Outline For Hepatitis Notes

1. Introduction – Hepatitis in Malaysia.

2. Causes of hepatitis
o Viral
o Drugs and toxins
▪ Alcoholic liver diseases (metabolic consequences of ethanol ingestion)
o Metabolic
o Autoimmune
3. Mechanism of liver injury and repair
o Hepatocyte and parenchymal response
o Scar formation and regression (cirrhosis)
o Inflammation and immunity
4. Portal hypertension
5. Liver failure
o Acute liver failure
o Chronic liver failure and cirrhosis
o Acute on chronic liver failure
o Sudden functional loss without evidence of morphological changes

Hepatitis in Malaysia
Hepatitis A Hepatitis B
• Hepatitis A has been • Hepatitis B is moderately
reportable since 1988. prevalent (1.5-9.8%).
• Government control • Transmission is often
programs reduced incidence. mother-to-fetus.
• About 50% of young • 1 million have chronic
Malaysians lack hepatitis A hepatitis B.
antibodies. • 75% of viral cases are
• prevented by reinforcing the hepatitis B, mostly in males.
hygiene status of the general • Chronic hepatitis B leads to
population most liver cancer cases.
• Hepatitis B vaccination
lowered prevalence to
0.01%.
Hepatitis C
• Hepatitis C is growing;
453,700 infected in 2009
(2.5% of 15-64 population).
• 59% got infected through
injections.
• HCV burden is high and will
rise without better treatment
and prevention.

Causes of hepatitis
1. Infections
a. Virus – hepatotropic – common
b. Other infectious organism – other viruses, bacterial, parasitic or helminthic - rare
2. Drugs and toxin induced – eg. Alcohol
3. Metabolic
4. Autoimmune

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Clinical outcomes vary according to
the types of hepatitis viruses, and
these include

1. Full recovery (usual outcome)

2. Chronic progression over the
years leading to cirrhosis.
3. Risk of hepatocellular
carcinoma (HCC).

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 a) Causes of hepatitis: Viral
HEP B HEP C HEP D
Clinical a) Asymptomatic a) Acute HCV infection is generally -
manifestation b) Subclinical infection (70%) asymptomatic
• Usual viral “prodrome”, malaise, lethargy, b) Less common than Hep B
• Nausea, fever etc.
• Upper respiratory tract infection.
c) Symptomatic hepatitis (30%)
• Jaundice, dark urine, stool chalky.
• Acute fulminant severe hepatitis (liver failure) (0.10-0.5%).

Serum - -

Transmission Varies according to geographic areas. Major route of transmissions are inoculation Groups at risks:
Usually and blood transfusion. • IVDU
• IVDU • IVDU-60% • Hemophiliacs
• Homosexual activity • Hemodialysis patients and health • Homosexuals
• Needle stick accidents among health care workers care workers- less than 5% • Health care workers
• Transfusion of blood and blood products • Sexual transmission-presumed risk
• Contact with body secretions through minor breaks in skin factors in 15%
and mucous membranes. • Perinatal transmission-6% of births
(from infected mothers)
high prevalence regions (eg. Africa, Asia) • Transfusion prior to 1991- 10%
• infected mother to a neonate during childbirth (vertical
transmission) is common.
• The majority of infections are contracted postnatally or
• perinatally.
• Carrier state → defined as presence of HBs Ag in the serum
for 6 months or longer after the initial detection.

