Section 4: Hepatitis D

Section 4: Hepatitis D Hepatitis D, abbreviated as HDV, is a liver inflammatory disease caused by the hepatitis D virus, which was discovered by Italians in 1977. The hepatitis D virus is a defective RNA virus that can only infect humans when HBV infection is already present. The hepatitis D virus resides in the nucleus of hepatocytes and is encapsulated in the bloodstream by the hepatitis B surface antigen, forming particles with a diameter of 35–47 nm. When hepatitis B is complicated by hepatitis D virus infection, the condition often worsens, becomes chronic, and may even develop into fulminant hepatitis, making it an important issue in hepatitis prevention and control. The transmission route of the hepatitis D virus is the same as that of the hepatitis B virus, mainly through extra-intestinal routes. The occurrence of hepatitis D virus infection is related to injections, needle sticks, blood transfusions, or the use of blood products. Intravenous drug users, homosexuals, hemophiliacs, and patients undergoing dialysis are high-risk groups. Overcrowded living conditions, poor sanitation, open skin lesions, and mosquito bites can all promote the spread of the hepatitis D virus. Mother-to-infant transmission of the hepatitis D virus is relatively rare. Screening blood donors for HBsAg cannot completely rule out HDV infection, but it can reduce the likelihood; according to reports, if blood donors who test positive for HBsAg are excluded before transfusion, the risk of HDV transmission can be reduced to 1/3000. Wards for dialysis and kidney transplantation, due to frequent contact with blood, are also prone to transmission.
Hepatitis D does not have any special clinical features. There are two types of hepatitis D virus infection: co-infection with hepatitis B virus (also called superinfection) and re-infection with hepatitis D virus on the basis of chronic hepatitis B virus infection (called overlapping infection). Co-infection is often acute (self-limiting hepatitis), with a small number potentially developing into severe hepatitis or becoming chronic; overlapping infection mostly manifests as chronic hepatitis and cirrhosis, and may also lead to severe hepatitis.
Individuals who are simultaneously infected with hepatitis D virus and hepatitis B virus are called co-infected, with an incubation period of 4–20 weeks. Like typical acute hepatitis B, they exhibit symptoms such as fatigue, loss of appetite, dark urine, jaundice, abdominal pain, liver pain, and hepatomegaly. In these cases, liver lesions are mild, and HBsAg is often detected transiently in the serum, with only anti-HD-IgM being positive, resulting in a transient, self-limiting course. Therefore, hepatitis D virus infection is often missed. Such acute hepatitis is commonly seen after blood transfusions, use of blood products, and among intravenous drug users.
Individuals who are chronic hepatitis B virus carriers and then become co-infected with hepatitis D virus are called overlapping infected, which is more common than simultaneous infection. Although overlapping infection with hepatitis D virus can be asymptomatic, most cases exhibit more severe hepatitis symptoms than simultaneous infection, manifesting as acute exacerbations of chronic hepatitis or even fulminant hepatitis.
When any of the following situations occur, the possibility of hepatitis D should be considered: HBsAg carriers exhibit acute hepatitis-like symptoms or recurrent hepatitis attacks; acute hepatitis B shows biphasic transaminase elevation; chronic hepatitis B is active but without hepatitis B virus replication; existing hepatitis B is complicated by severe hepatitis or liver failure. The main diagnostic method is based on detecting HDV-RNA (viral ribonucleic acid), HDAg (hepatitis D antigen), anti-HDV-RNA, and determining HDAg and HDV-RNA in liver tissue. However, serological methods for detecting antigens and antibodies are the most common.
Section 5: Hepatitis E Hepatitis E, abbreviated as HEV, is an acute infectious disease caused by the hepatitis E virus, formerly known as non-A, non-B hepatitis. Since the 1980s, about 20 countries in Asia, Africa, and Latin America have reported outbreaks of this disease, and in 1986, southern Xinjiang in China experienced a hepatitis E epidemic. Its clinical manifestations are similar to those of hepatitis A, but hepatitis E is more likely to present with jaundice, commonly affecting young and middle-aged adults, and the incidence of severe hepatitis is higher than that of hepatitis A. Pregnant women are highly susceptible, the condition is more severe, and the mortality rate is higher. However, with timely treatment, the prognosis is relatively good.
In 1983, Soviet scholars first reported a particle of a non-A, non-B hepatitis virus, and later American scholars further studied it and found that this viral particle exists in the bile, feces, and hepatocytes of infected individuals or animals during the acute phase. Research shows that this viral particle is clearly different from the hepatitis A virus in both serological and morphological aspects, and it is a new hepatitis pathogen transmitted through the intestinal tract, hence the name hepatitis E virus (HEV). The prevalence of this disease is closely related to socioeconomic conditions, sanitary standards, and cultural level, and it occurs worldwide, especially in some developing countries in Asia and Africa. The disease has obvious seasonality, often occurring during the rainy season or after floods. The main source of infection is patient feces contaminating water sources or food. The main transmission routes are: ① Waterborne transmission, mainly caused by contamination of water sources by patient feces. Based on the epidemic situation, it can be divided into two types: one is short-term epidemic, where water sources are temporarily contaminated and the epidemic lasts for a few weeks; the other is long-term epidemic, where water sources are continuously contaminated. The epidemic can last for several months. ② Foodborne transmission, where patient feces (especially during the incubation period) contaminate food, causing localized epidemics. ③ Daily contact transmission, as this disease exhibits obvious familial clustering.
(1) This disease is most common among young and middle-aged adults, accounting for 70% of cases among those aged 15–39. The incidence rate among males is higher than that among females, with a ratio of 1.3–3.0:1. Pregnant women are highly susceptible, with more severe cases, higher rates of premature birth and stillbirth, and higher mortality rates among late-pregnancy patients. Due to different viral strains and varying virulence, the degree of lesion and clinical manifestations also differ. The onset of the disease is acute, and clinically it is divided into acute icteric type and non-icteric type. Similar to hepatitis A, symptoms include fatigue, loss of appetite, upper abdominal discomfort, dark urine, fever, joint pain, and skin itching. The course of the disease is generally 4–8 weeks. Patients with cholestasis may experience prolonged jaundice.
(2) Clinical manifestations and liver function of hepatitis E
It is indistinguishable from hepatitis A, and a definitive diagnosis is made mainly based on epidemiological data, fecal virus testing, and specific serological tests. For example, if anti-hepatitis E virus immunoglobulin M (anti-HEV-IgM) is positive during the acute phase, or if HEV particles are found in the patient's feces under electron microscopy during the acute phase, or if anti-hepatitis E virus antibodies (anti-HEV) are negative during the acute phase but positive during the recovery phase, a diagnosis of hepatitis E can be made. If it is not possible to perform the above specific serological tests, a serological exclusion method can be used: anyone whose serological tests do not match those of hepatitis A, B, or C, and whose hepatitis is ruled out as being caused by other factors, can be diagnosed as having hepatitis E. In areas with high incidence of hepatitis B, some patients with chronic hepatitis B may also be co-infected with hepatitis E, so when diagnosing hepatitis E, it is necessary to consider their past medical history and conduct relevant hepatitis B pathogen studies.

