Acute liver failure

Clinical signs of liver damage are not diverse: an increase in the size of the organ, its soreness on palpation, jaundice, intoxication, a number of pain points, which still do not allow us to judge the functional state of the organ. However, these symptoms may be absent, and acute liver failure will still occur, and it can only be established with the help of targeted laboratory and instrumental studies, many of which have become easily accessible, routine in most clinical laboratories. A tangible help in solving the etiological issues of hepatopathies is the determination of markers of viral hepatitis, the spectrum of which has significantly expanded in the last 2 decades.

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Major acute liver failure

Major liver failure - primary, endogenous, true (hepatargy, hepatodystrophy) - is a classic form of acute liver failure and has a fairly well-defined and clearly defined clinical and laboratory picture. This form of failure is based on either the destruction or replacement of normal liver elements as a result of infectious or toxic effects. The mass of the functioning liver is sharply reduced due to acute or subacute necrosis of hepatocytes. With regard to acute hepatitis, this variant is referred to as fulminant acute liver failure. It usually develops in the malignant form of viral hepatitis, rapidly progressing cirrhosis, poisoning, tumors, which quickly lead to death of patients.

There are 10 known main functions of the liver; their insufficiency is manifested by a violation of all types of metabolism, VEO, a disorder of bile formation and bile secretion, a change in the composition and properties of the blood, an increase in intoxication and damage to the central nervous system.

Morphologically, massive and submassive necrosis is usually found at autopsy in those who died from hepatodystrophy.

Minor acute liver failure

Minor acute liver failure, or hepatodepression, is observed in many severe diseases in children (poisoning, intestinal infections, pneumonia, meningitis, sepsis, etc.), but is rarely diagnosed. At the same time, autopsy of children who died from the underlying disease often reveals "goose" liver, morphologically manifested by protein and fatty degeneration, less often - centrilobular necrosis. Hepatogenic encephalopathy in such patients is absent or (more often) the clinical picture is dominated by symptoms of the underlying disease, dysfunction of other organs and systems, which explains the observed intoxication, impaired consciousness and nervous activity. This acute liver failure is often part of the MOF syndrome, but its specific weight in the sum of other toxic-hypoxic effects on the body, as a rule, is not taken into account. In this case, the blood test shows predominant changes in indicators of hepatic depression and shunting of hepatic blood flow.

In addition to those listed above, there are also clinical and laboratory variants of acute liver failure: shock, portal and false (electrolyte) failure.

"Shock" liver, or acute circulatory liver failure, is often of exogenous origin and is caused by hemodynamic disorders - centralization of blood flow, prolonged ischemia, which naturally develops with different forms of shock. In shock, blood passes through a shortened path of vascular anastomoses bypassing the bulk of liver cells. With prolonged circulatory disorders (more than 1 day), liver cell damage may develop with a sharp increase in the permeability of cytoplasmic membranes for water and enzymes, fatty infiltration and centrilobular necrosis.

The main morphological picture of liver and kidney damage in shock is the occurrence of centrilobular necrosis in the liver (the level of glutamate dehydrogenase in the blood increases sharply) and necrosis of the epithelium of the renal tubules (reduced concentration function of the kidneys), less often - focal or total cortical necrosis. Patients experience oliguria, decreased RPM, increasing azotemia against the background of increased liver shunting indices and hepatodepressive syndrome of acute liver failure.

In the development of portal insufficiency, or portal-hepatic insufficiency (portosystemic encephalopathy, coma), the main role is played by the "disconnection" of the liver or bypass of its blood flow against the background of portal hypertension caused by primary carcinoma or its cirrhosis in the terminal stage. Clinically, this acute liver failure usually does not have symptoms of jaundice, the phenomena of encephalopathy with a relatively shallow impairment of consciousness, tremor (parkinsonism) dominate. During the coma, patients resemble people who are deeply and calmly sleeping (hypnargia).

False acute liver failure is often associated with hypokalemia, which potentiates decreased liver function. Clinically, it resembles the previous form, in addition, children have intestinal paresis, which aggravates intoxication. The potassium level in the blood plasma drops to 1.8-2.9 mmol / l. Alkalosis is possible. Against the background of alkalosis, ammonia is more toxic, since it easily penetrates into the cell.

Symptoms of Acute Liver Failure

The main clinical symptoms of acute liver failure.

Increase in neuropsychiatric disorders:

• intention tremor, which changes handwriting in older children, flapping tremor;
• cogwheel-type muscle rigidity, high (initially) tendon reflexes;
• attacks of excitement, disorientation, loss of consciousness with retrograde amnesia, clonic convulsions.

