| disease | Viral Hepatitis A |
| alias | Hepatitis A, HA, Viral Hepatitis A |
Hepatitis A is an acute infectious disease caused by the hepatitis A virus. It is distributed worldwide, with China being a high-prevalence area, where it ranks first among all types of hepatitis in terms of incidence. People infected with HAV can acquire long-lasting immunity and have a good prognosis.
bubble_chart Epidemiology
It is generally believed that there are no chronic carriers of hepatitis A virus, but in recent years, cases of acute hepatitis A with prolonged illness have been observed. During the late stage of the 1988 Shanghai hepatitis A epidemic, 1.5% to 18.5% of cases exhibited a sexually transmitted disease-like course. Sjogren et al. followed 256 cases of acute hepatitis A and found that 17 cases relapsed after clinical recovery, with anti-HAV IgM positivity and re-detection of hepatitis A virus (HAV) in stool. In rural areas, approximately 80% of 10-year-old children have been infected with HAV, whereas in some major cities, only 15% of 10-year-old children have immunity to HAV. The age of HAV infection has shifted later, leading to an increasing incidence of hepatitis A in adults. For example, during the 1988 outbreak in Shanghai, over 310,000 people were infected, with the 20–39 age group accounting for as high as 89.5% of cases.
In the fields of etiology and molecular biology, HAV is an RNA virus belonging to the Picornaviridae family. It was originally classified as enterovirus type 72 but is now considered to belong to a separate genus (Hepatovirus). This is because HAV exhibits the following characteristics: ① Hepatotropism; ② Long cell culture cycle, generally not causing cytopathic effects; ③ The virus resides intracellularly and is rarely released extracellularly; ④ Heat resistance, remaining infectious after 60℃ for 1 hour.
The HAV-RNA genome contains only 38% guanine and adenine nucleotides, significantly lower than other enteroviruses.HAV has been successfully cultured in vitro. It primarily replicates in liver parenchymal cells, and replication in other tissues has not been demonstrated. Currently, there is only one serotype and one antigen-antibody system.
Regarding HAV genotypes, in 1981, a portion of the HAV genome complementary DNA (cDNA) was cloned. The nucleotide sequence of wild-type HAV genomes has now been fully elucidated. The HAV genome (HAV-RNA) consists of three parts: ① The 5'-noncoding region, located at the front of the genome, is crucial for HAV replication; ② The coding region, i.e., the open reading frame (ORF), which encodes only one polyprotein; ③ The 3'-noncoding region, located after the ORF, has no function in encoding viral proteins. Based on its genomic sequence, HAV can be divided into seven genotypes. Human HAV can be classified into types I, II, III, and VII, with most being types I and III, and only a few strains being types II and VII. Simian HAV is divided into types IV, V, and VI. Several strains isolated in China share the same genotype. It is now known that HAV not only undergoes natural variation but can also be induced to produce genetic mutant strains through serial passage in animals or cell cultures.
Research on the mechanism of disease of hepatitis A is relatively limited and has not yet been fully elucidated. After oral infection with HAV, there is a brief viremic stage before the onset of illness, followed by localization in the liver. It was previously believed that HAV directly damages hepatocytes. However, recent studies have shown that neither hepatocytes in animals experimentally infected with HAV nor HAV-infected cell cultures in vitro exhibit cytopathic effects. Additionally, an increase in the CD+
bubble_chart Pathological Changes
The pathological features of hepatitis A are characterized by: primarily acute hepatitis lesions, but it can also cause cholestatic hepatitis and severe hepatitis. The main pathological changes are:
1. Hepatocyte degeneration and necrosis
The most common early manifestation is swelling of hepatocytes, presenting as ballooning degeneration, accompanied by eosinophilic changes and the formation of eosinophilic bodies in hepatocytes, leading to the disappearance of hepatic sinusoids and causing disarray in the arrangement of hepatocytes within the hepatic lobules. Hepatocytes around the central vein of the hepatic lobules undergo lytic necrosis.
2. Inflammatory cell infiltration can be observed in the portal area, mainly consisting of large mononuclear cells and lymphocytes.
