Acute liver failure

Clinical signs of liver damage do not differ in variety: this is an increase in the size of the organ, its painfulness upon 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 still will be, and it can be established only through 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 identification of markers of viral hepatitis, the spectrum of which has significantly expanded in the last two decades.

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Major acute hepatic impairment

Major hepatic insufficiency - primary, endogenous, true (hepatarga, hepatodystrophy) - is a classic form of acute hepatic insufficiency and has a well-defined and well-defined clinical and laboratory picture. This form of insufficiency is based on either destruction or replacement of normal liver elements as a result of an infectious or toxic effect. The weight of the functioning liver is sharply reduced due to acute or subacute necrosis of hepatocytes. In the case of acute hepatitis, this variant is referred to as fulminant acute fulminant liver failure. It usually develops with a malignant form of viral hepatitis, rapidly progressive cirrhosis, poisonings, tumors that quickly lead the patients to death.

There are 10 basic liver functions; their insufficiency manifests itself as a violation of all types of metabolism, VEO, bile formation and bile secretion, changes in blood composition and properties, increased intoxication and CNS damage.

Morphologically, autopsies in the deceased from hepatodystrophy usually involve massive and submissive necrosis.

Small acute liver failure

Small 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, autopsies of children who died of the main disease often find a "goose" liver, morphologically manifested by protein and fatty dystrophy, less often - centripetal necrosis. Hepatogenic encephalopathy in such patients is absent or (more often) in the clinical picture the symptoms of the underlying disease, the deficiency of the functions of other organs and systems prevail, which explains the observed intoxication, impairment of consciousness and nervous activity. This acute liver failure is often included in the syndrome of PON, but its specific weight in the sum of other toxic-hypoxic effects on the body, as a rule, is not taken into account. In the analysis of blood in this case, changes in the indicators of hepatodepression and shunting of hepatic blood flow predominate.

In addition to those listed above, clinical and laboratory variants of acute hepatic insufficiency are also highlighted: shock, portal and fake (electrolyte) insufficiency.

"Shock" liver, or circulatory acute liver failure, is more often exogenous and is caused by hemodynamic disorders - centralization of blood flow, prolonged ischemia, regularly developing with different forms of shock. In shock, blood passes through a shortened path of vascular anastomoses, bypassing the bulk of the liver cells. With prolonged impairment of blood circulation (more than 1 day), hepatic cell damage can occur with a sharp increase in the permeability of cytoplasmic membranes for water and enzymes, fat infiltration, and centripetal necrosis.

The main morphological picture of the damage to the liver and kidneys in shock is the occurrence of centrilolkovic necrosis in the liver (the level of glutamate dehydrogenase in the blood sharply increases) and necrosis of the epithelium of the renal tubules (a decrease in the concentration function of the kidneys), less often - focal or total cortical necrosis. Patients are observed oliguria, a decrease in OPM, an increase in azotemia amid increased liver shunting and a hepatodepressive syndrome of acute hepatic insufficiency.

In the development of portal insufficiency, or portal-hepatic insufficiency (portosystemic encephalopathy, coma), the main role is played by "turning off" the liver or bypassing its blood flow against the background of portal hypertension caused by the primary carcinoma or its cirrhosis in the terminal stage. Clinically this acute hepatic insufficiency symptoms of jaundice do not usually exist, the phenomena of encephalopathy with a relatively shallow disturbance of consciousness, tremor (parkinsonism), dominate. In the period of coma, patients resemble deeply and calmly sleeping people (hypnagogy).

False acute hepatic insufficiency is more often associated with hypokalemia, potentiating lowered liver function. Clinically, it resembles the previous form, in addition, the children have a paresis of the intestine, aggravating intoxication. The level of potassium in the blood plasma drops to 1.8 - 2.9 mmol / l. Possible alkalosis. Against the background of alkalosis, ammonia is more toxic, as it easily penetrates the cell.

Symptoms of Acute Hepatic Insufficiency

The main clinical symptoms of acute hepatic insufficiency.

Increase of neuropsychic disorders:

• intentional trembling, changing handwriting in older children, clapping tremor;
• rigidity of muscles as a cog-wheel, high (at first) tendon reflexes;
• attacks of excitement, disorientation, loss of consciousness with retrograde amnesia, clonic convulsions.

