Hepatitis E

　　Hepatitis E virus infection is a zoonotic disease, mainly caused by drinking contaminated water and eating contaminated food. The specific causes and mechanisms are described as follows.

　　1. Causes of hepatitis E virus infection

　　Currently, the medical community believes that the sources of infection include clinical patients with hepatitis E, subclinical patients, and animals infected with hepatitis E virus (HEV). Humans are the only natural host and source of infection for HEV-1.2, while pigs are the main animal source of infection for HEV-3.4. It is now widely recognized that hepatitis E is a zoonotic disease.

　　In 1983, Balayan and others first discovered HEV in fecal specimens from infected individuals using immunoelectron microscopy. In 1989, Reyes and others obtained cDNA clones using molecular cloning technology and officially named this virus as hepatitis E virus (HEV).

　　HEV is an enveloped spherical particle with a diameter of 27-34nm, characterized by protuberances and notches on the surface, and an uneven internal density. In 1989, Reyes and others were the first to obtain the gene clone of HEV. The HEV genome is a single-stranded positive-sense DNA, with a full length of 7.2-7.6kb, encoding 2400-2533 amino acids, consisting of a 5' non-structural region (NS) and a 3' structural region (S). Both ends have non-coding regions (NC), with lengths of 28bp and 68bp, respectively. Additionally, there is a poly(A) tail at the 3' end, composed of 150-300 adenine residues. This virus is unstable and requires storage in liquid nitrogen for long-term preservation. Magnesium or manganese ions help maintain the integrity of the viral particles. It is sensitive to high salt, cesium chloride, and chloroform, and is relatively stable in alkaline environments. The classification and attribution of HEV have not been finally confirmed. Initially, it was classified as a minute RNA virus, but later, its morphology and biological characteristics under an electron microscope were found to be similar to those of caliciviruses, so HEV was also classified into caliciviruses. However, recent analysis of the nucleotide sequence homology of the HEV genome has found that it is different from caliciviruses. Comparative analysis of the NS region genome sequences shows that it is similar to rubella virus and beet necrotic yellow vein virus, so some people suggest that HEV should be classified into the alpha virus subgroup of the rubella virus family.

　　2. Pathogenesis

　　The exact pathogenesis of hepatitis E is not yet fully understood. From primate experiments and research on volunteers, it is speculated that the virus is mainly transmitted through the fecal-oral route, through drinking contaminated water and eating contaminated food, and through eating improperly cooked animal tissues or organs, blood transfusion, and cross-infection between humans and animals. The virus enters the liver through the blood from the intestines, replicates and proliferates within liver cells, and is then excreted into the blood and bile, and finally excreted out of the body with feces. Experiments also show that the liver lesions are mainly mediated by cell-mediated immune responses induced by the virus, leading to liver cell lysis.

　　The pathological changes of hepatitis E are similar to those of hepatitis A. The pathological changes of the liver tissue in most patients with hepatitis E are moderate damage, occasionally with large areas of necrosis. There is infiltration of neutrophils in the portal areas, and Kupffer cells are hyperplastic; punctate necrosis, balloon-like transformation of liver cells, eosinophilic change, and eosinophilic bodies are visible within the lobules. The inflammatory response is mild, and cholestasis and capillary bile thrombosis within liver cells are more common.

　　The complications of hepatitis E include hepatic encephalopathy, hemorrhage, hepatorenal syndrome, and so on. The specific complications are described as follows.

　　1. Hepatic encephalopathy:The main clinical manifestations are disturbance of consciousness, abnormal behavior, and coma.

