HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

HEPATITIS pruritus, pedal edema, esophageal and intestinal varices,
encephalopathy
 Injury to the liver characterized by inflammation and impaired liver
function PRESENTATION OF PATIENTS WITH HEPATITIS
 Usually caused by viral infection  Cirrhotic habitus – Ascites
 Other causes are alcohol, drugs, toxin, autoimmune, alpha 1
antitrypsin deficiency, metabolic disorders like Wilson disease,
hemochromatosis, glycogenosis – pwede silang differential
diagnosis ng hepa

HEPATITIS VIRUS
 A, B, C, D, E – 95% of viral infection
 Enteral (A & E) or parenteral group (B, C, D)
 Other causes of viral infection are HS, CMV, EBV, YFV, adenovirus,
mumps virus, rubella virus, rubeola, coxackie B
 F(?), G Ascites grading:
 Can be acute or chronic hepatitis 1. Mild, only visible on ultrasound
 Chronic hepatitis – B, C, D (not seen in A and E) 2. Detectable with flank bulging and shifting dullness
3. Directly visible, confirmed with fluid thrill
Phases of hepatitis:
 Incubation phase or period – period between actual infection and  Caput medusa
presence of SSx
 Preicteric phase – non specific ssx
 Icteric phase – icteresia/ jaundice
 Convalescent phase

ACUTE VIRAL HEPATITIS

 Clinical Characteristics of acute viral infection are the same (all
hepa viruses)
 Mild to fulminant
 Asymptomatic in younger patients
 Initially present as nonspecific flu-like symptoms: fever, N/V, Due to opening of the round ligament secondary to increased
diarrhea, malaise (95%), myalgia, arthralgia, diarrhea  not all pressure
these symptoms are present in one patient  Esophageal varices
 Later present with anorexia, abdominal pain, dark colored urine,
jaundice (33%)
 Tender hepatomegaly (10%)
 Splenomegaly and lymphadenopathy (5%)

May present as:

1. Subclinical – does not present any ssx, or very minor (loss of
appetite)
2. Anicteric – no jaundice, but with nonspecific ssx, and elevation
of liver enzymes and billirubin
3. Fulminant hepatitis – jaundice, very high liver enzymes,
hepatic encephalopathy, death  Icteric sclera

CHRONIC VIRAL HEPATITIS

FOR HEPA B, C AND B&D
 Asymptomatic (incidental finding) or mild symptoms some have
return of acute symptoms
 Usually discovered by abnormal blood test: abnormal LFT, presence
of relevant serologic markers, viral isolation
 May present signs and symptoms of cirrhosis
 Loss of weight, abdominal discomfort
 May develop to liver tumor/hepatocellular Ca, secondary to
chronic viral hepatitis
 6 months and above
 Hepatosplenomegaly, ascites, spider nevi, esophageal varices, low
grade fever, weight loss, gynecomastia, easy bruisability, jaundice,

Magno Opere Somnia Dura Page 1 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

 Spider nevi & palmar erythema 3 PATTERNS OF ABNORMAL LIVER FUNCTION TEST
1. Hepatocellular
 Inc. serum transaminases (AST,ALT)
2. Cholestatic
 Inc. Alkaline phosphatase
 Inc. GGT
3. Impaired synthetic function
 Inc. protime
 Dec. albumin

ALT - primarily found in the liver, indicates liver parenchymal injury

 Gynecomastia AST – found in other parts of the body, kidneys, brain, muscles, heart
*mas reliableang ALT/SGPT
*in practice, both are requested

 High levels of liver enzymes do not always reveal the degree of

liver inflammation or damage or prognosis
 It only measures liver damage at one point in time – di sya
reliable.

 AST:ALT Ratio –
o >2.0 – alcoholic hepatitis
o <1.0 – viral hepatitis
 Macronodular Cirrhosis (walang picture) - >3mm, caused
by hepatitis & C (most common), but it can also be caused
SERUM TRANSAMINASES
by wilson’s disease, and alpha-1-AT deficiency.
 Major elevations (>1000 IU/L)
o Toxic damage
o Acute viral hepatitis
o Autoimmune hepatitis
o Ischemic liver injury

 Moderate elevations (100-300 IU/L)

o Alcoholic hepatitis
o NASH
o Autoimmune hepatitis
o Wilson’s disease

 Minor elevations (<100 IU/L)

o Chronic hepatitis B&C
o Hemochromatosis
HEPATIC ENCEPHALOPATHY STAGES: o Fatty liver

CHOLESTASIS
 Increase in ALKALINE PHOSPHATASE
 Most common cause: biliary obstruction
 Other causes: stone, tumor, lymph node enlargement
 Very high alkaline phosphatase (2000 and above) – consider
hepatic infiltration, with malignancy or granulomatous lesion (TB,
sarcoidosis, etc.
 Alkaline phosphatase: not exclusively produced by biliary tree,
SPLEEN meron din sa bones, kidney, intestines and placenta.
“Sugar icing / hyaline perisplenitis”
Itching in absence of jaundice, consider:
EXCESS ESTROGEN Primary biliary cirrhosis (PBC)
- Gynecomastia Primary sclerosing cholangitis (PSC)
- Inc in estradiol – due to increase of peripheral conversion of
androgen to androstinedione and testosterone GAMMA GLUTAMYL TRANSFERASE
- Testicular atrophy  if elevated, there is a pathology in the biliary system
- Spider nevi
- Palmar erythema