1. Vomiting is repeated, in the subsequent type of "coffee grounds".
2. Hemorrhagic syndrome in the form of skin rashes, bleeding on the background of coagulopathy of consumption, deficiency of 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 smaller the child, the less jaundice is expressed.
4. Hepatic smell is caused by a violation of methionine metabolism and the accumulation of methyl mercaptan, methionine sulfoxide.
5. Body temperature usually increases significantly in the terminal stage of acute hepatic insufficiency; often it is torpid to the action of antipyretics, which is due to the release of a large number of pyrogen in the destruction of liver tissue.
6. Reducing the size of the body, its mass (an optional symptom).
7. Oliguria with an increase in the concentration of urea, creatinine, fluid retention (secondary hyperaldosteronism due to a violation of the metabolism of the hormone), in subacute - with edema, ascites.

Among the listed symptoms, the most important clinical significance is hepatogenic encephalopathy, the degree of which corresponds to the severity of acute hepatic insufficiency. NI Nisevich, VF Uchaikin (1982) distinguish the stages of precursors, precoma and the 2nd stage of coma. In a number of works, the preComa is divided into 2 sub-stages - precursors and actually prekoms.

If the pathological process in the liver is delayed, the role of extrahepatic components, caused by massive bleeding, bacterial infections, increases in the development of encephalopathy. In the pathogenesis of hepatogenic encephalopathy, the development of cerebral edema, its hypoxia, acidosis, the effect of toxic metabolites, endotoxins of intestinal bacteria, the products of their metabolism play an important role.

How is acute liver failure diagnosed?

To clarify the diagnosis and severity of acute liver failure should use a wide range of laboratory indicators, including:

1. Decrease in prothrombin index (<30% and even <10%), decrease in blood levels of other procoagulants.
2. Blood test: leukocytosis, neutrophilia, ESR <2 mm / h.
3. An increase in the concentration of bilirubin is mainly due to its indirect, unbound fraction.
4. The activity of cytoplasmic, mitochondrial, lysosomal enzymes decreases; at the beginning of hepatodystrophy, it sharply increases tens and hundreds of times and rapidly (over hours) decreases, sometimes to normal.
5. Ammonemia is observed in most patients, especially during the period of coma growth.
6. A severe form of hypoglycemia is noted in 40% of patients with hepatodystrophy.
7. The sodium content decreases, and osmolarity increases, metabolic acidosis at the terminal stage can be replaced by respiratory alkalosis.

It is accepted to distinguish 6 basic laboratory syndromes of defeat of the hepatobiliary system:

1. cytolytic syndrome;
2. hepatodepressive syndrome;
3. mesenchymal-inflammatory syndrome;
4. cholestatic syndrome;
5. syndrome of portocaval shunting, or "shutdown";
6. syndrome of regeneration and tumor growth.

Direct and high diagnostic value in the definition of acute hepatic insufficiency have hepatodepressive syndrome and portocaval shunting syndrome. All the other syndromes listed above reflect the defeat of the hepatic stroma and parenchyma (of various origins). Nevertheless, their presence in practice makes it possible to associate dynamically developing encephalopathy and thrombohemorrhagic syndrome with a high degree of probability with liver pathology.

Cytolytic syndrome occurs due to disorders in the structure of hepatocytes and is the main one in the diagnosis of hepatitis. Characterized by increased permeability of the cell membrane for intracellular substances and especially enzymes. The increased permeability of the membrane promotes the "washout" of intracellular enzymes into the extracellular space, and subsequently they enter the systemic bloodstream, which increases their concentration in the blood. It is important to emphasize that cytolysis in a typical situation is not identical to cell necrobiosis (in the clinical practice use the term "necrosis"). Destroyed completely the cell ceases to produce enzymes, so at the height of massive necrosis, their activity in the blood drops 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, ACT, etc.). Exceeding their upper limit of the norm is 1.5-5 times that of a moderate or small hyperfermentemia, 6-10 times in hyperfermentemia of an average degree, more than 10 times with a large hyper-enzyme. Development of acute liver failure is preceded by a sharp and significant increase in the activity of enzymes in the blood (100 times or more) and its rapid drop (sometimes to normal).

Determination of de Ritis coefficient (ACT / ALT> 1.0) to a certain extent helps to determine the depth of liver damage (in the norm it is equal to 0.9). This is due to the fact that ACT is an intramitochondrial enzyme, and ALT is cytoplasmic, i.e. Is located in the hepatocyte closer to the outer membrane and easier to wash out of it into the bloodstream if the latter is damaged.

With normal enzyme parameters, acute damage to the liver, exacerbation of its chronic disease is unlikely. Under the syndrome of hepatodepression, oppression of the functional (primarily synthetic) ability of hepatocytes and a decrease in the total biochemical activity is understood.

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

Load tests - bromsulfaleinovaya (Rosenthal-White test) and vofaverdinovaya (indocyanovaya) - reflect the absorptive-excretory function of the liver and are usually used in chronic processes in it.