　　2. Hemorrhage

　　3. Hepatorenal syndrome

　　4. Secondary infection

　　5. Liver failure

　　A small number of cases can present with acute or subacute severe hepatitis, or chronic hepatitis. Severe complications include hepatic encephalopathy, hepatorenal syndrome, secondary infection, hemorrhage, electrolyte disorders, primary peritonitis, and so on. Typical acute jaundice hepatitis is divided into the pre-jaundice stage, the jaundice stage, and the recovery stage. The onset is acute, with general viralemia and obvious gastrointestinal symptoms, such as fever, fatigue, loss of appetite, aversion to oil, nausea, vomiting, and yellow urine, which usually enters the jaundice stage after about 10 days, with yellowing of the eyes and skin. Some cases have enlargement of the liver, tenderness and percussion pain in the liver area, and a few have splenomegaly. After the onset, liver function tests show that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are significantly elevated. In cases with jaundice, there are positive urobilinogen and urobilin in the urine, and the total bilirubin, indirect bilirubin, and direct bilirubin in the blood are all increased.

　　The symptoms of hepatitis E virus vary according to the type of hepatitis, and the specific clinical manifestations are described as follows.

　　1. The incubation period of hepatitis E virus is not yet unified. The epidemiological characteristics of different regions are not entirely the same, the statistical conditions are inconsistent, the number of viral infections, and the differences in some virus strains lead to different incubation periods. Comprehensive reports from China and abroad show that the incubation period of hepatitis E is slightly longer than that of hepatitis A and shorter than that of hepatitis B, usually 2 to 9 weeks, with an average of 6 weeks.

　　2. Clinical manifestations: Currently recognized clinical types include acute hepatitis, severe hepatitis, and cholestatic hepatitis. There is still controversy about chronic hepatitis.

　　1. Acute hepatitis E:Accounts for 86.5% to 90.0% of hepatitis E, including acute jaundice type and acute non-jaundice type, with a ratio of about 1:5 to 10.

　　(1) Acute jaundice type:Accounts for 75% of acute hepatitis E, with clinical manifestations similar to hepatitis A, but with a longer jaundice phase and more severe symptoms.

　　① Pre-jaundice phase:The onset is acute, with symptoms such as chills, fever, headache, sore throat, nasal congestion, and upper respiratory tract infection (approximately 20% incidence), joint pain (7% to 8%), fatigue (60% to 70%), followed by anorexia (75% to 85%), nausea (60% to 80%), vomiting, discomfort in the upper abdomen, liver pain, bloating, and diarrhea. Some patients have mild liver enlargement with tenderness and percussion pain. This period lasts for several days to a month, and by the end of this period, urine color becomes darker, and bilirubin and urobilinogen are present in the urine, with an increase in blood bilirubin (Bil) and alanine aminotransferase (ALT).

　　② Jaundice phase:Body temperature returns to normal, jaundice deepens rapidly, urine becomes as dark as strong tea, stool becomes light in color, skin itching (29%), gastrointestinal symptoms worsen, and can gradually alleviate only after jaundice stops rising. This period usually lasts for 2 to 4 weeks, with some cases lasting up to 8 weeks. Liver function tests also show that all indicators reach their peak and then gradually alleviate.

　　③ Recovery phase:Symptoms, signs, and laboratory tests show comprehensive improvement, with a good prognosis. Various symptoms alleviate to disappearance on average within 15 days, liver shrinkage and liver function recovery on average within 27 days. This period usually lasts for 2 to 3 weeks, with a few cases lasting up to 4 weeks.

　　(2) Acute non-jaundice type:There are two stages: acute phase and recovery phase, but the symptoms are milder than those of jaundice type. Some patients have no clinical symptoms, presenting as subclinical type, while adults tend to show clinical infection.

　　2. Severe hepatitis E:Accounting for about 5% of hepatitis E. Investigations have found that this type is more common in women than in men (2:1 to 5:1), with 60% to 70% being pregnant women, followed by the elderly and those with viral superinfection, especially in patients with hepatitis B who are reinfected with HEV, where severe hepatitis is more likely to occur. Acute severe hepatitis is more common in severe hepatitis E, with a ratio of about 17:1 compared to subacute severe hepatitis.