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 Phases of
Phase 1: Early Infection
Phase 1: Early Infection
• The virus infects liver cells (hepatocytes).
• HBs Ag (Hepatitis B surface antigen) appears before symptoms and
peaks during disease.
• HBsAg levels decline after disease onset and become undetectable
within 24 weeks.
• Anti-HBs antibodies do not increase until after the acute disease is
over.
• HBeAg and HBV DNA appear after HBsAg, indicating active viral
replication and high infectivity.
• Liver shows minimal changes at this stage.
Phase 2: Acute Infection
1. Anti-HBe antibodies appear, signaling the peak of acute infection.
Phase 2: Acute Infection
2. Liver enzymes (ALT levels) increase due to infected hepatocyte
breakdown.
3. This phase lasts for months to years, based on immune system
efficiency.
4. Persistent HBe Ag progression to chronic disease.
5. Severe chronic hepatitis is seen histologically.
6. Patient's outcome depends on the liver injury's duration and
severity in this stage.
7. IgM anti-HBcore is detectable before symptom onset, along with
elevated liver enzymes.
8. IgM anti-HBcore is replaced by IgG anti-HBcore.
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1. Virus Entering Liver Cells: At the beginning, the virus goes into the liver
cells (hepatocytes), like sneaking into a house.
2. HBsAg Shows Up: Something called HBsAg (like a flag for the virus)
appears first, even before you feel sick. It gets really high when you're
sick.
3. Flag Goes Away: The HBsAg flag starts to go down after you start feeling
sick, and in about 24 weeks (like 6 months), it's gone completely.
4. Good Soldiers Arrive Late: Special soldiers called anti-HBs antibodies
come after you've already gotten better from being sick. They're a bit late
to the party.
5. Virus Replicates: The virus starts making copies of itself actively, which is
like making lots of copies of a book to share with others.
6. Liver Looks Mostly Okay: Your liver doesn't change much in how it looks
during this time. It's like your room staying tidy even though there's a
little party going on inside.
1. Soldiers Change: The anti-HBe soldiers show up now, signaling that the
worst part of the infection is happening.
2. Liver Enzymes Rise: The liver starts releasing more enzymes (like little
workers) because some of its cells are being damaged. It's like workers
cleaning up a mess after a big party.
3. Long Party: This phase can last for a few months to even a few years. It's
like the virus having a party in your liver that takes a while to finish.
4. Chronic Disease Warning: If one particular type of flag (HBeAg) stays
around, it could mean the party is getting out of hand and might continue
for a long time, which is not good.
5. Liver Gets Hurt: Your liver can get hurt pretty bad during this time. It's like
your room getting messy after a big, wild party.
6. Future Depends on Liver: How you feel later on depends on how bad the
liver got hurt during this time.
7. Different Soldiers Arrive: At first, you have one type of soldier (IgM anti-
HBcore) that appears when you're about to feel sick. Then, another type
of soldier (IgG anti-HBcore) takes over after you're better, like changing
guards.
 Pathogenesis Persistent HBV infection • Majority of infected individuals a) Causes infection only when it is
Characterized by inefficient CD4+(helper) T cell priming early in the infection progress to chronic disease. encapsulated by HBs Ag.
and subsequent development of ineffective CD8+(cytotoxic) T cell response • Effort to develop vaccine has c) Arises in two settings:
with viral persistence contributed by been unsuccessful due to 1. Acute coinfection
• immunological tolerance genomic 2. Superinfection of a
• mutational epitope inactivation • instability and antigenic chronic carrier of HBV
• T-cell receptor antagonism variability. with a new inoculum of
• incomplete down-regulation of viral replication and infection. HDV
• (Overall effect: virus evade/escape the immune response) d) Rarely develop chronicity.

This is characterized morphologically by

• Chronic liver cell injury.
• Regeneration.
• Inflammation with widespread DNA damage.
• Insertional deregulation of cellular growth control genes.
Morphological Initial changes - -
Changes • Inflammation of the liver → hepatocytes enlargement → oedema,
inflammatory infiltrate.
• Hepatocytes necrosis and apoptosis

Chronic ongoing changes

• Damage to hepatocytes with reparative and regenerative process
→ fibrosis, regenerative nodules, loss of normal architecture →
some will eventually become cirrhotic

Complications chronic hepatitis B (as persistence of the infection for > 6 months) Majority of infected individuals progress to Rarely develop chronicity
• 10% chronic hepatitis chronic disease
• liver cirrhosis
• 15-40% complication of Hepatocellular carcinoma

Treatment HBV vaccine and screening of blood donation - -

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 HEP A HEP E
Clinical - -
manifestation
Serum - -
Transmission Endemic in countries with substandard hygiene and sanitation. Enterically transmitted, waterborne infection.
• Occurs as outbreaks in schools and nurseries.
• consumption of raw or steamed shellfish (cockles, oysters, muscles
and clams).

