Virology (BIOL 312) Module 6 Pt. 2

Heptitissss

What is the role of albuminin the context of bilirubin?

It binds to unconjugated (indirect) bilirubin in the blood and transports it to the liver, where the bilirubin will be taken up by hepatocytes

How is bilirubin conjugated?

After entering the hepatocyte, bilirubin is enzymatically bound to glucuronic acid, making it more soluble

What happens to conjugated (direct) bilirubin when the liver is functioning properly?

It travels down the bile duct, joins with the pancreatic duct, and ends up in the small intestine

Why is unconjugated (indirect) bilirubin in the blood increased?

The damaged hepatocytes are less efficient at conjugating the bilirubin to glucuronic acid, meaning unconjugated bilirubin backs up in the blood

Why does hepatitis cause conjugated (direct) bilirubin in the blood to increase?

While less conjugated (direct) bilirubin is being made, way more of it remains in the blood rather than being excreted because the damaged hepatocytes are unable to effectively transport it to the biliary system due to obstructed/ineffective transporters and less tight junctions between hepatocytes. This allows conjugated bilirubin to return to the blood stream rather than ending up in the small intestine

Hepatitis clinical manifestations

Fever, nausea, vomiting, jaundice, abdominal pain, hepatomegaly, dark urine, pale feces, encephalopathy

General lab features of hepatitis

• Liver biopsy showing inflammation and hepatocyte necrosis (and fibrosis if chronic)

• Blood containing ALT, LST, and elevated total bilirubin

How does alanine aminotransferase (ALT) in the blood indicate hepatitis?

ALT is an enzyme found within the cytoplasm of hepatocytes. If there is a significant amount present in the blood, it indicates hepatocyte damage, which is often caused by hepatitis

How does aspartate aminotransferase (AST) in the blood indicate hepatitis?

It is an enzyme found in many different types of cells (liver, heart, muscle, RBCs) and significant levels in the blood indicate cellular damage of some sort. Paired with elevated ALT, it signals hepatitis

Hepatitis A and E route of transmission

Fecal-oral

Which type of hepatitis is the most common?

HAV

What increases the risk of contracting HAV?

• Travelers (including international exchanges).
• Sexual practices that increase the fecal exposure.
• Drug users.
• Occupational risk for exposure.
• Homelessness.
• Close contacts of persons with HAV infection

Hepatitis A replication sites (primary and secondary, and how it travels)

Ingestion of fecal matter → primary replication in GI epithelium → travels through portal blood to liver → replicates in hepatocytes

HAV incubation period

25-30 days on average

Which types of hepatitis are acute?

A and E

Which types of hepatitis tend to be chronic?

B, C, and D

HAV-specific laboratory features

• Virus appears in blood early in infection, disappears in 2 weeks

• IgM peaks around 2 weeks after elevation of liver enzymes and then declines to non-detectable levels

• IgG appears early and persists for decades

Hepatitis A, D, and E treatment

None really, just supportive care. Can give IgG within 2 weeks of exposure as prophylaxis

Who is the HAV vaccine recommended for?

Travellers, children, high-risk groups

Which types of hepatitis can result in fulminant disease?

D and E (in pregnant peeps like 20% of the time)

Hepatitis B genome

• dsDNA (negative strand complete, positive strand is partial)

• Circular

Hepatitis A genome

(+)ssRNA

Hepatitis A envelope

Contains HBsAg (hepatitis A surface antigen) and lipid

Dane particles

Full, infectious HBV virions, containing genome

HBV S gene

Structural proteins: Makes different forms of HBsAg using three start points (S, preS1 (larger) and preS2)

HBV X protein

Acts as a regulatory protein to help the virus replicate

HBV P protein

Has 4 functions:

• DNA Polymerase

• Reverse transcriptase

• RNase H
  activity

• Tyrosine residue for primer activity

HBV C gene

• Encodes core proteins

• Makes HBcAg and HBeAg

HBV high-risk groups

Infants (vertical transmission), healthcare workers, IV drug users, and sexually active

HBV transmission

• Source: Blood and bodily fluids (e.g., semen, vaginal secretions).
• Mode of Transmission: Sexual contact, shared needles, mother-to-
child transmission during childbirth.
• Portal of Entry: Mucous membranes, bloodstream (via needlestick
injuries, blood transfusion, etc.

HBV incuation period

50-180 days

How often does HBV become chronic?

• In about 10% of adults

• In most infants

HBV diagnosis (acute infection)

• HBsAg: Indicates active infection

• IgM anti-HBc: Acute infection

• HBeAg: Active viral replication and high infectivity.

• HBV DNA: Used to assess viral load and monitor chronic infection

Which types of hepatitis most commonly cause cancer?

HBV and HCV

HBV treatment

• Acute Infection: Supportive care; no specific antiviral therapy.

• Chronic Infection: First-line antivirals: Pegylated interferon, tenofovir (NtRTIs), entecavir (nucleoside analogue)

HBV prevention

• Vaccination: Universal HBV vaccination (recombinant DNA derived vaccine)
  particularly for newborns and high-risk groups.

• Infection Control: Safe injection practices, blood screening, and sexual health
  education

Hepatitis C genome

(+)ssRNA

Which type of hepatitis is the most commonly chronc?

HCV

HCV transmission

• Vertical transmission (during pregnancy or delivery, 3-10%)

• Healthcare worker and those partaking in high-risk sexual activity (1%)

• IV drug use (about 80%)

• Transfusion recipients before 1987 (10%)

What percent of people with HCV develop chronic hepatitis?

70-90%

What percent of people with HCV develop hepatocellular carcinoma at some point?

1-5%

HCV clinical manifestation

• Usually clinically mild (minimal/moderate elevation of liver enzymes)

• Many people are asymptomatic.

• 20-30% have jaundice

• 10-20% have only non-specific symptoms (anorexia, malaise, abdominal pain)

HCV diagnosis

• Serologic assay

• Antibodies can be dtected at onset of symptoms in 50-70% of patients

Where does HCV replicate?

Only in hepatocytes

What was the historical standard treatment for chronic hepatitis C, and why is it no longer used?

Pegylated interferon-α + ribavirin was the historical standard. It relied on immune stimulation rather than viral targeting, required long treatment courses, had significant toxicity (flu-like symptoms, depression, anemia), and achieved modest cure rates (~40–50%). It has been replaced by direct-acting antivirals.

The three main classes of direct-acting antivirals used in HCV treatment and their targets

• NS3/4A protease inhibitors → block cleavage of the HCV polyprotein

• NS5A inhibitors → disrupt replication complex assembly and virion production

• NS5B RNA-dependent RNA polymerase inhibitors → block viral RNA synthesis (e.g. sofosbuvir)

Together, these directly inhibit viral replication

Why can’t chronic HBV be cured?

cccDNA persists in hepatocytes