(I) Definition
Liver failure is a group of clinical syndromes caused by severe liver damage due to multiple factors, resulting in severe impairment or loss of compensation of its synthesis, detoxification, excretion and biotransformation functions, with the main manifestations of impaired coagulation mechanisms and jaundice, hepatic encephalopathy and ascites.
The recommendations of the International Federation of Gastroenterology on the nomenclature of hepatic encephalopathy are shown in Table 2.
(II) Etiology
The main etiology of liver failure in China is hepatitis virus (mainly hepatitis B virus), followed by drugs and hepatotoxic substances (such as ethanol, chemical agents, etc.). In Europe and the United States, drugs are the main cause of acute and subacute liver failure; alcoholic liver damage often leads to chronic liver failure [2]. Liver failure in children is also seen in genetic metabolic diseases (Table 3).
II. Classification and diagnosis of liver failure
(I) Classification
Based on the pathological histological features and the rate of progression, liver failure can be classified into four categories (Table 4): acute liver failure (ALF), subacute liver failure (SALF), slow-on-chronic liver failure (ACLF), and chronic liver failure (CLF). Acute liver failure is characterized by an acute onset and liver failure syndrome characterized by hepatic encephalopathy of degree II or higher within 2 weeks of onset; subacute liver failure has a more acute onset and liver failure syndrome occurs within 15 d to 26 weeks of onset; slow-on-acute (subacute) liver failure is acute liver failure based on chronic liver disease; chronic liver failure is progressive decompensation of liver function based on cirrhosis, resulting in liver failure with ascites or portal hypertension, coagulation dysfunction and hepatic encephalopathy as the main manifestations of chronic liver failure [3-7].
(ii) Staging
According to the severity of clinical manifestations, subacute liver failure and slow plus acute (subacute) liver failure can be divided into early, intermediate and late stages [8].
1, Early stage
(1) Extreme malaise with severe gastrointestinal symptoms such as marked anorexia, vomiting and abdominal distention. (2) Progressive deepening of jaundice (serum total bilirubin ≥171μmol/L or daily rise of ≥17, 1μmol/L). (3) Bleeding tendency, 30% < prothrombin activity (PTA) ≤40%. (4) No hepatic encephalopathy or significant ascites.
2.Middle stage: Based on the early manifestations of liver failure, the disease further develops and one of the following two items appears
(1) The appearance of hepatic encephalopathy below grade II and/or obvious ascites.
(2) Significant bleeding tendency (bleeding spots or petechiae), and 20% < PTA≤30%.
3. Late stage: On the basis of the manifestation of middle stage of liver failure, the disease is further aggravated and one of the following three items appears
(1) There are refractory complications, such as hepatorenal syndrome, upper gastrointestinal hemorrhage, severe infection and electrolyte disorders that are difficult to correct.
(2) The presence of hepatic encephalopathy of grade III or higher.
(3) There is a severe bleeding tendency (petechiae at the injection site, etc.) with PTA≤20%.
(C) Diagnosis
1, clinical diagnosis: the clinical diagnosis of liver failure needs to be determined based on a comprehensive analysis of the medical history, clinical manifestations and auxiliary examinations.
(1) Acute liver failure: those with acute onset and hepatic encephalopathy of degree II or higher (classified according to the classification of degree IV [9]) within 2 weeks and with the following manifestations (1) Extreme weakness with severe gastrointestinal symptoms such as obvious anorexia, abdominal distension, nausea and vomiting. (ii) Progressive deepening of jaundice in a short period of time. ③Significant bleeding tendency, PTA≤40%, and other causes are excluded. ④Progressive shrinkage of the liver.
(2) Subacute liver failure: those with a more acute onset and the following manifestations in 15d to 26 weeks: ① extreme weakness with obvious GI symptoms. (2) rapid deepening of jaundice, total serum bilirubin greater than 10 times the upper limit of normal values or a daily rise of ≥17, 1μmol/L. (3) markedly prolonged prothrombin time, PTA≤40% and exclude other causes.
(3) Slow plus acute (subacute) liver failure: on the basis of chronic liver disease, the main clinical manifestations of acute liver function loss in a short period of time.
(4) Chronic liver failure: on the basis of cirrhosis, progressive decompensation and loss of liver function. The main points of diagnosis are: ① there is ascites or other manifestations of portal hypertension. (2) There may be hepatic encephalopathy. ③Total serum bilirubin is elevated and albumin is significantly decreased. ④There is coagulation dysfunction, PTA≤40%.
