Pediatric liver failure

　　First, Etiology

　　1. Infection Viral hepatitis is the leading cause, and in recent years, there has been a significant increase in hepatitis B virus infections. In addition, EB virus, herpes virus, cytomegalovirus, etc., can also cause it.

　　2. Poisoning includes poisoning by drugs such as isoniazid, rifampicin, acetaminophen, and tetracycline, food poisoning caused by mushrooms, etc., as well as chemical poisoning by carbon tetrachloride, snakebite, etc.

　　3. Hereditary metabolic defects A few cases of liver-brain degeneration, galactosemia, fructose intolerance, tyrosinemia, and glycogen storage disease type IV can also lead to liver failure.

　　4. Other

　　(1) Liver-brain fatty degeneration syndrome, Reye's syndrome (Reyessyndrome).

　　(2) Severe multiple trauma, major surgery, large-area burns, sepsis, ischemic and hypoxic damage, various causes of shock, etc.

　　(3) Other diseases that invade the liver, such as malignant proliferative histiocytosis, Langerhans cell histiocytosis, etc.

　　Second, Pathogenesis

　　Liver failure occurs when liver cells are attacked again after being damaged. The occurrence of liver failure is the result of the synergistic action of various factors. Liver necrosis is the fundamental cause of liver failure. In recent years, with the deepening of research and understanding of cell apoptosis, the research and understanding of liver necrosis have been continuously deepened.

　　1. Viral factors Hepatocellular necrosis caused by hepatitis viruses accounts for about 85% to 95%. Among them, HBV and HCV are more common, while HAV and HEV are less common. HDV is rare, and the role of HGV in causing liver necrosis is still controversial.

　　2. Inflammatory mediators mainly include mononuclear macrophages (Macrophage). Monokines, endotoxins (Endotoxin, ET), and leukotrienes (Leukotriene, LT) play a significant role, sometimes even a key role, in the occurrence of liver necrosis.

　　3. The most studied and concerning immune changes leading to liver necrosis in the pathogenesis of liver failure are the immunological alterations. In-depth studies have been conducted on the immunology of liver necrosis caused by HBV, HAV, and HDV. Taking HBV as an example, the main factors include:

　　(1) Cytotoxic effect mediated by cytolytic T lymphocytes (CTL).

　　(2) Cytokines: Cytokines are the products of immune reactions and can also promote immune damage, which are lymphotoxins secreted by target cells. They form a cascade reaction of cytokines, leading to the continuous amplification of immune damage. The main cytokines related to liver necrosis are tumor necrosis factor (TNF), interleukin 1 (IL-1), IL-6, IL-8, platelet activating factor (PAF), transforming growth factor-β1 (TGF-β1), and others.

　　4. Other factors

　　(1) Drugs and toxins: The common feature of liver necrosis caused by drugs and toxins is the history of drug use or contact with toxins, and these substances have been confirmed to have hepatotoxic effects.

　　(2) Metabolic abnormalities: mainly Wilson's disease and Reye's syndrome.

　　(3) Ischemia: The typical case is shock liver.

　　5. Pathological characteristics caused by hepatitis viruses, drug poisoning, and mushroom poisoning are extensive liver cell necrosis, disappearance of liver cells, and shrinkage of liver volume. Generally, there is no regeneration of liver cells, collapse of reticular framework, residual liver cells cholestasis, and inflammatory cell infiltration in the portal area.

　　Liver failure is a life-threatening clinical syndrome caused by widespread necrosis of liver cells or acute and severe damage to liver function due to various reasons. Severe cases often complicate with hepatic encephalopathy and hemorrhage, especially gastrointestinal hemorrhage, which is the most common. Large amounts of hemorrhage can lead to shock, and complications such as ascites, brain edema, and disorders of water and electrolyte balance are common, with hypokalemia, hypoproteinemia, and hyponatremia being common, and it is prone to hypoglycemia and secondary infections.

