Fulminant hepatic failure

　　The pathogenesis of this disease has not been fully elucidated. It was previously believed that the onset of FHF is mainly due to primary immune injury, followed by liver microcirculatory disorders. With the in-depth study of the effect of cytokines (Cytokine) on vascular endothelial cells and the role of liver microcirculatory disorders in the pathogenesis, it is believed that Schwartz reaction is related to the onset of FHF. Cytokines are a group of biologically active protein mediators that arise after the study of lymphokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxin (LT). Among them, TNF is a product of the stimulation of mononuclear macrophages by endotoxins and can act on vascular endothelial cells and liver cells, leading to Schwartz reaction. Therefore, TNF is considered to be one of the main pathogenic mechanisms of FHF. In addition, endotoxemia can exacerbate liver cell necrosis and lead to organ damage (such as renal failure), which is also an important pathogenic factor.

　　During the acute phase of the disease, it is mainly manifested as hepatic encephalopathy, followed by the following symptoms, and the transitional stage is not easily separated.

　　1, Cerebral edema:When there are ankle clonus and positive pyramidal tract signs, there is already cerebral edema, or conjunctival edema, dilated and fixed pupils, slow and irregular breathing, and papilledema, all indicating cerebral edema.

　　2, Coagulation dysfunction and hemorrhage:Bleeding sites are commonly found in the skin, gingiva, nasal mucosa, conjunctiva, and gastric mucosa, etc.

　　(1) Abnormalities in platelet quality and quantity:During FHF, platelets are smaller than normal, and electron microscopy shows vacuoles, pseudopods, and a blurred plasma membrane. Platelets are normal without encephalopathy. Due to bone marrow suppression, splenic hyperfunction, and consumption by intravascular coagulation, platelet count may decrease.

　　(2) Coagulation factor synthesis disorder:All coagulation factors in the plasma are decreased, especially Factor VII, which is synthesized outside the liver, and is increased instead. The prothrombin time is significantly prolonged.

　　(3) DIC with secondary local fibrinolysis:Both plasma plasmin and its activators are decreased, while the products of fibrin/fibrinogen degradation are increased.

　　3, Infection:The most common is respiratory tract infection, other urinary infections are mostly G- bacilli, G+ cocci, and can also be anaerobic bacteria and fungal infections.

　　4, Renal failure:In FHF, renal dysfunction reaches 70%, acute tubular necrosis accounts for half, with high urine sodium, isotonic urine, and tubular necrosis. It is related to factors such as liver cell necrosis, endotoxemia, inappropriate use of diuretics, gastrointestinal bleeding leading to hypovolemia and hypotension. There are reports that renal failure accounts for the first place among the causes of death in FHF, which deserves attention.

　　5, Electrolyte acid-base balance disorder:Hyponatremia, hypocalcemia, hypomagnesemia, hypokalemia, respiratory alkalosis, hypochloremic alkalosis, and metabolic acidosis, etc.

　　6, Other:Hypoglycemia, hypoxemia, pulmonary edema, arrhythmia, portal hypertension, and acute pancreatitis, etc.

　　First, early symptoms

　　1. Jaundice has 3 characteristics:

　　(1) Jaundice deepens rapidly in a short period after the appearance of jaundice. If the total bilirubin is >171μmol/L, and there are other manifestations of severe liver function damage, such as bleeding tendency, prolonged prothrombin time, and increased ALT, if there is only deep jaundice without other severe liver function abnormalities, it indicates intrahepatic cholestasis.

　　(2) Jaundice lasts a long time. The general规律 of the fluctuation of jaundice is to deepen, persist, and then fade. If jaundice does not fade after 2-3 weeks, it suggests a serious condition.

　　(3) There is no improvement in the condition after the appearance of jaundice. According to the general规律 of acute jaundice type hepatitis, after the appearance of jaundice, the appetite gradually improves, and nausea and vomiting decrease. If there is no improvement in symptoms for 1 week after the appearance of jaundice, one should be vigilant for severe hepatitis.

