bubble_chart Overview

Fulminant hepatic failure is a syndrome caused by various diseases leading to massive necrosis of liver cells and severe liver function damage, with no prior history of liver disease and the onset of hepatic encephalopathy within 8 weeks of illness. It is characterized by acute onset, rapid progression, and a high mortality rate. Early diagnosis and treatment can reduce the mortality rate.

bubble_chart Pathogenesis

The pathogenesis of this disease has not yet been fully elucidated. It was previously believed that the onset of FHF was primarily due to primary immune injury, followed by secondary hepatic microcirculation disorders. With the deepening of research on the effects of cytokines on vascular endothelial cells and the role of hepatic microcirculation disorders in the pathogenesis, it is now believed that the Schwartz reaction is related to the onset of FHF. Cytokines are a group of biologically active protein mediators that emerged following the study of lymphokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxin (LT). Among these, TNF is a product of internal toxin stimulation of mononuclear macrophages and can act on vascular endothelial cells and hepatocytes, leading to the Schwartz reaction. Therefore, TNF is considered one of the main mechanisms of FHF. Additionally, internal toxinemia can exacerbate hepatocyte necrosis and lead to visceral injury (such as renal failure), which is also an important disease-causing factor.

The pathogenesis of hepatic encephalopathy is very complex, and several theories have been proposed over the years, each with its own evidence, but none can fully explain the issues in clinical and experimental research. However, protein metabolism disorders may be the core factor. It is known that ammonia poisoning is an important cause of nitrogenous or exogenous hepatic encephalopathy. For patients with hepatic encephalopathy without elevated blood ammonia, studies have confirmed that most have increased ammonia levels within red blood cells, so the role of ammonia in causing encephalopathy deserves attention. Recent studies on blood amino acid levels have found that increased tryptophan can lead to encephalopathy, along with increases in methionine, phenylalanine, and tyrosine. Measuring tryptophan not only aids in the diagnosis of hepatic encephalopathy but can also serve as an indicator of acute hepatitis progressing to severe disease and prognosis. Branched-chain amino acids (BCAA) are either normal or reduced. In FHF, the BCAA/aromatic amino acid ratio can drop from the normal 3-3.5 to below 1.0. Recent studies suggest that changes in amino acids may be related to increased blood ammonia, proposing a unified theory of blood ammonia and amino acids. The theory of pseudo-neurotransmitters (such as octopamine) causing hepatic encephalopathy has not been confirmed by repeated experiments. Only when there is an imbalance in amino acid metabolism do aromatic amino acids cross the blood-brain barrier, increasing inhibitory neurotransmitters like serotonin and reducing norepinephrine and dopamine, thereby inhibiting the brain and causing consciousness disorders. Experiments have shown that even without changes in neurotransmitter concentrations in the brain, changes in neurotransmitter receptors can also lead to encephalopathy, thus proposing the theory of neurotransmitter receptor dysfunction. In summary, the occurrence of hepatic encephalopathy is the result of the combined synergistic effects of multiple toxic substances and various disease-causing factors leading to structural and functional abnormalities in neural transmission, resulting in a clinical syndrome.

bubble_chart Pathological Changes

FHF caused by hepatitis virus, drug poisoning disease, and mushroom poisoning is characterized by extensive hepatocyte necrosis, disappearance of hepatocytes, and reduction in liver volume. Generally, there is no hepatocyte regeneration, often with collapse of the reticular framework, cholestasis in residual hepatocytes, and inflammatory cell infiltration in the portal area.

The hepatic pathological features of acute fatty liver during pregnancy and Reye's syndrome are characterized by severe mitochondrial damage in hepatocytes, leading to metabolic dysfunction. The cells in the mid-zone of the hepatic lobules are enlarged, with the cytoplasm filled with fatty vacuoles, presenting a honeycomb appearance, without massive hepatocyte necrosis. The liver shrinkage is less pronounced than in acute severe hepatitis.

bubble_chart Clinical Manifestations

During the course of the disease, multiple organs are involved, resulting in complex and varied clinical symptoms. The onset is acute, and the condition progresses rapidly.

I. Early Symptoms

1. Jaundice has three characteristics:

(1) Jaundice deepens rapidly within a short period after its appearance, such as total bilirubin >171 μmol/L, accompanied by other signs of severe liver dysfunction, such as bleeding tendency, prolonged prothrombin time, and elevated ALT. If there is only deep jaundice without other severe liver function abnormalities, it indicates intrahepatic cholestasis;

(2) Jaundice lasts for a long time. Generally, the pattern of jaundice is deepening, persisting, and then subsiding. If jaundice persists for 2-3 weeks, it suggests a severe condition;

(3) The condition does not improve after the appearance of jaundice. Generally, in acute jaundice hepatitis, appetite gradually improves and nausea and vomiting lessen after the appearance of jaundice. If symptoms do not improve one week after the appearance of jaundice, severe hepatitis should be suspected.