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Section 6: Hepatitis G Hepatitis G, abbreviated as HGV, was first isolated by American scholars in 1996 from the serum of chronic hepatitis patients. The genetic structure of the hepatitis G virus is similar to that of the hepatitis C virus. It has now become a hot topic in international liver disease research, but many questions remain unclear and require further in-depth study. Current research mainly focuses on the following aspects: ① Genetic typing of the virus and its role in hepatitis G; HGV infection is almost globally distributed, and has been found in Beijing and other places in China, with partial nucleotide sequence determination conducted. ② The role of HGV infection in the onset of viral hepatitis and its pathogenesis; acute HGV hepatitis often presents with moderate transaminase elevation and bilirubinemia, with clinical symptoms improving after the acute phase and not progressing to chronic, but viral replication may still persist. ③ Regarding the diagnosis of HGV, the main methods currently are RT-PCR (reverse transcription polymerase chain reaction) and ELISA (enzyme-linked immunosorbent assay). The former mainly measures HGV-RNA (i.e., HGV-RNA) in the serum, while the latter is used to detect antibodies in the serum, serving only as an indicator of infection. Due to differences in the antibodies used for coating, detecting different antibodies in the serum can also indicate recovery from infection.
Section 7: Diagnostic criteria for viral hepatitis These criteria were established in 1995 (Beijing) at the Fifth National Conference on Infectious and Parasitic Diseases.

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The revised standard for the prevention and treatment of viral hepatitis (trial implementation). Viral hepatitis presents with complex clinical manifestations; when making a diagnosis, it is crucial to avoid subjective and one-sided reliance on a single symptom or a single abnormality to confirm the diagnosis. Instead, a comprehensive analysis should be conducted based on epidemiological data, clinical symptoms, physical signs, and laboratory tests, combined with the patient's specific condition and dynamic changes, to ensure accurate differential diagnosis. Only after confirming the etiology through specific diagnostic tests can a definitive diagnosis be made.