　　2. Persistent low fever:The onset of the disease may be accompanied by low fever, and the body temperature may decrease to normal after the appearance of jaundice. If persistent low fever is accompanied by jaundice, it suggests liver cell necrosis or endotoxemia.

　　3, Extremely poor general condition:Such as fatigue, drowsiness, loss of appetite, and even inability to take care of oneself.

　　4, Obvious gastrointestinal symptoms:Frequent nausea, vomiting, hiccups,明显 abdominal distension, disappearance of bowel sounds, and intestinal paralysis.

　　5, Bleeding tendency:If there are ecchymosis, purpura, epistaxis, gingival bleeding, and a few cases of upper gastrointestinal bleeding, it indicates coagulation dysfunction and liver failure.

　　6, Rapid onset of ascites:Due to the long half-life of albumin (about 2 weeks), hypalbuminemia usually appears 2 to 3 weeks after the disease, and ascites is common in patients with a course of disease exceeding 2 to 8 weeks.

　　7, Change in personality:If the original personality is cheerful, it suddenly becomes melancholic, or vice versa, the sleep rhythm is reversed, language repetition, inability to构思, disorientation, eccentric behavior, and defecating anywhere, all are signs of hepatic encephalopathy, followed by disturbance of consciousness and entering hepatic coma.

　　8, Progressive liver shrinkage, liver odor, flapping tremors, increased muscle tone, positive pyramidal tract signs, ankle clonus, etc., indicating severe liver damage.

　　9, Heart rate acceleration, hypotension, related to endotoxemia or internal hemorrhage.

　　Symptoms in the late stage:

　　During the acute phase of the disease, it is mainly manifested as hepatic encephalopathy, followed by the following symptoms, and the transitional stage is not easily separated.

　　1, Cerebral edema:When there are ankle clonus and positive pyramidal tract signs, there is already cerebral edema, or conjunctival edema, dilated and fixed pupils, slow and irregular breathing, and papilledema, all indicating cerebral edema.

　　2, Coagulation dysfunction and hemorrhage:The bleeding sites are common in the skin, gingiva, nasal mucosa, conjunctiva, and gastric mucosa, etc.

　　(1) Abnormality in platelet quality and quantity: In FHF, platelets are smaller than normal, electron microscopy shows vacuoles, pseudopods, and unclear plasma membranes. Platelets are normal without encephalopathy, due to bone marrow suppression, splenic hyperfunction, and consumption by intravascular coagulation, which can lead to thrombocytopenia.

　　(2) Deficiency in coagulation factor synthesis: All coagulation factors in plasma are decreased, especially factor VII, which is synthesized outside the liver and increases instead, leading to a significant prolongation of prothrombin time.

　　(3) DIC with secondary local fibrinolysis: Both plasmin and its activator substances in plasma are decreased, while the degradation products of fibrin/fibrinogen increase.

　　3, Infection:The most common is respiratory tract infection, other urinary infections are mostly G- bacilli, G+ cocci, and can also be anaerobic bacteria and fungal infections.

　　4, Renal failure:In FHF, renal dysfunction reaches 70%, acute tubular necrosis accounts for half, with high urine sodium, isotonic urine, and tubular necrosis. It is related to factors such as liver cell necrosis, endotoxemia, inappropriate use of diuretics, gastrointestinal bleeding leading to hypovolemia and hypotension. There are reports that renal failure accounts for the first place among the causes of death in FHF, which deserves attention.

　　5, Electrolyte acid-base balance disorder:Hyponatremia, hypocalcemia, hypomagnesemia, hypokalemia, respiratory alkalosis, hypochloremic alkalosis, and metabolic acidosis, etc.

　　6, Other:Hypoglycemia, hypoxemia, pulmonary edema, arrhythmia, portal hypertension, and acute pancreatitis, etc.

