Acute Hepatitis

Dr Monem Alshok

12/3/2017

Viral Hepatitis

NoneInterferon +Interferon

Ribavirin

IFN

Lamivudine

NONETherapy

NONEHBV vaccineNONEImmune globulin

Recombinan vacc

Immune globulin

Inactivated vacc

Prophylaxis

+++HCCancer

1 – 2%

None

5 – 20 %

Common

0.1 %

Infect 80-90%

Hepatitis –70%

0.1 – 1 %

Neonates 90%

Adults 1-10%

0.1 %

None

Clinical

Fulminant

Progression to

chronicity

Fecal - oral+++

+

++

+++

variable

+

Parenteral +++

Perinatal +++

Sexual ++

Fecal – oralTransmission

AcuteAcute / insidiousInsidiousAcute / insidiousAcuteOnset

6 weeks4 – 12 weeks7 weeks4 – 12 weeks4 weeksIncubation

HEVHDVHCVHBVHAV

HEPATITIS A

RNA Virus

Fecal-oral

Incubation 15-50 days

Anti -Hepatitis A IgM present during acute illness.

TX/Prevention: Vaccine, Immune serum globulin for contacts

Px: Good – doesn’t become chronic rarely fulminant liver failure.

Hepatitis A

RNA virus with 4 genotypes but one serotype.

Fecal-oral route but also sexual (homosexual!), IVDA, and most common in USA international travel.

Incidence has significantly decreased with vaccination.

Hepatitis A

Usually acute self limited rarely fulminant especially if associated with chronic hep C.

Manifestations vary with age, more silent in children.

Incubation period of 30 days followed by abrupt prodromal symptoms then jaundice.

Extrahepatic manifestations : vasculitis, optic neuritis, thrombocytopenia, aplastic anemia, transverse myelitis.

Hepatitis A

IgM anti HAV is the gold standard for diagnosis.

Start at the onset of symptoms and remain positive 4-6 months.

Infected individuals are contagious during incubation and for a week after jaundice appears.

Handwashing is very important !!! As HAV survives for up to 4 hrs on fingertips.

Hepatitis A

Treatment is usually supportive.

Prevention is mainly by good hygiene and vaccination ( travel to high risk areas).

IM Immunoglobulin are available for people allergic to vaccine and immunocompromised, they provide passive immunity for up to 6 months.

HBV infection

Introduction HBV infection

More than 2 billion people have been infected with the hepatitis B virus, and this

includes 350-400 million chronic carriers of the virus. Of the 400million

chronically infected 15% to 40% get complication or sequel

Transmission of hepatitis B virus results from exposure to infectious blood or body

fluids such as semen and vaginal fluids, while viral DNA has been detected in

the saliva, tears, and urine of chronic carriers with high titer DNA in serum.

Vertical or Perinatal infection is a major route of infection in endemic (mainly

developing) countries.

Other risk factors for developing HBV infection include working in a health care

setting, transfusions, and dialysis, acupuncture, tattooing. Capping .

However, Hepatitis B viruses cannot be spread by holding hands, sharing eating

utensils or drinking glasses, kissing, hugging, coughing, sneezing, or

breastfeeding.

HEPATITIS B

DNA Virus

Consists of surface and core

Core consists of Core antigen and e-antigen

Most infections are subclinical, but can present with arthralgias, glomerulonephritis, urticaria

Parenteral or sexual transmission.

Hepatitis B continued

Hepatocellular necrosis occurs due to the body’s reaction to the virus rather than due to the virus itself . Therefore patients who have a severe illness from hep B are more likely to clear the virus.

SEROLOGY: Remember Acute infection has IgM , chronic has IgG

Anti Core IgM is present during acute phase( Window period ) , Anti Core IgG indicates chronic infection.

Patients with Hep B e Ag have continued active replication

Immunized or previously exposed people have Negative HBsAg and HBeAg, they have IgG Anti HB Core, and Positive anti Hep Bs and e.

