Viral Hepatitis

Acute hepatitis may be associated with all five types of hepatitis and rarely exceeds 6
months in duration. Chronic hepatitis (disease lasting more than 6 months) is usually
associated with hepatitis B, C, and D. Chronic viral hepatitis may lead to the development
of cirrhosis and may result in end-stage liver disease (ESLD) and hepatocellular carcinoma
(HCC). Complications of ESLD include ascites, edema, hepatic encephalopathy,
infections (eg, spontaneous bacterial peritonitis), hepatorenal syndrome, and esophageal
varices. Therefore, prevention and treatment of viral hepatitis may prevent ESLD and
HCC.

Symptoms: In most patients infected with any type of viral hepatitis have no symptoms.
Symptomatic patients may experience a flu-like syndrome, fevers, fatigue/malaise,
anorexia, nausea, vomiting, diarrhea, dark urine, pale-appearing stools, pruritus, and
abdominal pain.

Signs: Jaundice may be evident in the whites of the eyes (scleral icterus) or skin. An
enlarged liver (hepatomegaly) and spleen (splenomegaly) may be present. In fulminant
hepatitis with hepatic encephalopathy, patients may have asterixis and coma .

Hepatitis A (HAV)
Hepatitis A is a nonenveloped single-stranded RNA virus, and the hepatic cells as the
main site for viral replication. HAV affects 1.4 million people yearly worldwide. The
prevalence is highest in economically challenged and underdeveloped countries. HAV is
primarily detected in contaminated feces and infects people via the fecal–oral route.
Outbreaks typically occur in areas of poor sanitation or consumption of food or water
infected with the HAV. individuals at greatest risk of acquiring HAV are:
 International travelers to endemic areas (eg, Africa, Asia, and parts of South
America)
 Men having sex with other men
 Persons who use illegal drugs (injection)
 Persons experiencing homelessness
 Persons who work in food service establishments
 Health care providers with direct or indirect patient contact and child care centers
 Workers exposed to sewage

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Hepatitis A infections are usually self-limiting and do not lead to chronic disease; rarely, it
may result in fulminant hepatitis, which occurs in less than 1% of cases. Hepatitis A is
diagnosed by detecting immunoglobulin antibodies to the capsid proteins of the HAV.
Detectable IgM anti-HAV in the serum indicates acute infection and usually appears about
3 weeks after exposure and becomes undetectable within 6 months. In contrast, IgG anti-
HAV appears in the serum at approximately the same time that IgM anti-HAV develops
but indicates protection and lifelong immunity against the HAV.

Good personal hygiene and proper disposal of sani tary waste are required to prevent
HAV fecal–oral transmission. Individuals at risk of acquiring HAV should receive serum
Immune Globulin (IG) and/or the hepatitis A vaccine.

IG provides short-term passive immunization against HAV. IG administration is indicated

for individuals:
(a) at high risk of acquiring the HAV infection,
(b) who elect not to receive the hepatitis A vaccine,
or (c) who cannot receive the hepatitis A vaccine (eg, because of allergic reaction).
Preexposure and postexposure prophylaxis dosing is based on patient’s age, indication,
and health status.
Persons at risk of acquiring HAV should receive the hepatitis A vaccine to provide pre- and
postexposure prophylaxis. Two inactivated hepatitis A vaccines are available in the United
States: HAVRIX and VAQTA. The recommended regimen is to administer two injections 6
months apart (at months 0 and 6). These vaccines are considered interchangeable.
The hepatitis A vaccine may provide immunity for about 20 years in children more than 2
years of age and adults who completed the two-dose hepatitis A vaccination series. The
most common and often self-limiting adverse effects in adults include injection-site
reactions (eg, tenderness, pain, and warmth), headaches, fatigue, and flu-like symptoms.

