China is a high prevalence of viral hepatitis, and the five types of viral hepatitis A, B, C, D, and E are widely present, while heavy hepatitis caused by hepatitis viruses has a rapid development and dangerous prognosis. The hepatitis E virus is susceptible to severe hepatitis only when it infects pregnant women; and mixed infection with two or more hepatitis viruses is also an important cause of severe hepatitis, with about 50% of cases being mixed infections. Due to the specificity of the clinical presentation and treatment of severe hepatitis, it was classified as a separate type of viral hepatitis in 1983. After a few more changes, the “China Viral Hepatitis Control Program” was adopted at the 10th National Conference on Viral Hepatitis in Xi’an in 2000. The program divided viral hepatitis in China into five clinical types: acute hepatitis, chronic hepatitis, severe hepatitis, biliary hepatitis, and hepatitis cirrhosis. Among them, heavy hepatitis is further divided into three clinical types: acute heavy hepatitis, subacute heavy hepatitis, and chronic heavy hepatitis. Huang Lei, Department of Hepatobiliary Surgery, Peking University People’s Hospital
1, the specific diagnostic criteria of heavy hepatitis
(1) Acute heavy hepatitis: acute jaundice type hepatitis, within 2 weeks of the onset of extreme weakness, obvious gastrointestinal symptoms, the rapid emergence of degree II or more (divided by degree IV) hepatic encephalopathy, prothrombin activity (PTA) less than 40%, and exclude other causes, the progressive narrowing of the liver turbid cirrhosis, jaundice sharply deepened; or jaundice is very shallow or even jaundice has not yet appeared but have the above performance should be considered The disease should be considered.
(2) Subacute severe hepatitis: the disease starts with acute jaundiced hepatitis, and within 2 weeks to 24 weeks, extreme weakness and obvious gastrointestinal symptoms appear, while prothrombin time is significantly prolonged, PTA ≤ 40%, and other causes are excluded. Jaundice rapidly deepens and can rise ≥ 17.1 μmol/ L per day or total serum bilirubin greater than 10 times the normal value. The first to appear more than II degree hepatic encephalopathy, called encephalopathy type (including cerebral edema, brain hernia, etc.); the first to appear ascites and its related symptoms (including pleural fluid, etc.), called ascites type.
(3) Chronic severe hepatitis: the basis for the development of this type are: a history of chronic hepatitis or cirrhosis; a history of chronic hepatitis B virus carriage; no history of liver disease or no history of virus carriage, but there are signs of chronic liver disease (such as liver palms, spider nevus, etc.), imaging changes (such as spleen thickening, etc.) and biochemical changes (such as elevated gammaglobulin, decreased or inverted albumin/globulin ratio); liver histopathological examination supports chronic Hepatitis. In cases of chronic hepatitis B or C, or in chronic hepatitis B carriers with overlapping infection with hepatitis A, E or other hepatitis viruses, specific analysis should be performed to exclude acute or subacute severe hepatitis caused by hepatitis A, E or other hepatitis viruses. The clinical manifestations of chronic severe hepatitis are the same as those of subacute severe hepatitis at the beginning of the disease, and worsen as the disease progresses, reaching the diagnostic criteria of severe hepatitis (PTA ≤ 40%, total serum bilirubin > 10 times normal).
For the purpose of determining the efficacy and estimating the prognosis, subacute severe and chronic severe hepatitis can be divided into early, middle and late stages according to their clinical manifestations. Early stage: The basic conditions of severe hepatitis are met, such as severe malaise and gastrointestinal symptoms, rapid deepening of jaundice, serum bilirubin >10 times normal, PTA ≤30-40%, or confirmed by pathology. However, no obvious encephalopathy occurred, and no ascites appeared. Intermediate stage: hepatic encephalopathy of degree II or marked ascites, bleeding tendency (bleeding spots or petechiae), PTA ≤ 20-30%. Late stage: refractory complications and hepatorenal syndrome, gastrointestinal hemorrhage, severe bleeding tendency (petechiae at injection site, etc.), severe infection, uncorrectable electrolyte disorder or hepatic encephalopathy of degree II or above, cerebral edema, PTA ≤ 20%.
