VIRAL HEPATITIS

Evaluation of patients with liver diseaseEvaluation ofpatients with liverdisease

should be directed at:(1) establishing the etiologic diagnosis,(2) estimating the disease severity (grading),(3) establishing the disease stage (staging).

Diagnosis should focus on the category of disease, such as: hepatocellular, cholestatic, mixed injury specific etiologic diagnosis.

Grading assess the severity or activity of disease: active or inactive, mild, moderate, or severe.

Staging estimate the place in the course of the natural history of the disease: acute or chronic; precirrhotic, cirrhotic, or end-stage.

Clinical forms of acute viral hepatitisThe course of viral hepatitis is affected by: viral charge and host response.Clinical forms Complains Jaundice Hepatomegaly Biochem.

abnormal.Ag /Abrespons

Jaundice form +++ +++ +++ +++ +++Nonjaundice form ++ abs ++ ++ +++Slight pronounced form + + + + +++Subclinical form abs abs abs + +++Inapparent form abs abs abs abs +++The typical developmentalstages of the acute viralhepatitis:

incubation period prejaundice period jaundice period convalescent period

Particularity of acute viral hepatitis evolution depending on etiological agentVHA VHB VHD

coinfectionVHDsuperinfection

VHC VHE

Nucleic acid RNAPiconarvirus

DNAHepadnaviridae

RNADeltavirusHDAg are encapsidated byHBsAg

RNAFlaviviridae

RNA

Majortransmission

Fecal–oral:-person-person-contaminatedfood/water

ParenteralSexual

ParenteralSexual

ParenteralSexual-rarePerinatal 5%

-G/type 1,2:fecal - water-G/type 3,4:

swineEpidemics Yes Sporadic Sporadic Sporadic YesMost common Young

children inendemic area

All All All Symptomaticin 15-40 years

Maximuminfectivity

1/2 incub.few days onset

Latter half of incubation period all the period of viremia Same as inVHA

Incubation 7-50days

45-180 as in VHB 1-2mo 20-120 14-50 days

Cause of liverinjury

directcytopathiceffects of viralproteins

immunemediated

VHB - immune mediatedVHD - direct cytopathiceffects of viral proteins

combinationof directcytopathicand immunemediated

directcytopathiceffects of viralproteins

Integration intohost DNA

No episomal-freeintegrated

VHD - No No No

Prejaundice periodLength 0-2 weeks 0 -6 weeks 0-10 days 0-10 days 0-2 weeks 0-2 weeksDyspepticsyndrome

+ + ++ ++ +/- +

Arthralgicsyndrome

- + + - - -

Intoxicationsyndrome

+ + ++ ++ +/- +

Fever + - +/- +/- - +Hepatomegalia + + + ++ + +Splenomegalia - - - + - -

Jaundice periodState afterjaundice

better same orworse

worse worse same same

Hepatomegalia + + ++, soft +++, firm + +Splenomegalia - + + ++ + -Length ofjaundice period

1-2 weeks 2-4 weeks 2-6 weeks 2-8 weeks 2-4 weeks 1-2 weeks

Extrahepaticmanifestations

- + + because of HBV + -

Fulminant <0,5% 1% 2-20% <0,1% 20%pregnant:-liver failure-haemorrhage-Hb-uria,acute renalfailure

Chronicity No 5-7% inadults;90% atbirth

coinf. 5-7%, super. 100% 50-70% No

Cause ofchronicity

highlyvariablenucleotidesequence

Liver cancer No Yes Yes Yes No

The main types of VHC isolatesIt is not yet clear whether immunity to one type prevents subsequent infection with anotherTypes 1-3 almost all infections in Europetype 4 prevalent in Egypt & Zairetype 5 South Africatype 6 Hong Kong

EARLY CHILDHOOD HBV INFECTION - RISK OF CHRONICITY

Age at Infection (years) Proportion who become carriers (%)

<1 70-90

2-3 40-70

4-6 10-40

>7 6-10

The majority of infected children are asymptomatic. The younger the child, the more asymptomatic.

Extrahepatic manifestations in VHB and VHC ARTHRITIS-DERMATITIS GIANOTTI SYNDROME (Infantile papular acrodermatitis):Papular skin eruptions with generalized

lymphadenopathy in children under eight years. NERVOUS SYSTEM: Guillain-Barre' syndrome, peripheral neuropathy, mononeuritis multiplex. These

symptoms resolve at the end of the acute illness. CARDIO-VASCULAR SYSTEM: Pericarditis, myocarditis may occur especially in the fulminant type.