　　One, symptom classification

　　Clinical manifestations of liver failure patients include progressive liver damage, varying degrees of hepatic encephalopathy, increased intracranial pressure, hemorrhage, and symptoms of the underlying disease due to different etiologies.

　　The classification of liver failure is not unified. Currently, most scholars in China and abroad believe that liver failure can be classified into 3 types:

　　1. Fulminant liver failure: It refers to the onset of hepatic encephalopathy within 8 weeks after acute hepatitis in patients without a history of liver disease, including acute fulminant hepatitis with brain disease appearing within 2 weeks and subacute fulminant hepatitis with brain disease appearing between 2 and 8 weeks.

　　2. Delayed liver failure: It refers to the onset of hepatic encephalopathy or other liver failure syndromes within 2 to 6 months after the onset of liver disease, which is more severe than that of fulminant liver failure.

　　4. Chronic liver failure: It refers to the gradual deterioration of chronic liver disease, eventually leading to liver failure. In China, liver failure caused by viral hepatitis is called severe hepatitis.

　　Two, clinical manifestations

　　1. Progressive liver damage: Children with viral hepatitis show significant exacerbation of gastrointestinal symptoms, including decreased appetite, nausea, vomiting, abdominal distension, and occasional diarrhea; jaundice deepens rapidly, usually to moderate or above; the liver progressively shrinks, especially the right lobe, and the progression of liver atrophy is extremely fast after the condition worsens, with a few cases accompanied by splenomegaly; children are more prone to edema and ascites, and severe cases may have a liver odor in exhalation, which is a sign of poor prognosis in the late stage.

　　2, Hepatic encephalopathy (hepaticencephalopathy) or hepatic coma: Depending on the primary disease, hepatic encephalopathy can be divided into endogenous and exogenous types. Endogenous types are more common in fulminant hepatitis, and the child may enter a coma within a few days of onset, without prodromal symptoms before the coma. Exogenous hepatic encephalopathy belongs to portosystemic shunt encephalopathy and is more common in liver cirrhosis, characterized by chronic recurrent coma and obtundation, often with precipitating factors. The survival time after the onset of hepatic encephalopathy varies depending on the speed and extent of liver function failure, and most cases are of slow onset with gradual deepening of coma.

　　3, Increased intracranial pressure: About 80% of patients have cerebral edema, manifested as increased intracranial pressure. Infants may have dazed eyes, crying, irritability, vomiting, bulging of the anterior fontanelle. Older children may have severe headaches, frequent projectile vomiting, increased blood pressure, seizures, and disturbance of consciousness. They may also have rigid twisting of limbs, positive pathological reflexes. Due to cerebral circulatory disorders, high fever, and excessive peripheral vascular constriction, the skin becomes pale, the extremities turn blue, feel cold, and when the tentorial hernia occurs, the two pupils are not equal in size. When the foramen magnum hernia occurs, the pupils become dilated, the breathing rhythm is irregular, and even stops.

　　4, Hemorrhagic phenomena: Liver failure patients have varying degrees of hemorrhage, mild cases include skin and mucosal hemorrhage or bleeding, and nosebleeds and gingival hemorrhage are more common. Severe cases may involve internal bleeding, with the most common being gastrointestinal bleeding, which can cause vomiting of blood or fresh stools, or coffee-ground vomit and black stools. It often leads to shock due to a large amount of bleeding in one episode, or it can exacerbate hepatic encephalopathy; there may also be bleeding in other parts such as hemoptysis, hematuria, or intracranial hemorrhage, and massive hemorrhage is often a direct cause of death.

　　5, Hypoglycemia: When the liver of the child is severely damaged, the glycogenolysis is weakened, and in addition, due to vomiting, the child cannot eat, the storage of glycogen in the liver is significantly reduced, so it is very easy to develop hypoglycemia and worsen coma. The phenomenon of hypoglycemia can also be ignored due to the concurrent coma. The children often have cold hands and feet, sweating, low blood pressure, or occasionally spasms in the morning. It is very easy to develop hypoglycemia if the fasting child does not receive intravenous glucose infusion all night.

