Severe hepatitis

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Ou Weini	(Deputy Chief Physician)	Hepatology Center of Beijing Ditan Hospital
Cheng Danying	(attending physician)	Hepatology Center of Beijing Ditan Hospital
Xing Huichun	(Chief physician)	Hepatology Center of Beijing Ditan Hospital

Severe hepatitis is a serious liver disease characterized by necrosis of a large number of hepatocytes, which can cause hepatic failure Even endangering life is one of the main causes of death of patients with liver disease. There are many causes of severe hepatitis, including hepatitis B virus infection, A, E virus and other pan tropic viruses such as EBV, CMV, etc, Drug poisoning , chronic alcoholic liver damage, etc., its clinical classification is often divided into acute, subacute and chronic severe hepatitis.

Common location: liver
Common causes: Hepatitis virus infection, drug poisoning, chronic alcoholic liver damage, etc

common symptom: Symptoms vary in different periods ， Can be extremely weak ， anorexia ， ascites ， etc.
Western medicine name: Severe hepatitis
Department: Internal Medicine - Department of Gastroenterology

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nine Diet attention
ten disease prevention

Disease Overview

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Severe hepatitis affects the life span of patients because of its severe condition and poor prognosis. In China, the most common cause of severe hepatitis is hepatitis B virus infection, accounting for about two-thirds of all severe hepatitis. In addition, hepatitis A, C, D and E viruses can also cause severe hepatitis, and other viruses such as cytomegalovirus (CMV) EB virus, herpesvirus, adenovirus dengue fever Virus and Rift vnlley virus can also cause drug-induced liver damage Alcoholic hepatitis 、 Autoimmune liver disease The severe hepatitis caused by it also occurs from time to time in clinical practice, especially drug-induced hepatitis hepatic failure , which accounts for a high proportion of severe hepatitis in the United States. With the promotion of anti viral drugs in the field of hepatitis B, the severe hepatitis caused by hepatitis B is also on the decline in China, so drug hepatitis Alcoholic hepatitis The proportion of severe hepatitis caused by hepatitis B is increasing. In addition, gestation acute Fatty liver It is also a special type of severe hepatitis. The characteristics of severe hepatitis disease: severe illness, multiple complications, poor prognosis, and high mortality.

Pathophysiology

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In general, severe hepatitis has a series of pathophysiological processes caused by liver failure after a large number of hepatocyte necrosis. The commonly used classification method of severe hepatitis in China is to classify it according to the length of pathology, that is, it can be divided into three categories: acute severe hepatitis, subacute severe hepatitis and chronic severe hepatitis. Different types have different pathological manifestations. ① Acute severe hepatitis was also called acute liver atrophy. From one week to two weeks after the onset, hepatocyte necrosis accounted for about 2/3, showing large, sub large or bridging necrosis, surrounded by neutrophil infiltration, no fibrous tissue proliferation, and the gross size of the liver was significantly reduced. The liver was red with yellow green, so it was called red or yellow liver atrophy. ② Subacute severe hepatitis: The hepatocytes show sub massive necrosis, and the necrotic area is less than 1/2. The regeneration of hepatocytes can also be seen around the liver lobule, forming regenerative nodules, which are surrounded by proliferative collagen fibers, accompanied by the proliferation of small bile ducts, obvious cholestasis, and the gross liver shows nodules of different sizes. ③ Chronic severe hepatitis: chronic hepatitis or cirrhosis On the basis of lesions, sub massive or massive necrosis occurs, and bridging and debris necrosis can still be seen in most cases.

Pathophysiology of severe complications of severe hepatitis: ① jaundice : It is caused by massive necrosis of hepatocytes and dysfunction of bilirubin uptake, binding and excretion jaundice And cholestasis. ② hepatic encephalopathy (Liver coma): A large number of hepatocytes are necrotic, and the detoxification function of the liver is reduced cirrhosis When the portal vena cava is short circuited, a large number of harmful substances enter the systemic circulation directly from the portal vein. ③ Hemorrhage: hepatocyte necrosis, reduction of coagulation factor synthesis or cirrhosis Hour Hypersplenism Thrombocytopenia. ④ Hepatorenal syndrome Renal failure: In severe hepatitis, endotoxemia causes renal vasoconstriction, renal ischemia, prostaglandin E2 reduction, effective blood volume decline and other factors, which lead to the reduction of glomerular filtration rate and renal plasma flow. ⑤ Hepatopulmonary syndrome During severe liver disease, due to hemodynamic changes, pulmonary capillary dilatation, arteriovenous shunt, and serious impact on gas exchange function. ⑥ Ascites: In severe hepatitis, a large number of hepatocytes necrosis, sodium water retention due to the reduction of inactivated aldehyde, ketone and natriuretic hormone, and hypoproteinemia due to the decrease of synthetic albumin are the main causes of ascites.

