Viral hepatitis: Pathology review

Definitions & Key takeaways

Viral hepatitis is defined as inflammation of the liver parenchyma and it is most commonly caused by hepatitis viruses A, B, C, D, and E. When a person is infected with a hepatitis virus, the virus targets and infects liver cells, leading to inflammation and damage to the liver tissue. This can result in a range of symptoms, including fatigue, nausea, abdominal pain, jaundice, and in severe cases, liver failure.

In acute viral hepatitis, the immune system responds to the infection by producing antibodies that help to clear the virus from the body. However, in some cases, the virus can persist and lead to chronic hepatitis, which can cause ongoing liver damage and increase the risk of cirrhosis and liver cancer.

The severity and course of the infection can vary depending on the specific virus involved, as well as other factors such as the individual's age, immune status, and underlying health conditions. Treatment options also vary depending on the virus and the severity of the infection and may include antiviral medications, supportive care, and in some cases, liver transplantation.

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Case Study0:00–1:30

At your clinic. 44 year old Colin comes to the office because of abdominal pain for the past three 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.
His temperature is 38.2 °C or 100.76 °F pulse is 98 eight per minute. Respirations are 19 per minute and BP is 1 26/84 millimeter of mercury.
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 per minute. Respirations are 15 per minute and BP is 1 20/75.
Mm. Both Colin and Megan have viral hepatitis which is inflammation of the liver parenchyma caused by hepatitis viruses.

Pathology1:30–4:14

ABCD or E based on the duration of symptoms, hepatitis can be acute which lasts less than six months chronic, which last more than six 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 nonspecific 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.
This is called ballooning degeneration. Second, there is 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. Lastly, there's pan lobular mononuclear infiltration where macrophages and lymphocytes move into the lobules in order to contain the infection and clear out the debris.
Ok. So each lobule can be divided into three zones, zone one is closest to the portal triad.
So it's also called the periportal zone. If we move towards the center, we have zone two or the transitional zone and closest to the central vein, we have zone three or the pericentral zone.
A high yield concept to remember is that viral hepatitis affects zone one first, ischemic injury and metabolic toxins, like those from alcohol and acetaminophen metabolism affect zone three first.
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 or serum ast is higher than at and the ratio is usually one to greater than 1.5.
So remember in viral hepatitis at is higher. The exception is when there's progression to advanced hepatic fibrosis and cirrhosis, the ast will then become higher than at.

Hepatitis A Virus4:14–6:20

Ok. 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 Picorna virus which is transmitted by the fecal oral root 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 HIV IgM antibody is produced early in the infection. So, if detected, it means there's an active infection.
The anti HIV IgG antibody is the protective antibody produced later on or even after the infection has passed and it suggests prior infection or vaccination.
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 is a complete recovery within 3 to 6 weeks. Finally, hepatitis A vaccine made from killed or inactivated HIV 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 HIV should be given to individuals who were in close contact with an infected person.
The second type is hepatitis E virus or H EV. Hepatitis E virus is a single stranded RNA virus that belongs to the Hepavis family.

Hepatitis E Virus6:20–8:00

It's transmitted by the fecal oral root such as undercooked seafood or contaminated water. And it can cause waterborne epidemics that are especially common in Asia and the Middle East.
Hepatitis E virus is characterized by its short incubation period and usually lasts for six weeks after the incubation period.
Individuals with hepatitis E virus infection typically present with a 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 at the early stages of infection. While the person is still asymptomatic, there is increased H ev antigen or H EV 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 H VI GM can be detected.
Remember that I GM indicate an active hepatitis infection. On the other hand, anti H VI GG are produced during the latest stage and they signal recovery from the infection.
Finally, the treatment for hepatitis E infection is supportive and there is currently no commonly used vaccine moving on to the third type, which is Hepatitis B virus or HBV.

