AssessmentsViral hepatitis: Pathology review
USMLE® Step 1 style questions USMLE
A 54-year-old man presents to an infectious disease specialist for follow-up regarding a new diagnosis of hepatitis C. He was diagnosed with chronic hepatitis C several weeks ago after he presented with malaise, fatigue, and elevated liver enzymes. He is a healthcare provider and thinks he may have contracted the disease via an accidental needlestick injury several years ago. He was initially prescribed medications to help treat the disease. His viral titer at today’s visit remains high, and his physician subsequently prescribes an additional medication that works by preventing viral maturation through inhibition of protein synthesis. Which of the following is the most likely side effect of the aforementioned medication used to treat this patient’s condition?
Contributors:Elizabeth Nixon-Shapiro, MSMI, CMI, Jennifer Montague, PhD, Alex Aranda, Marisa Pedron, Filip Vasiljević, MD
At your clinic, 44-year-old Colin comes to the office because of abdominal pain for 3 months.
He has not been to a physician in 10 years and has been using IV drugs since he was 17.
He does not drink alcohol and has no significant family history.
Physical examination shows a large distended abdomen, yellow sclera, palmar erythema, and spider angioma on his abdomen and extremities.
Lab results reveal the following: Hepatitis A IgM antibody negative, Hepatitis B surface antigen negative, Hepatitis B surface antibody positive, Hepatitis B core antibody negative, and HCV antibody positive.
At the same time, a 32-year-old pregnant individual named Megan comes to the emergency department because of vomiting and fever.
The patient worked as a global health nurse and her medical history is relevant for recent traveling to Nepal.
Physical examination shows yellowing of the skin and sclera, right upper quadrant tenderness, and hepatomegaly.
Her temperature is 38.5°C or 101.3°F, pulse is 97/min, respirations are 15/min, and blood pressure is 120/75 mmHg.
Based on the duration of symptoms, hepatitis can be acute, which lasts less than 6 months, or chronic, which lasts more than 6 months.
Individuals with acute viral hepatitis typically present with fatigue, malaise, nausea, vomiting, anorexia, low-grade fever, jaundice, dark urine, and right upper quadrant tenderness; whereas individuals with chronic viral hepatitis can be asymptomatic or they can present with non-specific symptoms such as malaise and fatigue.
Regardless of the virus that’s causing it, histopathology of viral hepatitis is characterized by two main findings: first, there’s hepatocyte injury where the damaged hepatocytes swell up, and this is called ballooning degeneration; second, there’s hepatocyte death and necrosis.
The dead cells are replaced by scar tissue which disrupts the normal architecture of hepatic lobules.
If the damage is severe enough, dead hepatocytes can become confluent and form stripes that connect zones of adjacent lobules, which is called bridging necrosis.
Other histopathological findings include Councilman, or apoptotic bodies, which are dying eosinophilic hepatocytes surrounded by normal liver parenchyma.
Lastly, there’s panlobular mononuclear infiltration, where macrophages and lymphocytes move into the lobules in order to contain the infection and clear out the debris.
Okay, so each lobule can be divided into 3 zones.
Zone I is closest to the portal triad, so it’s also called the periportal zone.
If we move towards the center, we have zone II, or the transitional zone, and closest to the central vein, we have zone III, or pericentral zone.
As far as laboratory findings go, viral hepatitis is associated with increased levels of serum aspartate transaminase, or AST, and alanine aminotransferase, or ALT.
It’s important to note that in viral hepatitis, drug-induced liver injury, and ischemic hepatitis, levels of serum ALT are higher than AST, in contrast to alcoholic hepatitis, where serum AST is higher than ALT and the ratio is usually 1 to >1.5.
So remember, in virAL hepatitis, ALT is higher!
The exception is when there’s progression to advanced hepatic fibrosis and cirrhosis, the AST will become higher than ALT.
Okay, now let’s focus on the specific viruses, starting with hepatitis A and hepatitis E viruses.
These viruses are naked viruses that do not rely on an envelope.