Pathogenesis

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The pathogenesis of severe hepatitis is complex, from cell damage and dysfunction to cell apoptosis and necrosis, its mechanism has not been fully clarified yet. For severe hepatitis caused by virus infection, its pathogenesis is not only related to the pathogen, but also related to the body's immunity.

The relationship between pathogenesis and pathogen: viruses can directly cause damage to hepatocytes, and finally form necrosis of large hepatocytes. For example, when hepatitis A and hepatitis E occur, the serious pathological changes (dissolution and necrosis) of hepatocytes are the direct consequences of the massive replication of these viruses in hepatocytes. That is to say, the more hepatocytes damaged by infection, the more serious the disease. As far as hepatitis B is concerned, the amount of virus infected is mostly a factor, but the gene mutation of the virus is also another factor. After gene mutation, the number of virus increases, which is also related to the occurrence of severe hepatitis B.

The relationship between pathogenesis and immunity: the occurrence of severe hepatitis in patients with hepatitis B accounts for 2/3 of the severe hepatitis, but it is not because there are many hepatitis B viruses in these patients. The more important mechanism is the abnormal immune response caused by hepatitis B virus. When the body is over immunized by hepatitis B virus, a large number of antigen antibody complexes are produced and activate the target system tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), endotoxin and other factors are involved, leading to massive necrosis of hepatocytes and severe hepatitis.^[1]

Etiological classification

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The causes and inducements of severe hepatitis are complex. The most common is the immune activation after the change of immune status. On the basis of hepatitis B, hepatitis E, hepatitis A infection, hepatitis B gene mutation gestation Excessive fatigue, mental stimulation, alcohol consumption, use of liver damaging drugs, combined bacterial infection, and other diseases such as hyperthyroidism 、 diabetes Its classification is mainly divided into acute, subacute and chronic severe hepatitis according to the speed of disease development. Among them, chronic is divided into slow and urgent hepatic failure And chronic liver failure.

classification

According to the histopathological characteristics and the speed of disease development, severe hepatitis can be divided into four categories:

(1) Acute hepatic failure (acute liver failure, ALF): also known as fulminant hepatitis, which is characterized by acute onset, and degree II or above within 2 weeks of onset hepatic encephalopathy Characteristic hepatic failure symptom. There are many inducements. The mortality of this type of disease is high, and the course of disease does not exceed three weeks.

(2) Subacute hepatic failure (subacute liver failure, SALF): also called subacute liver necrosis. The onset of the disease is relatively acute, and symptoms of liver failure occur within 15 days to 26 weeks. The first occurrence is above II degree hepatic encephalopathy Is called encephalopathy type; Ascites and its related symptoms (including hydrothorax, etc.) are called ascites type. Late stage may have refractory complications, such as brain edema , massive hemorrhage of digestive tract, severe infection, electrolyte disorder and acid-base imbalance. Leukocyte increased, hemoglobin decreased, hypoglycemia, low cholesterol, low cholinesterase. Once it appears Hepatorenal syndrome The prognosis is very poor. The course of this type of disease is longer, often more than 3 weeks to several months. Easily converted into chronic hepatitis or cirrhosis 。

(3) Chronic acute liver failure (ACLF): It refers to the acute decompensation of liver function based on chronic liver disease.

(4) Chronic liver failure (CLF): cirrhosis On the basis of that, the progressive decline of liver function leads to ascites or portal hypertension, coagulation dysfunction and hepatic encephalopathy The main manifestation is chronic decompensation of liver function.

by stages

According to the severity of clinical manifestations, subacute liver failure and chronic acute liver failure can be divided into early, middle and late stages.

(1) Early stage: ① extremely weak, with obvious anorexia, vomiting, abdominal distension and other serious digestive symptoms; ② jaundice Progressive deepening (serum TBil ≥ 171 μ mol/L or daily increase ≥ 17.1 μ mol/L); ③ Bleeding tendency, PTA ≤ 40%; ④ No hepatic encephalopathy Or obvious ascites.

(2) Medium term: based on the early manifestations of liver failure, the condition further develops, and one of the following two conditions occurs: ① Hepatic encephalopathy of degree II or above and (or) obvious ascites; ② The bleeding tendency is obvious (bleeding spots or ecchymosis), and 20%<PTA ≤ 30%.