2, laboratory tests for severe hepatitis
The purpose of liver function tests in patients with severe hepatitis is: to provide a basis for diagnosis and differential diagnosis; to understand the extent of liver damage; to observe important indicators of disease development; to predict prognosis; and to guide treatment. The liver function test indexes commonly used for severe hepatitis in clinical practice are as follows.
(1) Prothrombin time (PT) and PTA: The liver plays an extremely important role in the coagulation mechanism, and the ability to synthesize coagulation factors reflects the functional status of hepatocytes, so the coagulation test to determine the coagulation factors produced by the liver is actually a liver function test. PT is a primary screening test to detect the reduction of prothrombin, factors II, VII, X and fibrinogen in exogenous (tissue) clotting blood alone or in combination, and its The normal value is generally 11 to 13 s. PT test results can vary greatly in different laboratories, or in different generations of the same laboratory, and the analysis of its clinical significance cannot be based on a single data. pta is calculated from PT, eliminating the differences in PT in each laboratory, facilitating comparison and unification. Scholars at home and abroad have recognized PTA < 40% as a major biochemical index for the diagnosis of heavy hepatitis, which is one of the most sensitive and reliable methods due to its rapid changes and ease of early diagnosis. The lower the PTA, the higher the incidence of bleeding and death rate. A problem that clinicians should pay attention to is that in patients with heavy hepatitis and cirrhosis in the decompensated stage, the same value of PTA does not mean the same prognosis for both, and its significance is not the same.
(2) Serum bilirubin: Patients with severe hepatitis have increased serum direct bilirubin and indirect bilirubin (hepatocellular jaundice) due to severe necrosis and damage to hepatocytes, decreased function, metabolic damage to bile secretors in hepatocytes, and bile duct rupture, or bilirubin pooling due to blockage by detached and decomposed cells. In severe hepatitis complicated by liver failure, hepatocellular jaundice is often induced or aggravated by reduced blood flow to the liver, hypoxia and endotoxemia. In severe hepatitis, hepatocytes are severely necrotic and damaged, and total bilirubin is usually >171 μmol/L. Acute severe hepatitis may not be too high within 3-5 days of onset due to rapid destruction of hepatocytes in a short period of time, but as hepatocyte necrosis progresses, serum bilirubin rises at an average rate of 17.1-34.2 μmol/L per day, which is one of the characteristics of acute severe One of the characteristics of hepatitis, the rate of bilirubin elevation is more meaningful. In subacute and chronic severe hepatitis, serum bilirubin levels are higher and increase with the duration of the disease. In a group of patients with severe hepatitis with a mean total bilirubin > 342 μmol/L, the morbidity and mortality rate was 65%; in another group of patients with a mean total bilirubin > 531 μmol/L, the morbidity and mortality rate was 95%. It can be seen that the higher the bilirubin, the higher the mortality rate and the worse the prognosis.
(3) Enzyme bile separation: While bilirubin continues to increase progressively, ALT gradually decreases after reaching a certain peak, and can even drop to normal at last, but the condition does not decrease but worsens, forming a phenomenon of separation from bilirubin, referred to as “bile enzyme separation”, suggesting a poor prognosis. This is because about 80% of ALT exists in the hepatocyte plasma, and when the hepatocytes are damaged, the permeability of the cell membrane is changed or destroyed, and ALT escapes into the blood, causing ALT to rise in the early stage of the disease. However, after a period of time, ALT is depleted, and its half-life is short, so its serum value gradually decreases. The phenomenon of “bile enzyme separation” is more pronounced after 10 days of severe hepatocellular necrosis, but not in all cases of severe hepatitis. The phenomenon of “bile enzyme separation” is more common in chronic severe hepatitis, but not in the early stage of acute severe hepatitis or in survivors.
(4) AST/ALT ratio: 80% of the portal aminotransferase (AST) is found in the mitochondria of hepatocytes and only 20% in the cytoplasm. Alanine aminotransferase (ALT) is only distributed in the cell plasma, so the AST/ALT ratio of normal liver cell plasma is about 0.6. In acute hepatitis, AST is lower than ALT, with a ratio < 1. In this case, the mitochondria remain intact despite the damage to the hepatocytes. In severe hepatitis, the mitochondria are also damaged, AST is released from the mitochondria, and the AST/ALT ratio increases. The ratio of the two reflects the severity of hepatocyte damage and can be used to estimate the prognosis. Some domestic data show that the AST/ALT ratio in survivors of severe hepatitis ranges from 0.31 to 0.63, while in those who die it is more than 1.2.