Hepatitis A vaccination is recommended for certain high risk groups and

include
• People travelling internationally (countries with increase rate of
HAV).
• Peoples in high risk profession, e.g. health care
• Peoples engaged in high risk behavior e.g. IVDU and non injection
illegal drugs.
• Care providers in childcare or institutional facilities.
• Persons with chronic liver disease.
Phases of - A self-limiting disease, usually resolve in 2-4
weeks.
Pathogenesis - -
Morphological - -
Changes
Complications • Does not cause chronic hepatitis and carrier State • high mortality rate among pregnant
• Can cause fulminant hepatitis (acute liver failure). (Rare) women (20%).
• Not associated with chronic liver
disease or persistent viraemia.
Treatment • Immunization with hepatitis A vaccine can effectively prevent • A vaccine to prevent hepatitis E
hepatitis A infection. It gives virus infection has been developed
• about 12 months protection after the first dose and is licensed in China
• and about 5 years after the second dose (for children) and 10 years
for adult.

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 INFECTIOUS HEPATITIS NON-INFECTIOUS HEPATITIS
Infectious mononucleosis (EBV) • Drugs and toxin – eg: alcoholic hepatitis
• Cytomegalovirus (CMV) o NSAIDS
• Yellow fever o Birth control pills
• Rubella o Erythromycin
• Adenovirus, etc. o Statins (lipid lowering drugs)
Non-viral hepatitis: • Metabolic
• Bacterial • Autoimmune
o Staph. aureus (toxic shock)
o Gram-Negatives (cholangitis)
• Parasitic:
o Malaria
o Schistosomes
o Liver flukes (Fasciola hepatica)
o Ameba (abscesses)

b) Causes of hepatitis: Drug and toxin induced liver disease (Alcoholic)

c) Causes of hepatitis: Autoimmune
ALCOHOLIC LIVER DISEASE AUTOIMMUNE HEPATITIS
Clinical - Clinical presentation is like other forms of chronic hepatitis
manifestation
Transmission Excessive alcohol consumption is the leading cause of liver disease in most A chronic hepatitis with histologic features that may be indistinguishable from
/Source western countries. those of chronic viral hepatitis.

Three forms of alcohol related liver Usually have the following characteristics:
disease: • Female predominance (78%)
• Hepatic steatosis (fatty liver) • Absence of viral serologic marker
• Alcoholic hepatitis • Elevated serum IgG and γglobulin levels
• Alcoholic cirrhosis • High titers of serum auto Antibodies in 80% cases (ANA, ASMA)
• Negative anti mitochondrial antibody (AMA)
Pathogenesis a) Alcohol causes steatosis (fatty change) by:
• Shunting substrates toward lipid biosynthesis (more lipid is formed,
brought to be stored in the liver)
• Impairing lipoprotein assembly and secretion
• Increasing peripheral fat catabolism (degradation into fatty acids,
brought to be stored in the liver)
b) Overall, increase amount of fat deposited into liver cells.
c) Alcohol causes cellular injury through formation of:
• Free radicals
• Acetaldehyde generated from alcohol that induce lipid peroxidation
• Immunologic attack on hepatic antigens.
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 • Nutrients displacement.
d) This injury results in inflammation – hepatitis

Pathogenesis of alcoholic cirrhosis

a) Inflammation of a prolonged duration (chronic) triggers the process of healing
with fibrosis
b) Fibrosis results from collagen deposition by perisinusoidal stellate cells (HSC).
c) Healing process occurs with replacement of dying hepatocytes with
regeneration of new hepatocytes forming nodules (regenerative nodules)
d) Progressive fibrosis causes loss of normal architecture and eventually causes
abnormal hepatic blood flow.
Complications Complications: • Untreated severe disease, 40% may die within 6 months
• Hepatic coma • Cirrhosis develops in at least 40% of survivors.
• Massive gastrointestinal hemorrhage
• Intercurrent infection
• Hepatorenal syndrome
• Hepatocellular carcinoma HCC
Treatment • Immunosuppressive therapy and liver transplantation offer excellent
prospects.

