Viral hepatitis is liver inflammation caused by a

viral infection and it can either be acute or

chronic, and five important causes are hepatitis A,
B, C, D and E.

Acute viral hepatitis lasts for less than six months

and the individual has nausea, vomiting, and right
upper quadrant pain. Sometimes if there’s a high
total bilirubin, it can lead to jaundice, pruritus,
dark urine, and clay- colored stools.

Chronic viral hepatitis lasts for more than six

months and the individual can sometimes be
asymptomatic. Other times, chronic viral hepatitis
can cause fever, fatigue, and loss of appetite, as
well as extrahepatic symptoms like arthralgias and
skin rashes.

On the physical examination, with acute hepatitis,

there’s typically hepatomegaly, but with chronic
hepatitis, the liver may feel normal on palpation,
and if there’s cirrhosis, the lower margin of the
liver can feel irregular.

A diagnostic workup for viral hepatitis includes a

CBC, AST, ALT, total bilirubin and unconjugated
bilirubin, alkaline phosphatase, and PT, PTT, INR.
Thrombocytopenia, prolonged PT and prolonged
PTT as well as an elevated INR can be present in
both acute and chronic hepatitis.

In acute hepatitis, levels of AST, ALT are over 100

international units per liter and sometimes the
alkaline phosphatase and total bilirubin are
elevated as well. If the total bilirubin is above 2
milligrams per deciliter, then an individual can
appear jaundiced.

With chronic hepatitis, elevation of AST and ALT

persists for more than six months but levels don’t
usually rise above 400 international units per liter.
In addition, total bilirubin and alkaline phosphatase
levels can also be elevated.

During viral hepatitis, medications that are

metabolized by the liver, like aspirin, or
medications that can damage the liver, like
acetaminophen, should be used with caution,
because they can further damage the liver.

Okay, now let’s start with hepatitis A which only

causes acute hepatitis. It’s caused by
contaminated food and water and often affects
travelers.
In hepatitis A, serum anti-hepatitis A virus IgM
antibodies are elevated for about 6 weeks , and
anti-hepatitis A IgG antibodies begin to rise a
couple weeks after IgM antibodies and usually
persist for life.

So, if there are IgG antibodies and no IgM

antibodies, that means that the person was
vaccinated for hepatitis A or had a prior infection
and developed immunity.

Hepatitis A usually resolves within a few weeks,

and the main treatment is giving fluids in case of
dehydration.

Hepatitis A can be prevented by vaccinating

children, as well as adults that are about to travel
in countries with a high rate of hepatitis A
infection. Two doses of the vaccine are given 6
months apart.

Next up is Hepatitis E - which typically causes

acute hepatitis, but can also cause chronic
hepatitis in immunocompromised individuals.

Like hepatitis A, it’s also caused by contaminated

food and water, but it can also be transmitted from
mother to child during birth. Usually the symptoms
are mild, but if it develops in pregnancy, it can be
severe and lead to acute liver failure.

In acute hepatitis E, anti-hepatitis E virus IgM are

elevated for about 2 months and IgG antibodies
begin to rise around the same time as IgM
antibodies, but they don’t persist for more than a
few years. HEV RNA - which is a marker of virus
replication- is also checked in the stool or in the
serum to confirm the infection and levels are
usually high.

With chronic hepatitis E, HEV RNA is detected in

the serum or in the stool for more than six months.

Acute hepatitis E usually resolves within a few

weeks, and the main treatment is giving fluids in
case of dehydration. However, in acute liver
failure, a liver transplant may be needed.

In immunocompromised individuals with chronic

hepatitis E, treatment involves lowering the doses
of immunosuppressants and giving ribavirin for 12
weeks.

Next is hepatitis B which can cause acute

hepatitis and chronic hepatitis. It’s caused by
contact with blood - like sharing needles or
syringes, and contact with body fluids - like
unprotected sex and during passing from mother to
child during labor and delivery.

Testing for hepatitis B requires sending serology.