HBV Serology

Genotypes : A – J

( Genotype A North Europe & US , Genotypes B and C are confined to populations in eastern Asia and the Far East, but changes in immigration patterns have resulted in an influx of Asian HBV carriers with these genotypes into the United States,Genotype D is found worldwide but is especially prevalent in the Mediterranean area, Middle East, and south Asia.Genotype E is indigenous to western sub-Saharan areas, and Genotype F prevails in Central America. Cases of genotype G have been reported in the United States and France. Genotype H has been described in Mexico. Genotypes I and J are the most recently discovered and have been observed in Vietnam and the Ryukyu Islands in Japan, respectively

Serological Patterns of Acute & Chronic Hepatitis B

Question

A 48 yo woman plans to travel to Abroad ( South America ) with her husband and 11 year old child. The family have no known history of liver disease or hepatitis and no members of the family have had immunizations for hepatitis. What immunizations would you recommend:

A . Hepatitis A vaccination for both parents and child

B . Hepatitis A Vaccination for parents and child and Hepatitis B vaccination for the child

C . Hepatitis A and Hepatitis B vaccination for both parents and the child

D . Screen parents for previous Hep A infection, and recommend Hep A vaccination for the child

E . Screen all members of the family for Hep A and B exposure.

ANSWER B

All children should now get Hep B. vaccination as babies, if they miss this they should have catch up vaccination as 11-12 year olds

Previous Hep A infection is unlikely in children and adults not in high risk populations therefore it is safe to vaccinate without antibody testing.

QUESTION

A 40 yo married man with two children was recently evaluated for fatigue and elevations of liver function tests and was found to have chronic Hep B. Physical examination reveals a few spider angiomata on his chest and upper extremities.

Labs:

HBsAg Pos

HBeAg Pos

HBV DNA90 (low)

ALT156 U/L

Albumin3.8

INR 1.5

A liver biopsy is performed and shows cirrhosis with moderate inflammatory activity

The most appropriate recommendation for this patient isA . He should receive the Hepatitis A Vaccine

B . His Wife and Childern should receive the Hepatitis B Vaccine

C . He should be treated with Interferon Alpha

D . All of the above

ANSWER: D

All patients with Liver disease should have the Hepatitis A vaccine as they have decreased hepatic reserve and the mortality of Hepatitis A in a patient with Hepatitis B is considerably increased

Household contacts of patients with Hepatitis B should be vaccinated

Patients with HBeAg are candidates for Interferon therapy, this is most likely to benefit patients with HBV DNA <200 and evidence of ongoing immune mediated liver cell damage on biopsy.

Hepatitis C

Structure of hepatitis c

Dr.T.V.Rao MD20

Hepatitis C- global infection

More than 200 million infected worldwide(the (WHO)

estimates about 3% of the world’s population has been

infected with HCV)

In 2000 that Egypt had the highest number of reported

infections22%, largely attributed to the use of

contaminated parenteral antischistosomal therapy.

Many do not experience symptoms

Chronic HCV is the only Chronic Viral infection that can be

cured by Antivirus

21

Genotypes

The sequences cluster into 6 major genotypes (designated by numbers), with sequence similarities of 60% to 70%, and more than 70 subtypes (designated by a lower-case letter) within these major genotypes,with sequence similarities of 77% to 80%.

In a study in Iraq on 230 HCV patients , Genotype 1b 44.6 % , genotype 4 36.9% ( Akram etal )

Global geographic differences exist in the distribution

ofHCV genotypes, as well as in the mode of acquisition

United States, genotype 1a is the most prevalent, accounting for approximately 57% of HCV infections, followed by genotype 1b in 17%, genotype 2 in 14%, genotype 3 in 7%, and genotype 4, 5, or 6 in less than 5% .

Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC

In Europe, the most prevalent genotype is 1b (47%), followed by 1a (17%), 3 (16%), and 2 (13%)

HCV genotypes

Genotype 4 is found mainly in Egypt, the Middle East, and Central Africa. In Egypt,approximately 15% of the population is infected with HCV, and more than 90% have HCV genotype 4.

Genotype 5, although originally isolated in South Africa, is also seen in specific regions of France, Belgium, and Spain

Genotype 6 is found predominantly in Asia.

Hepatitis C

Flaviviridae family; the prototype Hepacivirus

Rapid replication rate

High mutation rate that allows him to escape the immune recognition.

Hep C infection can present as acute hepatitis, chronic hepatitis, cirrhosis, HCC or extrahepatic

Hepatitis C

Incubation period : 6-7 weeks and seroconversion time 8-9 weeks.

Acute symptomatic cases occur in 10-30% while fulminant hepatitis occurs almost exclusively in patients with HBV.

Most cases progress slowly to chronic infection. Mechanism is unknown. Viral, host and other factors play role.