(5) Serum cholinesterase (CHE): CHE is mainly synthesized in hepatocytes and is closely related to the synthesis of albumin and coagulation factors, divided into acetylcholinesterase and butyrylcholinesterase, the latter is manufactured in hepatocytes, and the latter is mainly detected clinically, with a normal value of 30-80u/dL. If this enzyme is < 10u/dL, it indicates serious damage to hepatocytes. In acute hepatitis, the activity of this enzyme increases, but in severe hepatitis, the hepatocytes are severely necrotic and damaged, and the activity of serum CHE decreases. che is also an indicator to judge the prognosis of severe hepatitis, but its sensitivity is not as good as that of PTA.
(6) Plasma cholesterol (CHO): CHO is synthesized in hepatocyte particles, and the normal serum cholesterol level is 3.3-5.9 mmol/L. 60-80% of plasma cholesterol comes from the liver, and in severe hepatocellular injury, cholesterol synthesis in the liver is reduced, so plasma cholesterol decreases significantly. In acute severe hepatitis, serum cholesterol levels can be reduced to a low level, and a prognosis of less than 2.6 mmol/L is a sign of a poor prognosis. Among 272 patients with acute and subacute severe hepatitis, a mortality rate of 91% was reported in 101 cases with plasma CHO < 2. 6 mmol/ L. This indicates the prognostic role of reduced CHO levels. The phenomenon of "one high and three low" biochemical indicators of heavy hepatitis (high serum bilirubin, low PTA, low cholesterol and low ALT) seen clinically is a sign of advanced development of heavy hepatitis and a sign of poor prognosis.
(7) Blood ammonia: ammonia is more toxic. In normal individuals, blood ammonia does not exceed 100 ug%. Endogenous ammonia is produced by the deamination of amino acids in the body. Exogenous ammonia is mainly ammonia absorbed from the digestive tract. Normal individuals absorb about 4 grams of ammonia per day from the intestine (mainly the colon), so the intestine is the main source of ammonia in the body. In a very large majority of patients with hepatic encephalopathy, elevated ammonia concentrations are seen in the blood or cerebrospinal fluid. In cases of hepatic impairment, ammonia can still be converted to urea in the liver. Blood ammonia can also be normal in patients with acute severe hepatitis, and there is no significant relationship with prognosis. However, patients with subacute and chronic severe hepatitis with increased ammonia have a poor prognosis.
(8) Serum alkaline phosphatase (ALP): The liver is the main organ that produces this enzyme and excretes it from bile. In obstructive jaundice, bile secretion is impaired and serum ALP is often significantly elevated; in hepatocellular jaundice, hepatocellular damage or hepatocyte regeneration, stimulating excessive production of this enzyme, this enzyme is also elevated. In patients with severe hepatitis, a decrease in the level of such an enzyme often indicates severe and extensive damage to hepatocytes. Therefore, ALP activity is a sensitive indicator of biliary obstruction and intrahepatic obstruction, and can also assist in determining the prognosis of liver disease.
(9) Lactic acid (Lac): normal people produce about 15-20 mmol/ Kg of lactic acid daily, mainly from pyruvate metabolism. Since lactic acid must be metabolized by the liver under aerobic conditions, under conditions such as tissue hypoxia or severely impaired liver function, excessive lactic acid production in peripheral tissues and easy accumulation of lactic acid in the blood can lead to elevated blood lactate. Viral hepatitis, especially severe hepatitis, has varying degrees of elevated blood lactate. Moreover, blood arterial partial pressure of oxygen decreases when the liver is severely damaged, and there is a negative correlation between blood lactate and arterial partial pressure of oxygen. In severe hepatitis, if blood lactate > 2 mmol/L is used as a predictor of poor prognosis, it has a sensitivity of 92%, specificity of 71% and accuracy of 85%. It is suggested that in liver failure, if lactate > 2 mmol/ L is another indicator of poor prognosis.
