Viral hepatitis

Viral Hepatitis

Mohammed AdemB.pharm, M.clinpharm

Lecturer and clinical pharmacist

04/12/23 Mohammed Adem 1

Liver disease: syndromic approach

1. Hepatocellular: injury, inflammation, and necrosis of liver cells/liver parenchyma

2. Cholestatic: inhibition of bile flow

3. A mixed pattern : features of both hepatocellular and cholestatic disease

• The pattern of onset and prominence of symptoms can rapidly suggest a

diagnosis• Laboratory pattern is characteristic


Hepatitis

• Inflammation of liver parenchyma or hepatocytes:

• The are two types : duration based

– Acute hepatitis: duration for < 6 months

– Chronic hepatitis: lasting for ≥ 6 months


Acute hepatitis: causes

Acute Hepatitis< 6 months

Viral HepatitisA, B/D, C, E

EBVCMV …

DrugsAcetaminophen

IsoniazidAlcohol …

ToxinsMushrooms

carbon tetrachloride

VascularHypotensionBudd-Chiari

AutoimmuneHepatitis

MetabolicWilson's Disease


Chronic hepatitis: causes

Chronic Hepatitis> = 6 months

Viral Hepatitis B/D, C

DrugsMTXINH

Amiodarone

alcohol NAFLD

AutoimmuneHepatitis

PBCPSC

A1ATHHC

Wilson's


Acute viral Hepatitis

• a systemic infection affecting predominantly the liver

• almost all cases are caused by of the five hepatitis viral agents:

HAV, HBV/HDV, HCV, HEV

• all of these human Heptitis viruses are RNA viruses except HBV

• HDV is a defective RNA virus


Acute viral Hepatitis…o Although these agents can be distinguished by their molecular

and antigenic properties all of them produce clinically similar illnesses.

These range from

• asymptomatic and inapparent to fulminant and fatal acute

infections common to all types, and

• from subclinical persistent infections to rapidly progressive

chronic liver disease with cirrhosis and even HCC , common to

the blood borne types (HBV, HCV, and HDV)


Acute viral Hepatitis…• Although the rates of acute infection have declined, viral hepatitis remains

a major cause of morbidity and mortality with a significant impact on

healthcare costs.

• Significant therapeutic advances have occurred with hepatitis B with the approval of new agents and updated guidelines for care.

• For hepatitis C, the challenge remains of increasing successful outcomes while minimizing side effects of therapy


Acute viral Hepatitis…

• Incubation period & risk factors vary with each hepatitis virus

• may mimic other systemic infections

• most symptoms are non-specific

• most patients are asymptomatic


Incubation Period

• Hepatitis A: 15-45 days (30)

• Hepatitis B: 30-180 days (70)

• Hepatitis C: 15-160 days (50)

• Hepatitis D: 21-140 days (35)

• Hepatitis E: 15-65 days (40)

• Hepatitis G: (14- ? days)


Acute viral hepatitis: clinical features

• Prodromal Sx of acute viral hepatitis are systemic and variable

• Constitutional Sx may precede the onset of jaundice by 1–2

weeks. – Anorexia, nausea, vomiting, fatigue, malaise, arthralgia, myalgia, headache,

photophobia, cough and coryza– Low-grade fever

• Sx and signs related to liver dysfunction – Dark urine, clay-colored – By the time of jaundice appears, these will go away or diminish – Enlarged and tender liver– Splenomegaly– Cervical lymphadenopathy


Mini-case 1• Eden and Bruk, Ethiopian couples returned from their

honeymoon trip to Central America and develops nonspecific abdominal symptoms followed by clinical jaundice.

• They stayed at a resort, and ate fresh fruits and salads. Serology for hepatitis virus spread by the fecaloral route is positive. One of the following is the most likely:

• hepatitis A virus; • hepatitis B virus• hepatitis E virus• A and C• hepatitis C virus• hepatitis D virus04/12/23 Mohammed Adem 12

Mini-case 2E.T., a 34-year-old medical sales representative, presents to the ED at Black Lion

Hospital with acute onset of jaundice and “dark urine.” He was in good health

until 2 weeks ago, when he noted feeling fatigued and weak, which he attributed

to his demanding work schedule.