First, there’s HBsAg and Anti-Hbs, which is the

antibody to Hepatitis B surface antigen. Usually, if
one is positive, the other’s negative, sort of like yin
and yang. One exception is if an individual has
never been exposed to the hepatitis B virus or
vaccine in their life - in which case they’re both
negative.

Another exception is when a person has actually

cleared the hepatitis B infection so the HBsAg is
gone, but levels of Anti-Hbs still haven’t risen high
enough to be detected, so it appears to be
negative, even though technically there is Anti-Hbs
floating around. That’s called the “window period”.

But most of the time, if HBsAg is positive and Anti-

Hbs is negative, that means - there’s an acute or
chronic hepatitis B infection.

And if HBsAg is negative and Anti-Hbs is positive,

that means that an individual has been immunized
or has recovered from a natural infection - either
way, they’re protected from hepatitis B.

After looking at HBsAg and Anti-Hbs, the next step

is to look at antibodies made against HBcAg,
which is hepatitis B core antigen.

There’s IgM-anti-HBc, which is IgM antibodies

against hepatitis B core antigen, and there’s total
anti-HBc, which is total antibodies against
hepatitis B core antigen, mostly made up of IgG
antibodies. Neither of these rises with the vaccine.

Now, in acute hepatitis, both the IgM-anti-HBc and

the total anti-HBc become positive. But as weeks
go by, the IgM-anti-HBc becomes negative, while
the total anti-HBc remains positive. That happens
if the person clears the hepatitis B infection, or if
there’s chronic hepatitis - so it really tells you
about the passage of time.

Finally there’s HBeAg, which is hepatitis B e

antigen - try saying that 3 times quickly. If it’s
positive then the virus is actively replicating, and
that means that the person is highly infectious. If
it’s negative, it could be because the virus isn’t
actively replicating or because there’s no virus
around at all.
There’s also HBV DNA PCR, or Hepatitis B virus
DNA PCR that can be sent, and it usually mirrors
HBeAg but gives even more information.

High HBV DNA levels mean that the virus is

actively replicating and highly infectious low HBV
DNA levels mean that the virus is around but not
actively replicating, and having no detectable HBV
DNA means that there’s no virus.

Now let’s put these Hepatitis B serological

markers into a table and go through some
scenarios. In someone that’s susceptible to
hepatitis B and hasn’t been immunized, HBsAg,
Anti-Hbs, IgM-anti-HBc, total anti-HBc, HBeAg, and
HBV DNA are all negative.

In someone that is immunized, Anti-Hbs becomes

positive, while HBsAg is negative, and the rest
remain negative as well.

Now in someone with acute hepatitis B infection,

HBsAg is positive and Anti-Hbs is negative, and
because it’s acute - IgM-anti-HBc and total anti-
HBc are positive. Typically the virus is actively
replicating at this stage so HBeAg and HBV DNA
levels are elevated as well.
After a number of weeks later, IgM-anti-HBc
becomes negative, while total anti-HBc remains
positive for life.

Finally, if the infection gets brought under control

to the point where the virus is no longer actively
replicating, then the HBeAg becomes negative and
the HBV DNA levels fall, and anti-HBe antibodies
appear.

Finally there’s chronic hepatitis B infection, which

has a few phases. The immune-tolerant phase
usually develops in individuals that were infected
during birth, and it can last a few decades. There’s
minimal liver inflammation, so the ALT and AST
may be normal or slightly elevated.

During this phase, HBsAg is positive and Anti-Hbs

is negative, and because it’s chronic - IgM-anti-HBc
is negative, while total anti-HBc remains positive.

Typically the virus is actively replicating at this

stage so HBeAg and HBV DNA levels are elevated
as well.

Then there’s the immune-active phase with

positive HBeAg- which is when there’s more liver
inflammation so ALT and AST are elevated, and as
a result the HBV DNA levels start to fall a bit, but
in other ways the labs are the same.

HBsAg is positive, Anti-Hbs is negative, IgM-anti-

HBc is negative, and total anti-HBc remains
positive.

And the virus is still actively replicating so HBeAg

is positive.