3. Hyperplasia of Kupffer cells in the sinusoid wall
The above lesions are reversible and return to normal 1–2 months after jaundice subsides. The lesions in anicteric cases are similar to those in icteric cases but are less severe. For cholestatic hepatitis and severe hepatitis, refer to the relevant section on hepatitis B in Section 2.
The incubation period is 15 to 45 days (average 30 days). Clinically, it is classified into acute jaundice type, acute non-jaundice type, cholestatic type, subclinical type, and severe type. The entire course lasts 2 to 4 months.
I. Acute jaundice type
1. Pre-jaundice phase: The onset is sudden, with most patients experiencing fever and chills, with body temperature ranging between 38–39°C. The average fever duration is 3 days, with a few cases lasting up to 5 days. Symptoms include general weakness, loss of appetite, aversion to oily food, nausea, vomiting, a feeling of fullness in the upper abdomen, or grade I diarrhea. A few patients primarily exhibit symptoms of upper respiratory tract infection. The urine gradually darkens to a strong tea color. This phase lasts 5–7 days.
2. Jaundice phase: Subjective symptoms improve, and jaundice appears after the fever subsides. Yellowing of the sclera and skin to varying degrees can be observed, along with liver pain, hepatomegaly, tenderness, and percussion pain. Some patients may have splenomegaly. During this phase, stool may temporarily lighten in color, and cutaneous pruritus may occur. Liver function is markedly abnormal. This phase lasts 2–6 weeks.
3. Convalescence phase: Jaundice gradually fades, symptoms improve and eventually disappear, and the liver and spleen shrink back to normal size. Liver function gradually recovers. This phase lasts from 2 weeks to 4 months, averaging 1 month.
II. Acute non-jaundice type
Less common than the jaundice type. The onset is milder, with relatively mild clinical symptoms, including only weakness, loss of appetite, liver pain, and abdominal distension and fullness. Hepatomegaly is the main feature, while splenomegaly is rare. Recovery usually occurs within 3 months.
III. Cholestatic type
Previously called cholangiolitic hepatitis, it has now been proven that the primary lesion lies in the bile secretion mechanism of hepatocytes rather than the bile capillaries, so the original term is no longer used.
This type is a special manifestation of the jaundice type. Its clinical characteristics include milder gastrointestinal symptoms, longer fever duration, and prolonged intrahepatic obstructive jaundice (lasting weeks to months). Symptoms may include abdominal distension and fullness, cutaneous pruritus, transient lightening of stool color, dark urine resembling strong tea, hepatomegaly, and tenderness. It needs to be differentiated from other intra- and extrahepatic obstructive jaundice.
IV. Subclinical type
Some patients show no obvious clinical symptoms, but liver function exhibits grade I abnormalities.
V. Severe hepatitis
Relatively rare. The older the adult infected with HAV, the higher the proportion of severe hepatitis cases. Refer to the relevant section on hepatitis B in Section 2.
bubble_chart Auxiliary Examination
1. Routine Blood Test The total white blood cell count is normal or low, with a relative increase in lymphocytes. Atypical lymphocytes may occasionally be seen, generally not exceeding 10%.
2. Urinalysis In the late pre-jaundice stage, urobilinogen and bilirubin begin to test positive. During the jaundice stage, urinary bilirubin is positive, while urobilinogen decreases.
3. Liver Function Tests Include the following five items:
(1) Serum Enzyme Assay In the early pre-jaundice stage, serum alanine aminotransferase (ALT) begins to rise, while serum bilirubin increases toward the end of the pre-jaundice stage. The peak serum ALT occurs before the peak serum bilirubin and usually returns to normal 1 to several weeks after jaundice subsides. ALT measurement aids in the early diagnosis of hepatitis. Elevated ALT is nonspecific; only when ALT is more than twice the normal value, other causes are excluded, and combined with clinical manifestations and immunological dynamic observation, does it have diagnostic value. Acute anicteric and subclinical types are often characterized by isolated ALT elevation. Generally, the level of ALT in serum correlates with the degree of hepatocyte necrosis. In severe hepatitis, jaundice deepens rapidly while ALT decreases, showing a "bilirubin-enzyme dissociation," indicating massive hepatocyte necrosis. In cholestatic hepatitis, serum alkaline phosphatase (ALP) rises but not as significantly as in extrahepatic obstructive jaundice. Severe liver damage leads to a marked decrease in serum cholinesterase activity. Lactate dehydrogenase isoenzymes also have reference value.