2. Persistent low-grade fever: There may be low-grade fever at the onset of the disease, and body temperature returns to normal after the appearance of jaundice. If persistent low-grade fever accompanies jaundice, it suggests hepatocyte necrosis or internal toxinemia.

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

4. Significant gastrointestinal symptoms: Frequent nausea, vomiting, hiccups, obvious abdominal distension and fullness, disappearance of borborygmi, and intestinal paralysis.

5. Bleeding tendency: Such as skin ecchymosis, purpura, epistaxis, gum bleeding, and a few cases of upper gastrointestinal bleeding, indicating coagulation dysfunction and liver failure.

6. Rapid appearance of ascites: Due to the long half-life of albumin (about 2 weeks), hypoalbuminemia generally appears 2-3 weeks after the onset of the disease. Ascites is common in cases where the course exceeds 2-8 weeks.

7. Personality changes: Such as a sudden change from a cheerful personality to depression or antagonism. Sleep rhythm reversal, repetitive speech, inability to think, disorientation, eccentric behavior, and incontinence are all signs of hepatic encephalopathy. This is followed by consciousness disturbance, leading to hepatic coma.

8. Progressive liver shrinkage, liver odor, flapping tremor, increased muscle tone, positive pyramidal tract signs, and ankle clonus indicate severe liver damage.

9. Increased heart rate and hypotension are related to internal toxinemia or internal bleeding.

II. Late Stage [Third Stage] Symptoms

During the peak of the disease, hepatic encephalopathy is the main manifestation, followed by the following symptoms, with the transitional stages not easily distinguishable.

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

2. Coagulation dysfunction and bleeding: Common bleeding sites include the skin, gums, nasal mucosa, bulbar conjunctiva, and gastric mucosa.

(1) Abnormal platelet quality and quantity: In FHF, platelets are smaller than normal, and vacuoles, pseudopods, and blurred plasma membranes can be seen under electron microscopy. Platelets are normal without hepatic encephalopathy. Platelet reduction can be caused by bone marrow suppression, hypersplenism, and consumption by intravascular coagulation.

(2) Impaired synthesis of coagulation factors: All coagulation factors in plasma are reduced, especially factor VII, which is synthesized outside the liver and is instead increased. Prothrombin time is significantly prolonged.

(3) DIC with local secondary fibrinolysis: Plasmin and its activators in plasma are reduced, while fibrin/fibrinogen degradation products are increased.

3. Infection: Respiratory infections are the most common, followed by urinary infections, mostly caused by G^- bacilli, G⁺ cocci, and possibly anaerobic bacteria and fungal infections.

4. Renal Failure In FHF, renal dysfunction occurs in 70% of cases, with acute tubular necrosis accounting for half of these. There is high urinary sodium, isosthenuria, and tubular necrosis. This is related to factors such as hepatocyte necrosis, internal toxinemia, inappropriate use of diuretics, gastrointestinal bleeding leading to hypovolemia, and hypotension. It has been reported that renal failure is the leading cause of death in FHF, which warrants attention.

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

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

bubble_chart Auxiliary Examination

1. Prothrombin Time Measurement

This test is one of the most valuable indicators for accurately reflecting the severity of damage and aids in early diagnosis. The test requires strict conditions and must be conducted by experienced personnel to ensure accuracy. It manifests as a significant prolongation of prothrombin time.

2. Cholinesterase Measurement

This enzyme is synthesized by liver cells, so in cases of severe liver damage, serum cholinesterase levels are significantly reduced.

3. Enzyme-Bilirubin Dissociation Phenomenon

Bilirubin gradually increases while ALT decreases. 80% of ALT is located within the cytoplasm of liver cells. When liver cells are damaged, the permeability of the cell membrane changes, allowing ALT to leak into the bloodstream. Early on, ALT levels may rise, but as the condition worsens, the enzyme becomes depleted over time, and due to its short half-life, serum ALT levels decrease, indicating a poor prognosis.

4. Dynamic Observation of AST/ALT Ratio

Measurement within 10 days after the onset of illness has certain significance for predicting the course and prognosis of the disease. ALT is mainly located in the cytoplasm of liver cells, while AST is mostly found in mitochondria. The normal AST/ALT ratio is 0.6. When liver cells are severely damaged, AST is released from mitochondria, and the ratio becomes >1.

