veins of the third zone of the acinus, which are particularly sensitive to toxic agents.

Acute hepatitis has been 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. Liver damage is detected approximately 5-8 days after the start of drug intake. The pre-icteric period is characterized by non-specific symptoms of anorexia, dyspepsia, adynamia. In the icteric period, achola, darkening of urine, hepatomegaly, correlating with an increase in transaminase activity, are observed. When the drug that presumably caused the disease is discontinued, regression of clinical symptoms occurs quickly, but fulminant liver failure may develop. It is impossible to clinically and morphologically distinguish liver damage of this type from acute viral hepatitis; the severity of inflammatory infiltration varies, and necrosis often develops.

Chronic hepatitis resembles autoimmune hepatitis in its symptoms: there are no markers of viral infection, and in some cases autoantibodies may be detected. Chronic drug-induced hepatitis is often detected by chance, without a previously diagnosed episode of acute hepatitis. The morphological picture is characterized mainly by acinar and periportal localization of lesions, the presence of a large number of plasma cells in the infiltrate, and sometimes by pronounced fibrosis. Of the drugs that can cause liver damage of this type, isoniazid, nitrofurans, and antibiotics can be noted.

Hypersensitivity reactions are caused by sulfonamides, NSAIDs, antithyroid and anticonvulsants. The morphological picture is "variegated" necrosis, involvement of the bile ducts in the process, significant eosinophilic infiltration of the liver 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 when taking hormonal drugs (androgens, estrogens) containing a cyclopentane perhydrophenanthrene ring. In addition, this liver pathology is caused by anabolic steroids, cyclosporine A. The pathophysiology of the process is based on a decrease in the flow of bile, which does not depend on bile acids, a decrease in the fluidity of sinusoid membranes and the contractility of peri-tubular microfilaments, and a violation of the density of intercellular contacts. The morphological sign is the preserved architectonics of the liver, 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 skin itching with an insignificant level of bilirubin, a transient increase in the activity of transaminases, while an increase in the activity of alkaline phosphatase (AP) is not always recorded, it often remains within normal values.

In parenchymatous-tubular cholestasis, more significant damage to hepatocytes is observed. The main drugs causing this type of liver damage are sulfonamides, penicillins, macrolides (erythromycin). The morphological picture is represented by a cholestatic component, mostly in zones III and I of the acinus, with a pronounced cellular reaction localized mainly portally, while eosinophils are found in large quantities in the infiltrate, and granuloma formation is also possible. A clinically distinctive feature is a long-term cholestatic syndrome (several months or years, despite drug withdrawal).

Intraductal cholestasis. Ducts and tubules are filled with clots containing bilirubin and concentrated bile, without an inflammatory reaction in the surrounding tissues. This drug-induced liver injury is very rare (a similar reaction has been described with the use of only benoxyprofen, treatment with which is currently prohibited).

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

Sclerosing cholangitis develops when antitumor agents (5-fluorouracil, cisplatin) are administered 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 by which this complication can be distinguished from primary sclerosing cholangitis is the intactness of the pancreatic ducts.

Diagnostics

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Laboratory research

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

Cell Integrity Study

Clinical symptoms are expressed by intoxication and jaundice of varying severity. Enzyme tests are highly sensitive indicators of hepatocyte cytolysis, which determines their role in the primary diagnostics of acute hepatitis of various etiologies. The AST/ALT ratio is calculated, normally close to 1. Its decrease to less than 0.7 additionally confirms the liver, and an increase to more than 1.3 - non-liver genesis of hyperenzymemia. A particularly significant decrease in the ratio is considered an indicator of severe liver damage. To assess the nature of hyperenzymemia, its hepatogenic dependence, studies of the activity of the so-called liver-specific enzymes are used - sorbitol dehydrogenase (SDH), fructose-1-phosphate aldolase, urokinase and some others. More severe damage to the liver cell occurs due to the destruction of mitochondria and is accompanied by an increase in the level of glutamate dehydrogenase (GLD).

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Excretory capacity and cholestasis study

Bilirubin metabolism indices significantly supplement the clinical assessment of jaundice and determine the degree of damage to the liver parenchyma. The results of separate quantitative determination of free and bound fractions of bilirubin in the blood are more informative. The bilirubin index characterizes the ratio of the bound fraction to its total content in viral hepatitis and reaches 50-60%, while under physiological conditions the bound fraction is absent or its content does not exceed 20-25%. Clarification of the nature of jaundice (predominance of cytolysis or cholestasis) is important for substantiating the patient's treatment plan and choosing the most rational therapeutic agents. Cholestasis is a functional concept characterizing a violation of bile outflow. Accordingly, not only bile pigments (bilirubin glucuronides), as in jaundice of cytolytic nature, but also other components of bile (bile acids, cholesterol, excretory enzymes, i.e. alkaline phosphatase, leucine aminopeptidase (LAP), y-glutamyl transpeptidase (SGT), and in case of prolonged cholestasis, copper) accumulate in the liver and blood. The appearance of jaundice in itself does not indicate the development of cholestasis. Signs of impaired bile outflow are much less common in anicteric forms of liver failure. The criterion for cholestasis in this case is the ultrasound data of the liver, the detection of dilated bile ducts.