(3) Late stage: on the basis of the mid-term manifestations of liver failure, the condition is further aggravated, and one of the following three conditions occurs: ① There are refractory complications, such as Hepatorenal syndrome , upper gastrointestinal bleeding, severe infection, and electrolyte disorders that are difficult to correct; ② Occurrence of hepatic encephalopathy above grade III; ③ Severe bleeding tendency (ecchymosis at injection site, etc.), PTA ≤ 20%.^[2]

Diagnostic differentiation

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（1） When a patient with liver disease has the following symptoms, he/she should be highly alert to severe hepatitis:

1. Extreme fatigue and severe gastrointestinal symptoms.

2. Nervous and mental symptoms (such as lethargy, personality and behavior changes, irritability, coma, etc.).

3. Have obvious bleeding tendency: Epistaxis 、 Gingival bleeding It's hard to stop.

4、 jaundice Rapid deepening accompanied by toxic intestinal distention, liver odor, etc.

5. PTA<40%, Tml is 10 times higher than normal during assay.

（2） Diagnostics

"Three high and one low", that is, high fatigue, high jaundice High anorexia with flatulence; Low PTA (PTA<40%).

1. Acute severe liver disease: abnormal mental behavior with "three high and one low" within 2 weeks.

2. Subacute severe hepatitis: Hepatic encephalopathy occurs from more than 2 weeks to half a year after onset, and the symptoms of "three high and one low" are also detected.

3. Chronic severe liver disease: "three high and one low" on the basis of chronic liver damage or progressive liver failure on the basis of cirrhosis.

（3） Correlation detection

1. PTA: prothrombin time PT and prothrombin activity PTA are important basis for diagnosis of severe hepatitis. When the PTA is less than 40% due to PT prolongation, it should be suspected as severe hepatitis. The change of PTA is also the most sensitive laboratory index to judge the prognosis of severe hepatitis.

2. Liver function test: ALT and AST increased. ALT: alanine aminotransferase. AST: The rapid decline of aspartate aminotransferase ALT leads to ALT/AST<1, accompanied by the continuous increase of bilirubin - "enzyme bile separation" phenomenon, and the total bilirubin is often greater than 171 μ mol/L.

3. Cholinesterase: It is synthesized by hepatocytes. The decrease of its activity indicates that hepatocytes have been significantly damaged. The lower the value, the more serious the disease.

4. Serum albumin, blood lipid and blood sugar all decreased: albumin decreased significantly in severe hepatitis, and more than 40% of patients with severe hepatitis had hypoglycemic reaction, so blood sugar should be monitored, and attention should be paid to the differentiation between hypoglycemic coma and hepatic encephalopathy. When hepatocytes are severely injured, the synthesis of cholesterol in the liver is reduced, so the plasma cholesterol is significantly reduced. The lower the cholesterol, the more dangerous the prognosis is, but the cholesterol is increased in obstructive jaundice.

In addition, lactate dehydrogenase (LDH), D-acylglutamine transpeptidase (GGT), complement C3, etc. are also relevant detection indicators of the degree of liver damage, which are also commonly used in clinical practice.

Color Doppler ultrasound, CT, nuclear magnetic resonance and other impact studies are also essential in observing the size of the liver, the condition of the portal vein and the diagnosis of cirrhosis.

complication

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1. Hepatic encephalopathy: Neuropsychiatric syndrome caused by liver dysfunction can occur in severe hepatitis and cirrhosis.

Hepatic encephalopathy can be divided into four degrees according to clinical symptoms, signs and abnormal degree of brain waves: degree I, mild hepatic encephalopathy, mainly mental symptoms, with personality and behavior changes, timing, orientation, calculation and other abnormalities. Grade II, moderate hepatic encephalopathy Neurosis It is mainly characterized by flapping wing tremor, muscle tension enhancement, tendon hyperreflexia, lethargy, electroencephalogram There are abnormal θ waves, abnormal personality and behavior, which belongs to pre coma. Grade III, severe hepatic encephalopathy, lethargy, still responsive to stimulation, electroencephalogram Abnormal θ wave and three-phase slow wave can be seen, which belongs to coma period. Grade IV, deep coma, no response to stimulation, tendon reflex disappeared.

2、 Upper gastrointestinal bleeding ： The decrease of coagulation factors commonly used in acute severe hepatitis results in extensive erosion of gastric mucosa and ulcer bleeding, while sub severe liver and chronic severe liver often result from portal hypertension, esophageal fundus varicosity Rupture and bleeding, Upper gastrointestinal bleeding It can induce hepatic encephalopathy, ascites and abdominal infection Hepatorenal syndrome Etc.