Magno Opere Somnia Dura Page 2 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

CHOLESTATIC VARIANT HEPATITIS A HEPATITIS A
 Where, Hepa A positive and there is an increase in Alkaline -most common cause of hepatitis worldwide
phosphatase -highly endemic in developing countries
 Commonly caused by large duct biliary obstruction -outbreaks of hep A are commonly seen in child care centers, illicit
 And is also caused by: drug users, schools especially in the Philippines.
o CBD stone
o Chronic pancreatitis HEPATITIS A Virus
o Pancreatic Ca  Non enveloped Single stranded positive-sense linear RNA virus
o Cholangio Ca  Picornaviridae family
o PBC  Can live outside the body for months in fresh and salt water
o PSC  Killed by heat 85 degrees centigrade and chlorinated water
o Intrahepatic cholestasis of sepsis  4 human genotypes that are antigenically closely related
o Drug induced  One genotype confers immunity to other genotype
 Present in liver, bile, stool and blood- patient is communicable
Liver infiltration can also cause cholestasis – sarcoid, amyloid,
before the onset of symptoms and later part of the disease
granuloma, liver mets
CASE DEFINITION
IMPAIRED LIVER FUNCTION
 Discrete symptoms of acute viral infection
Pro time: acute or chronic
 Jaundice or increase liver enzymes (ALT & AST) in the serum
 Important predictor of outcome
 Serologic test positive for HAV IgM – even without signs and
 May rise up to >50secs in acute liver failure
symptoms
 In cirrhosis, 2-5 secs
 Most common cause of viral hepatitis worldwide
 >20 secs, poor outcome
Albumin
TRANSMISSION
 Measures chronic condition of liver, because albumin has long
half life (20-30 days) hence, not a good indicator of acute liver  Person to person transmission through oral-fecal route – usually by
injury close personal contact with an infected household member or
 You have to rule out first other non hepatic cause, ex: sexual partner
proteinuria, malutrition  Intake of fecal contaminated food and drinks – common source of
Jaundice outbreaks and sporadic cases
 Prehepatic  Replicates exclusively in the liver, pass thru the biliary tree and
O Inc. In the rate of hemolysis shed in the feces 1-2 weeks before & at least 1 week after the
O Malaria, HUS, sickle cell anemia, thalassemia, G6PD def onset of illness – Period communicability
 Hepatic  Vertical transmission – rare but documented
O Acute and chronic hepatitis, hepatotoxicity, autoimmune
hepatitis, PATHOPHYSIOLOGY
 Post hepatic Ingested virus enters mucosa  into the bloodstream  infect and
O Obstruction, stones, strictures multiply in the hepatocytes  biliary tree  feces (1-2 weeks
before, and 1 week after illness)
LABORATORY TEST AND FINDINGS
 Elevated liver enzymes ALT AST PATHOLOGY
 Elevated bilirubin  Liver
 Prolonged prothrombin time (decrease in platelets,  Inflammation and necrosis
thrombocytopenia)  due to increase in production of  Increased cellularity at portal areas due to immune response
thrombopoietin
 Abnormal imaging: high resolution ultrasound, CT scan, MRI CLINICAL COURSE
 Decrease in serum albumin  Incubation period 15- 50 days (28-30 days)
 Serologic test, PCR, viral isolation  Generally associated with abrupt onset of illness and fever for a
few days
 As ictericia ensues other symptoms improve and ictericia usually
last for less than 2 weeks
 Symptoms usually last for less than 2 months
 No chronic case
 No reinfection because of HAV IgG which give lifelong immunity
 Relapsing or biphasic hepatitis occurs in 1.5 -11.9% (10-15) with an
interval 4-15 weeks. (same as typhoid, may relapse)
 The enterohepatic cycling of the virus may contribute in such case
 Cholestatic variant occurs 8% of cases characterized by severe
pruritus, diarrhea, weight loss, malabsorption

Magno Opere Somnia Dura Page 3 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

DIFFERENTIAL DIAGNOSIS  It consists of viral envelope and a core particle made of
 Gall bladder diseases nucleocapsid protein, polymerase protein and viral genome
 Gastroenteritis (circular/partially double stranded)
 Drug induced hepa  Can survive outside the body for at least 7 days and still be capable
 Enteric bacterial infection of infecting

LABORATORY TESTS HBV MUTANT

 Inc. AST ALT (4-100x)- peaks 3-10days  Mutation in the HbSAg  failure to detect and
 Inc. serum billirubin – peaks 1-2wks treatment/immunity
 Inc. ProTime  Diagnostic failure – with Hepa B but has negative screening test
 Dec. in albumin
 (+) serology (HAV-IgM) disappear 4-6mo TRANSMISSION
 Imaging not needed, used to rule out other pathologies  Sex with an infected partner
 Liver biopsy not indicated  Injection drug use that involves sharing needles, syringes or drug-
preparation equipment
TREATMENT  Birth to an infected mother
 Supportive  Contact with blood or open sores of an infected person, contact to
 No specific drug therapy intact mucosa, buccal cavity, talsik ng dugo
 Resistant to most current antiviral  Needle sticks or sharp instrument exposures
 Hospitalization – if with consistent vomiting or suspected fulminant  Sharing items such as razors or toothbrushes with an infected
hepatitis or with encephalopathy person