He also recalled having a mild headache, loss of appetite, muscle pain, diarrhea,

and low-grade fevers from 99°F to 101°F.

He attributed these symptoms to the flu and took acetaminophen with plenty of

fluids. His symptoms persisted until yesterday, when they seemed to resolve

unexplainably. He then noted his urine was cola-colored.

This morning, he noted jaundice of his eyes and skin and sought medical attention.

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MH:

a recent respiratory tract infection, treated successfully with levofloxacin.

SH:

is significant for frequenting the local bar, where he regularly ingests raw meats. He

denies smoking and recent travel to heptitis A endemic areas, but admits to

occasional alcohol consumption.

E.T. has no Hx of sexual exposure, needle use, or transfusions. His current

medications include oral (PO) diazepam 5 mg at bedtime (HS) as needed (PRN)

for “muscle spasms,” but he has not taken diazepam for “several months.” He

also has a seizure disorder sustained after a motorcycle accident 2 years before

admission, for which he takes phenytoin 400 mg PO HS.

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Mohammed Adem 14

PE ;significant for a well-developed, well-nourished man in no acute distress. He is

alert and oriented, with a temperature of 99°F. His sclerae and skin are icteric, and his abdomen is positive for a tender, enlarged liver, and right upper quadrant (RUQ) pain.

Laboratory tests: reveal the following values:

Hgb, 16 g/dL (12.3–16.3); Hct, 44% (37.4%–47.0%); WBC, 5,500 cells/mm3 (3.28–9.29 × 103); AST, 120 U/L (5–40); ALT, 240 U/L (5–40);

AP, 86 U/L ( 21–91); total Bl , 3.2 mg/dL (0.2–1.0); Bl (D), 1.5 mg/dL (0–

0.2); and phenytoin concentration, 12 mg/L (10–20).

The albumin, PT, blood glucose, and electrolytes all are within normal limits.

E.T. is negative for anti-HCV, HBeAg, HBsAg, and hepatitis B core antibody (anti-HBc), but is positive for IgM anti-HAV.

What clinical features and serologic markers are consistent with viral hepatitis in E.T.?


HEPATITIS A : HAV


HAV…• HAVis often a self-limiting and acute viral infection of the liver

posing a health risk worldwide.

•

• The infection is rarely fatal.

• Although vaccine preventable, HAV continues to be one of the

most commonly reported infections.


Epidemiology• Faeco-oral route

– where hygiene is poor, infection is almost universal during childhood

– As hygiene improves, rate of childhood infection decreases common

• Close personal contact– Household, child-care centers– Identifiable risk sexual (Promiscuous MSM); household contact with person with HAV; IDUs

• Contaminated food, water– Infected food handlers, international travelers (endemic areas), immigration

• Blood exposure (rare)– 45-50% have no identified source

• Despite being detectable in saliva, there are no data to suggest transmission through this mode of contact.

NB: It almost always manifests with a self-limited clinical course


Etiology• HAV is a RNA virus. genus Hepatovirus , Picornaviridae family.

• Humans are the only known reservoir for the virus and transmission occurs primarily through the fecal–oral route.

• The virus is stable in the environment for at least a month. requires heating foods to a minimum of 85°C (185°F) for 1 minute or

disinfecting with a 1:100 dilution of sodium hypochlorite (bleach) in tap water for inactivation.

• Multiple genotypes of the virus exist and although the clinical implications of infection by particular type are unknown.

types I and III are the most commonly identified in human outbreaks


Pathophysiology• HAV infection is usually acute, self-limiting, confers lifelong

immunity.

• HAV's life cycle in the human host classically begins with ingestion of the virus.

• Absorption in the stomach or small intestine allows entry into the circulation and uptake by the liver.

• Replication of the virus occurs within hepatocytes & GI epithelial cells.

• New virus particles are released into the blood & secreted into bile by the liver.

• The virus is then either reabsorbed to continue its cycle or excreted in the stool.


Pathophysiology…• The enterohepatic cycle will continue until interrupted by antibody

neutralization.

• The exact mechanism of replication & secretion is unknown. however, the initial viral expansion does not seem to be associated with hepatic injury as peak viral fecal excretion precedes clinical signs and symptoms of infection.