1. Repeated vomiting, later of the “coffee grounds” type.
2. Hemorrhagic syndrome in the form of skin rashes, bleeding against the background of consumption coagulopathy, deficiency of blood clotting factors.
3. Jaundice is a symptom that is mandatory for severe forms of viral hepatitis, and, as a rule, its severity corresponds to the severity of intoxication, but the younger the child, the less pronounced the jaundice.
4. The liver odor is caused by a disturbance in methionine metabolism and the accumulation of methyl mercaptan, methionine sulfoxide.
5. Body temperature usually rises significantly in the terminal stage of acute liver failure; it is often resistant to the action of antipyretic drugs, which is due to the release of a large number of pyrogens during the destruction of liver tissue.
6. A decrease in the size of an organ, its mass (optional symptom).
7. Oliguria with increased concentration of urea, creatinine, fluid retention (secondary hyperaldosteronism due to impaired hormone metabolism), in the subacute course - with edema, ascites.

Among the listed symptoms, hepatogenic encephalopathy has the most important clinical significance, the degree of expression of which corresponds to the severity of acute liver failure. N. I. Nisevich, V. F. Uchaikin (1982) distinguish the stages of precursors, precoma and 2 stages of coma. In a number of works, precoma is divided into 2 substages - precursors and precoma proper.

If the pathological process in the liver is prolonged, the role of extrahepatic components caused by massive bleeding and bacterial infections increases in the development of encephalopathy. In the pathogenesis of hepatogenic encephalopathy, a major role is played by the development of cerebral edema, its hypoxia, acidosis, the impact of toxic metabolites, endotoxins of intestinal bacteria, and their metabolic products.

How is acute liver failure diagnosed?

To clarify the diagnosis and severity of acute liver failure, a wide range of laboratory parameters should be used, including:

1. Decreased prothrombin index (<30% and even <10%), decreased levels of other procoagulants in the blood.
2. Blood test: leukocytosis, neutrophilia, ESR < 2 mm/h.
3. The increase in bilirubin concentration is mainly due to its indirect, unbound fraction.
4. The activity of cytoplasmic, mitochondrial, and lysosomal enzymes decreases; at the onset of hepatodystrophy, it sharply increases by tens and hundreds of times and quickly (within hours) decreases, sometimes to normal.
5. Ammonia is observed in most patients, especially during the period of increasing coma.
6. Severe hypoglycemia is observed in 40% of patients with hepatodystrophy.
7. Sodium content decreases and osmolarity increases; metabolic acidosis in the terminal stage can be replaced by respiratory alkalosis.

It is customary to distinguish 6 main laboratory syndromes of damage to the hepatobiliary system:

1. cytolytic syndrome;
2. hepatodepressive syndrome;
3. mesenchymal inflammatory syndrome;
4. cholestatic syndrome;
5. portocaval shunt syndrome, or "disconnection" syndrome;
6. regeneration and tumor growth syndrome.

Hepatodepressive syndrome and portocaval shunt syndrome have direct and high diagnostic value in determining acute liver failure. All other syndromes listed above reflect the fact of damage to the liver stroma and parenchyma (of various origins). Nevertheless, their presence in practice allows us to associate dynamically developing encephalopathy and thrombohemorrhagic syndrome with liver pathology with a high degree of probability.

Cytolytic syndrome occurs due to disturbances in the structure of hepatocytes and is the main one in the diagnosis of hepatitis. It is characterized by increased permeability of the cell membrane for intracellular substances and especially enzymes. Increased membrane permeability promotes the "washing out" of intracellular enzymes into the extracellular space, subsequently they enter the systemic bloodstream, as a result of which their concentration in the blood increases. It is important to emphasize that cytolysis in a typical situation is not identical to cell necrobiosis (in clinical practice, the term "necrosis" is used). A completely destroyed cell stops producing enzymes, therefore, at the height of massive necrosis, their activity in the blood decreases sharply. At the same time, cytolysis indicators are the main indicators of direct damage to hepatocytes.

The most common and informative marker of cytolysis is the determination of aminotransferase activity (ALT, AST, etc.). Exceeding their upper limit of the norm by 1.5-5 times corresponds to moderate or minor hyperfermentemia, by 6-10 times - moderate hyperfermentemia, more than 10 times - major. The development of acute liver failure is preceded by a sharp and significant increase in enzyme activity in the blood (by 100 times or more) and its rapid decline (sometimes to normal).