Hepatitis E (HEV)
Hepatitis E is a nonenveloped single-stranded messenger RNA virus. The HEV is
transmitted via the fecal–oral route with the primary source being contaminated food and
water. Unfortunately, animals can acquire the HEV; thus, human consumption of these
animals is considered a risk factor. HEV infections are usually self-limiting and rarely
result in hepatic complications.
An estimated 20 million individuals worldwide are infected annually with HEV. The
highest prevalence is found in East and South Asia. HEV infection primarily occurs in
underdeveloped countries with poor sanitation.
Diagnosis of acute hepatitis E is based on the presence of IgM anti-HEV. IgG anti-HEV
emerges when the HEV infection resolves.
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Because hepatitis E is transmitted via the fecal–oral route, good personal hygiene and
proper disposal of sanitary waste are the most effective ways to prevent viral acquisition.
There are no commercially available vaccines. Hepatitis E vaccine has been licensed in
China since 2012 and may become available for countries with high HEV infection
incidence rates. In rare cases, HEV may lead to chronic hepatitis. PegIFN treatment has
been successful, primarily in the solid organ transplantation population.

Hepatitis B (HBV)
The HBV is a partially double-stranded DNA virus with a phospholipid layer containing
hepatitis B surface antigen (HBsAg) that surrounds the nucleocapsid. The nucleocapsid
contains the core protein that produces hepatitis B core antigen (HBcAg). Anti-HBc to
immunoglobulin M (IgM) indicates active infection, and anti-HBc to IgG indicates either
chronic infection or possible immunity against HBV. Viral replication usually occurs when
the hepatitis B envelope antigen (HBeAg) is present and circulating in the blood. Serum
HBV DNA concentration measures viral infectivity and quantifies viral replication.
More than 250 million people have chronic hepatitis B (CHB). The primary modes of
transmission of HBV are by blood and body fluids through perinatal, sexual, or
percutaneous exposure. Infants born to mothers who are infected with actively replicating
HBV have a 90% risk of becoming infected.

Approximately 90% of adults infected with the HBV develop anti-HBs, which results in
lifelong immunity. Unfortunately, about 90% of infants born to mothers with active HBV
infection will develop CHB. About 50% of adults with acute HBV infections are
asymptomatic, and those with symptoms may experience jaundice or fatigue.
Hepatitis B is diagnosed when HBsAg is detectable in the serum, but it does not
distinguish between acute and chronic HBV. The presence of IgM antibodies to HBcAg
indicates active infection. IgG anti-HBc indicates either chronic infection or possible
immunity against HBV.
In most cases, detectable HBeAg indicates active viral replication. Measurement of HBV
DNA determines viral infectivity and quantifies viral replication. Once HBV viral
replication ceases, anti-HBe is detected in the serum. Therefore, CHB infections may be
differentiated as either HBeAg-positive or HBeAg-negative.
The risk of acquiring the HBV may be minimized by avoiding contaminated blood
products and high-risk behavior and by receiving the hepatitis B vaccine.
In some cases, postexposure prophylaxis with hepatitis B immune globulin (HBIG) may
be recommended to prevent the development of acute infection and CHB. HBIG provides
short-term passive immunization to prevent CHB infections in persons who had sexual,