Hepatitis B Virus8:00–18:05

This virus belongs to the DNA hep adenovirus 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 be antigen within the capsid.
There's a partially double stranded viral DNA and DNA polymerase enzyme which has DNA and RNA, a 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 to the cytoplasm of the cell where it's 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 is parenteral transmission or via blood and individuals who are at risk include intravenous drug users, healthcare workers exposed to blood and needlestick 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 breastmilk.
So, the second 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 transmits the infection to her infant, either right before the 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, pruritis 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.
Ok. 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 to 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.
Interferon alpha is used in the treatment of chronic Hepatitis B infection. Hepatitis B virus can also cause extrahepatic manifestations which can be subdivided into hematologic such as aplastic anemia renal, which includes 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 surface 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 indicates active viral replication.
On the other hand, hepatitis B core antibody can be I GM, which is associated with recent Hepatitis B infection typically in the last six months or I GG which suggests resolved or chronic infection.
Finally, the hepatis be antigen also suggests active viral replication. Elevated levels of this antigen are closely linked to poor prognosis and high transmissibility.
A high yield factor remember is that this is especially true for vertical transmission. On the other hand, antibody to hepatitis be antigen is present after recovery from acute infection and 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 mumps and on the top are phases of infection. First, there's the incubation period that lasts two months, which is followed by prodrome and acute infection that lasts for three months.
The last phase is the recovery phase. One month after exposure to the virus, hepatitis B surface antigen starts to rise and peaks when the symptoms are most severe.
Soon after Hepatitis B surface antigen rises. Hepatitis be antigen and viral DNA appear and they indicate that the person is highly infectious.
These markers are further followed by the appearance of IgM antibody to Hepatitis B core antigen. In the next few months.
These will go down and get replaced by IgG antibody for your exam. You have to know that the hepatitis be antigen and viral DNA disappear before the Hepatitis B surface antigen.
Shortly after hepatitis be antigen disappears. Antibody to hepatitis be antigen can be detected and at this stage, the person is no longer highly infectious.
After that hepatitis B surface antigen will also disappear. And the acute infection has passed antibodies to hepatitis B.
Surface antigen will go up sometime after these antibodies remain undetectable for several weeks. And this period of infection without detectable hepatitis B surface antigen and antibodies to Hepatitis B surface antigen is referred to as the window period.
This is high yield because it's possible to miss the infection based on serological markers during this period, once detectable antibody to hepatitis B surface antigen rises and persists providing lifelong immunity.
Finally, we need to mention that at the end of the incubation period and during the acute phase of the infection, a person will have elevated liver enzymes especially alt.
Also, you should not forget that if Hepatitis B surface antigen persists after six months, the person has progressed to chronic Hepatitis B infection.
OK. Let's summarize the serological markers during the phases of infection.
An individual with an acute Hepatitis B infection has the following serological markers. Hepatitis B surface antigen and IgM antibody to Hepatitis B core antigen.
Next, during the window period of hepatitis B infection, an individual is positive for hepatitis be antibody and IgM antibody to hepatitis B core antigen.
An individual with chronic Hepatitis B infection who is highly infectious will have hepatitis B surface antigen. Hepatitis be antigen and IgG antibody to hepatitis B core antigen.
On the other hand, if an individual has chronic Hepatitis B infection and a low infectivity, he will have hepatitis B surface antigen and IgG antibody to hepatitis B core antigen.
So remember only individuals who have been infected with hepatitis B virus will be positive for IgG to hepatitis B core antigen after clearing the infection or transitioning to chronic infection.
Finally, during the recovery period of Hepatitis B infection, a person has the following serologic markers, antibody to hepatitis B surface antigen.
Hepatitis be antibody and IgG antibody to hepatitis B core antigen. While immunized individuals have only IgG antibody to hepatitis B surface antigen.
Since the other components are not in the vaccine, moving on to Hepatitis D virus or H DV. This virus is a single stranded RNA virus and is most commonly transmitted parenterally.