d) Causes of hepatitis: Metabolic Liver Disease

• NAFL/NASH (non alcoholic fatty liver/nonalcoholic steatohepatitis) Hemochromatosis
• Raised liver enzymes and hepatic steatosis in the absence of heavy • Excessive iron accumulation in various organ incl. liver
alcohol consumption.
Wilson’s disease
• Has strong association with: • Autosomal recessive disorder marked by toxic accumulation of copper in liver, brain and eye →
o Obesity Kayser Fleischer ring
o Dyslipidemia
o Hyperinsulinemia
Alpha-1-antitrypsin deficiency
o Insulin resistance
o Type 2 DM • Autosomal dominant disorder result in low serum levels of protease inhibitors → leads to
o Chronic liver disease emphysema and hepatic cirrhosis
o Low platelet level indicates progression to cirrhosis.

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Mechanism of liver injury and repair
a) Liver Injury in Chronic Hepatitis:
1. Infection by hepatitis B (HBV) or C virus stays in the body for a long time, leading to chronic hepatitis.
2. Continuous inflammation inside the liver causes cells to be damaged and then replaced, increasing the risk of
liver cancer (HCC).
3. Early in the infection, liver injury is caused by:
• Immune response (cytotoxic T cells) attacking infected liver cells.
• Direct harm from the virus itself.
4. More inflammation attracts non-specific inflammatory cells, creating areas of damage called necroinflammatory
foci.
5. The virus becomes resistant to elimination, leading to its persistence and the development of chronic hepatitis.
6. Treatment aims to control immune cells causing liver cell death, reducing liver damage.

b) Hepatocyte and parenchymal response

1. After liver injury, a special group of stem-like cells called hepatic or liver progenitor cells (LPC) can repair the
liver.
2. Other non-liver cells play roles too:
• Hepatic stellate cells (HSC) help regulate blood flow in the liver.
• Liver macrophages (Kupffer cells) clear old cells and harmful substances.
• Liver specialized endothelial cells (LSECs) allow exchange between blood and liver cells.
3. Liver regeneration occurs in the damaged area:
• Hepatocytes multiply.
• Blood vessels change shape (sinusoid remodeling).
• Non-liver cells activate and join in.
4. Activated Kupffer cells release a substance called interleukin-6 (IL-6), which helps liver cells multiply.
5. HSCs start liver regeneration by making materials like collagen (like how wounds heal).
6. If the liver damage is temporary, the repair process leads to healing.
7. Immune and non-immune cells interact, responding to ongoing inflammation, which is crucial for proper liver
regeneration.

c) Scar formation and regression (cirrhosis)

1. If injury continues, chronic inflammation can lead to fibrosis, where scar tissue forms.
2. Fibrosis can progress to cirrhosis, a serious liver condition.
3. Effective treatment for fibrosis involves removing the cause early.
4. Cirrhosis can sometimes be reversed by treating the underlying cause (e.g., antiviral treatment for hepatitis B).
5. Cirrhosis regression includes:
• Decrease in scar tissue (fibrosis).
• Repopulating damaged areas with new liver cells (hepatocytes).

d) Complications of chronic hepatitis

• Cirrhosis
• Liver failure
• Hepatic encephalopathy
• Hepatocellular carcinoma (HCC)
• Massive hematemesis from ruptured esophageal varices
• Vasculitis (immune complexes)
• Cryoglobulinemia

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CIRRHOSIS
• Definition: Scarring of the liver (fibrosis).
• Pathological definition: Diffuse transformation of the liver into nodules surrounded by fibrous bands and vascular
shunting.
• Usually arises from chronic liver disease.
• Common causes: alcohol abuse, viral hepatitis.
a) CIRRHOSIS TYPES
• Alcoholic
• Laennec's (nutritional)
• Biliary (primary or secondary)
• Post-necrotic (hepatitis B or C)
• Micronodular
• Macronodular
b) CAUSES & CLINICAL FEATURES
• Cirrhosis can develop in infants and children (e.g., galactosemia, tyrosinemia).
• Drug-induced (e.g., alpha methyldopa).
• Clinical features:
• 40% asymptomatic until advanced stage.
• Symptomatic: anorexia, weight loss, weakness, jaundice.
c) MORPHOLOGY (GROSS)