(2) Pigment Metabolism Function Test
Commonly used tests include total bilirubin, direct bilirubin, and urine three-bile tests. In icteric cases, both total and direct bilirubin are elevated. Cholestatic types show more significant increases, accompanied by marked rises in ALP and γ-glutamyl transpeptidase (γ-GT). For anicteric types, indocyanine green (ICG) retention test or sulfobromophthalein sodium retention test may be used to aid diagnosis.
(3) Protein Metabolism Function Tests Thymol turbidity test and serum hyaluronic acid levels are elevated. Decreased serum albumin and increased globulin often indicate chronic active hepatitis or cirrhosis. Acute hepatitis usually shows normal levels.
(4) Others A prothrombin activity ≤40% is significant for diagnosing severe hepatitis, while ≤50% suggests a tendency toward severe hepatitis. Decreased serum cholesterol indicates critical illness, whereas elevated levels are seen in obstructive jaundice.
(5) Specific Serological Tests Detection of anti-HAV IgM is a key indicator for confirming hepatitis A and is the most reliable and sensitive diagnostic method. A positive anti-HAV IgM confirms current infection, while a negative result rules it out.
4. Imaging Studies B-mode ultrasound, CT, etc., help assess liver size and morphology, aiding in hepatitis diagnosis.
5. HAV Antigen-Antibody and HAV-RNA Detection
(1) Anti-HAV IgM The hepatitis A-specific antibody (anti-HAV IgM) appears early, often detectable within days of onset, peaks during the jaundice stage, declines in titer over 1–2 months, and mostly disappears by 3–4 months. It is a crucial marker for early hepatitis A diagnosis. Common methods include enzyme-linked immunosorbent assay (ELISA) and solid-phase radioimmunoassay (SPRIA), which are highly sensitive and specific. It is a routine test for acute hepatitis patients. False-positive anti-HAV IgM may occur in rheumatoid factor-positive samples and should be noted.
(2) Anti-HAV IgG When symptoms of acute hepatitis A appear, anti-HAV IgG can be detected in the serum. In the initial stage [first stage], the titer is low and gradually increases, peaking at 3 months after the onset of illness. It remains at a relatively high level for 1 year and can persist at a low level in the blood for decades or even a lifetime. If the anti-HAV IgG titer in paired sera shows a 4-fold or greater increase during the stage of convalescence, a diagnosis of hepatitis A can be made. However, since patients often seek medical attention late, early-stage serum samples are rarely obtained, and a 4-fold increase in antibody titer is rarely observed. Therefore, this diagnostic method is rarely used clinically. Anti-HAV IgG is primarily used for detecting population immunity levels in epidemiological surveys.
6. Immunoelectron Microscopy for HAV Particles The peak period of HAV excretion in feces of hepatitis A patients occurs mainly in the late incubation period and early acute phase. Therefore, collecting fecal samples during the prodromal phase or within the first week of illness can detect hepatitis A virus antigen (HAV Ag) as well as HAV particles. Since there is no chronic carrier state for HAV, the detection of HAV particles in feces confirms recent infection. However, the duration of HAV excretion in feces is relatively short. By the time a patient is diagnosed with hepatitis, some may have already stopped excreting the virus. Thus, the absence of HAV in feces at this stage does not rule out recent HAV infection. Due to the specialized conditions required for HAV detection, this method cannot be used as a routine test.
7. HAV-RNA Using cloned HAV cDNA fragments as probes, the cDNA-RNA molecular hybridization technique can detect HAV-RNA in the serum and feces of patients during the acute phase of hepatitis A. Since the introduction of the polymerase chain reaction (PCR) in clinical practice, a more sensitive method for detecting HAV-RNA has become available. The reverse transcription PCR (RT-PCR) method first converts HAV-RNA into cDNA using reverse transcriptase, followed by PCR amplification. A positive HAV-RNA result serves as direct evidence of acute HAV infection.