Hepatitis C

Host factors:

HLA-DRB1, DQB1

Low peak levels of HCV during acute infection

Age

Ethnicity

Coinfections (HIV, Hep B)

High BMI

Hepatitis C

Viral factors:

Genotype 1B

Coinfection with >1 HCV genotype

Other Factors:

Marijuana

Alcohol

Amount of inflammation and fibrosis on liver biopsy

Corticosteroids

Hepatitis C

RNA virus

Blood Bourne i.e. Transmission from IV drug use and transfusion of blood products prior to 1990.

Can also be transmitted by snorting cocaine.

Vertical transmission and Sexual transmission is low.

Testing involves Anti HCV Antibody, and then viral load if positive.

85% of patients develop chronic infection.

Extrahepatic manifestations

Hematologic (mixed cryoglobulenimia, lymphoma)

Renal (membranoproliferative GN)

Autoimmune (thyroiditis)

Dermatologic ( porphyria cutanea tarda, Lichen palnus)

Diabetes mellitus.

Hepatitis C Diagnosis

Who should be tested? AASLD recommendations

Abnormal ALT

IVDU hx

Blood transfusion < 1992

Clotting factors <1987

Kids to HCV infected mothers

Current sexual partners to HCV infected subjects

Needle stick

Hepatitis C Diagnosis

Elisa

RIBA

PCR-RNA

Genotype

Liver biopsy

Management of Hep C

Interferon alpha with ribavirin for 6 to 12 months clears virus in approx 40% of patients.

There is an algorithm which is used to decide who is treated, but basically anyone with Hep C, high ALT and less than 40 yo. If older than 40 should have biopsy first which should at least show periportal inflammation or fibrosis.

Treatment

Counseling

Diet: NO alcohol . Smoking: controversial

Zofran( Ondansetron ) for fatigue 4 mg bid

The mainstay of treatment is Interferon and ribavirin, DAAD

Goals of treatment: eradicate HCV infection, slow disease progression, improve hepatic histology (function) and prevent hepatocellullar carcinoma

Interferon

Glycoproteins produced by cells in response to infection

Biological properties of interferons:

anti-viral , immunostimulatory , anti-proliferative anti-angiogenic

Pegylated Interferon

covalent attachment of variably configured polyethylene glycol (PEG) chains to sites on the interferon molecule delays absorption , decreases clearance rate , allows once per week dosing ,alters properties and activity of parent compound

prolongs immune activation and cytokine-derived antiviral effects

two pegylated interferons are now FDA-approved

peginterferon alfa-2a (Pegasys® - Roche)

peginterferon alfa-2b (PEG-Intron® - Schering)

Ribavirin

Guanosine analogue

active against many viruses in vitro and in vivo

mechanism of action against HCV uncleardepletion of intracellular triphosphate pools

inhibition of viral-dependent polymerase

Immunomodulatory & mutational deletion

Indications for treatment1 . stage 2-3 fibrosis and/or grade 3-4 necrosis/

inflammation on liver biopsy

2 . stage 4 fibrosis (cirrhosis) with compensated liver function

3 . genotype 2 or 3, viral load < 2 million IU/mL

4 . severe symptoms related to cirrhosis or extrahepatic symptoms (e.g., cryoglobulinemia)

5 . desire to be pregnant without risk of vertical transmission

Other issues regarding Hep C

Once pt with Hep C is cirrhotic their risk of developing hepatocellular Ca is 1-4% per year

Alcohol increases risk

Other viral hepatitis

Hep E: Acute hepatitis just like hep A unless you are PREGNANT in which case can progress to fulminant hepatitis

EBV, CMV, Herpes viruses can all cause acute hepatitis especially in immunocompromised.

QuestionA 38 yo woman was found to be Hep C positive 6 months ago after evaluation for raised AST. The infection was attributed to blood transfusions received during a car accident 15 years ago. She was pleased to learn last month that she is pregnant with her first child.

The physical examination is within normal limits . She would like further information concerning her prognosis and the risk of transmission of HCV to her husband and her child.

All of the following statements about HCV infection are true except:

A . The chance of transmission of HCV to the newborn is low in the 5% range.

B . Barrier precautions including safe sex are recommended for all couples in a monogamous relationship because of high risk of transmission to the partner

C . Low level transmission of Hep C is recognized within households (5-10%), and the risk for such transmission should be minimized by practices that avoid blood-blood exposure such as sharing dental implements and razors

D . In patients with Hep C the chance of developing cirrhosis over several decades is 20-35%

Answer B

Maternal-fetal HCV transmission is approx 5%, however if mother is co-infected with HIV then risk increases to 30%

Risk of sexual transmission between monogamous spouses is also low approx 5%

Transmission can occur between non-sexual household contacts therefore should be told to avoid sharing razors etc.