• Fibrosis
• Regenerative
nodules
• Loss of normal
architecture

•
d) PATHOGENESIS & FURTHER CHANGES
• Inflammation responds to stimuli/causes.
• Chronic inflammation leads to healing with fibrosis.
• Collagen deposition by perisinusoidal stellate cells (HSCs) causes fibrosis.
• Healing replaces necrotic hepatocytes with regenerated hepatocytes forming nodules.
• Progressive fibrosis disrupts normal architecture, altering hepatic blood flow and increasing hepatic venous
wedge pressure, resulting in portal hypertension.
• New vascular channels form, connecting portal region and central vein. Vascular shunting occurs, leading to
portal hypertension.
• Sinusoid walls thicken (like capillaries). impaired protein secretion (albumin, clotting factors, lipoprotein).

e) COMPLICATIONS
• Progressive liver failure.
• Portal hypertension-related complications (bleeding from esophageal varices).
• Hepatocellular carcinoma.

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Portal Hypertension

Pathogenesis Portal Hypertension

Formation of Scars and Nodules in the Liver:
1. Scarring and nodules develop in the liver due to various factors.
2. These changes cause the contraction of vascular smooth muscle and myofibroblasts.
3. Blood flow in the liver is disrupted, leading to increased resistance to blood flow in the portal system (sinusoids).
Sinusoidal Remodeling and Arterial-Portal Anastomosis:
1. Sinusoids (tiny blood vessels in the liver) undergo remodeling due to scarring.
2. Fibrous septae (fibrous tissue partitions) form, causing abnormal connections between the arterial and portal
systems.
3. These connections impose arterial pressure on the normally low-pressure portal venous system.
4. This combination of sinusoidal changes and anastomosis contributes to the development of portal hypertension.
Hyperdynamic Circulation:
1. Portal hypertension triggers changes in circulation.
2. Arteries in the splanchnic (intestinal) region dilate, leading to increased blood flow.
3. This arterial vasodilation redirects more blood into the portal venous system.
4. The increased blood flow into the portal system contributes to the elevated pressure in the portal veins, causing
portal hypertension.

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4 COMPLICATIONS OF PORTAL HYPERTENSION

1. ASCITES Ascites- refers to collection of excess fluid in the peritoneal cavity

• Presence of neutrophils → suggests secondary infection.
• Presence of red cells → indicates possible disseminated intraabdominal neoplasm.
2. PORTOSYSTEMIC Raised Portal System Pressure and Flow Reversal:
SHUNTS 1. When pressure in the portal system (blood vessels in the liver) increases, blood flow
can change its direction.
2. Collateral vessels (alternative paths for blood) can dilate (expand) and new vessels
can develop.
3. These changes create venous bypasses, where blood can bypass the liver and flow
directly into the general circulation.
Sites for Shunts:
1. Shunts can develop at specific locations in the body where the portal and systemic
circulations share capillary beds (network of tiny blood vessels).
2. Shunts can occur at different places:
• The rectum: This can cause hemorrhoids (swollen veins around the anus).
• Esophagogastric junctions: These are locations where the esophagus and
stomach meet. Shunts here can lead to esophageal varices, which can result
in severe bleeding.
• Retroperitoneum and falciform ligament of the liver: These involve the area
behind the abdomen and a ligament in the liver. Shunts here can cause
dilated subcutaneous veins (veins under the skin) extending from the belly
button towards the ribs, creating a pattern known as "caput medusae."

3. SPLENOMEGALY -
4. HEPATIC What is Hepatic Encephalopathy:
ENCEPHALOPATHY • Hepatic encephalopathy is a range of consciousness disturbances, from subtle
behavior changes to severe confusion, stupor (being unresponsive), coma, and even
death.
• It can develop slowly over days, weeks, or months.

Signs of Encephalopathy:
• Neurological signs can vary and may come and go.
• Signs include rigidity (muscle stiffness) and hyperreflexia (exaggerated reflexes).
• Asterixis is a specific tremor, like a flapping movement, usually seen in the hand
when the wrist is extended.