　　6, Hepatorenal syndrome (HRS): HRS is a serious complication in the late stage of liver failure. The renal histology of the children may be completely normal or slightly damaged. If liver disease can be reversed, renal function can be improved. The incidence of HRS during liver failure is about 30% to 50%, with a very high mortality rate. HRS often appears after strong diuretics, large amounts of paracentesis, upper gastrointestinal bleeding, or infection, and about 30% have no precipitating cause. The key points for diagnosis are:

　　7, Secondary infection: The incidence of concurrent infection in children with liver failure is high, with bacteremia being the most common, and complications such as pneumonia, biliary tract infection, or urinary tract infection may also occur. The pathogens are mainly staphylococcus, Escherichia coli, and infections with streptococci or anaerobic bacteria may also occur. Fungal infections may also be seen occasionally. The main clinical manifestations of the children are fever, while focal symptoms are not easy to find, and careful examination is required, or timely culture of body cavities such as blood, urine, and ascites is needed to make an accurate diagnosis.

　　8. Electrolyte imbalance: Children are prone to hypokalemia, which is caused by vomiting, inability to eat, large-scale use of potassium-wasting diuretics and glucocorticoids, increased aldosterone, large-scale glucose infusion, and other reasons. Low potassium levels can also lead to metabolic alkalosis, which is conducive to the production of ammonia. Due to insufficient intake, poor absorption, hypoproteinemia, and the use of diuretics, hypomagnesemia may occur. Decreased magnesium can cause increased excitability of the child's muscles, cramps in the hands and feet, delirium, similar to hypocalcium symptoms. Persistent hypocalcemia in the late stage indicates cell lysis and necrosis, poor prognosis, electrolyte imbalance, and can also be caused by improper fluid replacement.

　　Infection is the main cause of pediatric liver damage. Strengthening prenatal care, preventing various infectious diseases during pregnancy, especially infections with hepatitis B virus, cytomegalovirus, rubella virus, herpes simplex virus, congenital syphilis, and others, in order to prevent liver damage in children and the occurrence of this disease. There are hundreds of drugs and toxins that can cause liver cell damage. Avoid inappropriate use to prevent the occurrence of this disease. At the same time, rational feeding, balanced diet, doing a good job in various preventive vaccination work after birth, developing good hygiene habits, preventing and treating various chronic inflammatory bowel diseases, and so on. The prevention of liver failure, in addition to preventing and treating the primary disease, mainly should avoid the triggers that promote liver failure. Including restricting animal protein diet for patients with severe liver disease; preventing massive hemorrhage of viscera; using anesthetics, sedatives, and drugs containing amines with caution; preventing and treating infection; timely potassium supplementation; not too much and too fast abdominal fluid drainage; avoiding major surgery; avoiding overfatigue and drinking, and so on.

　　First, serological examination

　　1. Serum bilirubin: The total serum bilirubin is generally over 171.0 μmol/L (10 mg/dl), with an average daily increase of 17.1 μmol/L (1 mg/dl) or more, mainly due to the increase of direct bilirubin.

　　2. Enzyme-bilirubin dissociation: In severe liver disease, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) significantly decrease, showing a dissociation phenomenon with the rise of bilirubin, known as 'enzyme-bilirubin dissociation'. Alanine aminotransferase is mainly distributed in the cytoplasm of liver cells. In mild hepatitis or certain liver diseases, changes in cell membrane permeability lead to the release of enzymes from the cytoplasm into the blood, resulting in elevated alanine aminotransferase levels. When liver cells are severely damaged, the mitochondria are also affected, and the alanine aminotransferase in the blood decreases. Aspartate aminotransferase is distributed in the cytoplasm of liver cells and mitochondria. When the human body is infected with acute hepatitis, it is released into the blood, but it inactivates quickly, so it is lower than the alanine aminotransferase value. After the mitochondria are destroyed, aspartate aminotransferase is released into the blood circulation, the concentration in the blood increases and is higher than that of alanine aminotransferase, changing the ratio of alanine aminotransferase to aspartate aminotransferase. Therefore, monitoring the ratio of alanine aminotransferase to aspartate aminotransferase is of great significance in judging liver cell damage. A decrease in the ratio indicates severe liver cell necrosis and poor prognosis.

