12. Acute viral hepatitis (aetiology, pathomorphology, complicated forms)
Written by ms. worldwide, edited by Nikolas.
Introduction
Viral hepatitis is the inflammation of the liver parenchyme due to viral infection. It’s mostly caused by the hepatitis viruses (A to E) but can be caused by EBV and CMV as well. These viruses cause acute hepatitis. If the acute hepatitis was caused by hepatitis B or C the infection can progress into chronic hepatitis.
Acute hepatitis presents with hepatic jaundice (with both conjugated and unconjugated bilirubin) with dark urine, fever, malaise and nausea. Liver enzymes (ALT and AST) will be elevated in the blood, and ALT will be higher than AST. By definition acute hepatitis lasts for less than 6 months. If the infection lasts for longer the condition has progressed into chronic hepatitis.
An infection from hepatitis viruses can result in a number of clinical syndromes:
- Asymptomatic acute infection where there is only serologic evidence
- Acute hepatitis
- Fulminant hepatitis – massive hepatic necrosis and liver failure
- Chronic hepatitis, which may progress into cirrhosis
- Chronic carrier state, where the disease is asymptomatic
The acute and chronic forms of hepatitis are distinguished in part by duration and in part by the pattern of cell injury. We will discuss the general changes that happen during an acute viral hepatitis.
The gross changes can be seen as an enlarged, reddened liver. The microscopic changes in the parenchyma are many:
- Ballooning degeneration of hepatocytes
- Necrosis of hepatocytes
- Loss of normal architecture in the liver
- Regenerative changes like hepatocyte proliferation
- Accumulation of phagocytosed cellular debris in Kupffer cells
- Infiltration of mononuclear cells like macrophages and monocytes
Acute hepatitis causes more necrosis and less inflammation than chronic hepatitis. The source of acute hepatitis can only be distinguished by serology, but they also differ in the way of transmission.
- Hep A (HAV) – fecal-oral transmission
- Hep B (HBV) – blood/body fluids
- Hep C (HCV) – blood/body fluids
- Hep D (HDV) – blood/body fluids
- Hep E (HEV) – fecal-oral transmission
Acute viral hepatitis resolves by itself usually, but Hep B and Hep C can Become Chronic. These are also the most important types.
Let’s take a closer look at all of them.
Hepatitis A and E
Hepatitis caused by hep A or hep E is usually a benign and self-limiting disease with an incubation time of 2 to 6 weeks. It cannot progress into chronic hepatitis or a carrier state either. They’re both spread by the faecal-oral route by ingestion of contaminated water or foods (like shellfish from contaminated water) and is mostly sporadic in developed countries. It may occur as waterborne epidemics in developing countries where people live in overcrowded, unsanitary conditions.
Recall from microbiology that HAV is a small, nonenveloped, single-stranded RNA virus belonging to the picorna family. The virus replicates in hepatocytes but is not toxic. The injury of the liver is more likely a result of T-cell mediated damage of infected hepatocytes.
Hepatitis E virus is a nonenveloped, single-stranded RNA hepevirus. The antigen specific for it, HEV Ag, can be detected during active infection. The diagnostic marker for HAV is anti-HAV IgM antibodies.
Symptoms of HAV and HEV are fever, nausea and vomiting during the 1-2 weeks, also called the pre-icteric phase. After 2 weeks the onset of the icteric phase begins, with jaundice, dark urine and pale stool.
Hepatitis E infection is only dangerous for pregnant women. Pregnant women with HEV infection can develop fulminant hepatitis, where the whole liver becomes necrotic and dies. This liver in this case will be called atrophia hepatis flava, or yellow liver atrophy. This can only be cured by liver transplant.
Hepatitis B
The HBV is a common viral infection worldwide which spreads via sex, blood, body fluids or vertically (mother-foetus transmission). The virus is tough and can withstand extreme temperatures and humidity. The HBV is a member of the Hepadnaviridae.