2. Histopathological manifestations: Histopathological examination has an important value in the diagnosis, classification and prognosis determination of liver failure, but due to the severely reduced coagulation function of patients with liver failure, performing liver puncture has certain risks, which should be paid special attention in clinical work. In liver failure (except for chronic liver failure), extensive hepatocellular necrosis can be observed on liver histology, with the site and extent of necrosis varying depending on the etiology and course of the disease. According to the extent and degree of necrosis, it can be classified as massive necrosis (necrosis of more than 2/3 of the liver parenchyma), submassive necrosis (approximately 1/2 to 2/3 of the liver parenchyma), fusion necrosis (necrosis of adjacent patches of hepatocytes) and bridging necrosis (more extensive fusion necrosis with destruction of the liver parenchyma). In liver tissues of different stages of liver failure, one-time or multiple lesions with varying degrees of old and new hepatocyte necrosis can be observed. Currently, there is no consensus on the correlation between the etiology, classification and staging of liver failure and hepatic histological changes. Given that liver failure due to hepatitis B virus (HBV) infection is the most common in China, this Guideline introduces the typical pathological manifestations of various types of liver failure, taking liver failure due to HBV infection as an example [10].
(1) Acute liver failure: hepatocytes show one-time necrosis, with necrotic area ≥ 2/3 of the liver parenchyma; or submassive necrosis, or bridging necrosis, with severe degeneration of surviving hepatocytes and non-collapse or incomplete collapse of the reticular scaffold of the hepatic sinusoids.
(2) Subacute liver failure: submassive necrosis or bridging necrosis with varying degrees of old and new liver tissue; collapse of reticular fibers in older necrotic areas or collagen fiber deposition; varying degrees of regeneration of residual hepatocytes with fine and small bile duct hyperplasia and cholestasis.
(3) Slow plus acute (subacute) liver failure: on the basis of the pathological damage of chronic liver disease, new necrotic lesions of varying degrees of hepatocytes occur.
(4) Chronic liver failure: mainly diffuse liver fibrosis and abnormal nodule formation, which may be accompanied by unevenly distributed hepatocyte necrosis.
3. Diagnostic format of liver failure: Liver failure is not an independent clinical diagnosis, but a functional judgment. In clinical practice, a complete diagnosis should include etiology, clinical type and staging, and it is recommended to be written in the following format, for example
(1) Drug-related hepatitis
Acute liver failure
(2) Viral hepatitis, acute, type E
Subacute liver failure (intermediate)
(3) Viral hepatitis, chronic, type B
Viral hepatitis, acute, type E
Chronic plus acute (subacute) liver failure (early stage)
(4) Cirrhosis, schistosomal
Chronic liver failure
(5) Sub-acute liver failure (early stage)
Cause to be investigated (admission diagnosis)
Cause not yet known (discharge diagnosis) (write and put a question mark on the suspected cause)
III. Treatment of liver failure
(A) Comprehensive medical treatment
At present, there is a lack of specific drugs and means for the medical treatment of liver failure. In principle, early diagnosis and early treatment are emphasized, and corresponding comprehensive therapeutic measures are taken for different etiologies, and various complications are actively prevented and treated [11].
1. General supportive treatment
(1) Bed rest to reduce physical exertion and reduce the burden on the liver (III).
(2) Strengthen the monitoring of the condition (III).
(3) High-carbohydrate, low-fat, and moderate protein diet; for those who do not eat enough, intravenous supplementation of sufficient fluids and vitamins daily to ensure more than 6272 kJ (1500 kcal) of total calories daily (III).
(4) Actively correct hypoproteinemia, supplement albumin or fresh plasma, and supplement coagulation factors as appropriate (Ⅲ).
(5) Pay attention to the correction of water-electrolyte and acid-base balance disorders, especially to correct hyponatremia, hypochlorhydria, hypokalemia and alkalosis (Ⅲ).
(6) Pay attention to disinfection and isolation, strengthen oral care, and prevent the occurrence of intra-hospital infection (Ⅲ).
2. Treatment for etiology and pathogenesis
(1) Treatment for etiology or specific treatment: (1) For patients with HBV DNA-positive liver failure, nucleoside analogs such as lamivudine, adefovir, and entecavir can be used as early as appropriate on the basis of informed consent [12] (III), but attention should be paid to the possibility of viral mutation during subsequent treatment and exacerbation of the disease after drug discontinuation. (② For drug-related liver failure, drugs that may cause liver damage should be discontinued first; those caused by acetaminophen poisoning should be treated with N-acetylcysteine (NAC), preferably with oral activated charcoal plus NAC intravenously before the onset of liver failure (Ⅰ). (3) Mushroom poisoning can be treated with silymarin or penicillin G according to clinical experience in Europe and the United States [1] (III).
