HEPATITS

DEFINITION:
Hepatitis: --- is an inflammation of the liver. Hepatitis can be acute or chronic LD. Mainly
viruses followed by bacteria, toxic chemicals (Alcohol, drugs) & autoimmune diseases cause
hepatitis. Hepatitis leads to Cirrhosis if not treated.

Epidemiology of liver diseases

• Prevalence population Statistics of CLD

A. Global 50 million people

B. India • 10Lac new cases added/Y
C. Men • 33%
D. Women • 30%
E. Age (40-50Y) • More
F. Drinking alcohol • Genetic link (weak)
G. Japanese Americans • 6.9%
H. Latinos • 6.7%
I. White • 4.1%
J. Black • 3.9%

ETIOLOGY:

1. Viral infections (Hepatitis A, B, C, D & E) • Inflammation of liver (Acute)

2. Chronic alcohol drinking • Inflammation of liver
3. Non-alcoholic fatty liver (Obesity, Diabetes • Inflammation of liver
mellitus)
4. Autoimmune disorders Examples: • Inflammation of liver or bile duct
A. Autoimmune hepatitis obstruction
B. Primary biliary cirrhosis • Inflammation of liver
C. Primary sclerosing cholangitis • Destruction of bile ducts

5. Vascular abnormalities
Example: Budd-Chiary syndrome
6. Drugs
• Biliary stricture & cholestasis
• Obstruction of Hepatic venous outflow
• Liver cells damage or change liver cells
function

7. Inherited metabolic disorders Examples:

A. Haemachromatosis • ↑ dietary iron absorption & deposition in
liver
B. Wilson’s disease • ↑ dietary copper absorption & deposition
C. α1- Antitrypsin deficiency in liver
D. Glycogen storage disease • ↓ α1- Antitrypsin levels in liver
E. Gilbert’s syndrome • ↑ Glycogen accumulation in liver
• ↑ Bilirubin levels in blood

Pathophysiology Chemicals
↓
Liver cells damage
↓
Viral infections → Hepatitis
↓
(Long-period) Liver cells structure change
↓
Hepatic stellate cells ---- → Pericellular fibrosis around liver cells develops
↓
Liver cells starts dying
↓
Micronodular fibrotic bands further develops
↓
Cirrhosis
↓
↑ resistance to blood flow from portal system – Portal HTN
↓
Gradually Liver cells death
 ↓
↓ Functioning Liver cells
↓
Chronic Liver Failure

These viruses tend to target the cells in the liver, and when they get in and infect these cells,
they tend to cause them to present these weird and abnormal proteins via their MHC class 1
molecules, and at the same time, you've also got these immune cells infiltrating the liver and
trying to figure out what’s going on, and so the CD8 positive T cells recognize these
abnormal proteins as a sign that the cells are pretty much toast, and the hepatocytes go
through cytotoxic killing by the T cells and apoptosis.
Hepatocytes undergoing apoptosis are sometimes referred to as Councilman bodies, shown
on histology here, and this typically takes place in the portal tracts and lobules of the liver.
This cytotoxic killing of hepatocytes is the main mechanism behind inflammation of the
liver, and eventual liver damage in viral hepatitis!
Typically the serum amino transaminase, or the amount in your blood, is pretty low, but
when your hepatocytes start getting damaged they start leaking these into the blood, so a
common sign is a greater amount of both alanine aminotransferase, or ALT, and aspartate
aminotransferase, or AST, typically even though both are elevated, ALT will be greater than
AST in viral hepatitis and will also be the last of the two liver enzymes to return to normal.
Also, elevated levels of atypical lymphocytes are common to see with viral hepatitis, known
as atypical lymphocytosis.
The lymphocytes are usually like huge, very large, due to stimulation from antigens, in our
case the hepatitis virus antigens.
Patients often also end up developing jaundice, with a mix of both conjugated
bilirubin and unconjugated bilirubin.

