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Juan Herrera Salazar Clnica de Asma y Alergia Hepatitis C

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Presentacin basada en The ABCs of Hepatitis

Ian Williams, PhD, MS Division of Viral Hepatitis Centers for Disease Control and Prevention

Bibliografa Emedecine collection collection

HEPATITIS C AUTHOR: SANDEEP MUKHERJEE, AUTHOR: MUKHERJEE,

MB, BCH, MPH, FRCPC; CHIEF EDITOR: JULIAN KATZ, MD BCH, KATZ,
UPDATED , OCTOBER 26, 2011

HEPATOLOGY - A CLINICAL TEXTBOOK SECOND

EDITION EDITORS:STEFAN MAUSS ,THOMAS BERG,JRGEN ROCKSTROH , CHRISTOPH SARRAZIN,HEINER WEDEMEYER. WEDEMEYER.

See notes chapter 3

Bibliografa


Notes from the Field: Risk Factors for Hepatitis C Virus Infections Among Young Adults The Role of Bile Acid Retention and a Common Polymorphism in the ABCB11 Gene as Host Factors Affecting Antiviral Treatment Response in Chronic Hepatitis C Role of Hepatitis C Virus Genotype 3 in Liver Fibrosis Progression

Bibliografa Emedecine collection

  

Pediatric Hepatitis C Cutaneous Manifestations of Hepatitis C Hepatitis C Organism-Specific Therapy Organism1 Algorithm of Dufour et al for Evaluating an Enyzme Immunoassay (EIA) Result for Antibodies to Hepatitis C Virus 2 AP (Age and Platelet Count) Index of Poynard et al for Evaluating a Patient with Viral Hepatitis C 3 Assessment Tool of Nguyen et al for Predicting the Risk of a Hepatitis C Viral Infection 4 Causes for Cognitive Impairment in a Patient with Chronic Hepatitis C 5 CDC Recommendations for Reporting Results of Diagnostic Tests for Hepatitis C Virus (HCV)

New !
Antedecentes

HEPATITIS C..

Classification of Hepatitis Viruses

Virus HAV HBV HCV HDV HEV Family Picornaviridae Hepadnaviridae Flaviviridae Deltavirus (genus) ?
(Previously classified as a calicivirus)

DNA or RNA RNA* DNA** RNA* RNA*** RNA*

Envelope no yes yes yes no

*linear, single strand; ** circular, double strand; *** circular, single strand

See notesHCV-RNA notesHCVPEGPEG- INF alfa, Ribavirin

Pathophysiology


RNARNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities and generates a large number of mutant viruses known as

quasispecies. quasispecies.

Patofisiologa


The cause of hepatitis C, HCV, is a spherical, enveloped, single-stranded RNA singlevirus belonging to the Flaviviridae family and Flavivirus genus. The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic virusT lymphocytes and helper T cells.

HCV life cycleVirology ,

Hepatology - A Clinical Textbook Second Edition

Etiologa


Hepatitis C is caused by a spherical, spherical, enveloped, singleenveloped, single-stranded RNA virus belonging to the family Flaviviridae, Flaviviridae, genus Flavivirus. Lauer and Walker Flavivirus. reported that HCV is closely related to hepatitis G, dengue, and yellow fever viruses. viruses. HCV can produce at least 10 trillion new viral particles each day. day.

Etiology


Importancia del genotipo

History
    

Arthralgias (23%) Paresthesias (17%) Myalgias (15%) Pruritus (15%) Sicca syndrome (11%)

Decompensated liver disease



Symptoms characteristic of complications are related to synthetic dysfunction hypertension. and portal hypertension. These include mental status changes encephalopathy), (hepatic encephalopathy), ankle edema and abdominal distention (ascites), and hematemesis or melena ascites), (variceal bleeding). bleeding).