Causes of Hepatic Encephalopathy:

• The underlying cause is an increase in ammonia levels in the body.
• Elevated ammonia impairs the function of brain cells (neurons) and can lead to
swelling of the entire brain (generalized brain edema).
• liver plays a crucial role in ammonia detoxification. It helps convert ammonia into
urea and ensures its safe elimination from the body. When the liver is functioning
properly, it can efficiently clear ammonia from the bloodstream.

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Liver failure
• Hepatic failure is the most severe clinical consequence of liver disease.
• Cirrhosis is not a prerequisite for liver failure.
• Liver failure can occur in several ways:
1. Sudden and massive hepatic destruction (fulminant hepatitis/acute liver failure)
2. An endpoint of progressive damage of chronic liver disease (usually associated with cirrhosis).
3. Acute on chronic liver failure - sudden unrelated acute injury on top of well-compensated late-stage
chronic disease.
4. Sudden functional loss without significant morphological changes.
• Hepatic failure develops when 80-90% of hepatic functional capacity is lost.

a) Acute liver failure

• Definition: Sudden liver illness with encephalopathy and coagulopathy (INR >1.5) within 26 weeks of initial
injury, excluding cirrhosis or preexisting liver disease.
• Also known as acute fulminant hepatitis.
• Features:
• Jaundice
• Encephalopathy
• Fetor hepaticus (sweetish, musty breath)
• No signs of chronic liver disease (e.g., spider angiomas, etc.).

Causes of acute liver failure

1. Acetaminophen toxicity
2. Autoimmune hepatitis
3. Other drugs and toxins
• Halothane
• Anti-tuberculous drugs (rifampicin)
• Antidepressants (MAOI)
4. Hepatitis viruses (A and B)
5. Mushroom poisoning (amanita phalloides)
6. In Asia, predominant causes:
• Acute hepatitis B (East Asia)
• Acute hepatitis E (India)
7. Unknown causes (18%)

Morphologic changes
• Liver can shrink (500-700g) to a limp, red organ with wrinkled capsule
(Normal: 1400-1600g).
• Blotchy bile staining may appear.
• Microscopic:

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 • Hepatocytes destroyed in nearby lobules.
• Collapsed reticulin framework.
• Extensive hepatic necrosis.
• Wide loss of liver tissue around regenerating hepatocytes.
• Scarring/ductular reactions vary with insult nature/duration.
• Drug overdose leads to rapid changes (hours/days),
insufficient time for scars.
• Diffuse microvesicular steatosis.

EXTRAHEPATIC COMPLICATIONS
it refers to health problems that arise as a result of or in conjunction with liver dysfunction, but they affect organs or
systems outside of the liver itself.
• Coagulopathy and bleeding
• Cardiovascular instability
• Renal failure
• ARDS (Acute respiratory distress syndrome)
• Electrolyte and acid-base imbalance
• Sepsis
• Mortality rate: 25-90% without liver transplant

b) Sudden functional loss without evidence of morphological changes

• Gastrointestinal bleeding
• Systemic infection
• Electrolyte disturbances
• Severe stress such as major surgery or heart failure.
• Drugs that is normally non-toxic to normal liver.

Clinical features of underlying chronic liver disease

• Shunting of blood from portal to systemic circulation.
• Hyperestrogenemia – (increased conversion from androgens).
• Palmar erythema (localized vasodilation).
• Spider angiomas (dilated arteriole with radiating vessels).
• Hypogonadism.
• Gynecomastia (in males).

Complications of liver failure

• Jaundice (bilirubin retention)
• Hypoalbuminemia (peripheral edema)
• Hyperammonemia (hepatic encephalopathy, cerebral dysfunction)
• Coagulopathy (impaired clotting factors synthesis → bruising, intracranial bleeding, DIC)
• Portal hypertension (common in chronic liver failure)
• Fetor hepaticus (sweet, sour, or musty body odor)
• Hepatorenal syndrome (renal failure in liver failure, not due to intrinsic causes)
• Reduced urine output
• Elevated blood urea nitrogen (BUN) and creatinine (decreased GFR)
• Hyperosmolar, protein-free urine
• Low urine sodium content (sodium retention)
• Multiorgan failure
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 • Respiratory failure with pneumonia and sepsis

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