20-35% of patients with Hep C develop cirrhosis

23-year-old man was referred for abnormal LFT’s . HPI: The patient was

admitted for severe depression. His psychiatrist had obtained blood tests to

follow valproate (Depakote) therapy. Liver chemistries were abnormal (see

below). The patient was asymptomatic and denied any jaundice, fever,

abdominal pain, nausea and vomiting. He has never had blood

transfusions. He denies the use of medications other than those prescribed by

his psychiatrist. Patient admits using illicit drugs IV starting about 8 weeks

ago and has continued use to the present. PMH: Bipolar disorder

Medications: Depakote 500 mg XR qd, fluoxetine 40 mg qd, clonazepam 1 mg

prn. PH and SH: no excessive alcohol and tobacco use, no travel, recent IV

drug abuse as above

FH: father suffers from depression

Labs: Direct bili 1 mg/dL, Alk phos 188 u/L, ALT 1178 u/L, AST 746 u/L (all

significantly elevated); Anti-HCV negative on hospital day 1 and positive on

day 3, HCV-RNA PCR positive (done only on day 3); Hep A, B and D markers

are negative. Patient is diagnosed with Acute Hepatitis C

Questions:

In this case, what are the some clinical features that are typical for acute HCV?

How is the diagnosis of acute hepatitis C made?

What is the natural history for HCV infection?

What are the treatment strategies for acute HCV infection.

When is therapy initiated in chronic HCV patients and what is an example of a treatment regimen?

What are some of the limitations of available therapies?

what are the some clinical features that are typical

for acute HCV?

Most often, Hep C transmission occurs parenterally. Recent h/o of IV drug abuse suggests the possibility of hepatitis B, C, and D infection in this patient. For hepatitis C, the incubation period between the exposure and the appearance of clinical and serological evidence of acute hepatitis is between 4 and 20 weeks. The majority of patients, 40-75 %, remain asymptomatic or have mild symptoms not leading to medical attention. Our patient was asymptomatic and would not have been identified if he had not required lab follow-up for his valproatetherapy.

How is the diagnosis of acute hepatitis C made?

Clinically, acute hepatitis C is indistinguishable from other types of viral hepatitis; therefore it is important to exclude the possibility of other types of viral hepatitis by testing for HAV, HBV, and HDV markers, as was done in our patient. Laboratory diagnosis of acute HCV infection is made by documenting HCV antigen being present (going from anti-HCV negative to anti-HCV positive supports the diagnosis but can take up to 1 year to occur!).

What is the natural history of HCV infection?

An important feature of HCV is that up to 80% of patients will develop chronic hepatitis C. Chronic disease is usually diagnosed 10 or more years after the acute illness. More than 20% of those with chronic hepatitis C infection will progress to cirrhosis and eventually will develop end-stage liver disease in about 20 years. Some patients will develop hepatocellular carcinoma ~30 years after initial infection.

What are the treatment strategies for acute HCV infection?

Management of acute hepatitis is mostly supportive. Patients need to be advised to maintain healthy diet, avoid alcohol and hepatotoxic drugs. In our patient, consideration of discontinuation of valproate should be discussed with the psychiatrist. It is important to monitor patients with acute HCV for development of chronic disease (seropositive for anti-HCV> 6 months.). Interferon therapy has been tried for the treatment of acute HCV, and results have been mixed and unimpressive. Immune serum globulin does not work either.

When is therapy initiated in chronic HCV patients? and what is an example of a treatment regimen?

When the patient is seropositive for anti-HCV for greater than 6 months, patient is also seropositive for HCV RNA and patient has evidence of liver disease (LFTs are elevated).

One example: PEG INF alpha-2a or 2b + ribavirin is “standard of care” today (ribavirin dose used depends on genotype)

What are some of the limitations of available therapies?

Not all patients respond to interferon +

ribavirin therapy. Response is usually

monitored by HCV RNA testing. If patient

is not HCV RNA negative after 12 wk.of

therapy, treatment should be D/C.

Treatment must be continued for 2-4 years

to produce reasonable sustained response

rates (i.e. response after therapy has been

D/C'd).

THANK YOU