I. Definition and clinical typing of severe hepatitis
Acute liver failure (AHF) and severe hepatitis are two completely different concepts. The former involves a wide range of elements, it can be other pathogenic factors besides virus, physical and chemical (poisoning), biological (infection, aflatoxin), tumor ( primary malignant tumor of liver and metastatic tumor), congenital metabolic disorders (Wilson’s disease), congenital malformations (congenital biliary atresia) and other factors. AHF can occur in both acute viral hepatitis and chronic viral hepatitis (including chronic hepatitis with proven liver damage, viral carrier status, and hepatic steatosis).
Acute viral hepatitis with AHF is called acute severe hepatitis, while chronic viral hepatitis with AHF is called chronic severe hepatitis. The former refers to acute liver failure within 10 days of onset, while the latter refers to acute liver failure that occurs within 10 days to 2 months (8 weeks) after onset. In recent years, some scholars in China have proposed that acute liver failure occurring within 2 months to 6 months (24 weeks) after the onset of the disease is called slow-onset heavy hepatitis, but it has not been finally unified.
Second, the etiology of heavy hepatitis
1, hepatitis A virus (HAV): simple HAV cause heavy hepatitis is rare, accounting for about 10%, but mostly seen in the original HBV, HCV infection based on overlapping infection. 1988 Shanghai hepatitis A epidemic, the number of incidence of 300,000 people, and died of simple HAV infection 25 cases, according to foreign reports, acute hepatitis A occurrence of heavy hepatitis chance in 0.01 ~ 0.1% According to foreign reports, the chance of occurrence of heavy hepatitis in acute hepatitis A is between 0.01~0.1%.
2, hepatitis B virus (HBV): HBV is the main cause of heavy hepatitis. It is reported that the possibility of acute hepatitis B occurrence of heavy hepatitis is 1%. Since HBV infection is mostly transmitted vertically from mother to child, it is easy to form immune tolerance, thus the sudden occurrence of heavy hepatitis in HBsAg carriers is less common, and most of them occur on the basis of chronic liver disease (chronic hepatitis B, hepatic steatosis) caused by HBV.
3, hepatitis C virus (HCV): whether it can cause acute heavy hepatitis is still debated. According to reports from Taiwan and Japan, HCV can cause heavy hepatitis and is more common in subacute heavy hepatitis and a few in chronic or acute heavy hepatitis.
4, hepatitis E virus (HEV): HEV infection causes heavy hepatitis mainly in pregnant patients. Pregnant women have a significantly higher rate of HEV infection and death rate than non-pregnant women patients, the infection rate is more than 4-5 times that of non-pregnant women, and the death rate is 1-5% in general hepatitis E, while pregnant women reach 10-40%.
5, hepatitis G virus (HGV) and TTV: HGV and TTV pathogenicity is still difficult to determine, most scholars believe that HGV and TTV is a “concomitant infection” or a “bystander” in the course of other viral hepatitis. According to reports from Taiwan and the United States, HGV causing acute and subacute heavy hepatitis is very rare, while reports from Shenyang, China, suggest that HGV infection alone or infection based on overlapping other hepatitis viruses can cause heavy hepatitis, and that HGV-induced heavy hepatitis appears to be more severe and has a higher mortality rate.
6, other viral infections: other viruses that can cause heavy hepatitis such as cytomegalovirus (CMV), adenovirus (adenovirus), human microvirus (HPV), EBV (EBV), herpes simplex virus (HSV), varicella zoster virus (varicella zoster), etc., these viruses cause heavy hepatitis are mostly seen after organ transplantation, immunosuppressive therapy, cancer chemotherapy. Immunosuppressive therapy, tumor chemotherapy after.