HBV infection causes acute hepatitis, and approximately 5-10% of these cases progress into chronic hepatitis (in adults, the numbers are much higher if infected as a child). The diagnosis of HBV is based on serology, where the levels of different antigens and antibodies are detected in the blood.
The hepatitis B virus has three antigens. HBsAg, HBeAg and HBcAg. These antigens and antibodies against them appear at different phases of the disease. The antibodies can be either IgG or IgM. Recall from immunology that IgM is the first antibody which appears in response to infection, while IgG appears later.
The table below shows the different antigens and their corresponding antibodies.
| HBV antigen | Description | Corresponding antibodies | |
|---|---|---|---|
| HBsAg | Surface antigen | Protein on the surface of the virus. | Anti-HBs. Indicates immunity to HBV due to resolved infection or vaccination |
| HBcAg | Core antigen | Protein of the capsule | Anti-HBc. IgM antibodies shows recent or ongoing infection. IgG shows resolved or chronic infection. |
| HBeAg | Envelope antigen | Protein secreted by the virus. Indicates viral replication and infectivity | Anti-HBe. |
HBsAg is the most important serological marker. It’s the first marker to increase during infection, and if it persists in the blood for more than 6 months, the disease has progressed into chronic hepatitis.
After exposure to the virus, the patient will progress through three phases.
- Incubation period
- Acute disease phase
- Convalescence (resolving)
During the end of the incubation period HBsAg appears in the serum. The patient starts to experience symptoms like nausea, fever and abdominal pain. This period can take 1-6 months.
During the acute disease phase icterus develops, and the condition is now acute hepatitis. In this phase HBsAg, HBeAg and IgM anti-HBc are present in the serum. The anti-HBc antibodies are fighting the virus in this stage.
During the convalescence phase all antigens will disappear from the blood, while IgG anti-HBs and anti-HBc remain. The presence of anti-HBs indicates that the person “won the battle” against the virus and is now immunized.
If the disease progresses into chronic hepatitis instead of the convalescence phase HBsAg and HBeAg will remain in the blood while there will be no anti-HBs.
| Period | HBsAg | HBeAg | Anti-HBs | Anti-HBc |
|---|---|---|---|---|
| Incubation period | ↑ | Ø | Ø | Ø |
| Acute disease | ↑ | ↑ | Ø | ↑, IgM |
| Convalescence | Ø | Ø | ↑ | ↑, IgG |
| Chronic infection | ↑ | ↑ | Ø | ↑, IgG |
Hepatitis C
Hepatitis C is also a major cause of liver disease, and the major route for transmission is through blood. Intravenous drug use with a previously used needle is the biggest sinner of hepatitis C transmission. This type of hepatitis can resolve by itself after an acute inflammation, but it progresses into chronic hepatitis in most cases. We will discuss the acute changes done by HCV.
HCV is a positive-sense single-stranded RNA virus belonging to the Flaviviridae. The virus’ genome varies very much and makes it hard to develop a vaccine.
Little is known about acute hepatitis C. The incubation time takes usually 6-12 weeks, and the onset of acute hepatitis C can be asymptomatic and easily missed. The RNA from the virus can be detected in the blood within days or weeks from infection, and elevations of serum aminotransferase can be seen as well. Although strong immune responses involving CD4+ and CD8+ cells, which is enough to make the infection self-limiting, only a minority of patients are capable of clearing the HCV infection after the acute hepatitis incidence.
Hepatitis D
The HDV is a unique virus because it can’t cause any infection without being capsulated by HBsAg. So even if the HDV is different from HBV, it can only cause infection during a HBV coinfection. You can get infected from HDV in two settings:
- Coinfection – being exposed to both HBV and HDV simultaneously. The HBV must establish first and make sufficient amounts of HBsAg before HDV can replicate.
- Superinfection – If you already have HBV and get infected by HDV. This will accelerate the hepatitis into a chronic hepatitis, in worst case into a fulminant hepatitis.
In acute coinfections, most patients can clear both the viruses and recover after the acute hepatitis.
In the western world, HDV is usually seen in drug addicts and people who receives blood transfusions.