　　The pathogenesis of this disease has not been fully elucidated. It was previously believed that the pathogenesis of fulminant hepatic failure (FHF) is primarily due to primary immune injury, followed by liver microcirculatory disorders. With the deepening of research on the effects of cytokines (Cytokine) on vascular endothelial cells and the role of liver microcirculatory disorders in the pathogenesis, it is believed that the Schwartz reaction is related to the pathogenesis of FHF. Cytokines are a group of biologically active protein mediators that emerged after the study of lymphokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxin (LT). Among them, TNF is a product of endotoxin stimulation of mononuclear macrophages and can act on vascular endothelial cells and liver cells, leading to Schwartz reaction. Therefore, TNF is considered one of the main pathogenic mechanisms of FHF. In addition, sepsis can exacerbate liver cell necrosis and lead to visceral injury (such as renal failure), which is also an important pathogenic factor.

　　1. Prothrombin Time Determination

　　This test is one of the most valuable indicators for correctly reflecting the severity of damage and is helpful for early diagnosis. The test requires strict standards and should be conducted by experienced personnel to ensure accuracy. It is characterized by a significantly prolonged prothrombin time.

　　2. Cholesteryl Esterase Determination

　　This enzyme is synthesized by liver cells, so in severe liver damage, the serum cholesteryl esterase level is significantly reduced.

　　3. Bile Enzyme Separation Phenomenon

　　As the bilirubin level gradually increases, ALT levels decrease. 80% of ALT is present in the cytoplasm of liver cells. When liver cells are damaged, the permeability of the cell membrane changes, causing ALT to leak into the blood. In the early stages, ALT levels may increase. As the condition worsens, the enzyme is exhausted at a certain stage, and considering its short half-life, the serum ALT level decreases, indicating poor prognosis.

　　4. Dynamic Observation of AST/ALT Ratio

　　Testing within 10 days after the onset of the disease has certain significance for predicting the condition and prognosis. ALT is mainly present in the cytoplasm of liver cells, while AST is mostly located in the mitochondria. The normal AST/ALT ratio is 0.6. When liver cells are severely damaged, AST is excreted from the mitochondria, and the ratio exceeds 1.

　　5. Amino Acid (AA) Determination

　　This includes the total urinary amino acid content and serum arginine analysis. Since almost all amino acids are metabolized in the liver, synthesized by liver cells to produce the human body's essential proteins, when severe liver damage occurs, amino acids cannot be utilized, leading to amino acid metabolism disorders and imbalance. The first sign is a significant increase in the total urinary amino acid content, an increase in aromatic amino acids in the serum, and a decrease in the ratio of branched-chain to aromatic amino acids from the normal 3 to 3.5 to less than 1, indicating poor prognosis.

　　Diet should be regular and reasonable, mainly focusing on high-protein and high-vitamin foods. Choose plant or animal proteins with high nutritional value, such as milk, eggs, fish, lean meat, and various bean products. Various fresh vegetables and fruits are rich in vitamins and have high nutritional value. It is advisable to eat less processed food, as these foods contain preservatives and additives that can damage liver function and are not conducive to the recovery of liver disease.

　　One, etiology treatment

　　For FHF caused by hepatitis virus infection, such as HBV, HCV, HDV, or those with a slow progression of the disease in the early stage, antiviral drugs such as interferon can be used, and for those caused by drugs, the drug should be discontinued.

　　Two, immune regulation

　　It is not recommended to use adrenal cortical hormones and immunosuppressants, immunostimulants can be used appropriately, such as thymosin, the dosage is 6-20mg added to 250-500ml of 10% glucose solution, administered slowly by intravenous infusion, once a day, 30 days as a course of treatment, a skin test should be performed before taking the medicine, and fresh plasma can also be used.

　　Three, glucagon-insulin therapy (GI therapy)

　　Anti-hepatic cell necrosis, promote liver cell regeneration, the dosage is 1mg of glucagon, 10U of insulin added to 500ml of 10% glucose solution, administered slowly by intravenous infusion, 1-2 times a day, combined with preparations mainly containing branched-chain amino acids, the efficacy is good, generally 2-4 weeks as a course of treatment.