7, mixed infection: two or more viruses mixed infection is prone to cause heavy hepatitis, HDV / HBV simultaneous or overlapping infection caused by heavy hepatitis is a typical example. On the basis of chronic infection of HBV and HCV, both may be combined with HAV infection, and the disease seems to be more serious when it occurs in the latter, and there are also reports of severe hepatitis in people with HBV co-infection and HIV infection, who developed drug resistance during lamivudine treatment or discontinued the drug midway. I have also encountered a case of acute hepatitis A patient with CMV infection and a tendency to develop severe hepatitis.
So far, there are some unknown viruses that can cause severe hepatitis, and further research is needed.
III. Pathogenesis of severe hepatitis
The pathogenesis of severe hepatitis is not fully understood, the pathophysiology and regression of the same pathogen in different hosts or different pathogens in a host can be completely different, but the acute liver failure leading to severe hepatitis is caused by the necrosis of a large number of hepatocytes, and the mechanism leading to its necrosis can be divided into three causes.
(1) immune-mediated hepatocyte injury.
(2) Direct viral damage.
(3) Ischemic hepatocyte injury.
Fourth, the clinical manifestations of heavy hepatitis
1, acute heavy hepatitis: also known as fulminant hepatitis, generally refers to the onset of liver failure within 10 days after the onset of acute viral hepatitis. It is characterized by an acute onset and rapid development. Early psychoneurological symptoms are most prominent, such as personality changes, drowsiness, abnormal behavior, impaired consciousness, etc. There may also be a narrowing of the hepatic turbinate, increased bleeding tendency, fluttering wing-like tremor, ankle clonus, liver odor, and significant abnormalities in biochemical indicators of liver function, showing enzyme a jaundice separation, bile a jaundice separation. Prothrombin activity <40%.
2, subacute heavy hepatitis: acute viral hepatitis develops liver failure within 10 days to 8 weeks after the onset of the disease. On the basis of acute hepatitis with the following characteristics that should be considered.
(1) Extreme weakness and depression.
(2) Severe gastrointestinal symptoms (frequent nausea and vomiting).
(3) High degree of abdominal distension, which may include abdominal distention or large amounts of ascites.
(4) Rapid deepening of jaundice, with serum bilirubin reaching 170umol/L or more within a few days.
(5) Obvious bleeding tendency such as large skin petechiae, gastrointestinal bleeding, etc.
(6) The presence of hepatic encephalopathy of grade III or higher.
(7) Prothrombin activity <40%, enzyme-jaundice separation, and bile-jaundice separation. The above features can be manifested in various patients with varying degrees of severity, and may not be necessary to have both.
3, chronic heavy hepatitis: the most common type of heavy hepatitis, accounting for about 70-80%. It is in chronic active hepatitis or active hepatic steatosis based on the deterioration of the disease. Therefore, the clinical manifestations must have the characteristics of chronic hepatitis or hepatic steatosis. In some cases, the onset of the disease is slightly acute, the history is short, and it looks like the development of acute hepatitis, but the original hepatitis develops insidiously, and the symptoms are not obvious, but it has the signs and laboratory characteristics of chronic hepatitis or cirrhosis.
V. Prognosis of severe hepatitis
The prognosis of severe hepatitis is very poor and the mortality rate is extremely high. Foreign reports are 60% to 80%, and most domestic reports are above 60%. The causes of death are mostly brain herniation due to hepatic encephalopathy combined with cerebral edema, gastrointestinal hemorrhage, secondary infection, hepatorenal syndrome, and multi-organ failure. Survival depends on the degree of hepatocyte necrosis, the ability of residual hepatocytes to regenerate, and the management of complications. Factors affecting prognosis are as follows.
1. virus. The survival rate of heavy hepatitis caused by HAV, HBV, and NANBV is 66%, 38.9%, and 20%, respectively, and the mortality rate of HEV infection in pregnant women is higher. The mortality rate of multiple viral mixed infections is higher
2. age. The survival rate of patients <14 years old is 35%; between 14 and 45 years old, the survival rate is 22%; for those >45 years old, the survival rate is 5%.
3.Coma degree. The survival rates for grades II-IV were 66%, 42%, and 18%, respectively. The fewer the number of days between the onset of symptoms and deep coma, the more severe the degree of hepatocyte necrosis and the higher the mortality rate.