The diagnosis is mainly based on a comprehensive analysis of epidemiological data, clinical features, laboratory tests, and specific serological findings.
Attention should be paid to the season of onset, age, local prevalence of hepatitis A, history of close contact with hepatitis A patients, and individual or collective dietary hygiene conditions. Generally, the diagnosis of acute jaundiced hepatitis is not difficult, but in the pre-jaundice phase, it is easily misdiagnosed as a "common cold" or "acute gastroenteritis." Darkening of urine to a deep yellow color is an important clue to consider this disease. Anicteric and subclinical types are difficult to detect early and often rely on liver function tests and specific serological examinations for diagnosis. Chronic hepatitis is generally not considered for a hepatitis A diagnosis. Fulminant hepatitis caused by hepatitis A is very rare.
bubble_chart Treatment Measures
The treatment principles are as follows: prioritize adequate rest and proper nutrition, supplemented by selective use of medications. Alcohol should be avoided, overexertion prevented, and hepatotoxic drugs avoided. Medication use should adhere to the principle of simplicity rather than complexity.
1. Strict bed rest in the early stage is most important. Activity can be gradually increased as symptoms significantly improve, with the principle of avoiding fatigue. Treatment continues until symptoms disappear, the isolation period ends, and liver function normalizes, at which point the patient can be discharged. After 1–3 months of rest, the patient may gradually return to work.
2. The diet should consist of light, easily digestible foods that suit the patient’s taste. It should include a variety of vitamins, sufficient calories, and an appropriate amount of protein, with fat intake not overly restricted.
3. For patients with reduced food intake or vomiting, administer an intravenous drip of 10% glucose solution (1000–1500ml) with 3g of vitamin C, 400mg of glucurolactone, and 8–16U of regular insulin once daily. Energy合剂 (energy mixture) and 10% potassium chloride may also be added. For those with excessive heat, modified Yinchen Stomach Poria Decoction can be used; for those with dampness-heat predominance, modified Yinchenhao Decoction combined with Weiling Decoction; for liver qi depression, Peripatetic Powder; and for spleen deficiency with dampness retention, Stomach-Calming Powder. Some advocate the use of high doses of Red Peony Root for severe jaundice with good efficacy. Generally, acute hepatitis can be cured.
The prognosis of this disease is good, and it can be completely cured. There is no chronic progression, and liver failure is rare.
At least the following four items should be given due attention.
(1) Management of pestilence disease
Early detection and isolation of patients. The isolation period lasts for 3 weeks from the onset of the disease. After isolation, terminal disinfection should be carried out in the patient's living quarters and activity areas. If hepatitis A is detected in childcare institutions, close contacts should be placed under medical observation for 45 days.
(2) Cutting off transmission routes
Strengthen the management of water sources, diet, and feces. In particular, proper management of feces from hepatitis A patients can control the spread of hepatitis A. Shared tableware and drinking utensils should be disinfected, and a separate meal system should be implemented. Cultivate the good habit of washing hands before meals and after using the toilet.
(3) Protection of susceptible populations
For susceptible individuals who have had close contact with hepatitis A, human gamma globulin or human placental gamma globulin can be used for preventive injection, with a dosage of 0.02–0.05 ml/kg, preferably administered within 2 weeks after exposure. The fundamental measure to prevent hepatitis A outbreaks is the widespread vaccination. In China, human embryonic lung diploid cell culture has been used, with continuous low-temperature passage, to obtain the HAV H2 and LA-1 attenuated vaccine strains, and an attenuated live vaccine has been developed. Preliminary applications have proven its safety and ability to induce specific antibody production, but the production volume is limited and the cost is high. Abroad, inactivated HAV vaccines have been approved for widespread use. In China, research has been conducted on both inactivated vaccines and recombinant vaccines, and the development of genetically engineered hepatitis A vaccines is the future direction.
The differentiation from acute viral hepatitis B, C, D, and E relies primarily on specific serological tests, in addition to considering epidemiological data, history of blood transfusion and blood product use, and clinical features. For key points in distinguishing from other diseases, refer to the section on hepatitis B.