3、 Hepatorenal syndrome ： It is often the terminal manifestation of severe liver disease. The main manifestations are oliguria or anuria, azotemia, and electrolyte imbalance.

4. Ascites and spontaneity peritonitis ： Severe hepatitis often has ascites due to low protein and decreased aldosterone inactivation, and spontaneous ascites due to low immune function peritonitis After bacterial infection, endotoxemia is the cause of further aggravation of liver damage.

Disease treatment

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The treatment principle of severe hepatitis is to save and repair seriously damaged hepatocytes, so that patients' hepatocytes have the opportunity to "regenerate", thus improving the survival rate. Therefore, basic treatment, supportive treatment, intensive care and appropriate antiviral treatment are effective and necessary. When the effect of advanced medical treatment is not good, waiting for liver transplantation by artificial liver and liver transplantation are the final means.

Supportive treatment

Patients should rest in bed, implement intensive care, closely observe the condition, and prevent nosocomial infection 。 Carbohydrate based nutritional support treatment should be given daily to reduce the decomposition of fat and protein. The amount of fluid replacement is about 1500~2000ml/d. Pay attention to the balance of the amount of fluid in and out. If there is too much urine, the amount of fluid replacement can be appropriately increased. Pay attention to maintaining electrolyte and acid-base balance. Supply sufficient albumin, reduce protein in diet as much as possible, so as to control the source of ammonia in the intestine, maintain positive nitrogen balance, blood volume and colloid osmotic pressure, and prevent brain edema And ascites. Supplement sufficient vitamin B, C and K. Fresh plasma, albumin or immunoglobulin were infused to strengthen the supportive treatment. Drugs harmful to liver and kidney are prohibited.

Treatment of complications

(1) Hepatic encephalopathy: Low protein diet; Keep the stool unobstructed, take orally lactulose, norfloxacin, etc. to inhibit intestinal bacteria, use lactulose or weak acid solution to retain enema, timely remove the ammonia content in the intestine, keep the pH value in the intestinal acid environment of 5~6, and reduce the formation and absorption of ammonia; Regulating intestinal microenvironment with microecological agents; Intravenous administration of acetylglutamine, sodium glutamate, arginine, potassium magnesium aspartate has a certain ammonia lowering effect; Levodopa can be used to correct false neurotransmitters; Appearing brain edema The performer can use 20% mannitol and furosemide for rapid infusion, and pay attention to the water electrolyte balance. While treating hepatic encephalopathy, we should actively eliminate its inducements.

（2） Upper gastrointestinal bleeding ： Histamine H2 receptor antagonists, such as ranitidine, and omeprazole can be used to prevent bleeding; Supplement vitamin K and C; transfuse prothrombin complex, fresh blood or plasma, concentrated platelet, fibrinogen, etc. When bleeding, you can take thrombin or norepinephrine or Yunnan Baiyao orally and apply pituitrin. The bleeding caused by portal hypertension in cirrhosis can also be treated surgically.

(3) Secondary infection: Severe hepatitis patients are easy to be infected, so it is necessary to strengthen nursing and strict disinfection and isolation. Once it appears, antibiotics should be applied as early as possible, and antibiotics should be selected according to the results of bacterial culture and clinical experience. The use of immunomodulatory drugs such as thymosin can improve the body's defense function and prevent secondary infection.

(4) Hepatorenal syndrome: Avoid the use of drugs for kidney damage, and avoid various factors that cause blood volume reduction. At present, prostaglandin E or dopamine can be applied intravenously with diuretics, so that the 24-hour urine volume is not less than 1000ml, most of which are not suitable for dialysis treatment. A large amount of intraperitoneal paracentesis and drainage of refractory ascites often fail to achieve satisfactory results, and there is a risk of inducing hepatic encephalopathy. Terlipressin can be used in combination with albumin.

Antiviral therapy

Antiviral treatment should be given as soon as possible. Antiviral drugs are mainly nucleoside drugs, and interferon is generally not recommended.

Artificial liver support treatment

The main function is to remove toxic substances in the blood of patients and supplement bioactive substances. After treatment, the blood bilirubin can be significantly reduced and PTA can be increased, but some cases return to the original level after a few days. Artificial liver support treatment has a good effect on early severe hepatitis, and it can also help to buy time for liver cell regeneration or prepare for liver transplantation for late severe hepatitis.

Indications: ① In the early and middle stages of liver failure caused by various reasons, PTA should be between 20% and 40% and platelet>50 × 10/L; ② Waiting for donors before liver transplantation for patients with advanced liver failure, rejection of abnormal reactions after liver transplantation, and nonfunctional period of liver transplantation.