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I. Clinical Diagnosis (1) Clinical Classification ① Acute hepatitis, which can be divided into acute non-jaundiced type and acute jaundiced type. ② Chronic hepatitis, which can be divided into mild, moderate, and severe types. ③ Severe hepatitis, which can be divided into acute severe hepatitis, subacute severe hepatitis, and chronic severe hepatitis. ④ Cholestatic hepatitis. ⑤ Post-hepatitis cirrhosis. (2) Diagnostic criteria for each clinical type

1. Acute Hepatitis (1) Acute non-jaundiced hepatitis. The diagnosis should be made comprehensively based on epidemiological data, symptoms, physical signs, laboratory tests, and etiological testing, while excluding other diseases. ① Epidemiological data: Close contact history refers to individuals who have shared meals, living quarters, daily activities, or frequent exposure to hepatitis virus-contaminated materials (such as blood or feces) with confirmed cases of viral hepatitis (especially during the acute phase), or those who have had unprotected sexual contact. Injection history refers to individuals who have received blood transfusions, blood products, poorly sterilized drug injections, immunizations, acupuncture treatments, etc., within the past six months. ② Symptoms refer to persistent symptoms lasting several days or more in the recent period that cannot be explained by other causes, such as fatigue, loss of appetite, and nausea. ③ Physical signs include hepatomegaly with tenderness, percussion pain over the liver area, and in some patients, mild splenomegaly. ④ Laboratory tests mainly indicate elevated serum ALT activity. ⑤ Positive etiological testing. If the laboratory test is positive and two out of the three criteria—epidemiological data, symptoms, and physical signs—are also positive, or if both the laboratory test and physical signs (or laboratory test and symptoms) are markedly positive, and other diseases have been ruled out, then a diagnosis of acute non-jaundiced hepatitis can be made. If only serum ALT is elevated, or if there are only symptoms and physical signs, or if there is only an epidemiological history plus one of items ②, ③, or ④, then these are considered suspected cases. Suspected cases should be monitored dynamically or diagnosed in conjunction with other examinations (including liver biopsy). If the etiological diagnosis of a suspected case is positive and other diseases have been excluded, then a definitive diagnosis can be made. (2) Acute jaundiced hepatitis. Anyone who meets the diagnostic criteria for acute non-jaundiced hepatitis and has a serum bilirubin level >17.1 μmol/L, or a positive urine bilirubin test, and whose jaundice is not caused by other factors, can be diagnosed as having acute jaundiced hepatitis.
2. Chronic Hepatitis Individuals with a prior history of hepatitis B, C, or D, or HBsAg carriage, or those who have had acute hepatitis for more than six months and still exhibit hepatitis symptoms, physical signs, and abnormal liver function tests can be diagnosed as having chronic hepatitis. If the onset date is unknown, or even without a history of hepatitis, but imaging, laparoscopy, or liver biopsy pathology shows changes consistent with chronic hepatitis, or if a comprehensive analysis of symptoms, physical signs, and laboratory tests leads to a corresponding diagnosis, then chronic hepatitis can also be diagnosed. To reflect the degree of liver damage, clinical classification can be divided into: ① Mild (equivalent to original CPH or mild CAH). The condition is relatively mild, with inconspicuous symptoms, or although symptoms and physical signs are present, only one or two biochemical indicators show mild abnormalities. ② Moderate (equivalent to original medium CAH). Symptoms, physical signs, and laboratory tests fall between mild and severe. ③ Severe. There are obvious or persistent hepatitis symptoms such as fatigue, poor appetite, abdominal distension, and loose stools. Patients may also exhibit hepatic facies, palmar erythema, spider angiomas, or hepatosplenomegaly, provided that other causes have been ruled out and there is no portal hypertension. Laboratory tests show recurrent or sustained elevation of serum ALT, decreased albumin, abnormal A/G ratio, or significant increase in gamma globulin. If any one of the following conditions is met—albumin ≤32 g/L, bilirubin >85.5 μmol/L, or prothrombin activity 40%–60%—then a diagnosis of severe chronic hepatitis can be made. Currently, there is a lack of indicators that can reflect the degree of liver fibrosis. Tests such as serum hyaluronic acid (HA), procollagen type III peptide (PⅢP), type IV collagen (IV-C), laminin (LN), and prolyl peptidase (PCD) can reflect the state of collagen synthesis. Institutions with the necessary resources can actively conduct these tests and, based on the degree of abnormalities, combine them with pathological findings to determine the mild, moderate, or severe degree of fibrosis in chronic hepatitis (see appendix). 3. Severe Hepatitis (1) Acute severe hepatitis. Within 10 days of the onset of acute jaundiced hepatitis, if patients rapidly develop neuropsychiatric symptoms (classified according to V degree, with hepatic encephalopathy at II degree or above), prothrombin activity drops below 40% and other causes are ruled out, while the patient often exhibits progressive reduction of the dullness border of the liver, rapid deepening of jaundice, and obvious abnormalities in liver function (especially serum bilirubin >17.1 μmol/L), then special attention should be paid to prodromal symptoms of coma (abnormal behavior, personality changes, consciousness disturbance, psychiatric abnormalities) to enable early diagnosis. Therefore, if patients with acute jaundiced hepatitis experience severe gastrointestinal symptoms (such as loss of appetite, frequent vomiting, abdominal distension, or hiccups), extreme fatigue, and simultaneously exhibit prodromal symptoms of coma, then this disease should be considered. Even if the jaundice is very mild or has not yet appeared, but the patient presents with the aforementioned symptoms, this disease should also be considered. Appendix: Reference Indicators for Abnormalities in Laboratory Tests