Physical examination


Hand signs - Palmar

erythema, erythema, Dupuytren contracture, asterixis, contracture, asterixis, leukonychia, leukonychia, clubbing

Head signs - Icteric sclera, sclera,

temporal muscle wasting, wasting, enlarged parotid, cyanosis parotid,

Abdominal signs Paraumbilical hernia ascites, ascites, caput medusae, medusae, hepatosplenomegaly, hepatosplenomegaly, abdominal bruit Ankle edema Scant body hair Skin signs - Spider nevi, nevi, petechiae, petechiae, excoriations due to pruritus




Fetor hepaticus
Gynecomastia, Gynecomastia, small testes

Extrahepatic manifestations of chronic hepatitis C. C.

HCVHCV-associated thrombocytopenia

    

Thrombocytopenic conditions (platelet counts below 150 x 103/uL) 103/uL) Advanced liver cirrhosis Lack of hepatic derived thrombopietin Ab against platelets as ITP. Standard Sandoglobulin, splenectomy A new orally Sandoglobulin, active thrombopoetin-receptor agonist, elthrombopag, may thrombopoetinelthrombopag, be used in thrombocytopenic HCV patients in the future. Caution Pgel+ribavirin Consider rituximax Pgel+ribavirin rituximax

Extrahepatic manifestations
        

Cryoglobulinemia: Cryoglobulinemia: Membranoproliferative glomerulonephritis Idiopathic thrombocytopenic purpura Lichen planus Keratoconjunctivitis sicca Raynaud syndrome Sjogren syndrome Porphyria cutanea tarda Necrotizing cutaneous vasculitis NonNon-Hodgkin lymphoma

Differential Diagnosis of Acute Hepatitis

Viral infections Bacterial infections hepatitis A, B, C, D, and E, CMV, EBV, HSV, VZV, yellow fever typhoid fever, Q fever, RMSF, leptospirosis, secondary syphillis, sepsis toxocariasis, liver flukes ASA, acetaminophen, INH, rifampin, oral contraceptives, anti-seizure meds, carbenicillin, sulfonamides Alcohol, carbon tetrachloride Autoimmune hepatitis, SLE

Parasitic infections Drugs

Toxins Autoimmune diseases

Diagnstico diferencial
Hepatitis de otra etiologa
      

Embarazo edad peditrica

Alcoholic Hepatitis Autoimmune Hepatitis Dermatologic Manifestations of Hepatitis C Hepatitis B Hepatitis C Hepatitis D Hepatitis E

    

Hepatitis in Pregnancy Pediatric Hepatitis A Pediatric Hepatitis B Pediatric Hepatitis C Viral Hepatitis

Differential Diagnosis


Autoimmune Hepatitis Cholangitis Hepatitis, Viral

Chapter 12. Hepatology 2nd. Ed.

Diagnostic test in acute and Chronic Hepatitis C

 

Genotyping Quantitative and Qualitative HCV Rna assay assay substitute real time PCR

Chapter 12. Serologic testing HCV



Screening tests for coinfection with HIV or hepatitis B virus (HBV)

HCV core antigen assays

See other diagnostic kits by: Roche , Abbot Siemmens

Antibody test


EIA ( 1st, 2nd, 3er generation test) RIBA Recombinant Immunoblot Assay. Assay. Qualitative and Quantitative Assays for HCV RNA. ( PCR, Roche amplification system) system) HCV genotyping. genotyping.

Serologic testing
    

Antinuclear antibody (ANA; 41%) Rheumatoid factor (38%) Anticardiolipin antibody (27%) Antithyroid antibody (13%) Anti Antismooth muscle antibody (9%)

Diagnosis and management of acute and chronic hepatitis C



HCV RNA, and HCVAb HCVAb

see notes

Cold aglutinins HCV Disease

Cold agglutinin disease indistinguishable from cryoglobulinemia. Courtesy of Walter Reed Army Medical Center Dermatology.

Cryoglobulinemia, palpable purpura, dysproteinemic purpura, and leukocytoclastic vasculitis (small vessel vasculitis). Courtesy of Walter Reed Army Medical Center Dermatology.

Viral Hepatitis Historical Perspective

Infectious Viral hepatitis A Enterically E transmitted

NANB
Parenterally C transmitted

Serum

B D

F, G, ? other

Hepatitis C Prognosis

Disease progresion
 


Age 40-55 more rapid progression. 40progression. African americans less severe americans
Alcohol : increase HCV replication, progression to replication, chronic HCV, accelerates liver injury. injury.