5. Amino Acid (AA) Measurement

This includes the total urinary amino acids and serum amino acid analysis. Since almost all amino acids are metabolized in the liver, liver cells synthesize essential proteins for the body. In cases of severe liver damage, AAs cannot be utilized, leading to AA metabolic disorders and imbalance. Initially, the total urinary AA increases significantly, and aromatic amino acids in the serum rise. The branched-chain/aromatic amino acid ratio decreases from the normal 3-3.5 to <1, indicating a poor prognosis.

bubble_chart Diagnosis

Emphasize close observation of the condition for early diagnosis

① Onset of hepatic encephalopathy and neuropsychiatric symptoms within 8 weeks of illness; ② No signs of chronic liver disease; ③ Concurrent clinical manifestations of severe liver function impairment; ④ Routine generation and transformation and hematological tests show decreased hepatocyte function, early ALT elevation, and prolonged prothrombin time; ⑤ History of hepatitis exposure or liver damage caused by drugs or toxins; ⑥ Liver pathology examination reveals massive hepatocyte necrosis.

bubble_chart Treatment Measures

Basic principles: ① Strengthen monitoring and address issues promptly; ② Early diagnosis, early treatment; ③ Prevent complications.

I. Disease Cause Treatment

For FHF caused by hepatitis virus, antiviral drugs such as interferon can be used for those with HBV, HCV, HDV co-infections, or those in the early stages of the disease with a slower progression. For drug-induced cases, the causative drugs should be discontinued.

II. Immune Regulation

The use of adrenal corticosteroids and immunosuppressants is not recommended. Immune enhancers such as thymosin can be used appropriately. Usage: 6-20mg daily added to 250-500ml of 10% glucose solution, slowly intravenously dripped, once daily, for a 30-day course. A skin test should be conducted before use. Fresh plasma can also be used.

III. Glucagon-Insulin Therapy (GI Therapy)

Anti-hepatocyte necrosis, promotes hepatocyte regeneration. Usage: 1mg of glucagon and 10U of insulin added to 500ml of 10% glucose solution, slowly intravenously dripped, 1-2 times daily, combined with a preparation mainly composed of branched-chain amino acids, yields better efficacy. Generally, a course lasts 2-4 weeks.

IV. Hepatic Encephalopathy Treatment

1. 14-Amino Acid 800, 6-Amino Acid 520 The former is suitable for hepatic encephalopathy in cirrhosis. Both contain branched-chain amino acids and no aromatic amino acids. Usage: 6-Amino Acid 520, 250ml each time, twice daily, slowly intravenously dripped with an equal amount of 10% glucose solution plus 500mg of L-acetylglutamine, until consciousness improves, then halve the dose until fully conscious, for a course of 5-7 days. Then use 14-Amino Acid 800 to consolidate the effect. Note: Compound formula amino acids Sohamine or Freamine contain high levels of tyrosine, phenylalanine, and methionine, which can trigger hepatic encephalopathy.

2. Levodopa and Carbidopa Usage: 100mg of levodopa and 10mg of carbidopa added to 500ml of 10% glucose solution, slowly intravenously dripped, 1-2 times daily. Using both drugs together can reduce the side effects of levodopa. Note: Do not use with VitB₆, as VitB₆ has a dopa decarboxylase effect, causing levodopa to decarboxylate, reducing dopamine concentration in the brain and rendering it ineffective, with less than ideal efficacy.

3. Control Ammonia Production Should be approached from the following three aspects:

(1) Cleanse the intestines Use 30ml of vinegar with 1000ml of saline for enema, or saline enema, twice daily. After enema, use 30ml of 50% lactulose and 100mg of neomycin with 100ml of saline for retention enema.

(2) Oral metronidazole or ampicillin.

(3) Lactulose Therapy Can acidify the intestinal environment, reduce blood ammonia, and clear internal toxins. Usage: 50% lactulose 30-50ml, three times daily, orally (nasogastric feeding for unconscious patients), preferably after meals, aiming for two pasty stools daily.

V. Complication Treatment

1. Cerebral Edema

Prevention is better than treatment. When knee reflexes are hyperactive, ankle clonus or pyramidal signs are positive, the treatment is more effective.

(1) Dehydrating agents 20% mannitol or 25% sorbitol, 250ml each time, rapidly pressurized intravenously dripped, completed within 20-30 minutes, which is crucial. Then use every 4-6 hours, adding furosemide between dehydrating agents if necessary. If consciousness improves, halve the dose but do not extend the interval to avoid rebound. Sorbitol's dehydrating effect is slightly less than mannitol but without the side effect of causing hematuria. Sorbitol is safer for cerebral edema in severe hepatitis.

(2) Dexamethasone Usage: 10mg added to an appropriate amount of 10% glucose solution, intravenously injected, then 5mg every 4-6 hours combined with dehydrating agents, used continuously for 2-3 days.