Polyarteritis nodosa, vasculitis are seen in chronic hepatitis B. GASTRO-INTESTINAL TRACT: Pancreatitis. HBV can be replicated in the pancreas. URINARY SYSTEM: Membranous glomerulonephritis occurs in chronic hepatitis B. HEMOPOIETIC SYSTEM: aplastic anemia (rare), cryoglobulinemia of mixed type (the serum contains

cryoprecipitable IgG and IgM proteins with anti-gamma globulin activity producing purpura, arthritis,glomerulonephritis and generalized vasculitis apparently due deposits of immunoglobulin-complementcomplexes in the vascular wall. )

LABORATORY SYNDROMES IN ACUTE HEPATITIS :Cytolitic syndrome: high ALT, ASTCholestaticsyndrome:

high bilirubin level, 2/3 – conjugated, phosphate alkaline, b-lipoproteins, cholesterol are N.

Haepatodepresionsyndrome:

slightly low albumin levels, prolongation of the prothrombin time

Mezenchimal andinflamationsyndrome:

high - globulines, low sublime test, high tymole test (mostly inflammation)

Hematologicabnormalities:

leukopenia (ie, granulocytopenia) lymphocytosis increase in the sedimentation rate.

Laboratory testingVHA infection IgM anti-HAV (antibody to the capsid proteins)

becomes detectable 5-10 days before onset of symptomsdeclines to undetectable levels <6 months after infection

IgG anti-HAVappears later, remains detectable for the person's lifetimeprovides lifelong protection against the disease.

HAV RNAcan be detected in the blood and stool during the acute phase of infection

VHE infection IgM anti-HEVbecomes detectable 5-10 days before onset of symptomsdeclines to undetectable levels <6 months after infection

IgG anti-HEVdo not provides lifelong protection against the disease.

HEV RNAdetected in the blood and stool during the acute phase of infection

VHC infection IgM HCVAb-poz and HCV ARN – poz = Acute HCV total HCVAb-poz and HCV ARN – poz = Acute or chronic HCV total HCVAb-poz and HCV ARN – neg = Resolution of HCV; total HCVAb-neg and HCV ARN – poz = Early acute HCV inf.; chronic HCV in

immunosup.; false positive HCV RNA testsingle HCV-RNA negative sample or normal ALT during the late phase of acutehepatitis C do not prove resolution of infection and prolonged follow-up for at least12 months is necessary to prove that the infection has resolved.

VHB infection HBsAg (surface antigen) – is borne by surface viral proteinso Functions: attachment and penetration into hepatocytes; is the target of the

host’s humoral responseo Detectable 30-60 days after exposureo In acute and chronic infectiono not a marker of viral replicationo In certain cases of mutant-related hepatocellular carcinoma, only HBV-DNA

positivity is observed, HBsAg remaining seronegative. HBsAb (antibody to surface antigen)

o appear a few weeks after resolution of acute hepatitis Bo is considered the marker of resolution of HBV infectiono rarely appear after HBsAg disappearance in non replicative chronic HBV

carrierso generally persist for life, but may become undetectable after a few years.

total Anti-HBc/HBcAb (antibody to core antigen)o are directed against a viral capsid epitope or core antigeno appear early during infection and remain detectable for lifeo can be present in the absence of both HBsAg and anti-HBs antibodieso Anti-HBc is therefore detected in anyone who has been infected with HBV.

IgM anti-HBc (core antibody)o High titers of anti-HBc IgM are present early at the acute stage of HBV inf.o Low amounts of anti-HBc IgM can also be found in chronic HBV infection,

bearing witness to a strong and adapted anti-HBV immune response HBeAg (E antigen)

o borne by a nonstructural protein produced during viral replication inhepatocytes infected by so-called "wild-type" HBV.

o Pre-core mutant" HBV viruses are unable to produce the HBe protein.o Indicates HBV replication, but is not a reliable marker of HBV replication in

"pre-core mutant" HBV

Correlates with high infectivity Present in acute or chronic infection Anti-HBe (antibody to E antigen)

o In "wild-type" HBV, anti-HBe antibodies appear when replication ceaseso In "precore mutant" HBV, anti-HBe antibodies are present whether or not