PROGNOSIS HIGH RISK INDIVIDUALS

 Good prognosis with a case fatality rate of 0.4%  IV drug users
 Clinical severity is proportional to age  MSM
 Younger patients have milder clinical form  Heterosexual contact with multiple partners
 Fulminant hepatitis is rare in hepatitis A  Household contact with multiple partners
 Persons with hemophilia
PREVENTION  Patients/staff in hemodialysis centers
 Sanitation  Occupational exposure
 Active immunization – mainstay  Patients receiving immunosuppressants
 PEP-HAV immunoglobulin within 2 weeks after exposure is > 85%  Infants born on infected mothers
protective  Persons with chronic elevations of liver enzymes
 For high risk people – MSM, occupational, travel
 .02 ml/kg BWT PATHOGENESIS
 HAV inactivated vaccine (0-16)  Cytotoxic T cells lyse infected hepatocytes, involve CD4 and NK
Cells, and will generate Antibody production.
HEPATITIS B  Hepa B does not have cytopathic effect
 Can survive outside the body and can be a source of infection until  Direct cytopathic effect will show at heavy viral loads
7 days  Produce little or no cytopathic effect  viral amino acids are
 Highly communicable loaded to MHC class I and transported to liver cell surface 
 May cause hepatocellular Ca recognized and destroyed by virus specific cytotoxic T
lymphocytes  viral clearance  if failed, will result to chronic
EPIDEMIOLOGY infection  activation of crucial host genes that will result to
 350 million people are infected with hepatitis B hepatocellular Ca
 5% of world population, with chronic Hep B
 Genotypes: MOLECULAR PATHOGENESIS
o A & D – predominant in the US and Europe  HBV replicates its DNA genome via reverse transcription of
o Asia – Genotype B & C predominates pregenomic RNA
o Genotype B has better prognosis than Genotype C  HBV is not generally cytopathic to hepatocytes
 If hepB is acquired in the prenatal period, the baby has a high  Host immune responses (generally inadequate and/or
chance to develop chronic HepB inappropriate) are responsible for the liver disease of chronic
 If 1-5yo, 20-50% hepatitis B
 If adults, less than 5%  Two therapeutic approaches: (i) direct antiviral agents, (ii) immune
modulation: interferon alpha
HEPATITIS B VIRUS
 Double-shelled, 42 nm DNA virus DETERMINANTS OF CHRONIC INFECTION
 Hepadnavirus  Number of infected cells at time of immune response
 8 genotypes (A-H) o HBV cells low  self limited
 4 serotypes (adr, adw, ayr, ayw)  Strength of immune response at time of infection

Magno Opere Somnia Dura Page 4 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

COVALENTLY CLOSED CIRCULAR DNA (cccDNA)  Interpretation unclear; four possibilities:
 Partially double stranded viral DNA  Resolved infection (most common)
 Remains permanently in the nucleus  False-positive anti-HBc, thus susceptible
 Used as template in producing hepatitis B virus  “Low level” chronic infection
 Resolving acute infection
EXTRAHEPATIC SITES OF HEPATITIS B
HBe Antigen
 Lymph nodes  Associated with higher rate of viral replication
 Bone marrow  Enhance infectivity
 Lymphocytes  During the natural course it may be cleared with the rise in Anti-
 Spleen HBe and associated with dramatic decline in viral replication
 Pancreas
 These are sites where the virus may hide and may result to
recurrence after liver transplant

SEROLOGIC MARKERS
 Hepatitis B surface antigen (HBsAg): a protein on the surface of
HBV; it can be detected in high levels in serum during acute or
chronic HBV
 Hepatitis B surface antibody (anti-HBs): indicative of recovery and
immunity from HBV infection. Anti-HBs also develop in a person
who has been successfully vaccinated against hepatitis B.
 Total hepatitis B core antibody (anti-HBc): appears at the onset of
symptoms in acute hepatitis B and persists for life. Indicates
previous or ongoing infection with HBV in an undefined time
frame.
 IgM antibody to hepatitis B core antigen (IgM anti-HBc): positivity
indicates recent infection with HBV (<6 months). Its presence
indicates acute infection.
 Hepatitis B e antigen (HBeAg): a secreted product of the OCCULT HEPATITIS
nucleocapsid gene of the HBV that is found in serum during acute  HBV-DNA (+)
and chronic hepatitis B. Indicates that the virus is replicating and  HBsAg (-)
the infected person has high levels of HBV.  form of chronic hepa B associated with advanced fibrosis and
 Hepatitis B e antibody (HBeAb or anti-HBe): produced by the decreased response to interferon
immune system temporarily during acute HBV infection or  usually coinfected with hepatitis C
consistently during or after a burst in viral replication. Predictor of  discovered in 2002
long-term clearance of HBV in patients undergoing antiviral
therapy and indicates lower levels of HBV. DISEASE PROGRESSION OF HEPATITIS B
HBsAg (-) Susceptible
Anti-HBc (-)
Anti-HBs (-)