Determining the de Ritis coefficient (AST/ALT > 1.0) helps to some extent to determine the depth of liver damage (normally it is 0.9). This is due to the fact that AST is an intramitochondrial enzyme, and ALT is cytoplasmic, i.e. it is located in the hepatocyte closer to the outer membrane and is more easily washed out of it into the blood when the latter is damaged.

With normal enzyme levels, acute liver damage or exacerbation of chronic liver disease is unlikely. Hepatodepression syndrome is understood as the suppression of the functional (primarily synthetic) capacity of hepatocytes and a decrease in total biochemical activity.

Markers of hepatodepressive syndrome are functional (stress) tests, indicators of synthetic and metabolic function, and determination of the mass of the functioning liver.

Load tests - bromsulfalein (Rosenthal-White test) and wofaverdine (indocyanine) - reflect the absorption-excretion function of the liver and are usually used for chronic processes in it.

Synthetic function is determined by the concentration in the blood:

• procoagulants and anticoagulant components of the blood: fibrinogen, prothrombin, proaccelerin, antihemophilic factors (factors VII, VIII, IX, X);
• proteins synthesized only in the liver: albumin and, to a lesser extent, fibronectin, complement, a)-antitrypsin, ceruloplasmin, false (pseudo) cholinesterase.

Determination of the mass of the functioning liver is also used using radionuclide scintigraphy or computed tomography.

Mesenchymal-inflammatory syndrome is caused by damage to mesenchymal-stromal elements of the liver, as well as changes in humoral immunity indicators. The following tests are used to assess this syndrome: sedimentary reactions, the content of globulins, haptoglobin and other proteins of the acute phase of inflammation, as well as connective tissue metabolism products.

Sedimentary tests (thymol and sublimate) reflect the presence of dysproteinemia. The thymol test is positive in the first 5 days of mild to moderate viral hepatitis in patients with cirrhosis, remaining normal in the majority (95%) of patients with subhepatic (obstructive) jaundice. It reflects an increase in the blood content of y-globulins and other large acute-phase inflammatory proteins (C-reactive protein - CRP) with a relatively normal amount of albumin. The sublimate test is of greatest importance in advanced forms of cirrhosis, exacerbation of chronic hepatitis and at the height of acute liver failure (less than 1 ml); it reflects a significant decrease in the albumin level.

The content of globulins in acute hepatitis, as a rule, increases, especially IgM; in chronic hepatitis and liver cirrhosis, the concentration of IgA is also increased. A sharp deficiency of IgA in the blood contributes to the development of cholestatic forms of hepatitis, drug-induced cholestasis (during treatment with testosterone, progesterone, ajmaline, etc.). Deficiency of IgA entering the bile leads to an unfavorable course of inflammatory processes in the smallest bile ducts, contributes to the disruption of the formation of the bile micelle. The level of haptoglobin, seromucoid and a2-macroglobulin in the blood of patients increases in the acute phase of the disease.

In the blood of patients with hepatitis and cirrhosis, connective tissue metabolism products, oxyproline and proline (collagen metabolites, reflect fibrogenesis processes), as well as procollagen-3-peptide (found mainly in the liver, correlates well with inflammatory changes in the portal tracts, periportal zone) accumulate. Their content increases to the greatest extent in acute viral hepatitis; the excretion of uronic acids in the urine increases proportionally to the severity of viral hepatitis.

Cholestatic syndrome is characterized by primary or secondary disturbance of bile secretion. Icteric and anicteric variants of the syndrome are known.

The classic icteric form of cholestasis is characterized by:

• jaundice and itchy skin;
• hyperbilirubinemia, mainly due to the conjugated form (direct Jendrasik test);
• increased activity of enzymes - indicators of cholestasis - alkaline phosphatase (normally 2-5 units), 5-nucleotidase, leucine aminopeptidase,
• increase in lipid content - bile acids, cholesterol, beta-lipoproteins, etc.

Anicteric cholestasis is a pre-stage of icteric cholestasis, diagnosed by determining elevated concentrations of bile acids, alkaline phosphatase, etc. in the blood.

Liver shunt indicators. These are substances that normally enter the liver from the intestines via the portal vein system and are inactivated there. With portocaval shunting of blood, they appear in active circulation. The higher their concentration in the blood plasma, the larger the shunt. Liver shunt markers are:

• ammonia and its derivatives;
• phenol;
• amino acids - tyrosine, phenylalanine, tryptophan;
• short chain fatty acids.