Next there’s, immune-active phase with negative

HBeAg- which is when the ALT and AST remain
elevated, but the HBV DNA levels fall even lower,
and the HBeAg becomes negative - meaning that
the individual is less infectious.

In other ways the other labs are the same. HBsAg

is positive, Anti-Hbs is negative, IgM-anti-HBc is
negative, and total anti-HBc remains positive.

Next there’s the inactive chronic HBV phase-

which is when the ALT and AST normalize and HBV
DNA levels fall even lower, and the HBeAg remains
negative.

And as before the other labs are the same. HBsAg

is positive, Anti-Hbs is negative, IgM-anti-HBc is
negative, and total anti-HBc remains positive.

Finally, when someone successfully clears the

infection, Anti-Hbs becomes positive, while HBsAg
is negative, total anti-HBc remains positive as
well, and the IgM-anti-HBc, HBeAg, and HBV DNA
are negative.

Now, an important complication of chronic

hepatitis B is cirrhosis, which can lead to
hepatocellular carcinoma.

In fact, high titers of HVA DNA and HBsAg

correlate with a higher likelihood of developing
cirrhosis. So every 6 months, an ultrasound is done
and alpha fetoprotein levels can also be checked
to monitor for possible tumors.

Treatment of acute hepatitis B is mainly

supportive, like giving fluids and antiemetic
medications like metoclopramide.

Treatment of chronic hepatitis B largely depends

on the HBV DNA and ALT levels and whether or not
there’s cirrhosis.

Individuals without cirrhosis that have HBV DNA

levels above 20,000 international units or IU per
milliliter and ALT levels above 2 times the upper
limit of normal, are started on treatment.

If the HBV DNA levels are above 20,000 IU per

milliliter but ALT is below the 2 times upper limit
cutoff, then ALT levels are monitored every 3 to 6
months and if it ever reaches that cutoff, then
treatment is started.

If HBV DNA levels are between 2,000 and 20,000 IU

and levels of ALT are under 2 times the upper limit
of normal, then the labs are monitored every 1 to 3
months. If HBV-DNA remains between 2,000 and
20,000 international units per milliliter for 6
months, then treatment is started.

If the HBV DNA levels are below 2,000 IU and

levels of ALT are under 2 times the upper limit of
normal, then labs are monitored every 3 to 6
months. If ALT levels rise above 2 times the upper
limit of normal, then treatment is started.

Treatment options include Pegylated interferon- or

PegIFN- which is an antiviral agent that’s
administered by subcutaneous injection once a
week for 48 weeks.
Other options include nucleoside or nucleotide
analogues - like Entecavir or Tenofovir which are
given orally until HBeAg becomes negative and
then for one more year after that.

If HBeAg was initially negative and HBV DNA levels

rise above 2000 IU and ALT levels rise above 2
times the upper limit of normal then the treatment
is restarted, to prevent HBeAg from becoming
positive. This time, PegIFN is used for a year and
the nucleoside or nucleotide analogues are used
for several years.

Now treatment for chronic hepatitis B with

cirrhosis. First, in individuals with compensated
cirrhosis, where there’s no jaundice or ascites- and
HBV DNA is above 2,000 international units per
milliliter, Entecavir or Tenofovir is given
indefinitely.

In individuals with compensated cirrhosis, and

HBV DNA levels below 2,000 international units per
milliliter, Entecavir or Tenofovir is given only if ALT
levels are elevated.

And in individuals with compensated cirrhosis, if

HBV DNA levels are undetectable, then no
treatment is started.
In individuals with decompensated cirrhosis,
where there is jaundice or ascites, Entecavir is
started, regardless of ALT and HBV DNA levels.

In individuals with decompensated cirrhosis, and

undetectable levels of HBV DNA, a liver transplant
may be done.

Prevention of HBV infection is done by vaccination

in infants and in adults that are not immune to HBV
infection and have a high-risk for developing it,
such as healthcare personnel, injection drugs
users, and immunocompromised individuals. In
newborns, three doses are given, the first shortly
after birth, the next at one month of age, and the
last at 6 months. In adults, two doses are given,
one month apart.