HBV replicatesVHD infection HDAg is rarely detected in the serum

anti-Delta IgM is found in the serum and lasts 2 - 6 weeks Anti-Delta IgG may be present in a low level or perhaps not detectable at all HDV RNAdetected in the blood and stool during the acute phase of infection. HDV

seems to suppress HBV replication

Laboratory Criteria for Diagnosis of Acute Hepatitis CConfirmation ofacute hepatitis C isconfirmed by all ofthe following:

1) Marked elevation in ALT (>7 times the upper limit of normal, with or withoutsymptoms of acute hepatitis); and2) Negative tests for acute hepatitis A (IgM anti-HAV) and acute hepatitis B (IgManti-HBc); and3) A positive anti-HCV screening immunoassay (enzyme immunoassay, EIA, orchemoluminescence immunoassay, CIA) that is confirmed with one of the following:► An immunoassay with a signal to cut-off ratio predictive of a true positive for thatassay; or► An HCV RNA assay. (HCV RNA may be detected 1–3 weeks after exposure.However, viremia may be transient post-exposure, i.e., a negative HCV RNA does notrule out acute HCV infection.)

* HCV RNA is detectable in serum within days to 8 weeks following infection.* Antibodies to HCV (anti-HCV) are detectable 3 months after infection in 90% ofpatients.

HCV - infection

HBV is an extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive whenstored for 15 years at -80°C, for 24 months at -20°C, for 6 months at room temperatures, and for 7 days at 44°C.

Fulminant hepatic failureresults from massive necrosis of liver cells or

from sudden and severe impairment of hepatic function.

the termfulminant hepaticfailure

is restricted to pts in whom:o signs appear within 8 weeks of the onset of the illness ando has been no evidence of liver disease previously

Ammonia is a keyfactor in thepathogenesis ofHE.

Ammonia is released from several tissues (kidney, muscle), but its highest levels can befound in the portal vein. Portal ammonia is derived from both the urease activity ofcolonic bacteria and the deamidation of glutamine in the small bowel, and is a keysubstrate for the synthesis of urea and glutamine in the liver.

The blood-brain barrier permeability to ammonia is increased in patients with HE; as aresult, blood levels will correlate weakly with brain values, though recent studies indicatean improvement of this correlation by correcting the ammonia value to the blood pH

The alterations in neurotransmission induced by ammonia also occur after the metabolismof this toxin into astrocytes.

Manifestations Acute onset Severe mental changes Jaundice appears and deepens There may be gastrointestinal bleeding and renal failure Physical findings include asterixis and flapping tremors of the body and tongue. Fetor hepaticus refers to the slightly sweet, ammoniacal odor that is common in patients

with liver failure, particularly if there is portal-venous shunting of blood around the liver.

The Stage of encephalopathy

PHYSICALSIGN

Stage Iprodrome

Stage IIimpending coma

Stage IIIstupor

Stage IVcoma

Stage IVSevere coma

mental status alert; slowmentation; euphoria,occasionaldepression,confusion; sleeppattern reversal

stage I signsamplified; lethargic,sleepy,

arousable, butgenerally asleep;marked confusion

unarousable orresponds only to pain

unarousable

behavior restless, irritable,disordered speech

combative, sullen,loss of sphinctercontrol

sleeping, confusion,incoherant speech

none none

spontaneousmotor activity

uncoordinated withtremor

yawning, grimacing,blinking

decreased, severetremor

absent none

asterixis absent present present absent absent

reflexes normal hyperactive hyperactive+ Babinski

hyperactive+ Babinski

absent

respirations regular orhyperventilating

hyperventilating hyperventilating irregular apnea

oculocephalicoculovestibular

normal normal normal partial dysconjugate absent

EEG normal normal generalized slowing markedly abnormal markedlyabnormal

Glasgow comascale

15 15 11-13 3-9 3-4

eye opening spontaneous = 4 spontaneous = 4 spontaneous = 4 oronly to sound = 3

to pain only = 2 ornever = 1

never = 1

motor obeys commands = 6 obeys commands = 6 obeys commands = 6or localizes pain = 5

normal flexion = 4 orabnormal flexion = 3or extension = 2or no response = 1

extension = 2 orno response = 1

verbal oriented = 5 oriented = 5 confused = 4 orinappropriateresponses = 3

inappropriate = 3, orincomprehensible =2 or no response = 1

no response = 1

PRINCIPLE OF TREATMENT

Types of InterferonsInterferons are natural proteins that activate certain immune functions in the body and have anti-viral properties.