The size of the liver can be correctly estimated by B-mode ultrasound and CT scan.
5.Laboratory indicators. Serum bilirubin, transaminases, cholesterol, cholinesterase, and prothrombin activity have prognostic value, and AFP level also has prognostic value, and some reports suggest that the survival rate is 80% for those with positive serum AFP and 20% for the opposite.
Six, the diagnosis of each type of heavy hepatitis points
(A) Acute hepatitis
1, no previous history of hepatitis.
2, the onset of the first similar to acute jaundice, but the rapid development of the disease, the onset of psychiatric symptoms within 10 days, more than II degree of hepatic encephalopathy.
3, Bleeding tendency: bleeding spots or bruises on the skin, mucous membranes and penetration sites, even gastrointestinal bleeding. Serum prothrombin activity <40%
4, rapid deepening of jaundice.
5, narrowing of the hepatic turbinate, positive liver odor and fluttering tremor.
Diagnostic points of each type of severe hepatitis
(II) Subacute severe hepatitis
1, no previous history of hepatitis.
2, the initial onset of the disease is similar to acute jaundice hepatitis, but the disease is more severe, often showing the “four high” phenomenon, namely, high weakness, high gastrointestinal symptoms (nausea, vomiting, inability to eat), high jaundice (rising quickly, quickly reaching 171mmol / L or more), high abdominal distension, and later quickly appear obvious bleeding tendency and ascites. Hepatorenal syndrome may also appear, while hepatic encephalopathy often appears later (more than 10 days, within 8 weeks) or does not appear.
3. Prothrombin activity <40%.
(iii) Chronic severe hepatitis
1, there is often a history and signs of chronic hepatitis and hepatic steatosis (esophageal varices, a large number of spider nevi, hepatopathy face, liver palms, and a significantly enlarged spleen)
2, there are similar clinical manifestations of subacute heavy hepatitis.
3, prothrombin activity (PTA) <40% is not as significant as in acute and subacute heavy hepatitis, because severe hepatic steatosis itself can cause a significant decrease in prothrombin activity, if combined with common jaundice hepatitis, there is also the possibility of PTA <40%, and there can also be ascites, mild bleeding tendency, which is very easy to be misdiagnosed as chronic heavy hepatitis.
4. The decrease of plasma albumin is often more obvious, and the chance of ascites and endogenous infection is also higher than that of acute and subacute heavy hepatitis, and endogenous infection is also a causative factor for the deterioration of the disease.
VII. Treatment
Treatment principles There is no sure effective special treatment, still mainly comprehensive therapy. The principles are: to reduce hepatocyte necrosis, to promote hepatocyte regeneration, and to prevent and treat various complications. Whether liver failure can be reversed is determined by the number of residual hepatocytes. If the hepatocytes are necrotic and the reserve function is lost, there is no basis for regeneration. At this point, no drug can reverse the course of liver failure, and liver transplantation is the only effective treatment. Therefore, foreign scholars believe that heavy hepatitis should be treated in medical centers that are equipped for liver transplantation so that liver transplantation can be performed at any time when the condition requires it. Of course, artificial liver can be used both as an adjuvant treatment and as a bridge between medical and surgical treatment to prepare for liver transplantation to improve the success rate of treatment.
(i) Internal treatment
1. Reduce hepatocyte necrosis and promote hepatocyte regeneration
(1) Hepatocyte growth factor (PHGF). Animal tests have proved that it has obvious effects of promoting the synthesis of hepatocyte DNA, improving the function of withered cells, reducing TNF production and decreasing the mortality rate of animals with experimental liver failure. The dose of PHGF is usually 100mg~200mg/d in glucose solution until the patient’s liver function is significantly restored.