Okay, next is hepatitis D which can cause acute or

chronic hepatitis. It’s caused by hepatitis D virus-
or HDV- which is a defective virus that needs HBV
to cause an infection, because HBsAg makes up
the outer envelope within which the HDV genome
resides.

So like Hepatitis B, Hepatitis D, it’s transmitted

through blood and body fluids.
Now, acute hepatitis D, can be due to a
coinfection- meaning that both B and D viruses
infect the individual at the same time or a
superinfection- meaning that hepatitis D infection
occurs after there’s a preexisting chronic hepatitis
B infection.

Oftentimes, an acute hepatitis D infection doesn’t

get cleared, and it turns into a chronic hepatitis D
infection.

Testing for hepatitis D requires confirmation of

hepatitis B infection, as well as testing for HDV
IgM, which is IgM antibodies against hepatitis D,
total HDV antibodies, which is total antibodies
against hepatitis D, mostly made up of IgG
antibodies, serum HDV RNA, and HDAg which
usually remains positive only briefly.

In acute hepatitis D coinfection or superinfection,

HDV IgM is elevated, and total HDV antibodies may
be negative if the IgG levels haven’t climbed very
high.

HDV RNA is usually positive, and HDAg may be

positive or negative because it disappears so
quickly.
Whereas with chronic HDV infection, HDV IgM is
negative, total HDV antibodies are positive, HDV
RNA is positive, and HDAg is negative.

Treatment of hepatitis D is initiated in individuals

that have elevated HDV RNA levels and elevated
AST and ALT levels.

Pegylated interferon alfa-2a or alfa-2b is given

once a week for 12 months.

Prevention of hepatitis D is accomplished through

hepatitis B vaccination.

Next is hepatitis C which is caused by hepatitis C

virus and can cause acute or chronic hepatitis. It’s
caused by contact with blood - like sharing needles
or syringes, and contact with body fluids - like
unprotected sex and during passing from mother to
child during labor and delivery.

Hepatitis C can cause extrahepatic manifestations

like cryoglobulinemia- which is where the blood
viscosity is high and causes headaches and
confusion-, membranoproliferative
glomerulonephritis and dermatologic conditions,
such as porphyria cutanea tarda which can cause
erosions and blisters.

The first step in diagnosis is to look for anti-HCV

IgG antibodies. If they’re positive, then the next
step is to send HCV RNA PCR. If HCV RNA is not
detected, it likely means that it was a past
infection that has now cleared. If HCV RNA is
detected, then the individual has a hepatitis C
infection. If titers HCV RNA remains elevated for
more than 6 months, then it’s considered a chronic
hepatitis C infection, otherwise it’s considered an
acute hepatitis C infection.

Once the diagnosis is established, it’s helpful to

calculate the APRI score - which is the AST to
platelet ratio index. It’s calculated by dividing the
individual’s AST level by the normal value of AST,
and then dividing by the platelet count and
multiplying by 100. This estimates the degree of
liver fibrosis. If the score is below 0.5, there’s
minimal fibrosis, between 0.5 and 1.5 is in-
between, and above 1.5 means that there is
significant fibrosis.

In individuals with cirrhosis, there is a high-risk for

developing hepatocellular carcinoma, so an
ultrasound is done every 6 months, and alpha
fetoprotein levels can also be checked to monitor
for possible tumors.
Treatment of hepatitis C in individuals without
cirrhosis can be initiated using either Sofosbuvir
coupled with either velpatasvir or daclatasvir for
12 weeks or by using Glecaprevir and pibrentasvir
for 8 weeks.

In individuals with hepatitis C with compensated

cirrhosis, Sofosbuvir and velpatasvir can be used
for 12 weeks or Glecaprevir and Pibrentasvir can
be given for 12 weeks or Sofosbuvir and
daclatasvir can be given for 24 weeks.

In individuals with decompensated cirrhosis,

sofosbuvir plus velpatasvir for 24 weeks or
sofosbuvir plus daclatasvir for 12 weeks can be
used and some cases may require liver
transplantation.