(10) Glutathione-S-transferase (GST): GST is considered to be a new indicator of hepatocellular injury, which is a group of small molecule proteins related to hepatic detoxification and binding functions, also known as bilirubin binding proteins, present in the cell plasma with a short biological half-life. When liver injury occurs, it is more sensitive than ALT in reflecting hepatocyte injury because its molecular weight is smaller than that of ALT, and it is more likely to enter blood through hepatocytes. The normal value is 13.6 ± 5.81 u/ L. The magnitude of GST increase: severe hepatitis > chronic hepatitis > acute hepatitis > cirrhosis. Persistent elevation of GST level and progressive decrease of ALT in severe hepatitis is a sign of poor prognosis, suggesting the value of GST in predicting severe liver necrosis.
(11) Other indicators: In acute severe hepatitis, there is an increase in γ-globulin and a decrease in albumin even early in the course of the disease. With the improvement of the disease, γ-globulin may return to normal in patients with acute and subacute severe hepatitis, but chronic severe hepatitis always maintains a peak without decreasing, which has some significance in differentiating from the first two types of severe hepatitis. The aromatic amino acid/branched-chain amino acid (BCAA/ AAA) ratio is 3-4:1 in normal. BCAA may be mildly elevated in acute severe hepatitis, decreased in both subacute severe hepatitis and chronic severe hepatitis, and increased in AAA in all types of severe hepatitis. Patients with BCAA/AAA < 1 have a morbidity and mortality rate of 81% and a very poor prognosis. Therefore, BCAA/AAA can be used as a prognostic indicator for evaluating subacute and chronic severe hepatitis. The prevalence of endotoxemia in severe hepatitis is 64-100%. Guarner et al. found that plasma endotoxin in patients with heavy hepatitis and cirrhosis in the decompensated stage was significantly higher in those with ascites and was closely related to the occurrence of hepatorenal syndrome.
3.Surgical treatment of severe hepatitis
Heavy hepatitis has rapid onset, rapid development, severe disease, complex symptoms, high mortality rate, and no specific drug treatment. The prognosis is very dangerous, and the survival rate of medical treatment is only 20-40%, so severe hepatitis naturally becomes one of the indications for liver transplantation. The efficacy of liver transplantation for severe hepatitis is influenced by various factors, such as the cause of hepatitis, time of onset, preoperative status and timing of surgery, medical treatment, patient age, physical condition, quality of donor liver, and treatment experience at the transplantation hospital, etc. In 1998, UNOS reported a 1-year survival rate of 70% after transplantation, and recently, a 1-year survival rate of more than 90% was reported. Matsunami et al. reported the efficacy of liver transplantation for the treatment of severe hepatitis in Japanese universities before 2001, with survival rates of 56-100%.
However, there is still some controversy regarding the selection of liver transplantation indications for severe hepatitis, taking into account the limited source of donor livers, the huge trauma of liver transplantation, the high perioperative risks, the need for lifelong postoperative immunosuppressive therapy, and the fact that the efficacy of liver transplantation varies in different cases. Each country and region has its own criteria for determining which patients should undergo liver transplantation. In general, clinical transplantation physicians and hepatologists can make their own decisions based on objective indicators such as laboratory tests. If there are multiple changes in the above-mentioned tests that indicate a poor prognosis, the patient should be given the opportunity to begin preoperative preparation for liver transplantation rather than being treated with medical liver preservation. The criteria of other countries can also be taken into account here. For example, in France, the criteria are: if the patient is > 30 years old, PTA 45 years old
2. subacute severe hepatitis
3. PTA < 10 %
4. serum total bilirubin ≥ 18 mg/ dl
5. serum direct bilirubin / total bilirubin ratio ≤ 0.67
II Hepatic encephalopathy is predicted again after 5 days of medical treatment according to the following items, if all 2 items are met then the predicted survival is cancelled for liver transplantation, otherwise the registration should be continued for liver transplantation.
1. awakening of degree I hepatic encephalopathy, or improvement of lethargy in degree II or higher encephalopathy
2. Recovery of PTA to 50% or more
Excluded items: 1. Grade III or higher encephalopathy combined with cerebral edema; 2. Severe infection, circulatory failure, respiratory failure, renal failure, gastrointestinal bleeding, neurological symptoms and DIC, etc.
The above indications are still cumbersome to apply clinically, so in 2000, the Japanese Society for the Study of Acute Liver Insufficiency again proposed more concise indications for liver transplantation for severe hepatitis.
1. The interval between jaundice and encephalopathy >14 days
2. Total serum bilirubin >20mg/dl at the time of encephalopathy
3. liver volume measured by CT at the onset of encephalopathy