HBsAg (-) Immune due to

Anti-HBc (+) natural
Anti-HBs (+) infection

HBsAg (-) Immune due to

Anti-HBc (-) vaccine
Anti-HBs (+)

HBsAg (+) Acute infection

Anti-HBc (+)
IgM anti-HBc(+)
Anti-HBs (-)

HBsAg(+) Chronic infection

Anti-HBc (+)
IgM anti-HBc(-)
Anti-HBs (-)

HBsAg (-)
Anti-HBc (+)
Anti-HBs (-)

Magno Opere Somnia Dura Page 5 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

ACUTE HEPATITS B TREATMENT
CASE DEFINITION Antivirals are not generally recommended
 Clinical case definition:  95% will recover because immune system is fully developed
 Discrete onset of symptoms  You can also give antivirals if patient has severe course,
 Jaundice or elevated serum aminotransferase coagulopathy/bleeding tendency, marked jaundice >1-mg/dL,
 Laboratory criteria: severe symptoms >4wks, immunocompromised, if with
 AntiHBc positive concomitant Hepatitis C or D, elderly, hepatic encephalopathy
 HBsAg positive  Drugs: same as chronic hepatitis
 Interferon is avoided in acute because it can worsen hepatic
CLINICAL COURSE necroinflammation – because interferon boost local immune
 Incubation period – 60-150 days (90) response
 Acute infection ranges from asymptomatic/mild disease to rarely When to hospitalize acute hepatitis B patients:
fulminant  severe course, coagulopathy/bleeding tendency, marked
 Case fatality rate 0.5-1% jaundice >1-mg/dL, severe symptoms >4wks,
 Symptoms typically last for weeks (up to 6 months) immunocompromised, if with concomitant Hepatitis C or D,
 Clearing of HBsAg within 6 months in most patients elderly, hepatic encephalopathy
 If infected in the perinatal period, 90% of cases will progress from  changes in sensorium, cannot tolerate oral feeding
acute to chronic hepatitis
 If infected at the age of 1-5 years old 25-50% will be chronically CHRONIC HEPATITS B
infected CASE DEFINITION
 If infected during adulthood less than 5% will progress to chronic  (+) IgG
(95% will recover completely)  Clinical case definition:
 Approximately 25% of those who become chronically infected  Asymptomatic/symptomatic
during childhood and 15% of those who become chronically  Abnormal/normal LFT
infected after childhood die prematurely from cirrhosis or liver  Laboratory criteria
cancer and the majority remain asymptomatic until onset of  Anti-HBc IgM negative
cirrhosis or end-stage liver disease  Positive it HBsag or HBeAg or HBV DNA
OR
 Positve HBsag or HBV DNA or HBeAg 2x at least 6
months apart

FULMINANT HEPATITIS B
 Very high liver enzymes, Jaundice, Hepatic encephalopathy
 Massive lysis of infected hepatocytes HBsAg persisted >6mos
 Some pt will have negative HbSAg – halos naubos na kaya magiging
false negative pati yung HBV-DNA PHASES OF CHRONIC HEPATITIS B
 Immune tolerant
EXTRAHEPATIC MANIFESTATION OF HEPATITIS B o Virus can tolerate immune system because it is not fully
 Serum Sickness like syndrome developed
o Immune complex reaction o Minimal hepatitis
o Deposition of HbsAg and Ab in tissue and blood vessel leading to o + HBV DNA, HBsAg, HBeAg
a complement reaction  Immune clearance
 Glomerulonephritis o Competent immune system, virus clear
 Polyarteritis nodosa o Antibody response – enzymes elevated due to activation of
 Essential mixed cryglobulinemia immune response, more inflammation
 (pakibasa na lang daw yung manifestations nila) o Dec. or fluctuation of HBV DNA

Magno Opere Somnia Dura Page 6 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

 Immune inactive phase Recommendations: Whom to Treat (AASLD Guidelines 2007)
o Down immune system, patient serves as carrier  Treatment indicated for “active” disease
o Subside liver inflammation, decrease liver enzymes  ALT > 2 ULN
 Reactivation of Active phase  HBV DNA > 20,000 IU/ml
o Elevation of liver enzyme OR IF
o HBV DNA inc or fluctuate  ALT 1-2 ULN and > age 40, consider biopsy and treat if
significant fibrosis or necroinflammation is present
FACTORS ASSOCIATED WITH DISEASE PROGRESSION