The synthetic function is determined by the concentration in the blood:

• procoagulants and anticoagulant components of 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.

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

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

Sedimentary samples (timol and sulemic) reflect the presence of dysproteinemia. Timolovaya sample is positive in the first 5 days of viral hepatitis of mild and moderate degree in patients with cirrhosis, remaining normal in the majority (95%) of patients with subcutaneous (obturation) jaundice. It reflects the increase in blood levels of y-globulins and other large acute-phase inflammation proteins C-reactive protein-SRB) with a relatively normal amount of albumins. The sulphure assay has the greatest value at far-gone forms of a cirrhosis, an exacerbation of a chronic hepatitis and at height of an acute hepatic insufficiency (less than 1 ml); it reflects a significant decrease in albumin levels.

The content of globulins in acute hepatitis, as a rule, increases, especially IgM; In chronic hepatitis and cirrhosis, the concentration of IgA is also increased. A sharp deficit in the blood IgA promotes the development of cholestatic forms of hepatitis, drug cholestasis (in the treatment of testosterone, progesterone, aymalin, etc.). Deficiency of the IgA entering the bile leads to an unfavorable course of inflammatory processes in the smallest bile ducts, contributing to the violation 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, hydroxyproline and proline (metabolites of collagen, reflect the processes of fibrogenesis), as well as procollagen-3 peptide (mainly in the liver, correlate well with inflammatory changes in portal tracts, periportal zone) accumulate. To the greatest extent, their content increases with acute viral hepatitis; in proportion to the severity of viral hepatitis, the uronic acid excretion of uronic acids increases.

Cholestatic syndrome is characterized by a primary or secondary disturbance of bile secretion. There are jaundice and jaundiced variants of the syndrome.

For classical icteric forms of cholestasis are characterized by:

• jaundice and itching;
• Hyperbilirubinemia, mainly due to the conjugated form (direct test according to Endrashiku);
• an increase in the activity of enzymes - indicators of cholestasis - alkaline phosphatase (normal 2-5 units), 5-nucleotidase, leucinamine peptidase,
• an increase in the content of lipids - bile acids, cholesterol, beta-lipoproteins, etc.

Free-jaundiced cholestasis, a manifestation of icteric cholestasis, is diagnosed when blood concentrations of bile acids, alkaline phosphatase, etc. Are determined in the blood.

Indicators of liver shunting. These are substances that normally come from the intestine through the portal vein system into the liver and are inactivated there. With portocaval shunting of blood, they appear in active circulation. The higher their concentration in the blood plasma, the greater the shunt. The markers of liver shunting are:

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

Normally, the concentration of ammonia in the blood is up to 70 μmol / l. It is possible to carry out a sample with a load of ammonium chloride. Ammonia has a pronounced toxic effect on the central nervous system, especially against a background of metabolic alkalosis.

Phenol (normal concentration in the blood up to 50 μmol / l) is characterized by a pronounced toxic effect on the brain, produced in the intestines under the influence of microbes of intestinal origin. In the opinion of S. Bruner and co-workers. (1983), who worked on the creation of an artificial liver, phenol can be considered as a highly toxic substance, a good model of hepatogenic encephalopathy.

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

Fatty acids with a short chain - oily (butane - C4), valeric (pentane - C5), caproic (hexanoic - C6), caprylic (octane - C8) - are also highly toxic to the brain, especially oily and valerian.

Indicator of regeneration and tumor growth is considered to be a-fetoprotein (AFP) serum. Its main source is the hepatocyte. The higher the concentration of AFP (> 500 ng / ml), the greater the likelihood of carcinoma, a common bile duct cancer. Increasing it to 50-100 ng / ml may indicate acute hepatitis and other diseases, including regenerative processes, observed with cirrhosis of the liver. In the norm, AFP is practically absent.

Treatment of acute liver failure

The basis for the treatment of patients with a large form of acute hepatic insufficiency (hepatargia) is pathogenetic therapy, which includes a number of directions.

Nutrition of patients at the height of coma is carried out through the probe or parenterally in a volume of 50-75% of the normal age requirement. Energy demand is satisfied by 70% due to carbohydrates (mainly glucose) and by 30% - fat. The amount of protein is reduced by half in comparison with 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 desirable to use amino acid mixtures ("Heptamyl") with an increased relative content of branched chain amino acids (valine, leucine, etc.) and less - aromatic amino acids (phenylalanine, tyrosine, etc.). When calculating the protein requirement, it should not exceed 1 g / kg per day.