Hepatitis D Virus18:05–19:38

Less common modes of transmission include sexual and perinatal transmission. For your exam.
You have to know that hepatitis D virus requires the Hepatitis B surface antigen to enter and infect hepatocytes. Therefore, the virus can be acquired either as a coinfection with Hepatitis B virus where both infections happen at the same time or as a superinfection of a chronic HBV carrier where the person is infected with HBV first and then later with HDV.
It's important to note that the superinfection of a chronic HBV carrier is associated with a worse prognosis and increased risk of liver cirrhosis.
The incubation period is short and the clinical presentation of Hepatitis D infection is similar to Hepatitis B infection.
Also, hepatitis D virus is associated with an increased risk of hepatocellular carcinoma. Liver biopsy is similar to Hepatitis B infection.
But if serology reveals either IgM or IgG H DV antibodies, this suggests that a person has an active infection since IgG is not considered to be a protective antibody in hepatitis D infection.
Finally, vaccination against Hepatitis B virus also protects against hepatitis D virus since it needs Hepatitis B surface antigen to infect hepatocytes.

Hepatitis C Virus19:38–25:04

The next one is hepatitis C virus or HCV. This virus belongs to the flaviviridae family of viruses and it's an enveloped single stranded RNA virus with icosahedral capsid symmetry.
A very high yield fact to remember is that it lacks the three prime five prime exonuclease enzyme activity. In other words, this virus is not capable of proofreading to correct errors made during viral replication.
Eventually, this leads to variations in the antigenic structure of its envelope proteins. Now, there are six or more genotypes and multiple sub genotypes of hepatitis C virus due to genetic mutations of the region that codes envelope proteins.
As a result, individuals with hepatitis C infection typically have several different subspecies of the hepatitis C virus in their blood.
And due to the continuous formation of new mutant strains of the virus, the host's immune system lags in the production of antibodies as a result, these individuals fail to develop an effective immune response against hepatitis C virus.
Now, this virus is mainly transmitted parenterally. And individuals who are at risk include intravenous drug users.
Healthcare workers exposed to blood and needle stick accidents, patients on dialysis and blood transfusion recipients. Hepatitis C virus can also be transmitted sexually and perinatally.
But these modes of transmission are less common. The long incubation period that lasts from two weeks to six months is followed by an acute or chronic hepatitis C infection.
Acute infection can present as asymptomatic infection or mild hepatitis that typically resolves within a few weeks. But for your exam, you have to know that the virus more commonly causes stable chronic infection which can further progress to cirrhosis or hepatocellular carcinoma.
Hepatitis C virus can also cause extrahepatic manifestations which can be subdivided into hematologic which include essential mixed cryoglobulinemia, immune thrombocytopenia, autoimmune hemolytic anemia and increased risk of B cell non hodgkin lymphoma, renal like membranoproliferative glomerulonephritis, which is more common and membranous glomerulonephritis, which is less common vascular, which include leukocytoclastic vasculitis, dermatologic such as sporadic porphyria, cutanea tardia and lichen planus.
And finally, endocrine which include increased risk of diabetes, mellitis and autoimmune hypothyroidism just like in hepatitis B.
Hepatitis C does have a carrier state. Now, the best screening test for hepatitis C infection is the HCV antibody test which detects antibodies to the Hepatitis C virus.
While the gold standard test for Hepatitis C infection is the HCV RNA test which reveals the level of circulating virus.
Individuals with resolved HEPA C infection are anti HCV positive and HCV RNA negative. In contrast to individuals with a chronic infection who are anti HCV positive and HCV RNA positive.
Also, individuals with a chronic infection have persistently elevated liver enzymes as far as histopathology goes. Hepatitis C infection is associated with lymphoid aggregates and focal areas of macrovesicular steatosis which is characterized by one or more lipid droplets within the cytoplasm that displace the nucleus to the periphery of the hepatocyte.
Another high yield topic is the treatment of HCV, which includes several medications. But for your exam, you have to know that none of them is approved as a monotherapy based on their mechanism of action.
These medications are subdivided into several groups. First, we have nonstructural protein, five A inhibitors which include Ledipasvir and ombitasvir.
These medications inhibit the viral nonstructural five A phosphoprotein, thereby preventing the replication of the viral RNA.
Their main side effects include headaches and diarrhea, moving on to nonstructural protein five B inhibitors which include sofosbuvir and dasabuvir.
These medications act as chain terminators and inhibit the viral RNA dependent RNA polymerase thereby preventing the replication of the viral RNA.
A common side effects of these medications include fatigue and headache. Next, we have the nonstructural protein, 34 A inhibitors which include simeprevir and grazoprevir.
These medications inhibit nonstructural 34 A protease and subsequently prevent viral replication. For your exam, you have to know that grazoprevir can cause photosensitivity reactions and rash.
While simeprevir can cause headaches and fatigue. The last medication you should know for your exam is ribavirin, which works by inhibiting the synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase.
Ribavirin is typically used as a supplementary medication of the therapy rather than the essential medication. Finally, hepatitis B and C infections can be treated with Interferon alpha.
All right, as a quick recap viral hepatitis is defined as inflammation of the liver parenchyma. And it's most commonly caused by hepatitis viruses.