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perinatal, or acute exposure to an HBsAg-positive person. The efficacy, side effect profile,
and warnings of HBIG are similar to IG when used for immunization against HAV.
The first hepatitis B vaccines were Recombivax HB and Engerix-B, and Hepatitis A and B
Combination Vaccine Twinrix combines both inactivated HAV and HBV which are given
at months 0, 1, and 6 and approved to be administered intramuscularly at birth.
The hepatitis B vaccine is also indicated for postexposure prophylaxis to prevent CHB. All
individuals exposed to HBV should receive the hepatitis B vaccine with or without HBIG,
preferably within 24 hours of exposure based on the source of exposure and the
vaccination status of the exposed person. HBV vaccine is indicated in History of multiple
blood transfusions, Patients on hemodialysis, Health care workers, Injection drug users,
Infants born to HBsAg-positive mothers.
Effective immunity may last for more than 30 years in healthy individuals. However,
patients with poor immune systems may have an anamnestic response that requires booster
doses given.
The most frequent adverse effects are local injection-site reactions, flu-like symptoms,
nausea, dizziness, fever, and headaches. They are also not contraindicated during
pregnancy and should be safe to the fetus because they are inactivated vaccines.
Chronic Hepatitis B Treatment
It is recommended to treat HBeAg-positive patients with persistently elevated ALT (more
than two times the upper limit of normal) or significant histological disease and elevated
HBV DNA levels to delay progression to cirrhosis and prevent the development of ESLD.
The drug of choice for CHB depends on the patient’s past medical history, ALT, HBV
DNA level, HBeAg status, severity of liver disease, and history of previous HBV therapy.
All HBV therapies are effective with no agent showing superiority to others in reducing
the risk of developing HBV complications.
Entecavir, tenofovir, and pegylated (peg) IFN-α2a are recommended first-line therapies
due to profound HBV DNA suppression; the latter agent should be considered in patients
with compensated liver disease because of its finite treatment duration and lack of drug
resistance. Adefovir and lamivudine are not recommended due to high rates of resistance.
The side effect profiles for all oral HBV agents are mild; the most common complaints are
nausea, headaches, dizziness, and fatigue. Patients should be monitored for lactic acidosis
and severe hepatomegaly because some cases have been fatal.
Interferon and Pegylated Interferon
PegIFN-α2a (Pegasys) is the only IFN therapy approved for HBV that is effective in
suppressing, and in some cases ceasing, viral replication without inducing resistance.

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Approximately one-third of HBeAg-positive patients achieve HBeAg seroconversion after
48 weeks of pegIFN therapy.

Hepatitis D
The HDV is a defective single-stranded circular RNA virus that requires the presence of
HBV for HDV viral replication, causing either coinfection (both hepatitis B and D
infection occurring simultaneously) or superinfection (acquiring HDV after having long-
standing HBV disease). HDV infection is unique because it can only occur in people who
are also infected with the HBV. The most likely modes of transmitting HDV are similar to
those of HBV.

Hepatitis D is estimated to affect 20 million people worldwide. Areas with the highest
prevalence include the Middle East, parts of Africa, Northern and Southeast Asia, Eastern
Europe, the Mediterranean basin, and parts of South America.
Measuring HDV RNA levels confirms hepatitis D infection and is the most accurate
diagnostic test. The presence of IgM anti-HD indicates active disease, and IgG anti-HD
also becomes detectable if the infection does not resolve spontaneously. HDV antibodies
do not confer immunity.

Hepatitis D infection is possible only if the patient is also infected with HBV;
therefore, hepatitis B vaccination can indirectly prevent hepatitis D infections.
The recommended treatment for HDV is pegIFN for 48 weeks with several
adverse effects.

Hepatitis C (HCV)
It is estimated that 71 million people worldwide have chronic HCV. There are seven
genotypes (numbered 1–7) and 67 subtypes (eg, genotypes 1a, 1b, 2a, and 3b). Genotype
does not indicate disease severity but had been used during the non-pangenotypic HCV
therapy era to determine duration of therapy and the likelihood of a therapeutic response.
Hepatitis C is a blood-borne infection caused by a single-stranded RNA virus. Antibodies
against HCV (anti-HCV) in the blood indicate infection. Acute hepatitis C persists for less
than 6 months, occurs in about 15% of the population, and resolves without further
complications. If the infection persists longer than 6 months and viral replication is
confirmed by HCV RNA levels, the person has chronic hepatitis C (CHC), which occurs
in about 55% to 85% of cases. The most common risk factors for developing hepatic fibro-
sis include obesity, diabetes, heavy alcohol use, male sex, and coinfections with HIV or
HBV.

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 From 55% to 85% of CHC progress to mild, moderate, or severe hepatitis. Cirrhosis and
its complications may take several decades to develop in 15% to 30% of patients infected
with HCV. Once cirrhosis is confirmed, the risk of developing HCC is 2% to 4% per year.