Liver function tests

In case of extensive damage to the liver parenchyma, or fulminant PN, the synthesis of almost all plasma proteins is reduced. A decrease in the level of albumin, cholinesterase (ChE) and coagulation factors in the plasma accompanies chronic liver diseases.

Study of mesenchymal activity

The study is conducted 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 pronounced autoimmune processes.

Evaluation of the immune response

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

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Instrumental research

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

Treatment of liver failure during cancer chemotherapy

The treatment program should be comprehensive and include two main areas (etiotropic and pathogenetic therapy). Etiotropic therapy is aimed at correcting 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 - no manifestations to 4 - hepatic coma. Taking this into account, an adjustment of cytostatic doses has been developed depending on liver function. If laboratory parameters continue to deviate from the normal level, it is recommended to discontinue antitumor therapy.

Reducing the dose of anthracyclines by 50%, other cytostatics by 25% with an increase in the level of total bilirubin by 1.26-2.5 times, transaminases by 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.

The pathogenetic therapy program distinguishes between basic and non-specific therapy.

Basic therapy is a set of measures not associated with the use of medications and aimed at ensuring a protective regimen and adequate therapeutic nutrition.

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

Drug treatment

Drug therapy involves the use of drugs with a targeted effect on liver damage, drugs that reduce the absorption of ammonia formed in the colon, and drugs that improve the formation of ammonia in the liver.

Drugs that reduce the formation and absorption of ammonia and other toxins formed in the colon.

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 soft stool is achieved 2-3 times a day when prescribed.

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

The arsenal of drugs with targeted action for liver damage is small. These include ademetionine, ursodeoxycholic acid (UDCA), essential phospholipids, flumecinol, and metadoxine.

Ademetionine is available in vials with lyophilisate for injections and tablets in an enteric coating. The drug is initially prescribed parenterally at 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 the course of treatment is 30 days. If necessary, it is possible to extend or repeat the course. Patients at risk require constant intake of ademetionine throughout the chemotherapy. There are no contraindications to the use of ademetionine.

Indications for use:

• the appearance of jaundice and hyperfermentemia (increase in transaminases by 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 with a history of liver damage from previous courses of polychemotherapy,
• reduction of already developed manifestations of hepatopathy,
• planned high-dose polychemotherapy,
• bone marrow transplant.

UDCA is a tertiary bile acid formed in hepatocytes and the intestine, hydrophilic and non-toxic. When prescribing drugs, the following mechanisms are taken into account: choleretic, immunomodulatory, choleretic, antifibrotic action, as well as cytoprotective effect, which is aimed at hepatocytes and bile ducts. Prescribed at 10-15 mg / kg per day until cholestasis is resolved. Choleretic agents help maintain bile secretion and prevent bile thickening. It is recommended to use drugs only after complete acholia has ceased, otherwise stimulation of bile secretion can provoke biliary hypertension and contribute to the progression of cholestasis.

Choleretic bile-containing drugs bile (used after meals), immortelle flowers, corn silk, choleretic infusions, flacumin, tanacehol, rosehip fruit extract, fat-soluble vitamins retinol + vitamin E, vitamin E, retinol.

Phospholipids, or phosphoglycerides, belong to the class of highly specialized lipids, they are esters of glycerophosphoric acid. Their main function is to form a double lipid layer in cell membranes. The recommended regimen for 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 are prescribed 3 times a day, 4-6 weeks (before meals). When prescribing drugs of this group, it is possible to achieve clinically significant effects:

• reduction in the level of indicator liver enzymes in blood plasma,
• reduction of lipid peroxidation,
• reducing the severity of membrane damage,
• acceleration of hepatocyte regeneration,
• improving metabolic processes occurring in the liver.

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

Metadoxine is an ion pair of pyridoxine and pyrrolidone carboxylic acid. The drug is initially prescribed orally at 5-10 ml (300-600 mg) intravenously or intramuscularly for 10-14 days, and then at 500-1000 mg (1-2 tablets) 2 times a day. For intravenous administration, the required dose of the drug is diluted in 500 ml of isotonic sodium chloride solution or 5% glucose solution and administered dropwise over 1.5 hours. The duration of the course of treatment is 30 days. If necessary, the course can be extended or repeated. The use of metadoxine improves the subjective state of patients and reduces signs of depression. The use of metadoxine is indicated:

• patients with a history of alcoholic liver disease,
• patients with a history of toxic liver reactions during previous courses of polychemotherapy,
• during planned high-dose polychemotherapy,
• during bone marrow transplantation.

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

Scheme of application of ornithine

Granulate	Concentrate for infusions
Chronic hepatitis of various origins (including viral, alcoholic toxic), fatty degeneration	Chronic hepatitis of various origins (including viral, alcoholic toxic), fatty degeneration
For severe symptoms, 3 times 2 sachets of granules per day	For severe neurological symptoms (high dosage) up to 4 ampoules per day
For moderate symptoms, 2-3 times, 1 sachet of granules per day	Liver cirrhosis with moderate symptoms 1-4 ampoules per day
Liver cirrhosis with severe symptoms of PE 3 times 1-2 sachets of granules per day depending on the severity of the disease	Liver cirrhosis with severe symptoms of PE with disorders of consciousness (precoma) or comatose state up to 8 ampoules per day