The conjugated bilirubin leaks out when bile ductules are damaged or destroyed when
the hepatocytes die, which make up some of its lining!
Also, since these hepatocytes are dying, you start to lose the ability to
conjugate bilirubin and make it water soluble, and so you also end up with unconjugated
bilirubin as well.
So since there’s both conjugated and unconjugated bilirubin in the blood, some of the
water soluble conjugated bilirubin gets filtered into the urine, giving it a darker color.
If symptoms continue or the virus sticks around for more than 6 months, viral hepatitis goes
from being called acute to being called chronic hepatitis.
At this point, inflammation mostly happens in the portal tract, and if inflammation
and fibrosis keep persisting, we consider that a bad sign, since it might be progressing to
postnecrotic cirrhosis.
When things progress to cirrhosis, there may also be increased urobilinogen in the urine.
Normally, urobilinogen is made by intestinal microbes that convert
the bilirubin in bile to urobilinogen.
And usually, most of the urobilinogen is reabsorbed from the intestine and goes back to the
liver, where it’s converted back to bilirubin.
However, with cirrhosis, liver cells aren’t working properly anymore, so there’s a lot of liver
fibrosis, so hepatocytes can’t process the urobilinogen, which is redirected to the kidneys
and excreted, so you end up with more urobilinogen in your urine.

TYPES OF HEPATITIS:
Hepatitis A
 It istransmitted through ingestion of contaminated food or water, in other words
the fecal-oral route, and is known to be acquired by travelers.
 Hepatitis A virus, or HAV, is almost always acute only, and there is essentially no
chronic HAV.
 Serological markers: HAV-IgM antibody indicates an active infection, whereas HAV-
IgG antibody is a protective antibody and tells us that there’s been recovery from HAV
or vaccination in the past.

Hepatitis E
 This virus’s actually pretty similar to HAV, with the same route of transmission, oral-
fecal, and is most commonly acquired through
undercooked seafood or contaminated water.
 It also doesn’t have much of a chronic state, and HEV-IgM antibodies tell us there’s an
active infection and HEV-IgG antibody is protective and signals recovery.
 Two big differences to note though between these two guys, is that (1) only HAV has
the option for immunization and (2) HEV infection for pregnant women can be very
serious, and can lead to acute liver failure, also sometimes called fulminant hepatitis.

Hepatis C
 It is transmitted via the blood, so could be from childbirth, intravenous drug abuse,
and there’s also a small chance of getting it through unprotected sex, if there are open
lesions, like cuts or sores, in the genital area.
 HCV usually does move on to chronic hepatitis.
 There’re a couple tests that we use to help diagnose HCV, one way is by enzyme
immunoassay, so we’d screen for the HCV-IgG antibody, if present, it doesn’t
necessarily confirm acute, chronic, or resolved infection and it isn’t regarded as a
protective antibody like HAV and HEV, to get more specific confirmation, you might
use recombinant immunoblot assay which helps confirm HCV, it’s more specific but
less sensitive than the immunoassay, and clinically doesn’t provide much usefulness
and needs an additional supplemental test if positive.
 That said, the gold standard for HCV diagnosis is an HCV RNA test, using PCR
or polymerase chain reaction, this method can detect the virus very early on, as much
as 1 to 2 weeks after infection, basically it detects the levels of viral RNA in the blood,
which tells us the levels of virus circulating.
 If RNA levels begin to decrease, we know the patient’s recovering, if RNA remains the
same, the patient probably has chronic HCV.

Hepatitis B
 HBV’s just like HCV in that it’s contracted via blood, so the same routes
like childbirth and intravenous drug use, but there’s a greater chance
of transmission through unprotected sex than HCV.
 HBV, however, only moves on to chronic hepatitis in 20% of cases overall, but it also
depends on the age that someone gets infected, for example children less than 6 years
old are most likely to get chronic infections, about 50%, and that percentage increases
as they get younger.
 Also, chronic HBV is known to be linked to liver cancer.
 All these things make HBV and the serology of HBV a super important concept to
understand, as like hepatitis C we can use a variety of testing methods, like PCR, to
look for certain markers, especially the HBV antigens.