TREATMENT OPTIONS
 Supportive
 Interferon
AASLGD GUIDELINES: PERIODIC SCREENING FOR HCC o Interferon alpha 2b
 At risk hepatitis B carriers o Pegylated interferon alpha 2a – once a week
 Asian males > 40 years of age  Nucleoside/nucleotide analog – NRTI
 Asian females > 50 years of age o Lamivudine
 All cirrhotic hepatitis B carriers o Adefovir
 Family history of hepatocellular carcinoma o Entecavir
 Africans > 20 years of age o Tenofovir
 Those with high HBV DNA levels and those with o Telbivudine
ongoing hepatic inflammatory activity remain at o New – emtricitabine, clevudine
risk for hepatocellular carcinoma (HCC)  Combination-NRTI+interferon
 Liver ultrasound every 6 to 12 months  Fulminant – ICU care
 Liver transplant
TO IMPROVE QUALITY OF LIFE OF PATIENTS WITH CHB
 Serovonversion of HBs to Anti HBs WHY CONSIDER COMBINATION THERAPY?
 Long term suppression of viral production  Sequential monotherapy with nucleoside/tide analogs has led to
o cHB patients – eradication of virus is not possible because of HBV resistance
presence of cccDNA  persistence of production mechanism  There may be special populations in whom combination is
recommended:
TREATMENT ENDPOINTS  Cirrhotics in whom development of resistance may have
irreversible severe consequences
 Sustain suppression of HBV replication indicated by: loss of HBsAg
 HIV/HBV coinfected
& HBeAg, decrease in HBV DNA
 Changing to another nucleoside/tide after failure increases chance
 Remission of disease indicated by: normal ALT, improvement of
of poor or nonresponse and of resistance to next drug, (ex. ETV)
liver histology
 Multidrug-resistant mutants described after sequential
monotherapy
TREATMENT  Resistance has been low with combination therapy
 Chronic HBV is a dynamic disease  May lead to better long-term outcomes
 Regular monitoring needed to determine timing of treatment  At present no FDA-approved indications for use of combination
and other interventions therapy in patients with chronic HBV infection and no synergy in
 Primary determinant of treatment initiation are HBV DNA decline noted
 HBV DNA level > 20,00 IU/ml  Use in cirrhotic patients especially those with preexisting YMDD
 ALT level > 2 ULN mutations and in HIV/HBV patients appears warranted
 +Histological finding severity of disease
 Assessment of histology is most helpful in borderline ALT and HBV
DNA cases
 Cirrhotics: lower thresholds to treat

Magno Opere Somnia Dura Page 7 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

HBV THERAPY
 HBV replication is closely linked to the lifetime risk of disease
outcomes (HCC, ESLD)
 New treatment paradigm = long-term control of HBV replication:
 ↓ Hepatic inflammation and fibrosis
 ↓ risk of hepatic decompensation and/or HCC
 First-line therapy – high potency/low resistance
 Peg-IFN
 Tenofovir
 Entecavir
 Combination antiviral therapy?

Type 1 Interferon
 Achieve their potent antiviral effects through the regulation of
hundreds of IFN-stimulated genes (ISGs)
 ISG encoded proteins establish a general antiviral state within the
cell
LIVER DECOMPENSATION
Peg-IFN for Chronic HEPATITIS B  Abnormal clearance of proteins absorbed through the intestinal
 Finite duration tract, leading to ammonia retention and hepatic encephalopathy
 No resistance  Abnormal excretion, leading to an accumulation of bilirubin in the
 Higher rates of seroconversion blood, producing jaundice
 Poor tolerance  Ascites: increased sinusoidal pressure, as with severe inflammation
 SQ injection or scarring of the liver, leads to fluid accumulation in the abdomen
 High ALT activity that becomes more difficult to control with progressive liver
 Low baseline serum HBV DNA concentration decompensation
 Genotype A or B  Portal hypertension: scarred liver tissue acts as a barrier to blood
 Absence of comorbidities flow and causes increased portal blood pressure. A major
 No cirrhosis consequence is the rapture of esophageal varices, causing massive
 No decompensated liver disease and potentially fatal bleeding.

MANAGEMENT OF CHRONIC HBV INFECTION CLINICAL CONSEQUENCES OF DRUG RESISTANT HBV

 Flares in serum ALT
 Reduced HBeAg seroconversion
 Histological progression of liver disease
 Increased recurrence post-OLT
 Changes in HBsAg envelope antigenicity
 Transmission of drug resistant HBV

POPULATIONS WITH INCREASED RISK OF BECOMING INFECTED

WITH HBV
 Infants born to infected mothers
 Sex partners of infected persons
 Sexually active persons who are not in a long-term, mutually
monogamous relationship (ex. > 1 sexual partner during the
previous 6 months)
 Men who have sex with men
 Injection drug users

Magno Opere Somnia Dura Page 8 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

MANAGING RESPONSE IN THE TREATMENT OF CHB DELTA HEPATITIS AGENT
HEPATITIS D – HDV
 Small circular defective RNA virus that requires HBsAg for
structural integrity
 Enveloped hybrid particle w/ HBsAg coat and HDV core
 Propagate only in the presence of HBV

EPIDEMIOLOGY
 Worldwide distribution
 With 3 epidemiologic pattern
 Nonendemic:
o USA & northern Europe
o Percutaneous exposure to blood and blood products
 Endemic
o Southern Europe, Northern Africa, Middle east
o Non-percutaneous ex close contact