　　(1) Acute severe hepatitis E:More common in pregnant women (57% to 60%), especially in the late stages of pregnancy (about 70%). The disease progresses rapidly, with most pregnant women experiencing a sharp change in condition after normal delivery or early postpartum. A series of clinical manifestations of severe hepatitis can occur even when blood bilirubin levels are only slightly or moderately elevated, without enzyme-bilirubin dissociation, with the liver dullness shrinking in half of the cases. All patients present with hepatic encephalopathy, with cases of coma all showing cerebral edema, and the survival rate of those with grade III or above coma is extremely low. The degree of hemorrhage is positively correlated with the depth of jaundice, with some cases developing disseminated intravascular coagulation (DIC). The prognosis is positively correlated with the depth of coma, the degree of hemorrhage, the stage of pregnancy, and the frequency of organ failure, and has no significant relationship with the depth of jaundice. Although the course of the disease is long for survivors, no manifestations of post-hepatitis cirrhosis have been observed.

　　(2) Subacute severe hepatitis:In addition to pregnant women, it also occurs in the elderly and other viral infection carriers, especially HBV, with a relatively slower progression than acute severe hepatitis. Jaundice is deeper than that in acute severe hepatitis and lasts longer, with a higher incidence of enzyme-bilirubin dissociation. Most patients do not show shrinkage of the liver dullness. In some cases, there is mild enlargement of the liver and spleen, which often occurs in patients with hepatitis B who are reinfected with HEV. Almost all cases can present with ascites, lower limb edema, and hypoproteinemia, with a lower incidence of hepatic encephalopathy. The course is long, and various complications can occur, with the frequency of organ failure being liver, coagulation system, central nervous system, and kidney in that order.

　　3. Cholestatic hepatitis E:The clinical manifestations are similar to those of hepatitis A cholestatic type, with a longer jaundice period, presenting with long-term intrahepatic obstructive jaundice, such as pruritus, lightening of fecal color, liver enlargement, and obstructive jaundice. Laboratory results show an increase in direct bilirubin, and imaging studies find no dilation of bile ducts inside and outside the liver. The prognosis is good.

　　4. Chronic hepatitis E:There is still no consensus on whether there is a chronic process in hepatitis E and whether there are chronic viral carriers.

　　5. Clinical characteristics of hepatitis E in different physiological stages

　　(1) Hepatitis E during pregnancy:Not only is the incidence high and prone to develop into severe conditions, but the disease progresses rapidly. Often, when jaundice has not yet reached severe liver stage, hepatic encephalopathy occurs. Half of the patients show liver shrinkage, and pathological examination of liver tissue shows that liver cells are mainly characterized by degeneration and swelling. The liver tissue after massive hemorrhage simultaneously presents with ischemia and hypoxia. It is prone to spontaneous abortion, preterm birth, stillbirth, and postpartum infection. The condition often deteriorates rapidly after delivery, with the main causes of death being cerebral edema, postpartum hemorrhage, hepatorenal syndrome, upper gastrointestinal hemorrhage, and cerebral hernia. During the progression to severe conditions, there is a successive decrease in factors I, V, and VII. Most cases have normal platelets and fibrinogen, with only a few cases developing disseminated intravascular coagulation (DIC).

　　(2) Pediatric hepatitis E:With the increase of age, the incidence rate gradually increases, and there are no reports of neonatal onset. Compared with adults, the incidence rate in children is low, and the mortality rate is also lower than that of adults. The onset is acute, the symptoms are mild, and a large number of respiratory symptoms are present in the early stage of onset (6.7% to 20.3%), and the proportion of splenomegaly is higher than that of adults. Although the majority of cases are jaundice (98.2%), the increase in jaundice is not as significant as that in adults, and the duration is longer, with the main change in liver function being the increase in ALT.

　　(3) Elderly hepatitis E:The incidence rate accounts for about 3% to 10.9% of the total number of cases, which is lower than that of adults and higher than that of children, and the onset is more concealed. The clinical manifestation is mainly jaundice, with a higher proportion of cholestatic hepatitis, deep jaundice, and a long duration. The course of the disease is relatively long, the recovery is slow, and the hospitalization time is about twice as long as that of adults. Severe hepatitis is relatively more common, higher than the adult group but lower than that of pregnant women, with more complications and prone to secondary infection. The prognosis is good, the mortality rate is low, and there are no reports of chronic transformation.