Hepatitis A virus, or HAV, is an RNA picornavirus which is transmitted by the fecal-oral route, through ingestion of contaminated water or food, such as shellfish.
It’s the most common cause of acute viral hepatitis and populations at risk include travelers and those in daycare centers.
The incubation period, which typically lasts for 30 days, can be followed by a silent, or subclinical course, which is characterized by the absence of symptoms; or by the classic presentation of acute viral hepatitis, along with hepatomegaly, and aversion to smoking.
Also, keep in mind that hepatitis A infection is a self-limiting disease that does not progress to chronic hepatitis; therefore the prognosis is usually good and there’s no risk of cirrhosis or hepatocellular carcinoma.
A high yield concept to know is that the anti-HAV IgM antibody is produced early in the infection, so if detected, it means there’s an active infection.
Also, hepatitis A virus does not have a carrier state where infected individuals do not have symptoms, but can spread the infection to others.
Treatment is supportive and generally, there’s complete recovery within 3-6 weeks.
Finally, hepatitis A vaccine, made from killed, or inactivated HAV, is indicated for people traveling to, living, or working in endemic areas; individuals with chronic liver disease or clotting-factor disorders; and men who have sex with other men.
On the other hand, passive immunization with immune globulin against HAV should be given to individuals that were in close contact with an infected person.
The second type is hepatitis E virus, or HEV.
Hepatitis E virus is a single-stranded RNA virus that belongs to the hepevirus family.
It is transmitted by the fecal-oral route, such as undercooked seafood or contaminated water and it can cause waterborne epidemics that are especially common in Asia, Africa, and the Middle east.
Hepatitis E virus is characterized by its short incubation period and usually lasts for 6 weeks.
After the incubation period, individuals with hepatitis E virus infection typically present with the classic presentation of acute viral hepatitis, and during this period they shed the virus in the stool.
Just like hepatitis A, hepatitis E infection is also a self-limiting disease that does not progress to chronic hepatitis; therefore there’s no risk of hepatocellular carcinoma.
Also, you have to know that in pregnant individuals, this virus can cause fulminant hepatitis, which is a life-threatening condition with severe liver function impairment.
As far as serology markers go, early stages of infection, while the person is still asymptomatic, there’s increased HEV Antigen or HEV RNA.
When symptoms appear, there’s an increase in serum levels of ALT and AST because the liver gets damaged, and this is the stage when anti-HEV IgM can be detected.
Remember that IgM indicate an active hepatitis infection!
On the other hand, anti-HEV IgG are produced during the latest stage and they signal recovery from the infection.
Finally, the treatment for hepatitis E infection is supportive and there are currently no commonly used vaccine.
Moving on to the third type, which is hepatitis B virus or HBV.
This virus belongs to the DNA hepadnavirus family.
On the surface of the mature virion, there’s a lipid envelope with hepatitis B surface antigen.
Within the envelope, there’s a hexagonal protein capsid, which consists of proteins called hepatitis B core antigen or just core antigen.
Between the lipid envelope and capsid is a secretory hepatitis B e antigen.
Within the capsid, there’s a partially double-stranded viral DNA and DNA polymerase enzyme, which has DNA- and RNA-dependent activity.
Now, once the virion enters the cell, the viral DNA is transferred into the nucleus of the hepatocyte where DNA polymerase turns the partially double-stranded DNA into a fully double-stranded circular DNA.
Next, the host RNA polymerase transcribes the newly formed DNA to make viral RNA, which is sent into the cytoplasm of the cell where its used to synthesize viral proteins.
But that’s not all!
You have to know that the DNA polymerase then reverse transcribes the viral RNA into a new partially double-stranded DNA molecule, and this will be packaged together with the newly synthesized viral proteins to make a new virus.
Now, hepatitis B virus has several modes of transmission.
First, there’s parenteral transmission, or via blood; and individuals that are at risk include intravenous drug users, healthcare workers exposed to blood and needle-stick accidents, patients on dialysis, and blood transfusion recipients.