TRANSMISSION
 Percutaneous exposure to blood
PREVENTION o E.g: injection drug usage
 Sexual transmission
 Vaccination – pre-exposure
o Much less efficient than for HBV
 Sanitation - use 1:10 dilution of household bleach (chlorine) w/
 Perinatal transmission is rare
water to disinfect spilled fresh or even dried blood and other
contaminated body fluids.  Incubation period 30-180d (60-90)
 Acute
 Used of disposable cutting or pricking instrument and dispose them
o Onset is insidious or acute
properly
 Proper disinfection of non disposable hospital instrument  Chronic
o Common in HDV
 Strict compliance to standard precaution by health workers
Pre-exposure of vaccination (CDC 2006) CLINICAL SITUATION
 0, 1 & 6 mos * intramuscular-deltoid  Co-infection
 0, 1 & 4 mos o Simultaneous infection w/ HBV and HDV
 0, 2, & 4 mos  Super-infection
 0, 1, 2, 12 mos o HDV infection occurs in an already HBV infected patient
CO-INFECTION
Persons who are HBsAg-positive should:  Severe acute hepatitis w/ high mortality > than HBV alone
 Have their sexual contacts vaccinated  Rarely result in chronic infection than HBV infection alone
 Use barrier protection during sexual intercourse if partner is not  Both anti-HDV IgM and IgG are detectable plus markers of active
vaccinated or naturally immune infection
SUPERINFECTION
 Don’t share toothbrushes or razors
 Cover open cuts and scratches  Present as severe acute hepatitis in a previously asymptomatic hep
 Clean blood spills w/ detergent or bleach B
 Don’t donate blood, organ or sperms  Results in chronic HDV infection (the rule)
 >risk for cirrhosis and hepatocellular carcinoma compared to
Post exposure prophylaxis for Hepatitis B persons infected w/ HBV alone
 <7 days for needlestick exposure  Both anti-HDV IgM & IgG remain detectable plus HBV markers of
active infection
 <14 days for sexual exposure

DIAGNOSIS
Post exposure prophylaxis w/ non occupational exposure
 HB vaccine + HBIG  HBsAg (+) source  Anti-HDV
o During acute HDV infection anti-HDV igM predominates and
 HBIG alone
detected 30-40days after the s/s
 NAT-HDV RNA (PRC)
 HB vaccine alone  Unknown HBsAg
 HBV/HDV
status
o Co-infection: IgM anti –HBC + anti HDV
o Superinfection: HBsAg & anti-HBC IgG+ anti-HDV
Post exposure prophylaxis for health care personnel
HBIG 0.06ml/kg IM asap (w/in 7days) + HB vaccine at different site
 If vaccine is not started, repeat HBIG 1 month after

Magno Opere Somnia Dura Page 9 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

PROGNOSIS CHRONIC HEPATITIS C
 Good for acute infection  Majority are asymptomatic or with mild nonspecific, intermittent
o Fulminant in 5% symptoms
o Fatigue
 Poor for chronic infection o Mild right upper arm discomfort or tenderness (“liver pain”)
o Fulminant in 20% o Nausea
 HDV + HBV infection has the highest mortality rate among the viral o Poor appetite
hepatitis o Muscle and joint pain
 HDV + HBV has the greater chance of cirrhosis, liver
decompensation & HCC than HBV alone Clinical presentation of Chronic HCV
 P.E is likely to be normal or show only mild enlargement of the liver
TREATMENT or tenderness
 Some patient have vascular spider or palmar erythema
 Supportive
 ICU care for fulminant hepatitis
Extrahepatic Manifestation (1-2%)
 Liver transplant
 Cryoglobulinemia
 Experimental: interferon & antiviral
o Skin rashes: purpura, vasculitis, urticaria
o Joint & muscle aches
PREVENTION o Kidney dse
 HBV immunization o Neuropathy
o Cryoglobulins, rheumatoid factor & low-
HEPATITIS C complement levels in serum
 Glomerulonephritis
 Single-strand, positive sense RNA virus
 Porphyria cutanea tarda
 Genus hepacivirus
 6 genotype (1-6) w/ >50 subtypes*
OUTCOME OF CHRONIC HCV
 Family Flaviridae
 Does not replicate via a DNA intermediate thus does not integrate  80% will develop mild scarring/cirrhosis or experience fatigue or
in the host genome depression
 High mutation rate: interferes w/ effective humoral immunity  20-30% will develop sever scarring/cirrhosis
 Does not induce lasting immunity  1-5% of those w/ cirrhosis will develop cancer
o Neutralizing antibody are short live  30% of those w/ cirrhosis are also at risk of hepatic
decompensation over 10 yrs
EPIDEMIOLOGY
 Leading inindication for liver transplantation in the US ACCELERATED PROGRESSION TO CIRRHOSIS
 180 million people are infected worldwide  Older age
 Mortality related to HCV infection will continue to increase over  Obese
the next 2 decades  Immunosuppresed (e.g: HIV co-infection)
o Liver failure  Consumption of >50g of alcohol per day
o Hepatocellular carcinoma (HCC) “The optimal approach to detecting HCV infection is to screen
persons for history of risk of exposure to the virus and to test selected
TRANSMISSION individuals who have an identifiable risk factor”
 Blood transfusion
 Injection: drug use (sharing of needles) PATIENTS FOR HCV SCREENING
o Accident needle prick (2%risk)/razor
 Persons who have injected illicit drugs in recent and remote past,
 Hemodialysis
including those who injected only once and do not consider
 Birth to an HCV positive mother (uncommon: 6%)
themselves to be drug users
 High risk of sexual practice
 Persons w/ conditions assoc w/ a high prevalence of HCV infection
including
ACUTE HEPATITIS C o Persons with HIV infection
 Incubation period: 50-160d(50) o Persons w/ hemophilia who received clotting factor
 Onset is insidious concentrates prior to 1987
 Fulminant hepatitis is uncommon (0.1%)  Persons who have ever been on hemodialysis
 Progression to chronic is common (50-70%) 55-85%  Persons w/ unexplained abnormal aminotranferase levels
 Spontaneous resolution is common among infected infants and  Prior recipients of transfusion or organ transplants prior to July
young women than among persons who are older when they 1992
develop acute hepatitis  Children born to HCV-infected mother
 Health care, emergency medical & public safety workers after a
needlestick injury or mucosal exposure to HCV-positive blood
 Current sexual partners of HCV-infected persons