　　Hepatitis E virus is similar to hepatitis A in that comprehensive measures are mainly taken to cut off the transmission routes. To prevent waterborne transmission, it is mainly to protect water sources, manage feces to prevent contamination of water sources. Pay attention to food hygiene, improve sanitation facilities, and pay attention to personal hygiene. It is also very important to use different kitchenware for raw and cooked foods. Most reports show that the use of gamma immunoglobulin and human placental immunoglobulin for the prevention of hepatitis E is ineffective. Ultimately, it depends on vaccines, and the success of HEV molecular cloning has provided a foundation for vaccine development.

　　The basis for diagnosing hepatitis E virus is the etiological examination of serum, and the specific examination methods are described as follows.

　　1. Enzyme-linked immunosorbent assay (ELISA):It detects anti-HEVIgM in serum, which is an indicator for the diagnosis of acute hepatitis E.

　　2. Protein blotting test (Western Blot, WB):This method is more sensitive and specific than ELISA, but the operation method is more complex, and the time required for detection is longer.

　　3. Polymerase chain reaction(PCR):This method is used to detect HEV-RNA in the serum and feces of patients with hepatitis E, with high sensitivity and specificity. However, it is easy to cause false positives due to laboratory contamination during the operation process.

　　4. Immunoelectron microscopy technique (IEM) and immunofluorescence method(IF):This method is used to detect HEV particles and HEV antigens (HEAg) in the feces, bile, and liver tissue of patients with hepatitis E. However, both methods require special equipment and technology, and HEV exists for a short period of time in liver tissue, bile, and feces, with a low positive rate, and are not suitable as routine examinations.

　　Patients with Hepatitis E virus must be careful about food hygiene, wash hands before and after meals, and choose clean restaurants when eating out. Try to practice individual meals during group meals, and regularly disinfect tableware. Vegetables and fruits should be washed clean before eating, avoid eating food that has been stored for a long time, fresh food, and do not drink unboiled water, etc.

　　Sufficient high-quality protein can improve the body's immune function, increase liver glycogen storage, and is beneficial to the repair of liver cells and the recovery of liver function. However, since the increase in protein in the diet can increase blood ammonia, it is necessary to eat protein-rich foods with low ammonia production, such as dairy products.

　　Diet should be suitable for the patient's taste and easy to digest light food. It should contain a variety of vitamins, have enough calories and appropriate amounts of protein, and fat should not be restricted too strictly.

　　The treatment of Hepatitis E virus with strict bed rest is most important, and it is supplemented with medication. The specific treatment methods are described as follows.

　　Appropriate rest and reasonable nutrition are the main focus, with selective use of medication as a supplement. It is advisable to avoid alcohol, prevent overwork, and avoid using liver-damaging drugs. Medication should be simple rather than complicated.

　　Early bed rest is most important, and as the symptoms improve, the amount of activity can be gradually increased, with the principle of not feeling tired. Treatment continues until symptoms disappear, isolation period is over, and liver function is normal before discharge. After 1-3 months of rest, work can be gradually resumed.

　　Diet should be suitable for the patient's taste and easy to digest light food. It should contain a variety of vitamins, have enough calories and appropriate amounts of protein, and fat should not be restricted too strictly.

　　For those with little appetite or vomiting, 10% glucose solution 1000-1500ml should be added with 3g of vitamin C, 400mg of hepatoprotective, and 8-16U of regular insulin for intravenous drip, once a day. Energy supplements and 10% potassium chloride can also be added. For severe heat, Yu Chen Fei Lin decoction can be used with modifications; for both damp-heat, Yu Chen蒿汤 and Fei Lin combined formula can be used with modifications; for liver qi stagnation, use Xiaoyao Powder; for spleen deficiency and dampness, use Ping Wei Powder. Some advocate the use of red peony for deep jaundice, which is effective, and general acute hepatitis can be cured.