Chronic hepatitis C (CHC) is diagnosed by testing for anti-HCV in the serum and
confirmed by the presence of HCV RNA. HCV RNA levels quantify viral replication and
are used to determine if treatment is effective. Undetectable HCV RNA levels indicate
past infection or that the infection is resolved. The HCV genotype should be determined if
a nonpangenotypic regimen will be prescribed.
There are currently no vaccines to prevent HCV, but several are under development.
Avoiding high-risk behaviors such as sharing needles among PWID is the primary means
of acquiring HCV.

Treatment for HCV has been revolutionized over the past decade, with efficacy rates well
above 90% compared to 50% to 80% before 2011. The primary goal of HCV treatment is
to achieve a sustained virologic response (SVR), defined as undetectable HCV RNA levels
at 12 weeks or longer after treatment completion.

Interferon/Pegylated Interferon and Ribavirin

IFN and pegIFN are no longer recommended for chronic HCV because SVR rates (about
50%) are suboptimal along with a number of untoward events. The addition of ribavirin, a
synthetic guanosine analog that inhibits viral polymerase, had increased SVR rates with
pegIFN (50%–80%) and continues to be prescribed with direct-acting antivirals (DAA) for
certain patient populations to enhance SVR rates. Ribavirin causes a dose-related
hemolytic anemia that may require dosage reductions or discontinuation. Dermatological
effects (eg, rash, pruritus, and dry skin) occur commonly with ribavirin. Because ribavirin
can be teratogenic and embryocidal, all women of childbearing age and men who are able
to father a child must use two forms of contraception during HCV therapy containing
ribavirin and for 6 months after completion of treatment.

Direct-Acting Antiviral Agents

The two first-generation DAAs (boceprevir and telaprevir) and several second-generation
DAAs (eg, simeprevir) are no longer available because newer agents have superior
response rates, fewer adverse effects, reduced pill burden, simplified dosing regimens,
fewer drug interactions, and lower rates of viral resistance.
Third-generation DAAs have SVR rates well above 90%, once daily dosing, fewer adverse
effects, safety for all stages of renal dysfunction, shorter treatment durations with less
complex regimens, and several agents that are pangenotypic (treat all HCV genotypes).
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Selection of a DAA is based on previous HCV treatment history, severity of liver disease,
current medical conditions and medications, and the presence or absence of resistance-
associated substitutions (RAS).
Sofosbuvir and Velpatasvir (Epclusa) is the first FDC approved for all six HCV
genotypes (known as a pangenotypic DAA) and is indicated for patients older than 6 years
or weighing greater than 17 kg. Sofosbuvir, an NS5B polymerase inhibitor, is combined
with velpatasvir, an NS5A inhibitor. Once-daily DAA regimen for 12 weeks is highly
effective with minimal adverse effects.
Sofosbuvir, Velpatasvir, and Voxilaprevir (Vosevi) is a pangenotypic FDC tablet that
contains drugs targeting three different sites to inhibit HCV viral replication. Similar to
Epclusa, Vosevi also includes a NS3/4A protease inhibitor, voxilaprevir. The once-daily
FDC tablet is taken daily with food for 12 weeks for adults with or without compensated
cirrhosis who have been previously treated with an HCV regimen that included an NS5A
inhibitor or sofosbuvir. This triple therapy has SVR rates above 95%, particularly in DAA-
experienced patients.
Glecaprevir and Pibrentasvir (Mavyret) is the first pangenotypic FDC tablet containing
an NS3/4A protease inhibitor (glecaprevir) and an NS5A inhibitor (pibrentasvir). It is
approved for patients 12 years and older weighing at least 45 kg with or without
compensated cirrhosis or patients who are treatment experienced with either an HCV
NS3/4A or NS5A inhibitor. It may be administered for 8, 12, or 16 weeks. The 8-week
DAA treatment is effective for all HCV genotypes in: (a) noncirrhotic naïve-treated
patients, (b) patients with compensated cirrhosis, (c) patients coinfected with HIV, and (d)
patients with renal insufficiency.