 

Marijuana Marijuana stimulation of endogenous cannabinoid receptorrapid fibrosis receptorrapid progression. progression. Viral Co infection HB. Steroids increase the viral load.

Liver biopsy
  

The diagnosis is uncertain Other coinfections or disease may be present The patient being considered for treatment has normal liver enzyme levels and no extrahepatic manifestations The patient is immunocompromised

Treatment aproach considerations

This is intended for hepatologist

Interferons and Pegylated Interferons Interferons and Ribavirin Protease Inhibitors HIV-HCV Coinfection Hepatitis C and B Coinfection Interferon Response in Specific Populations End-Stage Renal Disease Nonresponse or Relapse Patients with Normal Liver Enzyme Levels Patients Using Alcohol or Injection Drugs Deterrence/Prevention Consultations and Long-Term Monitoring

Hepatology 2nd Edition 2010

Chapter 13: Hepatitis C Standard of care Markus Cornberg, Michael P. Manns, Heiner Wedemeyer


Chapter 14: New agents for treating hepatitis C Christian Lange, Christoph Christian Lange, Sarrazin

Liver transplantation

Medication Summary for Hepatologist

      

Interferon alfa-2b (Intron-A) alfa- (IntronInterferon alfa-2b (Intron-A) alfa- (IntronPeginterferon alfa-2b (PEG-Intron) alfa- (PEG-Intron) Pegylated interferon alfa-2a (Pegasys) alfa- (Pegasys) Ribavirin (Rebetol, Virazole, Copegus) Rebetol, Virazole, Copegus) Boceprevir (Victrelis) Victrelis) Telaprevir (Incivek) Incivek)

Basic Features of Hepatitis Viruses

Virus A B C D E
* Weeks

Transmission fecal-oral parenteral parenteral parenteral fecal-oral

Incubation Period* 4 (2-6) 8-12 (6-24) 6-9 (2-24) ? (2-10) 4-5 (2-9)

Chronic Infection No Yes Yes Yes No

Transmission of Bloodborne Viral Infections

Route


Mode
injection drug use needle stick injury blood/ serous fluid sex perinatal

Percutaneous  Apparent

 Inapparent

 Permucosal

Relative Transmission Efficiency of Bloodborne Viral Infections

HBV
Injection drug use Sexual Perinatal Occupational +++ +++ ++++ +++

HCV
++++ + + +/-

HIV
++ ++ ++ +/-

Risk Factors for Transmission of Hepatitis Viruses and HIV

Proportion of Infections

Risk Factor
Injection drug use MSM Heterosexual partners Transfusion Occupational No Identified Risk

HBV
14% 15% 40% rare 5-7% (past) 30%

HCV
60% 1% 20% Past 7- 20% <<1% 10%

HIV
31% 47% 10% Past 2% <<1% 9%

Disease Burden from Bloodborne Viral Infections

Outcome
Chronic infections

HBV
~1.2 (million)

HCV
~2.7 (million) ~40,000 8,000

HIV
~0.8 (million) ~40,000 18,000

New infections /yr Deaths /yr

~120,000 5,000

Prevalence of HCV Infection by Age United States, 1988-1994 19884 Prevalence of Anti-HCV (%) Average Prevalence = ~1.8% # Infected Nationwide = ~3.9 million 3

611

1219 2029 3039 4049 5059 6069 7079 Age (yr)

80+

Alter MJ. N Engl J Med. 1999;341:556 (NHANES III, 19881994).

Features of HCV Infection



Incubation period Acute illness (jaundice) Persistent infection Chronic hepatitis Immunity

Average, 67 wk 6 Range, 226 wk 2 Mild (20%30%) (20% 75% 75%85% 70% No protective antibody response identified

   

Acute Viral Hepatitis, United States, 19911991-1998

63% 28% 8%
Hepatitis A Hepatitis B Hepatitis C Non-ABCDE

1%
Source: Sentinel Counties Study, CDC

Risk of Fatal Outcome in Persons Who Develop Hepatitis C Infection

Time 100
15% 85%

Resolv e 15 Stable 68
Courtesy of Seeff, LB and Alter, HJ.