Magno Opere Somnia Dura Page 10 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

 Multiple sex partners  EIA Anti-HCV (+), HCV RNA (-)  RIBA (-) 
o False positive
DIAGNOSIS o Recovery from hepatitis C
o Continued virus infection w/ levels of virus too low to be
 HCV RNA is detectable w/in days to 8 weeks after infection
detected
o Titer fluctuates and maybe negative intermittently
 Liver enzymes become elevated 6-12 wks after infection
TREATMENT
 Anti-HCV become positive as early as 8 wks
 5-10% of acute cases will have negative anti-HCV while >95% of  Goal: prevent complications & death
chronic cases will be positive  Drugs
 Anti-HCV o Type 1 IFN (interferon) + Antiviral (rivabirin)
o Does not distinguish chronically infected and those cleared of  HCV genotyping
infection o Should be performed prior to interferon-based treatment
 Acute or Chronic???  Dosage & duration depends on the
o Difficult because anti-HCV and HCV RNA are present in both genotype
Negative Predictions of Response to Pegylated interferon &
LABORATORY TEST Ribavirin Therapy for Hepatitis C
Patient related factors Dse/viral-related factors
 Serologic assays: detect specific antibody to hepatitis C virus (anti-
HCV) Non-white ethnicity HCV genotype 1
 Molecular assays: detect viral nucleic acid High BMI Advanced fibrosis (stages 3-4)
Age over 40 yrs High baseline viral load (>/= 400,000
or >/= 600,000 IU/mL
Laboratory test
Male sex Steatosis on liver biopsy
 EIA
Metabolic syndrome HCV/HIV co-infection
 RIBA
Diabetes
 NAT-qualitative and quantitative
 Viral genotype
 Use to guide treatment dose & duration TREATMENT RESPONSE FOR HCV
 ALT-serial  Defined by surrogate virological parameter rather than a clinical
 Liver biopsy endpoint
 Hepatitis B, D, HIV testing  Short-term outcomes can be measured biochemically
o Normalization of serum ALT levels
EIA-enzyme immunosorbent assay
Virologic response
 Detect antibody to core and structural gene of HCV
 3
rd
generation EIA is 99% sensitive and specific in  Absence of HCV RNA ffrom serum by sensitive PCR based assay
immunocompetent
 Hemodialysis and immunodeficient patients rarely have false Histologic response
negative result  2 point improvement necroinflammatory score w/ no worsening in
 Autoimmune disorder may have false positive result fibrosis score

RIBA-recombinant immunoblot assay Virologic response
 Supplemental test w/ high specificity  RVR (@ 4 wks)
 Detect anti-HCV using HCV recombinant antigens & synthetic  EVR (@ 12 wks)
peptide  SVR (@6 mos)
 Use in patients w/ positive EIA but negative for HCV RNA SVR: sustain viral response
NAT: HCV RNA Testing should be performed in  Loss of detectable HCV RNA during treatment (<50 IU/mL) & its
 Patients with a positive anti-HCV test continued absence for at least 6 months after stopping therapy
 Patient for whom antiviral treatment is being considered, using a  SVR is durable in 95% of patient
sensitive quantitative assay  Probability of an SVR strongly depends on the early response to
 Patient with unexplained liver dse whose anti-HCV test is negative treatment (EVR)
and who are immunocompromised or suspected of having acute
HCV infection EVR: early viral response
 Defined as a declined of viral load by 2 log 10 after 12 wks (3mos)
INTERPRETATION OF TEST of therapy
 Anti-HCV (+) HCV RNA (+) o Complete
o Acute or chronic o Partial
 Anti-HCV (-) HCV RNA (+)  Patients with an EVR have good chance of being cured, w/ 65% of
o Acute HCV them achieving SVR
o Chronic HCV in immunosuppressed
 Anti-HCV (-) HCV RNA (-)
o Absence of HCV infection