• On biopsy, acute hepatitis is marked by hepatocellular degeneration, inflammatory infiltrate, and hepatocyte regeneration.

• Hepatocellular degeneration occurs as a result of immune-mediated injury and not as a direct cytopathic effect of the virus.

• Cytolytic T cells mediate hepatocyte lysis to eradicate the virus and mark the cellular immune response with rising hepatic enzyme levels.


Risk Factors

• Ingestion of contaminated food substances – Large outbreaks as well as sporadic cases have been traced to

contaminated: Food , Water, Milk

• Family member who is affected

• Poor personal hygiene

• Institutional resident who is affected • Child care centers • Neonatal intensive care units

• MSM, IVDU04/12/23 Mohammed Adem 22

Clinical presentations…

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Clinical presentations… Signs and symptoms

• Symptoms and severity of HAV vary according to age

• Children <6 years of age typically are asymptomatic.

• The preicteric phase brings nonspecific influenza-like Sx: anorexia, nausea, fatigue, and malaise

• Abrupt onset of anorexia, N, V, fever, headache & RUQ abdominal pain

• Icteric hepatitis is generally accompanied by dark urine, acholic (light-colored) stools, and worsening of systemic Sx.

• Pruritus is often a major complaint of icteric patients

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Clinical presentations• Incubation period : 15–45 days ; Mean: ~4 weeks

• Viremia occurs within 1-2 weeks of exposure as patients begin to shed the virus. viral shedding in feces,

• Peak fecal shedding of the virus precedes the onset of clinical Sx & elevated liver enzymes.

• Acute hepatitis follows, beginning with the preicteric or prodromal period.

The phase is marked by an abrupt onset of nonspecific symptoms, some very mild

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Clinical presentations…• unusual Sx : chills, myalgia, arthralgia, cough, constipation, diarrhea, pruritus,

and urticaria. Non-specific

• Liver enzyme levels rise within the first wks of infection, peaking

~ in the 4th wk and normalizing by the 8th wk.

• Conjugated bilirubinemia, or dark urine, precedes the onset of the icteric period.

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Clinical presentations…• The concentration of virus declines at this point and

patients are generally considered noninfectious ~ 1 week after the onset of jaundice.

• GI Sx may persist or subside during this time and some patients may have hepatomegaly.

• Duration of the icteric period varies and corresponds to disease duration. It averages between 7 and 30 days.

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Clinical presentations…Physical examination

• Icteric sclera, skin, and secretions

• Mild weight loss of 2–5 kg

• Hepatomegaly

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Clinical presentations…Laboratory findings

• Positive-serum IGM ,

• IgG replaces IgM and indicates host immunity following the acute phase.

• Mild elevations of serum bilirubin, -globulin, and ALT , AST values to about 2X normal in acute anicteric disease

• Elevations of AP, - GGT and total bilirubin in patients with cholestatic illness

• Serum HAV becomes detectable 5 - 10 days before the onset of symptoms and can persist for months

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Prognosis• HAV does not lead to chronic infections.

• Some pts may experience Sx for up to 9 months.

• Virtually all previously healthy patients with hepatitis A recover completely from their illness, with no clinical sequelae.

• Complete clinical and biochemical recovery is to be expected in 1–2 months.

• No chronic carrier state

• fatality rate: ~ 0.1%

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Complications• Rarely, patients experience complications from HAV, including

relapsing hepatitis, cholestatic hepatitis, and fulminant hepatitis

• Relapsing hepatitis :– Recurrence of symptoms – Elevated liver enzyme levels – Jaundice (occasionally) – Fecal excretion of HAV

– Even when this occurs, hepatitis A remains self-limited and does not progress to chronic liver disease.

• Cholestatic hepatitis – Characterized by protracted cholestatic jaundice and pruritus

• Fulminant hepatitis (massive hepatic necrosis): Rare 0.1% yet high fatality

– Primarily in older adults (50), younger children and in persons with underlying chronic liver disease


Diagnosis

• History: particular attention to risk factors

• Clinical Criteria: acute onset of fatigue, abdominal pain, loss of

appetite, intermittent nausea and vomiting, jaundice

• Laboratory: serum aminotransferases, and serologic testing for anti-HAV antibodies.