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 Liver Cirrhosis

Cirrhosis, or end-stage liver disease, can be defined as fibrosis of the hepatic parenchyma
(hepatocytes) resulting in nodule formation with the consequent altered hepatic function.
Cirrhosis has many causes:

Category Example
Infections Chronic viral hepatitis (types B and C)
Metabolic liver Hemochromatosis
disease Wilson’s disease
α1-antitrypsin deficiency
fatty liver
Immunologic disease Autoimmune hepatitis
Primary biliary cirrhosis
Vascular disease Budd–Chiari
Cardiac failure
Drugs and toxins Chronic alcohol consumption, isoniazid, methyldopa,
amiodarone, amoxicillin-clavulanate, nitrofurantoin,
diclofenac, methotrexate, propylthiouracil, valproate

The main pathophysiologic abnormalities that result from cirrhosis are:

 Portal hypertension and esophageal varices
 Ascites
 Spontaneous bacterial peritonitis
 Hepatic encephalopathy
 Hepatorenal syndrome
 Coagulation defects

Portal Hypertension
Portal hypertension means increased blood pressure in the hepatic portal system or the
portal venous system. Most commonly caused by hepatic cirrhosis in which the
hepatocytes are replaced by fibrotic tissue. This leads to narrowing of blood flow from the
portal vein to the vena cava. In portal hypertension the blood pressure within the portal

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system increased to more than 12 mmHg. This leads to the formation of portosystemic
shunts, diversion of blood flow.
This would lead to decreased blood flow to the liver, subsequently decreased liver
function, decreased blood detoxification and build-up of toxic metabolites like ammonia
which can pass BBB causing encephalopathy.
Portosystemic shunts occur at some points where systemic venous system and hepatic
portal system are connected in the oesophagus causing oesophageal varices. These varices
are very fragile and can easily rupture and causing massive GI bleeding. In the rectum and
anal canal, there may be haemorrhoids (which are large veins that can bleeds as well).
Hemorrhage from varices occurs in 25% -40% of patients with cirrhosis and is the cause
of death for one third of these patients.
Another consequence of portal hypertension, is that the endothelial cells lining the blood
vessels release more nitric oxide (the reason is not clear). Nitric oxide makes peripheral
arteries dilate, so blood pressure drops, this stimulates the release of aldosterone, which
tries to bring blood pressure back by telling the kidneys to retain more sodium and water,
in time, plasma volume expands so much that fluid in the blood vessels is more likely to
get pushed into surrounding tissues and across tissues into large open spaces, like the
peritoneal cavity. The accumulation of fluid in the peritoneal cavity is called ascites.
Bacteria can invade the peritoneal cavity causing spontaneous peritonitis.

Treatment options for acute bleeding are the combination of vasoconstrictive

pharmacologic therapy and variceal ligation to manage bleeding. Octreotide 50 to 100 mcg
bolus followed by an infusion of 25 to 50 mcg/hour for 18 hours to 5 days. Vasopressin
0.2 to 0.4 units/minute as a continuous infusion, increased every hour by 0.2 units/minute
until bleeding is controlled (maximum of 0.8 units/minute with therapy not to exceed 24
hours).
Balloon tamponade is used as a temporary measure (maximum of 24 hours) to stop
massive bleeding.

Ascites

The most commonly occurring major complication of cirrhosis is ascites, which is the
accumulation of an excessive amounts of fluids within the peritoneal cavity.

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The development of ascites is related to the activation of the renin-angiotensin-aldosterone
system (RAAS), with sodium and water retention. Also the decrease in synthetic function
leads to a decrease in production of albumin (hypoalbuminemia). Albumin is the major
protein involved in maintaining the intravascular oncotic pressure. Hypoalbuminemia and
reduced plasma oncotic pressure also contribute to the loss of fluids from the intravascular
compartment into the peritoneal cavity.
Treatment
1. Restriction of dietary sodium to 2 g/day.