Magno Opere Somnia Dura Page 11 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

RVR: rapid viral response Ribavirin
 Defined as serum HCV RNA undetectable after 4 wks (1mo) of  Synthetic nucleoside analogue
treatment  Monotherapy is not effective against CHC
 Over 85% of w/ RVR will achieve SVR  With pegylated interferon it helps stop making new HCV copies
 Only <20% of patients w/ genotype 1 have RVR
 60% of patients with genotype 2 and 3 show RVR Ribavirin Side effects
 Anemia (hemolytic)
Treatment w/ peginterferon alfa 2a+ribavirin  Fatigue and irritability
 SVR is seen in 40-80%  Itching
o SVR in genotype 2 & 3 is 80%  Skin rash
o SVR in genotype 1 is 40%  Nasal stuffiness, sinusitis, and cough
 EVR
 RVR During Therapy
 Do CBC & liver enzymes
Before start therapy o At wk 1,2 & 4 and @ 4-8 wk intervals thereafter
 Do a liver biopsy  Reduce ribavirin (by 200mg @ a time)
 Test for serum HCV RNA o If anemia occurs (hemoglobin less than 10g/dL or hematocrit
 Test for HCV genotype (or serotype) <30%)
 Measure blood counts and aminotransferase  STOP ribavirin
 Counsel the patient about the relative risks and benefits of o If severe anemia occurs (hemoglobin <8.5g/dL or hematocrit
treatment <26%)
DOSAGE  Reduce peginterferon if there are intolerable side effects:
Genotype Peginterferon Ribavirin tabs Duration o Severer fatigue, depression, or irritability or
alfa 2a dose dose o Decrease in WBC (absolute neutrophil count below
Genotype 1,4 180 mcg <75kg=1000mg 48 wks 500cells/mm3) or
>75kg=1200mg 48 wks o Decrease platelet counts (dec below 30,000 cells/mm3)
 With genotype 1, measure HCV RNA levels before therapy & again
Genotype 2,3 180 mcg 800 mg 24 wks
@ wk 12
o Stopped early if HCV RNA levels have not decreased by at least
Response to Definition SVR Duration of 2 log10 units
tx therapy (wks) o In situation where HCV RNA levels have not obtainable, repeat
Genotype 1 testing for HCV RNA by PCR (or TMA) should be done @ 24
RVR HCV RNA (-) @ tx wk 4 90% 24* - 48 wks and the therapy stopped if HCV RNA is still present, as a
cEVR HCV RNA (+) @ tx wk 70-80% 48 sustained response is unlikely
4 but HCV RNA  Reinforce the need to practice strict birth control during therapy
negative @ tx wk 12 and for 6 mos thereafter
pEVR ≥2log decline in viral <30% Extend to 72
load from baseline but After Therapy
detectable viruse @ tx
 Measure the liver enzymes every 2 mos for 6 mos
wk 12 & HCV RNA (-)
 6 mos after stopping therapy, test for HCV RNA by PCR (or TMA)
by wk 21 (slow
 If HCV RNA is still negative, the excellent for a long-term “cure” is
responder)
excellent
Nonresponse <2log decline in viral <2% Discontinue
o Relapse have rarely been reported after this point
load from baseline @
tx wk 12 or detectable
Future in treatment
virus @ tx wk 24
 Studies are ongoing because the standard tx w/c is ribavirin +
interferon achieve only 40-50% chance of viral suppression
Interferon common side effects
 New drugs
 Fatigue  Protease inhibitors: telaprevir & boceprevir
 muscle aches
 headache
Prognosis in HCV-HIV co-infection
 nausea and vomiting
 Spontaneous viral clearance < than mono infection
 skin irritation at injection ste
 More will develop fibrosis
 low-grade fever
 More than 2x the chance of developing cirrhosis & in a shorter
 weight loss
period (10 yrs)
 irritability
 Greater chance of developing cancer
 depression
 6x the risk of liver decompensation
 mild bone marrow suppression
 hair loss (reversible)

Magno Opere Somnia Dura Page 12 of 13 rye

HEPATITIS 2014 -2015

Dr. Yapendon Communicable Diseases

Prevention
 Avoid situations in w/c others will be exposed to patients blood
o Do not donate blood, body organs, other tissue or semen
o Do not share toothbrushes, dental appliances, razors, home
therapy items that might have blood on them
 No pre-exposure and post exposure immunization or antiviral drug
is currently recommended

Feature HAV HBV HCV HDV HEV

Incubation (days) 15-45, mean 30 30-180, mean 60- 15-160, mean 50 30-180, mean 60- 14-60, mean 40
90 90

Onset Acute Insidious or acute Insidious Insidious or acute Acute

Age preference Children, young Young adults Any age but more Any age (similar Young adults (20-
adult (sexual & common in adults to HBV) 40 yrs)
percutaneous),
babies, toddlers

Transmission

Fecal-oral +++ - - - +++

Percutaneous Unusual +++ +++ +++ -

Perinatal - +++ + + -

Magno Opere Somnia Dura Page 13 of 13 rye