　　3. Blood amino acid measurement: The molar ratio of branched-chain to aromatic amino acids is normally 3:1 to 4:1, but in severe hepatitis, it decreases to below 1:1 to 1.5:1. Free tryptophan levels are significantly increased, playing an important role in promoting the occurrence of hepatic encephalopathy.

　　4. Prealbumin measurement: Can react to liver failure early. Liver failure affects protein synthesis, and albumin has a half-life of about 20 days in the body, while prealbumin is only 1.9 days, so its concentration in the patient's blood decreases earlier.

　　5. Alpha-fetoprotein (AFP) positivity: Indicates a strong liver cell regeneration capacity, seen in normal neonates or patients with liver cancer. AFP is also positive when liver cell regeneration occurs after liver injury. If the hepatocytes are progressively necrotic, AFP changes from negative to positive, the concentration gradually increases, indicating liver cell regeneration and a good prognosis.

　　Second, coagulation examination

　　1. Prolonged prothrombin time or decreased prothrombin activity: It is of great significance for diagnosis and prognosis estimation. The prothrombin activity in mild cases is often below 60%, and in severe cases, often below 40%, indicating poor prognosis.

　　2. Diffuse intravascular coagulation-related detection: Abnormal red blood cell morphology,呈 triangular, spiny, or with fragments, progressive decrease in platelets, decreased fibrinogen, prolonged prothrombin time, are all early indicators of diffuse intravascular coagulation. If there is an increase in fibrin degradation products (FDP) and a shortened euglobulin lysis time, there is hyperfibrinolysis.

　　3. Pathogen detection uses enzyme-linked immunosorbent assay or radioimmunoassay to detect serum viral hepatitis-related antigens or antibodies, or DNA probe hybridization to detect viral nucleic acids to determine the pathogen. Necessary immunohistochemistry of the liver and in situ hybridization methods to detect viral antigens and viral nucleic acids. For concurrent bacterial or fungal infections, blood cultures and other examinations should be performed multiple times.

　　4. B-ultrasound examination can monitor the size, ultrasound images, and presence of ascites, masses, etc. of organs such as liver, spleen, gallbladder, and bile ducts.

　　5. Electroencephalogram examination shows abnormalities in patients with hepatic encephalopathy at an early stage.

　　6. Liver biopsy is performed using 1s needle puncture negative pressure aspiration technology, which is simple, safe, and has a high success rate. It can assist in the diagnosis of hepatitis and hereditary metabolic liver disease, or help judge the prognosis. Poor prognosis is associated with extensive severe necrosis of hepatocytes in viral hepatitis; a better prognosis is associated with cellular swelling.

　　Children with liver failure should limit the intake of protein (especially animal protein) in their diet; those with pre-coma signs should be strictly fasting, and the duration should vary according to the condition, generally 3 to 5 days. After the condition of coma improves, gradually start to eat, starting with a small amount of carbohydrates, and gradually increase protein foods as the condition stabilizes. During the fasting period, the daily calorie intake should not be less than 125.5 to 167.4 kJ/kg (30 to 40 kcal/kg). Appropriate amounts of vitamin B complex, vitamin C, vitamin D, vitamin E, vitamin K, adenosine triphosphate, and coenzyme A should be given to supplement nutrition.

　　One, the main measures should be targeted at

　　1. Reducing and eliminating toxic substances.

　　2. Preventing liver necrosis and promoting liver cell repair.

　　3. Supportive therapy and symptomatic treatment.

　　4. Prevention and treatment of complications.

　　5. Artificial liver support systems and liver transplantation.

　　Two, basic supportive therapy

　　1. Strict isolation: The child should be housed in an isolation ward, which should be disinfected, and care should be provided by a dedicated nurse. Electroencephalography, intracranial pressure, and B-ultrasound should be monitored.