2. Hemorrhage Prevention and Control

The following four methods:

(1) Supplementation of coagulation factors: Most coagulation factors have a short half-life, so fresh frozen plasma is preferred. The use of prothrombin complex concentrate (PPSB), which contains coagulation factors II, V, VII, and IX, is effective at a dose of 10U/kg per day.

(2) H^-₂ receptor blockers: Used to 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 is used instead, at a dose of 150mg once nightly, with fewer side effects and good efficacy.

(3) Reduction of portal pressure: Propranolol is used, with the dose adjusted to reduce heart rate by 25%. When used in combination with H^-₂ receptor blockers, the dose can be reduced.

(4) Thrombin: Effective for stopping bleeding from gastric mucosal erosion and oozing. After bleeding stops, the dose can be reduced or the interval between doses extended. The dosage is 2000-10000U per dose, every 4-6 hours, or as frequently as every 1-2 hours.

3. Prevention and treatment of infection:

(1) Strengthen oral and skin care, strictly enforce disinfection and isolation, and maintain aseptic techniques to purify indoor air and prevent respiratory infections.

(2) Internal toxinemia: Amoxicillin 0.5g can be taken hourly, effective against intestinal bacteria. Alternatively, Lactobacillus infusion granules, 10g per dose (each gram containing 10⁶ Lactobacillus), taken 2-3 times daily, can inhibit intestinal bacteria.

(3) Bacterial infection: Choose antibiotics that are non-toxic to the liver and kidneys. ① Ampicillin: 6-8g daily, administered by intravenous drip in divided doses. Suitable for large intestine bacillus infections. ② Ampicillin-cloxacillin: An equal mixture of ampicillin and cloxacillin, 6-8g daily, administered by intravenous injection in divided doses, effective against large intestine bacillus and Staphylococcus aureus. ③ Amikacin: 0.2g every 8 hours, intramuscular injection, or the same dose by intravenous drip twice daily in emergencies, with lower renal toxicity than gentamicin. ④ Cephalosporins: Suitable for severe infections, especially Gram-negative bacillus infections. Commonly used are cefazolin (Cefazolin V), cefuroxime (Zinacef), or third-generation cephalosporins such as ceftazidime (Fortum), ceftriaxone (Rocephin), and cefoperazone (Cefobid). ⑤ Metronidazole: Used for anaerobic infections, 400mg per dose, three times daily. For severe infections, adults can use 500mg of metronidazole added to 100ml of isotonic solution, administered by intravenous drip over 20-30 minutes, twice daily. Note: Contraindicated in pregnant women, nursing mothers, and patients with central nervous system diseases, heart disease, or blood disorders. ⑥ Antifungal drugs: For oral fungal infections, nystatin, amphotericin B, or miconazole can be used. For deep fungal infections, fluconazole can be chosen, with caution in patients with liver or kidney dysfunction. Ketoconazole should be used with caution due to potential liver damage. Garlicin injection can also be used, 60-120mg daily for adults, added to 500-1000ml of 5% glucose solution for intravenous drip, with a treatment course of 2 weeks.

4. Renal failure:

The leading cause of death in FHF, prevention is more important than treatment. Measures include controlling fluid intake, avoiding nephrotoxic drugs, early use of osmotic diuretics and microcirculation-improving drugs, and preventing hyperkalemia. Hemodialysis and peritoneal dialysis are rarely effective. Recently, prostaglandin E₁ and E₂ have been used to improve hepatorenal syndrome.

VI. Prevention and treatment of electrolyte and acid-base imbalance.

From the onset of the disease, adjust the treatment plan over time based on blood qi aspect analysis and electrolyte changes. Such as metabolic alkalosis, respiratory alkalosis combined with metabolic poisoning, metabolic acidosis, etc. Hyponatremia, hypocalcemia, hypomagnesemia, hypokalemia, etc.

VII. Liver Support Therapy

Hepatocyte Growth Factor Therapy (HGF): A Neijing multicenter collaborative study report indicates that adding HGF or prostaglandin E₁ to a comprehensive therapy, or using the integration of Chinese and Western medicine to treat fulminant hepatic failure and hepatic encephalopathy, significantly reduces the mortality rate compared to previous treatments. This improvement may be related to early diagnosis, enhanced comprehensive supportive therapy, and nursing care. Recent reports show that serum HGF levels are elevated to varying degrees in many liver diseases, and HGF receptor activation is associated with the c-met gene (a proto-oncogene). Therefore, before the widespread application of HGF, it is necessary to understand the benefits and risks of administering large doses of exogenous HGF and its potential to activate proto-oncogenes, which requires further in-depth research.

Plasma exchange and artificial liver are currently under study. Hepatocyte transplantation and liver transplantation have not yet been used clinically abroad, but research has begun domestically.