(2) Immunomodulatory therapy: there are still different opinions on the application of adrenocorticotropic hormones in the treatment of liver failure. Non-viral infectious liver failure, such as autoimmune liver disease and acute ethanol intoxication (severe alcoholic hepatitis), are indications. Early stages of liver failure due to other causes can be used as appropriate if the disease progresses rapidly and without serious infections, bleeding and other complications [13, 14] (III). To regulate the immune function of the organism in patients with liver failure and to reduce complications such as infection, immunomodulators such as thymidine α1 can be used as appropriate (III).
(3) Hepatocyte growth promotion therapy: To reduce hepatocyte necrosis and promote hepatocyte regeneration, drugs such as hepatocyte growth promoter and prostaglandin E1 liposome can be used as appropriate (III), but the efficacy needs to be further confirmed.
(4) Other treatments: intestinal microecological regulators, lactulose or lactitol can be applied to reduce intestinal bacterial translocation or endotoxemia; microcirculation improving drugs and antioxidants such as NAC and reduced glutathione can be used for treatment as appropriate (II-2).
3. Prevention and treatment of complications
(1) Hepatic encephalopathy: ① Remove causative factors, such as severe infection, bleeding and electrolyte disturbance (III). ② Restrict protein diet (III). (③ Apply lactulose or lactitol, orally or by high enema, which can acidify the intestine, promote ammonia excretion and reduce the absorption of toxins of intestinal origin (III). ④ Select ammonia-lowering drugs such as arginine and ornithine-menthylate as appropriate depending on the patient’s electrolyte and acid-base balance (III). ⑤ Use branched-chain amino acids or a mixture of branched-chain amino acids and arginine, as appropriate, to correct amino acid imbalance (Ⅲ). (6) Artificial liver support therapy (see the section on artificial liver in this Guideline).
(2) Cerebral edema: ① If there is increased intracranial pressure, give hypertonic dehydrating agents, such as 20% mannitol or glycerol fructose, but use with caution in patients with hepatorenal syndrome (Ⅰ); ② Loop diuretics, usually furosemide, can be used alternately with osmotic dehydrating agents (Ⅲ); ③ Artificial liver support therapy (see the artificial liver section of this guideline).
(3) hepatorenal syndrome: ① high-dose loop diuretic shock, furosemide can be pumped continuously (Ⅲ); ② limit the amount of fluid intake, the total 24h intake should not exceed the urine volume plus 500-700ml (Ⅲ); ③ the renal perfusion pressure is insufficient to apply albumin expansion or the addition of terlipressin and other drugs, but patients with acute liver failure, terlipressin should be used with caution, so as not to aggravate cerebral edema due to increased cerebral
(4) Infection: ① Patients with liver failure are prone to co-infection, commonly due to low immune function, imbalance of intestinal microecology, reduced intestinal mucosal barrier and more invasive operations. ②Common infections in patients with liver failure include spontaneous peritonitis, pulmonary infections and sepsis. ③The common pathogens of infection are gram-negative bacilli such as Escherichia coli, bacteria such as Staphylococcus, Streptococcus pneumoniae, anaerobic bacteria, Enterococcus and fungi such as Pseudomonas. ④ Once an infection occurs, the first step should be to use strong antimicrobial agents or a combination of antimicrobial agents according to experience, and microecological regulators can be added at the same time. As far as possible, pathogen isolation and drug sensitivity test should be conducted before applying antimicrobial agents, and medication should be adjusted according to the results of drug sensitivity test (II-2). Also pay attention to the prevention and control of secondary infections.
(5) Bleeding: ① For patients with portal hypertensive bleeding, in order to reduce portal pressure, growth inhibitor analogues are preferred, and posterior pituitary hormone (or combined application of nitrates) can also be used (Ⅰ/III); a three-lumen tube can be used to stop bleeding by compression; or endoscopic sclerotherapy or ligature treatment can be performed to stop bleeding. If conservative medical treatment is ineffective, emergency surgical treatment can be performed (Ⅲ). For patients with diffuse intravascular coagulation, fresh plasma, prothrombinogen complex and fibrinogen can be given to supplement coagulation factors, platelets can be transfused if platelets are significantly reduced (Ⅲ), small doses of low molecular heparin or normal heparin can be given as appropriate, and anti-fibrinolytic drugs such as tranexamic acid or hemostatic aromatic acid can be applied to those with evidence of hyperfibrinolysis (Ⅲ).