Chroni c 20% Cirrhosis 85 80% 17 25%

75%

Stabl e 13

Mortality 4

Etiology of Chronic Liver Disease United States

Birmingham, AL
CDC, unpublished data
HBV& Cryptogenic Alcohol 3% 17% HBV 11% Other 5% Alcohol 24% HCV 26% HCV & Alcohol 14% HCV & Alcohol 46%

Harlem, NYC
Frieden et al. Hepatology 1999
HBV & Alcohol 6% Other 6% HCV 11%

Alcohol 29%

HBV, HCV & Alcohol 2%

Prevalence of HCV Infection by Age and Race, United States, 1988-1994 19887 6

Anti-HCV+ (%)

5 4 3 2 1 0 611 1219

Black

Mexican American

White

2029

3039

4049

5059

6069

70+

Age (yr)
Alter MJ. N Engl J Med. 1999;341:556 (NHANES III, 19881994).

Prevalence of HCV Infection by Age and Gender, United States, 1988-1994 19886 Percent Anti-HCV Positive 5 4 3 2
Females Males Total

1 0 6-11 12-19 20-29 30-39 40-49 50-59 60-69 70+

Source: CDC, NHANES III

Age in Years

Future Hepatitis C Mortality and Costs

  

Future HCV-related mortality may double over the next 10 to 20 years $10.7 billion in direct medical care expenditures $ 75.5 billion in societal (indirect) costs

Wong JB, et al. AJPH 2000; 90(10): 1562-1569.

Public health , consideration



Policy

Posttransfusion Hepatitis, United States

Alter HJ and Houghton M. Hepatitis C virus and eliminating posttransfusion hepatitis. Nature Medicine 2000;6:1082-6.

HCV Infection - Estimates of Past Incidence and Future Prevalence

140 120 Infections per 100,000 100 80 60 40 20 0

Decline in cases among IDUs

Incidence

2.0% Prevalence 1.5% 1.0% 0.5% 0.0% 1960 1970 1980 1990 2000

Overall prevalence

Infected 20+ years

2010 2020 2030

Source: Armstrong GL et al. Hepatology 2000;31

Risk of HCV, HBV, and HIV Infection Among Injection Drug Users
Baltimore 19831988 1983
100

HCV
Seroprevalence (%)
80 60 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72

HBV

HIV

Duration of Injecting (mo)

Garfein RS. Am J Public Health. 1996;86:655.

Risk of HCV Infection Among Injection Drug Users

100

Seroprevalence (%)

Baltimore: 1983-1988

80 60 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Duration of Injection (months)

Garfein RS Am J Public Health 1996; 86:655. Thorpe LE JID 2000;182:158894. Diaz T Am J Public Health 2001; 91(1): 23-30.

Sexual Transmission of HCV



CaseCase-control, cross sectional studies

infected partner, multiple partners, early sex, nonnonuse of condoms, other STDs, sex with trauma MSM no higher risk than heterosexuals

Partner studies
low prevalence (1.5%) among long-term partners long infections might be due to common percutaneous exposures (e.g., unsafe injections, drug use)

male to female transmission more efficient

more indicative of sexual transmission

Relative Importance of Risk Factors for Remote and Recent HCV Infection
Remote (>15 yr ago)
Injection Drug Use Transfusion

Recent (<15 yr ago)

Injection Drug Use

Unknown Other* Transfusion Sexual Unknown Other* Sexual

*Nosocomial, occupational, perinatal

Sexual Transmission of HCV- II HCV

Occurs, but efficiency is low

Rare between long-term steady partners long Factors that facilitate transmission between partners unknown (e.g., viral titer, other STDs)

Accounts for 15-20% of acute and chronic 15infections in the United States
Sex is a common behavior Large chronic reservoir provides multiple opportunities for exposure to potentially infectious partners

Other Potential Exposures to Blood



No or insufficient data showing increased risk

intranasal cocaine use, tattooing, body piercing, acupuncture, military service

Limited number of studies showing associations that cannot be generalized

convenience or highly selected groups (mostly blood donors)

No associations in acute case-control or casepopulationpopulation-based studies

Other Potential Exposures to Blood - II



Biologically plausible but no data showing these practices, procedures, or histories alone place persons at increased risk for HCV May be limited to certain settings and account for small fraction of cases
e.g., prisons, unregulated practitioners, populations with certain cultural practices, etc.