　　2. Adjusting diet: For patients with significant digestive symptoms of hepatitis, protein intake (especially animal protein) should be restricted; for those with signs of impending coma, strict fasting should be enforced, the duration of which should vary according to the condition, generally 3-5 days. After the condition of coma improves, food should be gradually introduced, starting with small amounts of carbohydrates, and protein intake should be gradually increased as the condition stabilizes. During the period of fasting, daily calories should not be less than 125.5-167.4kJ/kg (30-40kcal/kg). Appropriate amounts of vitamin B complex, vitamin C, vitamin D, vitamin E, vitamin K, and adenosine triphosphate, coenzyme A, etc., should be administered to supplement nutrition.

　　3. Regulation of water and electrolyte balance: Those with hypokalemia, hypocalcemia, or hypomagnesemia should be corrected promptly. According to blood sodium measurement, if there is no significant hyponatremia, it is not advisable to supplement sodium salts excessively, maintaining physiological needs only to prevent brain edema. During the period of fasting, the daily fluid intake should be strictly limited to no more than 1200ml/m2, and glucose solution should be administered to maintain nutrition and provide calories. When hypocalcemia occurs, 5-10ml of 10% calcium gluconate is administered intravenously daily, and for every 200ml of citrate anticoagulated blood administered, an additional 1g of calcium (calcium preparations should not be added to the blood administered) is required. In cases of metabolic alkalosis, 20-60ml of 25% arginine is administered intravenously. Hypokalemia is prone to metabolic alkalosis, which may induce or exacerbate hepatic encephalopathy. Potassium should be supplemented promptly when urine output is normal.

　　Three, promoting liver cell regeneration

　　1. Glucagon-insulin therapy (G-I therapy): It has the effects of preventing liver cell necrosis, promoting liver cell regeneration, improving hyperammonemia, and adjusting amino acid metabolism balance. The two are used in appropriate proportions to produce a synergistic effect, with the dose varying with age. The commonly used dose of glucagon is 0.2-0.8mg, insulin 2-8U (ratio 1:8-1:10), infused intravenously in 100-200ml of 10% glucose solution, 1-2 times a day. The amount of glucose should be 4g per unit of insulin, and the course of treatment is generally 10-14 days.

　　2. Human albumin or plasma: The liver's function to synthesize albumin is impaired in liver failure. The administration of human albumin aids in the regeneration of liver cells, improves plasma colloid osmotic pressure, reduces ascites and brain edema; albumin can also bind bilirubin, reducing hyperbilirubinemia. Fresh plasma can supplement regulators and complement, enhancing the body's anti-infection ability. The dose of human albumin is 0.5-1.0g/kg, plasma 25-100ml each time, and both are administered alternately, once a day or every other day.

　　3. Promoter of liver cell growth (HGF): The method is to add 40-80mg of HGF daily to 100-200ml of 10% glucose solution for intravenous infusion, once daily, for a course of 1-2 months.

　　3. Immune regulation therapy Thymosin can enhance the ability to resist diseases and reduce serious infections. It can be administered intramuscularly or intravenously at a dose of 10-40mg daily, or 40-80mg, twice or three times a week by intravenous infusion.

　　Four, prevention and treatment of complications

　　1. Treatment of hepatic encephalopathy (see hepatic encephalopathy).

　　2. Control cerebral edema (see hepatic encephalopathy).

　　3. Prevention and treatment of gastrointestinal bleeding:

　　①Supplementing coagulation factors: Inject 110mg of vitamin K1, 1-2 times daily. The transfusion of thrombin complex factors is an effective measure for bleeding caused by decreased coagulation factors. The preparation is an extract of normal human plasma, containing concentrated II, VIII, IV, X factors, diluted with an appropriate amount of physiological saline for intravenous infusion; due to its short half-life, it needs to be injected every 6-8 hours to control massive bleeding.

　　②Transfusion of fresh blood or plasma: Used to supplement coagulation factors and lost blood volume.