Normally, the concentration of ammonia in the blood is up to 70 μmol/l. A test with ammonium chloride load can be performed. Ammonia has a pronounced toxic effect on the central nervous system, especially against the background of metabolic alkalosis.

Phenol (normally the concentration in blood is up to 50 μmol/l) is characterized by a pronounced toxic effect on the brain, it is produced in the intestine under the influence of intestinal microbes. According to S. Branner et al. (1983), who worked on the creation of an artificial liver, phenol can be considered a highly toxic substance that models hepatogenic encephalopathy well.

Aromatic amino acids, turning into tyramine and octopamine, act as false neurotransmitters, displacing dopamine and norepinephrine from receptors. To a certain extent, branched-chain amino acids - leucine, isoleucine, valine - are antagonists of aromatic amino acids. The latter are utilized in the body during gluconeogenesis, especially in brain cells. Normally, the ratio of valine + leucine + isoleucine/phenylalanine + tyrosine = 3-3.5. In portohepatic insufficiency, it is usually < 1.0. Such an amino acid profile is considered characteristic of shunt encephalopathy. Indole and skatole are formed from tryptophan, which also contribute to encephalopathy.

Short-chain fatty acids - butyric (butanoic - C4), valerianic (pentanoic - C5), caproic (hexanoic - C6), caprylic (octanoic - C8) - are also highly toxic to the brain, especially butyric and valerianic.

An indicator of regeneration and tumor growth is considered to be alpha-fetoprotein (AFP) of blood serum. Its main source is hepatocyte. The higher the concentration of AFP (> 500 ng/ml), the greater the probability of carcinoma, cancer of the common bile duct. Its increase to 50-100 ng/ml may indicate acute hepatitis and other diseases, including regenerative processes observed in liver cirrhosis. Normally, AFP is practically absent.

Treatment of acute liver failure

The basis of treatment for patients with severe acute liver failure (hepatargia) is pathogenetic therapy, which includes a number of areas.

Patients at the height of the comatose state are fed through a tube or parenterally in the amount of 50-75% of the normal age requirement. The energy requirement is satisfied by 70% due to carbohydrates (mainly glucose) and 30% - fats. The amount of protein is reduced by half compared to the norm. In the presence of vomiting "coffee grounds" or gastric bleeding, enteral nutrition is canceled and parenteral nutrition is prescribed. In this case, it is advisable to use amino acid mixtures ("Heptamyl") with an increased relative content of amino acids with a branched chain (valine, leucine, etc.) and a lower content of aromatic amino acids (phenylalanine, tyrosine, etc.). When calculating the need for protein, it should not exceed 1 g / kg per day.

Detoxification is provided by IT, plasmapheresis, hemofiltration, amino acid dialysis. Plasmapheresis or OPZ should be performed in large volumes - at least 1.0-1.5 BCC per day. In the presence of renal failure (in 50-70% of patients with hepatic coma), OPZ is combined with hemodialysis or amino acid dialysis. Low-flow hemofiltration is a modern method of treating severe intoxication, it is carried out for a long time, until the effect is achieved. During the procedure, up to 40-60 liters of ultrafiltrate are removed, therefore, continuous computer monitoring of the volume and composition of the administered solutions is necessary. At the beginning of treatment, it is important to use high enemas (such as intestinal lavage) with the introduction of a 2% solution of sodium bicarbonate or Ringer, as well as gastric lavage.

YAG is performed in a daily volume of 1.0-1.5 FP. In case of DVO, which is possible with frequent vomiting, the volume is corrected. To correct metabolic acidosis, a 4.2% sodium bicarbonate solution is administered on the 1st day at a rate of 2 ml/kg by drip, then under the control of acid-base balance parameters. In case of fluid retention, diuretics are prescribed (lasix, mannitol, veroshpiron).

DIC syndrome and gastric bleeding are observed in 70% of patients in a coma. To prevent DIC, heparin is prescribed at a rate of 100-200 U/kg per day under the control of a coagulogram (low molecular weight heparin at a dose of 0.1-0.3 ml 1-2 times a day is better). To prevent gastric bleeding, cimetidine (at a dose of 5 mg/kg 3-4 times a day) or famotidine (quamatel) are used intravenously, antacids (almagel, phosphalugel) orally. If gastric bleeding develops, the heparin dose is reduced to 50 U/kg or temporarily discontinued and dicynone, calcium preparations, vitamin K, FFP, cryoprecipitate are administered.

Antiproteolytic treatment of acute liver failure is provided by transfusion of contrical (at a dose of 1-2 thousand U/kg per day) or gordox, trasylol and other proteolysis inhibitors in an equivalent dose, fractionally intravenously by drip.