The natural interferons being used for chronic hepatitis B, C or both are called type I interferons and include thefollowing:

Interferon alpha 2b (Intron A). (Used for both hepatitis B and C.) Interferon alpha 2a (Roferon-A). (Mostly used for hepatitis C.) Interferon alfa-n1 (Wellferon). (Approved but mostly used in Canada for hepatitis C.)

They are given by injection and need to be taken three times a week.Newer synthetic interferons have been developed that are showing particularly promise:

Interferon alfacon-1 (Infergen). This agent is referred to as a consensus interferon (CIFN) because itwas genetically developed using the most commonly occurring amino acid sequences from each of the naturaltype 1 alpha interferons. It is usually given three times a week when used as initial treatment. CIFN is five to 10times more biologically active than natural type 1 interferons.

Pegylated interferon (PegINF). Pegylated interferons employ a small molecule called polytheleneglycol (PEG), which attaches to a protein and extends the activity of the interferon. This action allows the drugto be taken only once a week.

Of note, some evidence suggests that even in the absence of antiviral effects, interferon may reduceimportant factors that contribute to cirrhosis, inflammation and fibrosis (scarring). It may even have some effecton reversing liver damage. If this evidence holds up, then even patients whose viral and liver enzyme countsremain high or steady may still benefit from long-term use of these agents.

Contraindications to treatment with pegylated interferonand ribavirin

Absolute contraindicationo Pregnancy

Strong but not absolute contraindicationso Alcohol abuseo Hepatic decompensationo Coronary artery diseaseo Solid organ transplantation (except liver)

Relative contraindicationso Major depressiono Major psychosiso Autoimmune diseaseo Renal failure (including dialysis)o Patient characteristics that are

no longer considered to be contraindicationso Normal alanine aminotransferase levelo Injection drug useo Stable methadone maintenance

o Neutropenia, anemia or thrombocytopeniao Controlled seizure disordero Older than 65 years of ageo Alcohol use

Antiviral treatment in VHB:Treatment goals Sustained supression of HBV DNA Decrease necroinflammation (transition to inactive hepatitis B) Reduce risk of end stage liver disease and cancer

Treatment regiments in VHB:• Peginterferon alfa once a week // Standard interferon alfa 2b three times a week

plus one of the following:• Tenofovir 300mg daily, or• Telbivudine (Tyzeka, Sebivo) 600mg, or• Entecavir (Baraclude) 1mg, or• Lamivudine (Epivir) 100mg , or• Adefovir (Hepsera) 10mg

Antiviral treatment in VHC:Treatment goalsComplete elimination of the virus, which is termed a sustained virological response (SVR)Indications1. Inmates diagnosed with acute hepatitis C should be considered for antiviral therapy. Treatment can be delayed for 8 to 12 weeks after acute onset of hepatitis to allow

for spontaneous resolution of the infection. Patients should be considered for treatment with at least pegylated interferon. The benefits of including ribavirin in the regimen are unclear; therefore, decisions

about its use should be made on a case-by-case basis. The optimal duration of a treatment regimen for acute infection is unknown,

however, up to a total of 24 weeks may be considered. After 12 weeks of treatment, an HCV RNA assay should be obtained to assess the

response to treatment.

2. All patients with chronic hepatitis C who have compensated liver disease and have nocontraindications. The decision regarding if and when to initiate therapy should be basedon the balance between:

the perceived benefits of treatment risks of treatment the wishes of the individual patient.

Patients with extrahepatic manifestations of HCV infection should be considered forantiviral therapy.Persistently normal ALT does not exclude significant liver disease nor preclude theneed for antiviral.

Recommendations: 1. Close monitoring of hemoglobin levels is essential during antiviral treatment for

HCV, particularly during the administration of PIs.2. Management of anemia may include any of the following strategies:

a. RBV dose reduction,b. Transfusion of packed red blood cells,c. erythropoietin administration

3. Dosage reductions of boceprevir and telaprevir should not be utilized to managetreatment-related side effects

4. To prevent resistance, PIs must be stopped if either PEG-IFN or RBV arediscontinued

5. Treatment for HIV and HCV infections should not be initiated simultaneously.If the inmate is a strong candidate for HIV treatment (AIDS or CD4+ T-cell count<350 cells/mm3), he or she should be treated first with HIV antiretroviral therapy. Ifnot, consider initiating HCV antiviral therapy prior to initiating HIV treatment. It isgenerally recommended that several months elapse after initiating HIV antiretroviraltherapy prior to initiating HCV treatment—so that adverse effects associated withthe antiretroviral therapy can be distinguished from those associated with HCVtreatment.