IgM anti-HAV is the diagnostic test of choice• Appears very soon after infection

• Disappears 3–6 months later

• Incidental presence of rheumatoid factor can yield false-positive results

• IgG anti-HAV appears later in the acute phase but persists for decades 04/12/23 Mohammed Adem 32

Differential diagnosis1. Other hepatitis viruses

2. Other viral illnesses frequently affect the liver– Infectious mononucleosis , Cytomegalovirus , Herpes simplex

3. Many drugs and certain anesthetic agents

4. Alcoholic hepatitis

5. Acute Cholecystitis

6. Disorders in pregnancy that may be confused with viral hepatitis

• Acute fatty liver of pregnancy , Cholestasis of pregnancy , Eclampsia ,

7. Many, many more…


http://www.harrisonspractice.com/practice/ub/view/Harrisons%20Practice/141079/0/Infectious_mononucleosis

http://www.harrisonspractice.com/practice/ub/view/Harrisons%20Practice/141080/0/Cytomegalovirus

http://www.harrisonspractice.com/practice/ub/view/Harrisons%20Practice/141077/0/Herpes_simplex

Treatment• Mainstay of therapy is supportive care.

• Specific treatment is not necessary. – Most patients hospitalized with hepatitis A excrete little if any HAV

– Likelihood of HAV transmission from these patients during their hospitalization is low.

Nonetheless, universal precautions are recommended.

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TreatmentDesired Outcome

• The ultimate goal of therapy is complete clinical resolution.

• Other goals: reducing complications, normalization of liver function, and reducing infectivity and transmission.

• The majority of pts are expected to fully recover without clinical sequelae.

• clinical resolution within 6 months of the infection, & a majority will have done so by 2 months.

• Rarely, Sx persist for longer or patients relapse.

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Treatment…General Approach

• In pts who develop liver failure, transplant is the only option.

• Prevention and prophylaxis are key to managing the virus.

• Immunoglobulin: for pre- and postexposure prophylaxis

offers passive immunity.

• Active immunity is achieved through vaccination. Children and at-risk adults to reduce the overall incidence

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Treatment…• Most patients hospitalized with hepatitis A excrete little if any

HAV. Likelihood of transmission is low

• Prevaccination serologic testing to determine susceptibility is generally not recommended

if the cost of the test is less than that of the vaccine and if the person is from a moderate to high endemic area and likely to have prior

immunity

• Prevaccination serologic testing of children is not recommended.

• postvaccine serologic testing is not recommended. Due to high vaccine response

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Prevention

• HAV is easily preventable with vaccination.

• vaccine programs have targeted children as the most effective means to control HAV.

• vaccination programs among children from high-incidence states >70% reduction in the annual incidence of new HAV infections

• Two vaccines for HAV are available and are incorporated into the routine childhood vaccination schedule.


Prevention… Recommendation for HAV Vaccine


Prevention…

• Routine prevention of HAV transmission includes with soap and water after using the bathroom, Regular hand washing changing a diaper, and before food preparation.

• For travelers to countries with high endemic rates of HAV, even short-term stays in urban and upscale resorts are not risk free.

contaminated water fresh produce, and any uncooked foods pose a risk


Vaccines• Havrix and Vaqta: are available for pediatric and adult use. USA the two inactivated virus vaccines. 1995

• The differences in the two vaccines are in the use of a preservative and in expression of antigen content.

• Vaqta: formulated without a preservative and uses units of HAV antigen to express potency.

• Havrix: uses 2-phenoxyphenol as a preservative and antigen content is expressed as enzyme-linked immunosorbent assay

units.

• Pediatric dosing is indicated for children 1 to 18 years of age, and adult dosing is for patients ages 19 years and older


Vaccines …• Although high seroconversion rates of 94% are achieved with the

first dose, both vaccines recommend a booster shot to achieve the highest possible antibody titers.

• In situations of postexposure prophylaxis, previously only

immunoglobulin was indicated but recent guidelines changes allow the use of vaccines for this indication.

The change to the use of the vaccine is advantageous as vaccination confers the benefit of long-term immunity against HAV.

• Both vaccines may be given concomitantly with immunoglobulin and the two brands are interchangeable for booster shots.