Review25:04–27:28

ABCD. And E now, let's use this hepatitis worm to present the most common roots of transmission of each virus.
We write the letter A at the head, then BCD and finally, e at the tail, the two ends where the mouth and butt are have fecal oral root.
So that's HAV and H EV, everything else in between. So, HBV, HCV and H DV are most commonly transmitted parenterally but also sexually and perinatally.
Now, hepatitis A virus is an RNA picornavirus that has a short incubation period that typically lasts for 30 days. It can cause subclinical infection or acute hepatitis.
But the overall prognosis is good and there's no risk for hepatocellular carcinoma. Hepatitis B virus is a DNA Hepadnavirus that has a long incubation period from 30 to 180 days, which is followed by a prodrome and serum sickness like symptoms it can cause one of three syndromes, acute hepatitis with complete resolution, which is the most common outcome, chronic hepatitis with or without cirrhosis and hepatocellular carcinoma or fulminant hepatitis.
Hepatitis C virus is an RNA Flavivirus with a long incubation period from two weeks to six months. It can cause acute hepatitis, which can present as asymptotic infection or mild hepatitis or stable chronic hepatitis, which is more common and can progress to cirrhosis or hepatocellular carcinoma.
Hepatitis D virus is an RNA Delta virus that requires the Hepatitis B surface antigen to be infectious. Therefore, the virus can be acquired either as a coinfection with hepatitis B virus or as a more dangerous superinfection in a chronic HPV carrier.
Also, it's associated with an increased risk of hepatocellular carcinoma. Finally, the hepatitis E virus is an RNA hepavis with a short incubation period that usually lasts for six weeks.
In most individuals, it causes self limiting acute viral hepatitis and there's no risk for hepatocellular carcinoma. However, in pregnant individuals, this virus can cause life threatening fulminant hepatitis.
Now, let's go back to our case. Colin who came to the office because of abdominal pain for three months presented with a large distended abdomen, yellow sclera, palmar, erythema and spider angioma on his abdomen and extremities.

Summary27:28–29:06

The key to the diagnosis is in the lab results which revealed 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.
Now, since he has symptoms, we can narrow it down to either HCV or HPV infection or maybe both his history of IV drug use is a risk factor for both.
So that's no help. However, the lack of hepatitis B surface antigen means he doesn't have an active infection.
And the hepatis PSB surface antibody could be from a previous HBV infection that's resolved or he's been vaccinated against the virus.
So HCV infection is the most likely diagnosis. On the other hand, Megan, who came to the emergency department because of vomiting and fever presented with yellowing of the skin and sclera, right, upper quadrant tenderness and Hepatomegaly.
She worked as a global health nurse and she recently traveled to Nepal, which is an endemic area of he infections. Although hepatitis E infection is primarily a self-limiting disease.
Pregnant individuals like Megan can develop fulminant hepatitis. We can confirm the diagnosis by testing for IgM and IgG H ev antibodies in the serum.