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

JAG is conducted in a daily volume of 1.0-1.5 FP. With DVO, which is possible with frequent vomiting, volume correction is performed. To correct metabolic acidosis, 4.2% sodium bicarbonate solution is administered on the 1st day at a rate of 2 ml / kg dropwise, then under the control of CBS parameters. When fluid is delayed, diuretics are prescribed (lasix, mannitol, veroshpiron).

DIC-syndrome and gastric bleeding are observed in 70% of patients who are in a coma. To prevent ICE appoint heparin at a rate of 100-200 U / kg per day under the control of a coagulogram (preferably low-molecular-weight heparin at a dose of 0.1 -0.3 ml 1-2 times a day). To prevent gastric bleeding, cimetidine is used (at a dose of 5 mg / kg 3-4 times a day) or famotidine (quamate) intravenously, antacids (almagel, phospholugel) inside. With the development of gastric bleeding, the dose of heparin is reduced to 50 units / kg or temporarily canceled and injected with dicinone, calcium preparations, vitamin K, FFP, cryoprecipitate.

Antiproteolytic treatment of acute hepatic insufficiency is provided by transfusion of contrikal (in a dose of 1-2 thousand units / kg per day) or gordoksa, trasilol and other inhibitors of proteolysis in an equivalent dose of fractional intravenous drip.

When edema of the brain (observed in 40% of patients) is injected with protein preparations - 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 MT of the child intravenously drip, infants are rarely used). The presence of secondary hyperaldosteronism in patients with OPHCH is the basis for the appointment of aldactone, veroshpiron in a dose of 3-5 mg / (kg / day) for a period of at least 7-10 days. Effectively, the administration of dexamethasone in a dose of 0.5-1.5 mg / (kg / day) is divided intravenously by jet.

Stabilization of blood circulation is provided by a dropwise dopamine administration (2-5 μg / kg per minute) or dobutrex (2-5 μg / kg per minute); At a low blood pressure, the doses are increased to 15 μg / kg / day or the drug used is combined with a dropwise addition of norepinephrine (0.1-0.5 μg / kg per minute).

Anti-inflammatory treatment of acute liver failure

Domestic authors recommend the administration of prednisolone in a dose of 5-10 mg / kg / day in 4-6 receptions intravenously in a short stride, without taking into account the biological rhythm until the effect is obtained (usually 3-5 days or until the child leaves the coma). Foreign authors to the introduction of prednisone such patients are reserved. 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 hyperimmune state, autoaggression. Consequently, the appointment of immunosuppressors is justified when a so-called "parade" of antiviral antibodies occurs, when at the height of acute hepatic insufficiency all types of antibodies to the hepatitis B subunits simultaneously appear 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 (4 in-doses). Parenteral administration of antibiotics is possible.

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

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

Patients with small and other forms of acute liver failure are treated for the underlying disease. The lost or decreased functions of the liver (most often detoxication, synthetic and biliary excretion) are compensated:

• means of substitution therapy (enter FFP, albumin, clotting factors, vitamin K, if necessary);
• drugs that stimulate protein synthesis - introduce amino acid mixtures, anabolic hormones, activators of glucuronyltransferase (phenobarbital), stimulants of energy metabolism (insulin with glucose and potassium, ATP, cocarboxylase, pyridoxal phosphate, etc.);
• cholagogue (flamin, sorbitol, xylitol, magnesium sulfate, etc.) and spasmolytic (no-spa) therapy;
• inactivation of ammonia (glutamic acid), phenol and other derivatives of protein metabolism (plasmapheresis, hemosorption), improvement of hepatic blood flow (microcirculants, disaggregants, reoprotectors) and oxygenation of the blood (oxygen therapy, correction of anemia and improvement of oxygen binding capacity of hemoglobin). We emphasize that in conditions of acute hepatic insufficiency, the utilization of xenobiotics (the majority of therapeutics) is sharply disrupted, so treatment of such patients requires a rigid pathogenetic selection of medications, prevention of polyphragmasia.

Children who have suffered such a disease as acute liver failure, should be observed at least 6 months in a pediatrician and neurologist. Usually appoint table number 5 for 6-12 months or more (depending on the functional state of the hepatobiliary system). The courses of cholagogue agents, antispasmodics, hepatoprotectors, multivitamin preparations, mouth-watering teas are shown. If the child continues to have central nervous system dysfunctions, the course of therapy is spent for a long time, aimed at improving metabolism and blood circulation in the brain, in some cases prescribing anticonvulsant therapy, showing massage, gymnastics, and in a long time spa treatment. After hepatodephritis, which has developed against the background of viral hepatitis B and / or D, there are almost no chronic forms of hepatitis. However, in the next 6-12 months such children also need a sparing diet and the means that improve the functional state of the liver, reduce fibrosis of the tissues, improve the bile secretion.

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