Relative contraindications: ① severe active bleeding or DIC; ② Highly allergic to blood products or drugs such as plasma, heparin and protamine; ③ Circulatory failure; ④ heart cerebral infarction Unstable period; ⑤ gestation advanced.

Liver transplantation

At present, the technology is basically mature. In recent years, the use of nucleoside analogues and high titer anti hepatitis B immunoglobulin for antiviral treatment before and after transplantation has significantly improved the success rate of liver transplantation in patients with severe hepatitis caused by HBV infection. Liver transplantation is the main treatment for patients with end-stage hepatitis C, with a 5-year survival rate of 30%~40%. Due to the high price of liver transplantation, the difficulty of donor liver source, rejection reaction, secondary infection (such as cytomegalovirus) and so on, its wide application is hindered.

Indications:

(1) The curative effect of active medical treatment and artificial liver treatment on the middle and late stage liver failure caused by various reasons is not good.

(2) Various types of end-stage cirrhosis.

Contraindications:

(1) Absolute contraindications: ① Uncontrollable systemic infection; ② Extrahepatic malignant tumors that are difficult to cure; ③ Alcoholism or drug abuse that is difficult to quit; ④ Severe heart, brain, lung and other important organs STD Change; ⑤ An uncontrollable mental illness.

(2) Relative contraindications: ① over 65 years old; ② Malignant liver tumor with tumor thrombus or metastasis in the main portal vein; ③ merge diabetes , Heart myopathy Diseases with poor prognosis; ④ Biliary tract infection septicemia Serious infection; ⑤ Acquired human immunodeficiency virus infection; ⑥ Obvious door Venous thrombosis And other anatomical structure abnormalities.^[3-4]

Disease prognosis

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The prognosis is poor, and the case fatality rate is 50%~70%. The mortality rate of patients with younger age, timely treatment and no complications was lower. Survivors of acute severe hepatitis (liver failure) have a good long-term prognosis, and most do not develop into chronic hepatitis And cirrhosis; Most survivors of subacute severe hepatitis (liver failure) turn to chronic hepatitis Or cirrhosis after hepatitis; The mortality of chronic severe hepatitis (liver failure) is the highest, reaching more than 80%. The condition of the survivors can be repeated many times.

Diet attention

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It is difficult for patients with severe hepatitis to ensure adequate dietary intake, and hypoproteinemia, hypoglycemia, and hyperlipidemia are common. In addition to providing nutritional support, diet (or enteral nutrition) is important to maintain the function of the gastrointestinal tract, reduce intestinal flora imbalance and heterotopia, reduce the production and absorption of endotoxin, and prevent Stress ulcer The occurrence of bleeding. Therefore, if the patient's condition permits, try to provide appropriate food for the patient. Even if the patient can't eat, he or she should strive for enteral nutrition through nasal feeding through gastrointestinal tube.

The diet is dominated by carbohydrates, providing sufficient water-soluble vitamins, and properly supplementing dietary fiber, glutamine, branched chain amino acids and other preparations. Limit the intake of protein and fat foods to avoid aggravating or leading to hepatic encephalopathy. For the presence of ascites and edema The supply of salt and water should be limited for 30% of patients. The diet should be small and multi meal, mainly soft food and semi liquid food that are easy to digest. Severe hypoglycemia often occurs at night, which is extremely harmful to the regeneration of liver cells. Therefore, 2-3 meals should be added at night, and food with high sucrose, glucose or fructose content can be properly eaten. Principles of nutritional support in convalescent period of severe hepatitis and chronic hepatitis Same.

disease prevention

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1. Chronic hepatitis B carriers should try their best to develop good living habits and regular physical examination, avoid overlapping infection and the progress of diseases in hiding, and timely detect and deal with changes in the condition.

2. For chronic hepatitis B patients who take oral anti disease drugs for maintenance treatment, they must not stop taking drugs at will, but should decide whether to stop taking drugs after reaching the stop indication under the guidance of a specialist. In addition, regular reexamination shall be conducted as required after drug withdrawal.

3. With the application of nucleoside (acid) drugs, more and more chronic hepatitis B patients are receiving hepatitis B antiviral treatment. In the maintenance treatment phase, regular reexamination of HBV-DNA should be carried out to detect drug resistance in time to prevent severe hepatitis caused by drug resistance.

4. Do not abuse drugs and alcohol, especially HBsAg carriers.

5. Vaccine application: universal vaccination with hepatitis B and epidemic disease Mother infant block Prevent hepatitis B virus infection, inject hepatitis A vaccine, and prevent overlapping infection.

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