　　③Prevention and treatment of disseminated intravascular coagulation: If it is confirmed that the bleeding is caused by disseminated intravascular coagulation, heparin should be used for treatment, 1mg (125U)/kg each time, 1-2 times daily, until the bleeding is controlled. During the process, fresh whole blood should be transfused daily, and coagulation time monitoring should be strengthened to prevent excessive bleeding due to heparin overdose.

　　④Histamine H2 receptor antagonist: Such as cimetidine (Cimetidine), 0.05-0.1g each time, 2-4 times daily, this drug can also be used for prophylactic treatment, that is, to take the medicine even if there is no bleeding. The use of such preparations can significantly reduce gastrointestinal bleeding and also reduce the severity of bleeding. It can also be combined with normal saline plus norepinephrine infused through a gastric tube.

　　⑤Anticoagulant drugs: 5-10U of vasopressin combined with 50-100ml of 10% glucose solution for intravenous infusion, and can be repeated if necessary every 3-4 hours. Omeprazole (Losec) 5-20mg for intravenous infusion, once daily. Octreotide (octreotide, Sandet) 2-3g/kg each time, diluted with 20ml of 10% glucose solution for slow intravenous push, maintenance dose is 10-30g/kg each time, combined with 500-1000ml of 10% glucose solution for intravenous infusion for 20 hours. Somatostatin (Stilamin) 5-10g/kg for intravenous injection, maintenance dose is 60-100g/kg combined with 500-1000ml of 10% glucose solution for intravenous infusion for 12 hours, which can be used continuously for 24-72 hours. Terlipressin (Colyxin, glycylglycyllysine vasopressin), initial dose 0.04mg/kg for slow intravenous push, maintenance dose every 4 hours, 0.02-0.04mg/kg each time, intravenous push, maintenance for 24-36 hours until bleeding stops. Thrombin 50-200U combined with NS 50-100ml for oral administration, can be repeated every 2-8 hours. Yunnan Baiyao 0.1-0.5g, twice daily, taken orally.

　　4. Improve microcirculation: Anisodamine (654-2) has the effects of relaxing smooth muscle spasm and dilating microvessels, which can significantly improve microcirculation and reduce liver cell damage. The dosage is 0.5-1mg/kg, intravenous injection, twice a day, until the encephalopathy is significantly improved, then change to oral administration, and discontinue medication after liver function recovery. Traditional Chinese medicine Chuanxiong injection or compound Danshen injection have the effects of promoting blood circulation and removing blood stasis, and improving microcirculation. Chuanxiong is 3-4mg/kg per day, administered intravenously in two doses, diluted with glucose solution. Compound Danshen is 2-4ml per dose, administered intravenously diluted with glucose solution, 1-2 times a day. Either one can be chosen.

　　5. Prevention and treatment of secondary infection: Children with liver failure are prone to secondary infection, and concurrent bacterial and fungal infections are often hospital-acquired infections. In addition to strict isolation and regular disinfection of the room, early use of effective antibiotics should be selected when infection signs are found, but it should be avoided to use antibiotics and corticosteroids that damage the liver and kidneys. Generally, penicillin or antibiotics that inhibit Gram-negative bacteria are commonly used. Fungal infections should be promptly discontinued with broad-spectrum antibiotics.

　　6. Prevention and treatment of hepatorenal syndrome (HRS): The main method is to remove the triggers such as hypokalemia, infection, and hemorrhage. When it is difficult to distinguish between early renal pre-renal renal failure, expand the volume treatment can be carried out. If the urine output reaches more than 20-30ml/h after expansion, or exceeds the urine output before fluid replacement, continue to replace fluids. Vasoactive drugs can be used in HRS, such as 0.05-1.00mg/kg of anisodamine (654-2), intravenous infusion, 0.05-1.00mg/kg of dopamine added to glucose solution for intravenous infusion, etc. Early application of diuretics. Once renal tubular necrosis occurs, renal failure is irreversible. When oliguria or anuria occurs, strictly limit the intake of fluids. At present, there is still a lack of effective treatment methods.