TREATMENT-NAIVE PATIENTS WITH HCV GENOTYPE 1 with PEG-IFN, RBV and boceprevir A. Early responders B. Late responders C. Patients with cirrhosis (F4) or <1 log10 decrease in HCV RNA from baseline to week 4 after the lead-in

phaseIndicates discontinuation of all treatment due to futility in patients with HCV RNA ≥100 IU/mL at treatment week 12or detectable HCV RNA at week 24

1. Patients should receive a four-week lead-in period of PEG-IFN and RBV before the initiation of boceprevir.2. Boceprevir is given at a dosage of 800 mg (4 x 200 mg capsules) every 8 h with food.3. In noncirrhotic patients with undetectable HCV RNA at treatment weeks 8 through 24 (ie, four and 20 weeks

after starting boceprevir), all therapy may be discontinued at week 28.4. In patients with detectable HCV RNA at treatment week 8, triple therapy should be continued until week 28. At

this point, boceprevir should be discontinued and PEG-IFN and RBV should be continued for an additional 20

weeks.5. Patients with cirrhosis and those with <1 log10 decline in HCV RNA after the four-week lead-in period should

receive triple therapy for 44 weeks following the lead-in period.6. All treatment should be discontinued in patients with HCV RNA ≥100 IU/mL at treatment week

TREATMENT-NAIVE PATIENTS WITH HCV GENOTYPE 1 with PEGIFN,, RBV and telaprevirA Patients with an extended rapid virological responseB Patients who do not achieve an extended rapid virological responseC Patients with cirrhosi

1. Telaprevir should be started simultaneously with PEG-IFN and RBV and given for the initial 12 weeks oftherapy.

2. Telaprevir is given at a dosage of 750 mg (2 x 375 mg tablets) every 8 h with high-fat food.3. In noncirrhotic patients with undetectable HCV RNA at treatment weeks 4 and 12, telaprevir should be

discontinued at week 12 and PEG-IFN and RBV should be continued for an additional 12 weeks.4. In patients with detectable HCV RNA at weeks 4 or 12, telaprevir should be stopped at week 12 and PEG-IFN

and RBV should be continued for an additional 36 weeks.5. Patients with cirrhosis should receive 12 weeks of triple therapy followed by an additional 36 weeks of PEG-

IFN and RBV.6. All treatment should be discontinued in patients with HCV RNA >1000 IU/mL at treatment weeks 4 or 12, or

detectable HCV RNA at week 24 .

Recommendations for patients with genotypes 2 or 31. Patients with genotypes 2 or 3 should be treated with either of the following:

a. PEG-IFN-alpha-2a (Pegasys RBV, Hoffmann-La Roche Ltd, Canada) 180 μg subcutaneouslyonce weekly and RBV 800 mg per day given orally in two divided doses; or

b. PEG-IFN-alpha-2b (Pegetron, Merck & Co, Inc, Canada) 1.5 μg/kg subcutaneously once weeklyand weight-based RBV (600 mg to 1400 mg per day given orally in two divided doses)

2. The standard duration of therapy in patients with genotypes 2 or 3 is 24 weeks.Recommendations for patients with genotypes 4 to 61. Patients with genotypes 4 to 6 should be treated with either of the following:

a. PEG-IFN-alpha-2a (Pegasys RBV, Hoffmann-La Roche Ltd, Canada) 180 μg subcutaneouslyonce weekly and RBV 1000 mg (if weight <75 kg) to 1200 mg (if weight ≥75 kg) per day givenorally in two divided doses; or

b. PEG-IFNalpha-2b (Pegetron, Merck & Co, Inc, Canada) 1.5 μg/kg subcutaneously once weekly

and RBV 600 mg/day to 1400 mg/day given orally in two divided doses.2. The standard duration of therapy in patients with genotypes 4 to 6 is 48 weeks.