2. Water restriction in patients with severe dilutional hyponatremia.

3. Diuretics: Spironolactone (100 mg) as the initial diuretic of choice. The diuretic effect is
enhanced when combined with Na restriction (0.5–2 g/day). Furosemide (40 mg) can be
added to minimize the risk of hyperkalemia and enhance diuresis. The dose of both oral
diuretics can be increased simultaneously every 3 to 5 days, maintaining the 100:40 mg
ratio (maximum daily doses are spironolactone 400 mg and furosemide 160 mg).
Triamterine and amiloride are alternatives if intolerable side effects occur with
spironolactone.

4. Large-volume (>4 L) paracentesis (removal of ascitic fluid from the abdominal cavity)
is used for patients with tense ascites resulting in pulmonary distress or impaired
ambulation.

5. Concomitant infusion of albumin 25% solution can help prevent paracentesis- induced
circulatory dysfunction.

Spontaneous Bacterial Peritonitis (SBP)

SBP is a common and severe complication of ascites and is defined as the spontaneous
infection of the ascitic fluid. This condition has a mortality rate of about 30% to 50%.
The primary mechanism for SBP is bacterial translocation from the gut. Enteric Gram-
negative bacilli (most commonly E. coli and Klebsiella Spps. account for the majority of
SBP episodes). Patients may be asymptomatic, or may present with unexplained fever, or
nonspecific abdominal pain.
Treatment include: broad spectrum antibiotics: Third-generation cephalosporin or
Fluoroquinolones (ciprofloxacin or ofloxacin) may be used.
Albumin: Plasma volume expansion with albumin in addition to antibiotics decreases the
incidence of hepatorenal syndrome and improves survival.

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Hepatic encephalopathy (HE)

The symptoms of HE ranges from forgetfulness, mental confusion, lethargy, personality

changes, to somnolence, confusion, and coma. The symptoms are thought to result from an
accumulation of gut-derived nitrogenous substances in the systemic circulation. These
substances have the ability to enter the CNS and result in alterations of neurotransmitters
that affect consciousness and behaviour.
Treatment is aimed at reducing the amount of ammonia or nitrogenous products in the
circulatory system.
1. Daily intake of 35 to 40 kcal/kg of body weight and a protein intake of 1.2 to 1.5 g/kg
body weight has been recommended for patients awaiting transplantation.
2. Lactulose (10 g/15 mL) is effective for acute and chronic hepatic encephalopathy.
3. Rifaxamin (550 mg twice daily) or neomycin (500–1,000 mg orally four times daily) are
antibiotic options that reduce plasma ammonia concentrations.

Hepatorenal syndrome (HRS)

The hepatorenal syndrome (HRS) is a form of renal failure, but without renal pathology.
This renal failure occurs in about 10% of patients with advanced cirrhosis or acute liver
failure.
Type 1 HRS is characterized by progressive oliguria, a rapid rise of the serum creatinine
and a very poor prognosis. While type 2 HRS is more slowly progressive and chronic and
is associated with a better outcome than that of Type 1 HRS. Diuretic therapy must be
stopped as it can worsen kidney disease!
Guideline recommends the use of albumin plus octreotide and midodrine for type 1 HRS.
No particular treatment exists for type 2 HRS. Definitive treatment for HRS is liver
transplantation, an option that is generally considered in patients with refractory ascites,
severe hepatic encephalopathy, esophageal or gastric varices, and hepatorenal syndrome.

Coagulation defects

Most clotting factors are synthesized in the liver, and the levels of these factors can be
significantly reduced in chronic liver disease. The net effect of the coagulation disorders
that occur in cirrhosis is the development of bleeding tendency.

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Treatment is vitamin K (phytomenadione), 10 mg given IV for 3 days.

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