Recommended dosing of the Vaccines


Vaccines … monitoring issues

• Response to the vaccine as determined by detection of anti-HAV after vaccination.

• Vaccine efficacy may be reduced in certain pt groups. eg. In HIV infected pts, greater immunogenic response may correlate with higher baseline CD4 counts. females and patients with CD4 counts >200 high response rate

• most common S/E: soreness & warmth at the injection site, headache, malaise, pain

• Reported serious A/E: causality not yet established anaphylaxis, Guillain-Barré syndrome, transverse myelitis Reported brachial plexus neuropathy, multiple sclerosis, encephalopathy, and erythema multiforme.

Note: the incidence of these events was similar in the general population. Vacc vs unvacc

The vaccine is considered safe04/12/23 Mohammed Adem 44

Vaccines … Twinrix

• Twinrix is a bivalent vaccine for HAV and HBV. in 2001

• It is approved for people ages 18 and older and is given at 0, 1, and 6 months.

• Although seroconversion exceeds 90% for HAV after the first dose , the full three-dose series is required for maximal HBV seroconversion.

• The combined vaccine offers the advantage of immunization against both types of hepatitis in a single vaccine.


Immunoglobulin/Ig • Used in persons for whom vaccination is not an option. pre- or postexposure prophylaxis

• provides protection by passive transfer of antibody• is preferred for children <12 months of age and postexposure prophylaxis in patients aged >40 years, pts with chronic liver disease,

and persons allergic to any part of the vaccine.

• most effective if given in the incubation period of the infection. Receipt of Ig within the first 2 weeks of infection will reduce infectivity and moderate the

infection in 85% of patients.

Note: Patients who receive at least 1 dose of the vaccine at least 1 month earlier do not need pre- or postexposure prophylaxis with Ig.


Ig… • International travelers are the major patient population receiving

preexposure prophylaxis with Ig.

• vaccination or prophylaxis with Ig is recommended for travelers to countries with high endemic rates of HAV. A/E like anphylaxis IgA deficiency

• Patients who had an anaphylaxis reaction to Ig should not receive it. There is no C/I for use in pregnancy or lactation.

• Dosing of Ig is the same for adults and children.

• a single dose of 0.02 mL/kg IM: For postexposure prophylaxis and for short-term preexposure coverage of <3 months,


Ig… • For long-term preexposure prophylaxis of 5 months a single dose of 0.06 mL/kg is used.

• People recently exposed to HAV and not been previously vaccinated Ig is indicated for

a) close personal contact with an HAV-infected person; b) all staff and attendees of daycare centers when HAV is documented;c) common source of exposure (food handler)d) classroom contacts of an index case patient; ande) schools, hospitals, and work settings where close personal contact occurred with the

case patient

• Ig can be given concomitantly with the HAV vaccine. the response is protective


Ig… • The MMR (measles, mumps, and rubella) vaccine should be delayed for a minimum of

3 months after receipt of Ig.

• The varicella vaccine must be delayed for 5 months.

• Ig should not be given to patients who received the MMR within 2 weeks or the varicella vaccine within 3 weeks.

• In situations where the benefits of Ig outweigh the benefits of the other vaccines, revaccination can be performed after Ig administration.

• For the MMR, revaccination should be at least 3 months later, and for the varicella vaccine, at least 5 months later.

• Ig does not interfere with inactivated vaccines and may be administered safely with other vaccines traditionally given to travelers to some developing countries, such as the oral poliovirus or yellow fever vaccine.


Pharmacoeconomic Considerations

• The costs of an HAV outbreak are significant, yet routine vaccination of all individuals is not cost-effective. So,

• targeting at-risk populations, the majority of cases can be prevented. Children play a pivotal role in disease persistence

• Using vaccine is cost-effective in children and offers the most benefit to the personal contacts of children.

• The use of the combined HAV-HBV vaccine is effective in reducing costs associated with HAV among persons who are at increased risk for infection.


References

• Harrison’s principle of internal medicine 18th ed

• Joseph T dipro; Pharmacotherapy a

pathophysiologic approach 8th ed

• Applied therapeutics the clinical use of drugs 9th

ed


Health & Medicine

Viral hepatitis