(2) Prostaglandin E1 (PGE1). Its effect is to dilate liver blood vessels, increase liver blood flow, improve liver microcirculation and promote hepatocyte regeneration. And it can stabilize the lysosomal membrane, reduce the production of TNF and mitigate liver injury. The dose is 200ug/d, and 10~20 is a course of treatment. Reports suggest that PGE1 is more effective when applied early. However, due to the side effects of this drug, prone to high fever, headache, nausea, vomiting, phlebitis, and hypotension and other symptoms, greatly reducing its application rate.
(3) Glycyrrhizin preparation. There is a strong immune response and inflammatory response in the pathogenesis of severe hepatitis, which is involved in the inflammation and necrosis of hepatocytes. Although adrenocorticotropic hormone can inhibit certain pathological immune and inflammatory reactions, clinical studies over the years have proved that the application of adrenocorticotropic hormone is more harm than good, while glycyrrhizin agents such as potentin and glycyrrhizin have non-specific anti-inflammatory effects similar to corticosteroids without the side effects of hormones, and thus are beneficial in curbing the progress of the disease.
(4) Glucagon-insulin (G-I) therapy. Animal experimental research shows that G-I therapy has the effect of stopping hepatocyte damage and necrosis and promoting regeneration of hepatocytes, which is the basis for its clinical treatment of heavy hepatitis. G-I has been reported to be applied clinically both at home and abroad, and it is especially effective in encephalopathy of acute heavy hepatitis, which can significantly improve its impaired consciousness. However, some scholars have taken a negative attitude toward G-I therapy, especially suggesting that in chronic heavy hepatitis, G-I therapy should be prohibited because it increases portal pressure and is suspected of causing upper gastrointestinal bleeding. In recent years, the application of G-I therapy in China is less reported, which is related to its inaccurate efficacy and susceptibility to hypoglycemia and serious gastrointestinal reactions.
(5) Glutathione (GSH). Scholars at home and abroad have confirmed the existence of excessive free radicals, scopolamine, IL-6 and TNF-α in the body and liver of patients with viral hepatitis, which leads to hepatocyte plasma membrane dysfunction and violent oxidative metabolism (oxidative stress), generating a large number of reactive free radicals, and the antioxidant system of patients with viral hepatitis is also damaged to varying degrees. The antioxidant system of patients with viral hepatitis is also damaged to different degrees, as shown by the decrease of plasma superoxide dismutase (SOD), vitamin E and GSH content, and the more severe the disease, the more obvious the decrease. In response to the above pathophysiology, it is necessary to apply antioxidant therapy, the domestic application of reduced GSH preparations (TAD or guladin) as one of the comprehensive therapy for heavy hepatitis.
(6) potassium magnesium mentholate (including Pannanquin): has the effect of promoting hepatocyte metabolism to improve liver function and reduce bilirubin and maintain electrolyte balance, can be 20mg daily dissolved in 10% glucose solution intravenous.
(7) growth hormone (GH): has the effect of promoting the growth of hepatocytes. It has not yet been reported for the treatment of liver failure, but it may become a practical research topic in the future.
(8) Semtex: The main component of this product is adenosylmethionine. In cirrhosis and liver failure, the activity of adenosylmethionine synthetase in hepatocytes is significantly weakened, which reduces the detoxification and bioprotective effects of the liver, and the plasma clearance rate of methionine in the patient’s diet decreases. By replacing endogenous adenosine methionine with exogenous adenosine methionine, it performs important physiological functions, improves bile acid circulation, promotes the excretion of bile acids and bilirubin, and prevents intrahepatic bile stasis.
2.Immunomodulatory therapy
In the pathogenesis of heavy hepatitis, there is a serious immune disorder. On the one hand, due to the strong immune response and inflammatory response, is one of the reasons for the massive necrosis of hepatocytes; on the other hand, the whole immune system of the body is dysfunctional, non-specific cellular immunity and humoral immune function is reduced, and it is also easy to suffer further infections from various agents during the course of the disease, especially the refractory infections caused by some conditionally pathogenic bacteria with weak pathogenicity, which increases the difficulty of treatment, and immunomodulatory therapy. Immunomodulatory therapy, especially through the regulation of cellular immune function, to achieve the purpose of correcting immune disorders. Currently, two common types of immunomodulatory therapy are calf thymidine and porcine thymidine, which are used in clinical practice. The synthetic thymosin alpha-1 (Thymosin-α1, trade name Rituxan) has good efficacy in acute heavy hepatitis, the usage is: 1.6mg/d subcutaneous injection 10~20d for a course of treatment.