But remember, even though blood is the primary mode of transmission, hepatitis B virus can also be detected in other bodily fluids such as saliva, tears, sweat, semen, and breast milk.
So the 2nd route is sexual transmission, and together with parenteral, they are categorized as horizontal transmission.
The third type is perinatal transmission which is categorized as vertical transmission, and this is when a mother transmit the infection to her infant either right before birth via the placenta, or during and after birth via blood, body fluids, or breast milk.
So, once a person is infected, they will go through a long incubation period that can last from 30 to 180 days.
The incubation period is usually followed by a prodrome period which is characterized by malaise, fever, arthralgias, lymphadenopathy, pruritus, and rash.
Now after the prodrome the individual can develop acute hepatitis with complete resolution.
On the other hand, some people will develop chronic hepatitis, with or without cirrhosis.
In this case, they might be in the carrier state where damage to the liver stops, but they can still spread the infection to others.
Finally, they can also develop fulminant hepatitis, which is characterized by rapid and massive necrosis of liver parenchyma and subsequent liver atrophy.
Okay, so a high yield concept is that in adults, the possibility to progress to chronic hepatitis is less than 5%; in children, it is 20-30%; while in neonates this number goes up to 90%.
Therefore, a baby born to a mother with active hepatitis B infection has to receive anti-hepatitis B immunoglobulin and the initial dose of the hepatitis B vaccine.
Hepatitis B vaccine is a subunit vaccine, meaning that it contains a hepatitis B surface antigen, which stimulates the production of antibodies against this antigen.
Hepatitis B virus can also cause extrahepatic manifestations which can be subdivided into: hematologic, such as aplastic anemia; renal, which include membranous glomerulonephritis, which is more common, and membranoproliferative glomerulonephritis, which is less common; and vascular, such as polyarteritis nodosa.
Now, histopathology of an individual with chronic hepatitis B infection shows a granular eosinophilic “ground glass” appearance which is the hallmark of chronic hepatitis B infection.
This “Ground glass” appearance occurs when the cytoplasm of hepatocytes gets filled with bits and pieces of hepatitis B viral proteins.
It’s important to note that the virus itself is not cytotoxic.
Instead, the liver is damaged by the response of cytotoxic T-cells to antigens that are presented on infected hepatocytes, such as hepatitis B surface antigen and hepatitis B core antigen.
Now let’s move on to serological markers which are super high yield!
Let’s start with a hepatitis B surface antigen which indicates active hepatitis B infection; and hepatitis B surfatzce antibody, which suggests recovery from infection or immunity due to vaccination.
Next, there's hepatitis B core antigen which can only be detected after liver biopsy and if positive, it indicates active viral replication.
On the other hand, hepatitis B core antibody can be IgM, which is associated with recent hepatitis B infection, typically in the last 6 months; or IgG, which suggests resolved or chronic infection.
Finally, the hepatitis B e antigen also suggests active viral replication.
Elevated levels of this antigen is closely linked to poor prognosis, and high transmissibility.
A high yield fact to remember is that this is especially true for vertical transmission!
On the other hand, antibody to hepatitis B e antigen is present after recovery from acute infection and it is associated with low transmissibility.
Now let’s draw a graph of the serological markers in acute hepatitis B infection.
The vertical axis of the graph is the relative concentrations of serological markers; the horizontal axis of the graph is time after exposure measured in months; and on the top are phases of infection.
First, there’s the incubation period that lasts 2 months; which is followed by prodrome and acute infection that lasts for 3 months.
The last phase is the recovery phase.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "Rosen's Emergency Medicine - Concepts and Clinical Practice E-Book" Elsevier Health Sciences (2013)
- "Extrahepatic manifestations of chronic hepatitis C virus infection" Therapeutic Advances in Infectious Disease (2015)
- "Hepatitis C" Human Vaccines & Immunotherapeutics (2013)
- "Hepatitis E" New England Journal of Medicine (2012)