In case of cerebral edema (observed in 40% of patients), protein preparations are administered - 10% albumin solution, concentrated plasma, as well as diuretics - lasix (up to 3 mg / kg per day), mannitol (1 g of dry matter per 1 kg of the child's BW intravenously by drip; rarely used in infants). The presence of secondary hyperaldosteronism in patients with acute hepatic insufficiency is the basis for prescribing aldactone, veroshpiron at a dose of 3-5 mg / (kg per day) for at least 7-10 days. The introduction of dexamethasone at a dose of 0.5-1.5 mg / (kg per day) fractionally intravenously by jet stream is effective.

Stabilization of blood circulation is ensured by continuous drip administration of dopamine (2-5 mcg/kg per minute) or dobutrex (2-5 mcg/kg per minute); with low blood pressure, the doses are increased to 15 mcg/kg per day or the drug used is combined with drip administration of norepinephrine (0.1-0.5 mcg/kg per minute).

Anti-inflammatory treatment of acute liver failure

Domestic authors recommend administering prednisolone at a dose of 5-10 mg/kg per day in 4-6 doses intravenously by jet stream in a short course without taking into account the biological rhythm until the effect is achieved (usually 3-5 days or until the child comes out of a coma). Foreign authors are reserved about administering prednisolone to such patients. However, it should be remembered that, according to the modern theory of the pathogenesis of hepatic coma, in patients with viral hepatitis, the cause of active destruction of hepatocytes is a hyperimmune state, autoaggression. Consequently, the appointment of immunosuppressants is justified when the so-called "parade" of antiviral antibodies appears, when at the height of acute liver failure, all types of antibodies to the subunits of the hepatitis B virus simultaneously appear in the blood with the simultaneous elimination of antigens (HBeAg, HBsAg) from the patient's blood.

Respiratory support for breathing in patients with coma 2 should be provided by mechanical ventilation and oxygen therapy.

Decontamination of the intestine is achieved by oral administration of aminoglycosides: kanamycin at a dose of 20 mg/kg per day), gentamicin at a dose of 6-10 mg/kg per day (in 4 doses orally). Parenteral administration of antibiotics is possible.

Sedative and anticonvulsant therapy (if children have anxiety or convulsions) is carried out with drugs that are excreted in the urine (seduxen), with careful titration of their dose during the treatment process.

Antipyretic therapy is usually limited to physical methods of cooling the child's body, since analgesics can worsen acute liver failure.

Patients with minor and other forms of acute liver failure receive treatment for the underlying disease. Lost or decreased liver functions (most often detoxification, synthetic and bile excretion) are compensated:

• replacement therapy (administering FFP, albumin, blood clotting factors, vitamin K if necessary);
• drugs that stimulate protein synthesis - amino acid mixtures, anabolic hormones, glucuronyl transferase activators (phenobarbital), energy metabolism stimulants (insulin with glucose and potassium, ATP, cocarboxylase, pyridoxal phosphate, etc.) are administered;
• choleretic (flamin, sorbitol, xylitol, magnesium sulfate, etc.) and antispasmodic (no-shpa) therapy;
• inactivation of ammonia (glutamic acid), phenol and other derivatives of protein metabolism (plasmapheresis, hemosorption), improvement of hepatic blood flow (microcirculators, disaggregants, rheoprotectors) and blood oxygenation (oxygen therapy, correction of anemia and improvement of oxygen-binding capacity of hemoglobin). We emphasize that in conditions of acute liver failure, the utilization of xenobiotics (most therapeutic agents) is sharply impaired, therefore, the treatment of such patients requires strict pathogenetic selection of drugs, prevention of polypharmacy.

Children who have had a disease such as acute liver failure should be observed for at least 6 months by a pediatrician and neurologist. Usually, table No. 5 is prescribed for 6-12 months or more (depending on the functional state of the hepatobiliary system). Courses of choleretic agents, antispasmodics, hepatoprotectors, multivitamin preparations, and delicious teas are indicated. If the child still has CNS dysfunctions, a long-term course of therapy is carried out aimed at improving metabolism and blood circulation in the brain, in some cases anticonvulsant therapy is prescribed, massage, gymnastics, and in the long term, spa treatment are indicated. After hepatodystrophy, which developed against the background of viral hepatitis B and (or) D, chronic forms of hepatitis are practically not observed. However, in the next 6-12 months, such children also need a gentle diet and medications that improve the functional state of the liver, reduce tissue fibrosis, and improve bile secretion.

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