　　Four, treatment of hepatic encephalopathy

　　1. 14-aminocaproic acid 800, 6-aminocaproic acid 520:The former is suitable for liver cirrhosis and hepatic encephalopathy, both contain branched-chain amino acids and do not contain aromatic amino acids, the dosage is 6-aminocaproic acid 520, 250ml each time, twice a day, connected with an equal amount of 10% glucose solution and 500mg of L-acetylglutamic acid and administered slowly by intravenous infusion, reduce the dose by half when consciousness returns, until completely清醒，the course of treatment is 5-7 days, and then use 14-aminocaproic acid 800 to consolidate the efficacy, note that the compound amino acid Sohamine or Freamine contains a high amount of tyrosine, phenylalanine, and methionine, which can trigger hepatic encephalopathy.

　　2. Levodopa and carbidopa:The dosage is 100mg of levodopa, 10mg of carbidopa added to 500ml of 10% glucose solution, administered slowly by intravenous infusion, 1-2 times a day, both drugs can reduce the side effects of levodopa, note that it should not be used with VitB6, as VitB6 has dopa decarboxylase activity, causing levodopa to decarboxylate, reducing dopamine concentration in the brain and losing its effect, the efficacy is not very ideal.

　　3. Control the production of ammonia:The following three aspects should be addressed:

　　(1) Clean the intestines with 30ml of vinegar and 1000ml of physiological saline for enema, or use physiological saline for enema, twice a day, and after enema, use 30ml of 50% fructooligosaccharide and 100mg of neomycin added to 100ml of physiological saline for retention enema.

　　(2) Oral metronidazole or ampicillin.

　　(3) Fructooligosaccharide therapy can acidify the intestinal environment, reduce blood ammonia, clear endotoxemia, and the dosage is 30-50ml of 50% fructooligosaccharide, taken orally three times a day (nasogastric feeding can be used for coma patients), preferably after meals, and the standard is to have two bowel movements of paste-like stools per day.

　　V. Treatment of complications

　　1. Brain edema

　　Prevention is more important than treatment, when there is hyperreflexia of the patellar reflex, clonus of the ankle, or positive corticospinal tract signs, the efficacy is better.

　　(1) Diuretics include 20% mannitol or 25% sorbitol, 250ml each time, administered intravenously by rapid pressure infusion, completed within 20-30 minutes, this is very important, then use 1 time every 4-6 hours, if necessary, add furosemide between two diuretics, if consciousness improves, the dose can be halved, but the interval should not be extended to avoid rebound. Sorbitol has a slightly lower diuretic effect than mannitol, but has no blood-urinating side effects, and is safer to use sorbitol in the case of encephalopathy in severe hepatitis patients.

　　(2) Dexamethasone is administered by adding 10mg to an appropriate amount of 10% glucose solution and injected intravenously, then 5mg is used with a diuretic every 4-6 hours, for 2-3 days consecutively.

　　2. Prevention and treatment of bleeding

　　The following four methods:

　　(1) Supplementation of coagulation factors most coagulation factors have a short half-life, so it is better to use fresh frozen plasma. The thrombin complex (PPSB) contains II, V, VII, and IX four coagulation factors, with an effective dose of 10U/kg per day.

　　(2) H-2 receptor antagonists prevent gastric bleeding, these drugs are mainly metabolized in the liver and kidneys, there are reports that cimetidine has liver-damaging side effects, so ranitidine (Ranitidine) is used, the method is 150mg, once a night, with few side effects and good efficacy.

　　(3) Selecting propylthiouracil to reduce portal vein pressure, the dose should be to slow down the heart rate by 25%, when used with H-2 receptor antagonists, the dose can be reduced.

　　(4) Thrombin has satisfactory hemostatic effect on gastric mucosal erosion and bleeding, after bleeding stops, the dose can be reduced or the interval between taking the medicine can be extended, the method is 2000-10000U per time, once every 4-6 hours, the shortest every 1-2 hours.