Risk factor or high prevalence identified in selected subgroup cannot be extrapolated to the population

National Hepatitis C Prevention Strategy

Prevent HCV infection Detect and control chronic liver disease Evaluate effectiveness of activities Conduct surveillance and research

Prevention Activities
Primary = Prevent HCV Transmission

high risk activities - IDU, high risk sex nosocomial, occupational, transfusions and transplant
Secondary = Reduce Risk of Chronic Liver Disease

identify, test, counsel, medical management

Reasons to Identify Persons with Chronic HCV Infection

Medical management

evaluate for chronic liver disease

treatment if indicated substance abuse treatment (alcohol, drugs) if

Counsel to prevent disease transmission

household contacts sexual contacts drug use contacts

appropriate immunization (HB, HA, influenza, pneumo)

HCV Testing Routinely Recommended Based on increased risk for infection Ever injected illegal drugs

Received clotting factors made before 1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease
Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCVRelated Chronic Disease. MMWR 1998; 47: RR-19

HCV Testing Routinely Recommended

Based on need for exposure management  Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood HCV

Children born to HCV-positive women HCV-

Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCVRelated Chronic Disease. MMWR 1998; 47: RR-19

National Hepatitis C Prevention Strategy Communication of Information on Hepatitis C

education of health care professionals public service advertising education of persons in groups at risk of
infection

transfusion recipients injection drug users

Most difficult task: keeping messages factually correct

Geographic and Temporal Differences in the Epidemiology of HCV Infection



HCV infection is endemic in most parts of the world. Substantial geographic and temporal differences in endemicity of HCV infection
related to frequency and extent to which various risk factors contributed to transmission

Estimated Prevalence of Anti-HCV Anti-

WHO Global Burden of Disease Estimate, CDC, Unpublished data

Geographic Patterns of Age-Specific AgePrevalence of HCV Infection

50 Percent Anti-HCV Positive Egypt 40 30 20 10 0 0-9 10-19 20-29 30-39 40-49 50+ Japan, Italy U.S., Australia

Age Group (Years)

Geographic Differences in HCV Transmission Patterns

Exposures among prevalent infections Injecting drug use Transfusions Health-care related Unsafe injections Folk medicine
Importance of Exposures by HCV Endemicity

Low ++++ +++ +/+/-

Moderate ++ +++ ++++ ++++ ++

High + +++ ++++ ++++ No data

Children Playing with Medical Waste, Bangladesh

Relative Importance of Risk Factors for Hepatitis C and Prevention Strategies by HCV Endemicity
High/Moderate Endemicity
Nosocomial

Low Endemicity
Injection Drug Use

Transfusion

Other

Other

Sexual

Safe blood supply Infection control

Risk reduction counseling and services

Adequate resources

Identify persons at high risk for counseling, testing, and medical management

Viral Hepatitis - Overview

A Source of virus Route of transmission Chronic infection Vaccine Pre/Post prophylaxis Feces B Blood* C Blood* D Blood* E Feces

fecal-oral

Percutaneous yes

Percutanous yes

Percutaneous yes

fecaloral no

no

yes pre/post (IG)

yes post (HBIG)

no no

yes** no

no no

* Blood and blood-derived body fluids

**Prevention of Hep B with vaccine

Dermatologic manifestation of Hepatitis C

Cutis marmorata. Courtesy of marmorata. Walter Reed Army Medical Center Dermatology. Erythema multiforme, bull's-eye multiforme, bull'slesions. Courtesy of Walter Reed Army Medical Center Dermatology

Lesiones Dermatolgicas Hepatitis C dyschromicum Eythema

perstans. perstans. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema dyschromicum perstans. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of multiforme. Walter Reed Army Medical Center Dermatology

Erythema multiforme. Courtesy of multiforme. Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme of the oral mucosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme (Stevens-Johnson (Stevenssyndrome). syndrome). Courtesy of Walter Reed Army Medical Center Dermatology.