3.Anti-viral treatment
Oral nucleoside (acid) analogs lamivudine, adefovir, telbivudine and entecavir can be chosen according to the condition. Interferon is prohibited.
4.Anti-endotoxin treatment
(1) Intermittent application of broad-spectrum antibacterial drugs to inhibit the release of endotoxin from intestinal bacteria
(2) Oral micro-ecological agents such as Pefikon, Mia BM, and rectification
(3) Change the pH of the intestinal tract to maintain an acidic environment
(4) Keep the stool open to reduce the absorption of endotoxins
5.Prevent and treat various complications
(1) Hepatic encephalopathy
(2) Upper gastrointestinal bleeding
(3) hepatorenal syndrome
(4) Infection
(5) Hydropower disorders
(6) ascites
(7) Pleural fluid
6.Supportive therapy
In the comprehensive treatment of heavy hepatitis, supportive therapy has received a lot of attention from scholars. Since acute heavy hepatitis is more prone to cerebral edema and water and sodium retention, the intake should be limited, generally not more than 1500ml/d~2000ml/d, and the daily supply of calories should be 1.2~1.6 kcal to ensure the energy required for hepatocyte regeneration. In order to solve the contradiction between infusion volume and calorie supply, it is recommended to use energy combination containing hypertonic sugar or deep vein supply by subclavian vein cannulation. At the same time, early and active application of albumin, fresh plasma or lyophilized plasma has positive significance to improve the condition. In the case of combined hepatic encephalopathy, the application of branched-chain amino acids has certain pro-wake effect.
(ii) Artificial liver support therapy
As most of the hepatocytes in patients with heavy hepatitis have degenerative necrosis, liver failure, loss of liver biosynthesis, transformation and detoxification, accumulation of metabolites in the body, and serious disturbance of the internal environment, which are not conducive to the regeneration of hepatocytes and recovery of functions, it is often difficult to rely on internal medicine alone, which is also the reason for the high death rate of heavy hepatitis. The development of artificial liver has gone through three stages: physical artificial liver → intermediate artificial liver → biological artificial liver.
(iii) Liver transplantation
1. Timing of liver transplantation. At present, most scholars believe that liver transplantation is the best way to save heavy hepatitis, but success and failure often go hand in hand, and its risk is also the highest. How to minimize the wind of failure in response to treatment and determine whether its disease progression is progressive, irreversible, or reversible. For the former, early liver transplantation should be performed, while for the latter, aggressive medical combination therapy should be continued. Conversely, premature liver transplantation puts patients who would otherwise be effectively treated medically at unnecessary risk (short-term risks associated with surgery and long-term immunosuppressive therapy after surgery). Similarly, if the optimal timing of surgery is delayed, then the surgery is prone to various surgically unmanageable complications, reducing the survival rate to zero. Therefore, it is necessary to master the indications and counter indications for liver transplantation.
2. Emergency liver transplantation signs.
(1) Prothrombin time (PT) > 50 seconds
(2) Serum bilirubin >300umol/L
(3) Age <10 years or >40 years
(4) Time between onset of jaundice and hepatic encephalopathy >7 days
(5) Arterial blood ketone body ratio (acetates/β-hydroxybutyrate) <0.4
(6) Serum hHGF level >10mg/L
3. Liver transplantation counter-indications.
(1) Uncontrolled intracranial hypertension.
(2) Uncontrolled hypotension.
(3) Sepsis.
(4) Adult respiratory distress syndrome (FIO2>0.6).
(5) Pre-existing suicidal ideation.