VHA active immunizationIinactivated hepatitis A vaccine

administered 2 weeks beforeexpected exposure

expected >10 yr duration ofprophylaxis

VAQTA

HAVRIX

TWINRIX

for 12mos-18yrs: 25U per dose,for >18 yrs: 50U per two dose schedulebooster within 6-12 monthsfor 12mos-18yrs - 720EL.U per dose,for >18 yrs 1440El.U per two dose schedulebooster within 6-12 months>18yrs only, combines hepatitis A and hepatitis Bvaccines in three dose schedule (0,1, 6 months oraccelerated four dose schedule 0, 7, 21-30dfollowed by booster at 12 mos.

VHB active immunizationRecombinant vaccineThe vaccines presently used arecomposed of viral surface antigen(HbsAg) obtained from thecommon baker's yeast,Saccharomyces cerevisiae, byinserting into it a gene for thesynthesis of HbsAg. These areYeast-Recombinant vaccines.

Recombivax

Engerix-B

infants-18 mo: 5.0 mcg/0.5ml: at 0, 1, 6 months ofage> 18 mo: 10 mcg/1mL adults and 40mcg/1mldialysis at 0, 1, 4-6infants-18 mo: 10 mcg/0.5ml: at 0, 1, 6 months ofage> 18 mo: 20 mcg/1mL adults at 0, 1, 4-6

Immunosuppressed patients may be unable to develop antibodies or may require additional boosters.

Routine testing of patients with chronic hepatitis C virusCategory of testing Tests CommentsConfirmation andcharacterization ofchronic infection

HCV RNA

HCV genotype

Confirms chronicity and baseline for treatment responsesDirects choice and duration of therapy

Assessment ofliver disease

Complete blood countALT, AST, GGT,Alkaline phosphataseBilirubin,INR (or PT),AlbuminCreatinine,abdominal ultrasound

Thrombocytopenia may indicate cirrhosis and portalhypertension. Platelets needed for APRI calculation. Normalvalue does not preclude significant fibrosis. AST needed forcalculation of APRI (APRI AST/platelet ratio index)Elevated bilirubin or INR, or hypoalbuminemia may indicatesignificant liver dysfunction.

Viral coinfections Ig G anti-HAVHBsAganti-HBsanti-HIV

If negative, vaccinate against HAVExclude hepatitis B coinfection.If negative (& HBsAg neg), vaccinate against HVBExclude HIV coinfection

Exclude othercauses of liverdisease†

Alpha-1-antitrypsinCeruloplasminFerritin, serum iron,total iron-bindingcapacityANA, SMAAntimitochrondrial AbImmunoglobulin GImmunoglobulin AImmunoglobulin M

Alpha-1-antitrypsin deficiencyWilson diseaseIron overload

Autoimmune hepatitis (AIH)Primary biliary cirrhosis (PBC)Often elevated in AIH and cirrhosis of any causeOften elevated in fatty liver and alcoholic liver diseaseOften elevated in PBC

Contraindicationsto treatment

Serum / urine β-HCGElectrocardiogramThyroid-stimulatinghormoneFundoscopy

Exclude pregnancy in women of reproductive ageIf >50 years or history of cardiac diseaseExclude thyroid disease, which may be exacerbated by IFN

Exclude retinopathy in patients >50 years or with hypertensionor diabetes mellitus

APRI was calculated based on the following formula: APRI=(AST/ULN)/platelet x 100. *ULN=upper limit ofnormal

The elevation of AST according to fibrosis progression is due to its clearance deficit and, also, increasedmitochondrial damage

Compensated and Decompensated Cirrhosis

Compensatedcirrhosis is definedas:

bilirubin <1.5 mg/dL; INR <1.5; albumin >3.4 g/dL; and platelet count >75,000/mm3; aswell as no evidence of: ascites by liver ultrasound, esophageal varices by upper endoscopy,or hepatic encephalopathy.

Decompensatedcirrhosis is definedas:

evidence of significant liver disease (such as ascites, encephalopathy, markedthrombocytopenia, and bleeding esophageal varices), as well as loss of liver syntheticfunction (e.g., albumin < 3.4 g/dL, and INR >1.5).

BIBLIO:

1. RP Myers, A Ramji, M Bilodeau, S Wong, JJ Feld. An update on the management of chronic hepatitis C:Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol2012;26(6):359-375.

2. Federal Bureau of Prisons (BOP). Clinical Practice Guidelines. Evaluation and treatment of hepatitis C andcirrhosos. http://www.bop.gov/news/medresources.jsp.