 And the presence or absence of each at different timepoints tells us different things.
The key marker for an HBV infection is the HBV surface antigen, this is like the
supervillain in this story, and this evil door lives on the surface of the virus, here, and
we can call it HBsAg, meaning Hepatitis B surface antigen.
  Another marker though, is a core antigen, meaning that these antigens come from the
core of the virus, HBcAg, think of these like the dispensable henchmen that work inside
the villain’s evil factory.
 Finally there’s this other antigen called the ‘e’ antigen, which is secreted by infected
cells and so is a marker of active viral replication.
So the presence of HBe along with viral DNA in the blood tells us the virus is replicating and
infecting.
Alright, so at the onset of infection, during the acute phase, our surface antigen villain will be
positive and it’s layer will be pumpin’ out both viral DNA and e antigen, at this point
the immune system produces IgM antibodies, which are like your basic police force, against
the core henchmen.
These antibodies hack away at the core antigens and do their darndest, but in order to really
defeat the virus, you need to go for the supervillain, the surface antigen, so then we need a
superhero to go after it, and in this story the IgG antibody for the surface antigen is our
superhero.

At this point, the host enters this spooky phase called the window, where neither the
supervillain or superhero can be detected, because they’re so low, and this can last from
several weeks to months, it’s like the war’s being waged but we don’t know who’s coming out
on top.
The only thing you can detect during this stage is the IgM core antibodies, the police force.
At this point, two things can happen, if the superhero comes out, the IgG antibodies to the
surface antigen, we’re golden, and this means the day is saved and we win.
The other possibility is that the supervillain wins, and surface antigens are still again detected,
there may also be presence of HBV DNA and e antigen because it’s now replicating again, the
main point though is that there will not be the IgG for surface antigens, our superhero.
Regardless of who wins, the IgM antibodies, the police force, will be promoted to IgG by 6
months time, and this does not mean that the host is protected.
So it’s important to note that we need this surface IgG superhero to win, but we can have
core IgG and still lose.
If the battle’s lost, the host transitions into chronic viral hepatitis, defined by it continuing
after 6 months.
When chronic, the host could present as “healthy”, and will likely have the presence of surface
antigen, core antibody, and no DNA or e antigen, basically saying that the supervillain’s there,
it’s just not replicating, and at this point the host is contagious, but there’s lower risk.
The other option is that they’re infective, meaning the whole villain force is active along with
an overwhelmed police force.
This state increases the risk for postnecrotic cirrhosis and hepatocellular carcinoma.
One way to get around this whole fiasco is by immunization, which skips these steps and gets
you right to the IgG superhero antibody for surface antigen.

Hepatitis D virus
 This is unique in that it NEEDS HBV, it can only infect if the host also has HBV.
 If it infects at the same time, it’s called co-infection, if it infects sometime later, it’s
called superinfection, which is considered to be more severe that co-infection.
 If either the IgM or IgG antibody are present, that indicates an active infection, so in
this case the IgG is not a protective antibody.
Treatment of LD
1. Patient Specific Therapy 2. Disease Specific Therapy
Patient Specific Therapy (Based on clinically significant symptoms)
1. Pruritus: (Itching mainly due to cholestasis LD) Classification of drugs:
A. Anion exchange resins Ex: Colestyramine, Colestipol
B. Antihistaminics Ex: Cetirizine, Loratidine Chlorpheniramine, Hydroxyzine
C. Opioid antagonists Ex: Naloxone, Naltrexone, Nalmefene
D. Ursodeoxycholic acid (UDCA), Rifampicin
E. Calamine lotion, Menthol (2%) aqueous cream
F. Plasmapheresis, Liver transplantation