　　3. Prevention and treatment of infection

　　(1) Strengthen oral and skin care, strict disinfection and isolation, aseptic operation, purify the indoor air, prevent respiratory tract infections.

　　(2) Endotoxemia can be treated with oxacillin 0.5g every hour, effective against intestinal bacteria, or use Lactobacillus preparation 10g each time (containing 10^6 acid bacteria per gram), taken 2-3 times a day, which can inhibit intestinal bacteria.

　　(3) Select antibiotics with no toxicity to the liver and kidneys for bacterial infections,

　　Ampicillin: 6-8g per day, administered intravenously in divided doses, suitable for Escherichia coli infections,

　　Ampicillin: A mixture of equal parts of ampicillin and cloxacillin, 6-8g per day, administered intravenously in divided doses, effective against Escherichia coli and Staphylococcus aureus,

　　Tobramycin: 0.2g every 8 hours, intramuscular injection, can be used intravenously with the same dose in emergencies, twice a day, lower in nephrotoxicity than gentamicin,

　　Cephalosporins: Suitable for severe infections, especially Gram-negative bacilli infections, commonly used ones include cefazolin (Xianfeng V), cefuroxime (Xili Xin) or third-generation cephalosporins, such as cefotetan (Fudaxin), ceftriaxone (Junbizhi), cefoperazone (Xianfengbi),

　　⑤ Metronidazole (Flagyl): Used for anaerobic bacterial infections, the dosage is 400mg per time, taken three times a day, for severe infections, 500mg of metronidazole is added to 100ml of isotonic solution for adults, and intravenous infusion is performed within 20-30 minutes, twice a day. Pay attention to the prohibition of use in pregnant women, lactating women, central nervous system diseases, heart disease, and blood disease patients.

　　⑥ Antifungal drugs; Nystatin can be used for oral fungal infections, amphotericin B, miconazole (Miconazole), for deep fungal infections, fluconazole can be selected. Attention should be paid to the use of caution in patients with impaired liver and kidney function, and caution should be exercised with ketoconazole, as it may cause liver damage. Garlicin injection can also be used, 60-120mg per day for adults, added to 500-1000ml of 5% glucose solution for intravenous infusion, for a course of 2 weeks.

　　4. Renal Failure

　　The leading cause of death in FHF, prevention is more important than treatment, such as controlling fluid intake, avoiding drugs that damage the kidneys, early use of osmotic diuretics, drugs to improve microcirculation, preventing hyperkalemia, etc. Hemodialysis and peritoneal dialysis are rarely effective, and in recent years, prostaglandin E1 and E2 have been used to improve renal and hepatic syndrome.

　　6. Prevention and Treatment of Electrolyte Acid-Base Imbalance

　　From the onset, the treatment plan is adjusted according to blood gas analysis and electrolyte changes over time, such as metabolic alkalosis, respiratory alkalosis combined with metabolic acidosis, metabolic acidosis, hyponatremia, hypocalcemia, hypomagnesemia, hypokalemia, etc.

　　7. Liver Support Therapy

　　Hepatocyte Growth Factor Therapy (HGF): According to a multi-center collaborative research report in China, the addition of HGF or prostaglandin E1 to the comprehensive therapy, or the combination of traditional Chinese and Western medicine for the treatment of fulminant hepatic encephalopathy due to hepatic failure, can significantly reduce the mortality rate compared to the past, which may be related to early diagnosis, strengthened comprehensive support therapy and nursing. In recent years, many liver disease serum HGF levels have increased to varying degrees, and the activation of HGF receptor and cmet gene (cancer gene proto-oncogene) is related. Therefore, before the wide application of HGF, it is necessary to understand the benefits and risks of giving high-dose exogenous HGF, and the potential activation of proto-oncogenes, which requires further in-depth study.

　　Plasma exchange, artificial liver is under study, liver cell transplantation and liver transplantation have not been used in clinical practice abroad, but China has begun research.