Lesiones Dermatolgicas Hepatitis C

Palmar erythema. Courtesy of Walter Reed Army erythema. Medical Center Dermatology.

Granuloma anulare

Actinic porokeratosis
Disseminated porokeratosis

Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus. Courtesy of Walter planus. Reed Army Medical Center Dermatology.

Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus Lymphoma cutis

Lichen planus (oral lesions). Courtesy of Walter Reed Army Medical Center Dermatology.
Lichen planus hipertrfico Lichen planus lesiones orales

Purpura in hemophilia (factor VIII deficiency). All ecchymoses and bland petechiae are in the differential diagnosis of thrombocytopenic purpuras, including thrombocytopenia secondary to hepatitis C virus in which an autoantibody to platelets is present. Courtesy of Walter Reed Army Medical Center Dermatology.

HenochHenoch-Schnlein purpura. Courtesy of Walter purpura. Reed Army Medical Center Dermatology.

Cortesia de Walter Reed Army Medical Services



Purpura palpable

Progressive purpuric eruption

Progressive pigmented purpura (GougerotBlum disease). Courtesy of Walter Reed Army Medical Center Dermatology.

Progressive pigmented purpura (Schamberg disease). Courtesy of Walter Reed Army Medical Center Dermatology.

Thrombocytopenic purpura

Courtesy of Walter Reed Army Medical Center Dermatology.

Prurigo nodularis Prurigo nodularis

Prurigo nodularis

Urticaria Crnica

Nodular vasculitis. Courtesy of Walter Reed Army vasculitis. Medical Center Dermatology

Henoch-Schnlein purpura, palpable purpura, and leukocytoclastic vasculitis. Courtesy of Walter Reed Army Medical Center Dermatology.

Vitiligo. Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology.

Vitiligo. Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology

Waldenstrm hypergammaglobulinemic purpura. Courtesy of Walter Reed Army Medical Center Dermatology. Dermatology.

Chapter 17: Management of HBV/HIV Coinfection Stefan Mauss, Jrgen Rockstroh

This chapter is intended to the specialist In Infectious diseases an d Hepatologist

1 Algorithm of Dufour et al for Evaluating an Enyzme Immunoassay (EIA) Result for Antibodies to Hepatitis C Virus 2 AP (Age and Platelet Count) Index of Poynard et al for Evaluating a Patient with Viral Hepatitis C 3 Assessment Tool of Nguyen et al for Predicting the Risk of a Hepatitis C Viral Infection 4 Causes for Cognitive Impairment in a Patient with Chronic Hepatitis C 5 CDC Recommendations for Reporting Results of Diagnostic Tests for Hepatitis C Virus (HCV)

HEPATITIS C..

Bibliografia


References References Ver pie de pgina

HB Co-infection Co-

Assessment of hepatic fibrosis in chronic viral hepatitis

  

Liver biopsy the gold standard for staging of liver fibrosis Surrogate markers of liver fibrosis Transient elastography

Classification of HCC


Chapter 21: Diagnosis, Prognosis & Therapy Ulrich Spengler

Epidemiology


Survey cirrhotic patientssee notes patients

Surveillance of patients at high risk and early HCC diagnosis Surveillance using ultrasound at 6-month intervals is generally recommended for all patients with liver cirrhosis or other risk factors of HCC.

HC Cancer Prevention





Vaccination HBV, both HBe-antigen HBepositive & HBeantigen negative show reduced rates of HCC. Interfereon succesful treatment treatment
Finally, consumption of two or more cups of coffee per day seems to reduce the risk of liver cancer by 40-50% in patients with chronic viral hepatitis 40(Gelatti 2005; Bravi 2007; Larsson 2007; Wakai 2007).

Hepatic Cancer
 See


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