(ii) Artificial liver support therapy
1. Treatment mechanism and method
Artificial liver is a treatment method to remove various harmful substances, replenish essential substances, improve the internal environment and temporarily replace part of the function of the failing liver through mechanical, physicochemical or biological devices outside the body, which can create conditions for hepatocyte regeneration and liver function recovery or wait for the opportunity of liver transplantation. There are three types of artificial liver support systems: non-biological, biological and combined. The non-biological type of artificial liver has been widely used in clinical practice and has proven to be effective (II-2) [15]. The currently used non-biological artificial liver methods include plasma exchange (PE), hemoperfusion (HP), plasma bilirubin absorption (PBA), hemofiltration (HF), hemodialysis (HD), and hemodialysis. hemodialysis (HD), albumin dialysis (AD), plasmadiafiltration (PDF), and continuous blood purification (CBP). Since the principles of various artificial livers are different, different methods should be used alone or in combination according to the patient’s specific situation: PE combined with CBP, HF or PDF in case of cerebral edema or renal failure; PBA or PE in case of hyperbilirubinemia; HD or AD(III) in case of water-electrolyte disturbance. Attention should be paid to the standardization of artificial liver treatment operation.
Biological and combined biological artificial liver not only has detoxification function, but also has some synthetic and metabolic functions [16], which is the direction of artificial liver development and is now in the clinical research stage.
2. Indications [17] (III)
(1) Early and mid-stage liver failure from various causes, with PTA between 20% and 40% and platelets >50×109/L is appropriate; patients with advanced liver failure can also be treated, but complications are common and should be treated with caution; those who do not meet the diagnostic criteria for liver failure but have a tendency to liver failure can also be considered for early intervention.
(2) Advanced liver failure waiting for donor before liver transplantation, rejection reaction after liver transplantation, and non-functional period of transplanted liver.
3. Relative contraindications [17] (III)
(1) Those with severe active bleeding or diffuse intravascular coagulation.
(2) Those who are highly allergic to blood products or drugs used in the treatment process, such as plasma, heparin and fisetin.
(3) Those with circulatory failure.
(4) Non-stable stage of heart and brain infarction.
(5) Late stage of pregnancy.
4. Complications [17] (III)
Complications of artificial liver therapy include allergic reaction, hypotension, secondary infection, bleeding, imbalance syndrome, hemolysis, air embolism, disorders of water-electrolyte and acid-base balance, etc. With the development of artificial liver technology, the incidence of complications is gradually decreasing, and once they occur, they can be treated accordingly according to the specific situation.
(iii) Liver transplantation
Liver transplantation is the most effective treatment for advanced liver failure [18] (II-3). There are various surgical procedures for liver transplantation, and this guideline refers to allogeneic in situ liver transplantation.
1. Indications
(1) Intermediate to advanced liver failure due to various causes, with poor outcome with aggressive medical and artificial liver therapy.
(2) Various types of end-stage cirrhosis.
2. Contraindications
(1) Absolute contraindications: (1) systemic infection that is difficult to control. (2) Malignant tumors outside the liver that are difficult to eradicate. (3) Alcoholism or drug abuse that is difficult to quit. (4) Combination of serious organic lesions of the heart, brain, lungs and other important organs. (5) Psychiatric diseases that are difficult to control.
(2) Relative contraindications: ① Age greater than 65 years. (2) Malignant tumor of the liver with portal vein trunk cancer embolism or metastasis. (3) Combined diabetes mellitus, cardiomyopathy and other diseases with poor prognosis. ④Severe infections such as sepsis due to biliary tract infection. ⑤Acquired human immunodeficiency virus infection. ⑥Anatomical abnormalities such as obvious portal vein thrombosis.
3. Prevention and treatment of hepatitis virus reinfection in transplanted liver
(1) HBV reinfection: The prevention program for HBV reinfection is the use of nucleoside antivirals such as lamivudine, adefovir or entecavir for more than 1 month before surgery, and the application of high potency hepatitis B immunoglobulin with nucleoside antivirals for a longer period of time during and after surgery.
(2) Hepatitis C virus reinfection: There is no effective prevention method for hepatitis recurrence after liver transplantation in patients with hepatitis C virus infection. Combined antiviral therapy with interferon α and ribavirin can be given after transplantation as appropriate (III).
Liver Failure Treatment Guidelines