Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Daniel Shouval Liver Unit Hadassah Hospital Hebrew University JerusalemIsrael

Liver Unit - Hadassah

Clinical Manifestations Clinical Manifestations of of

Hepatitis C Virus InfectionHepatitis C Virus Infection

Daniel ShouvalDaniel ShouvalLiver UnitLiver Unit

Hadassah HospitalHadassah HospitalHebrew UniversityHebrew University

JerusalemJerusalemIsraelIsrael


Clinical Manifestations of Clinical Manifestations of Hepatitis C Virus InfectionHepatitis C Virus Infection

Key ConceptsKey Concepts Disease is usually insidious and subclinicalDisease is usually insidious and subclinical

Persistent HCV infection may progress over decadesPersistent HCV infection may progress over decades to chronic hepatitis with fibrosis, cirrhosis, portalto chronic hepatitis with fibrosis, cirrhosis, portal hypertension, encephalopathy and hepatocellular ca.hypertension, encephalopathy and hepatocellular ca.

HCV is the main indication for liver transplantationHCV is the main indication for liver transplantation

Although the liver is the main target for HCV, extra-Although the liver is the main target for HCV, extrahepatic manifestations are commonhepatic manifestations are common

HCV may complicate the course of other diseasesHCV may complicate the course of other diseases I.e. HIV, HBV, chronic liver disease,hemophilia,I.e. HIV, HBV, chronic liver disease,hemophilia, renal failure, organ transplantationrenal failure, organ transplantation


Clinical Manifestations Clinical Manifestations of Hepatitis C Virus Infectionof Hepatitis C Virus Infection

Background - Pathology Background - Pathology • Viral hepatitis is defined as a diffuse necro-Viral hepatitis is defined as a diffuse necro- inflammatory liver disease causedinflammatory liver disease caused by by hepato-hepatotropic virusestropic viruses• The basic morphologic pattern of acute orThe basic morphologic pattern of acute or chronic hepatitis due to different hepatitis chronic hepatitis due to different hepatitis viruses are very similar irrespective of viruses are very similar irrespective of causative viruscausative virus• Despite of the above, there are unique Despite of the above, there are unique characteristic morphologic patterns in chroniccharacteristic morphologic patterns in chronic HCV infection incl: HCV infection incl: lymphoid aggregates(57%),lymphoid aggregates(57%), bile duct injury (60%) and steatosis (52%).bile duct injury (60%) and steatosis (52%).


Liver Biopsy in Chronic Hepatitis Liver Biopsy in Chronic Hepatitis C – is it still necessary?C – is it still necessary?

Background:Background:

Little correlation between the inflammatory process Little correlation between the inflammatory process observed by microscopy and the clinical orobserved by microscopy and the clinical or laboratory manifestationslaboratory manifestations

The impact of clinical presentation on theThe impact of clinical presentation on the rational for performing a biopsy:rational for performing a biopsy:• Establish diagnosisEstablish diagnosis• Assess grade and stage (Metavir score etc)Assess grade and stage (Metavir score etc)• Exclude other or additional conditionsExclude other or additional conditions (i.e alcohol, NASH, CLD, HBV )(i.e alcohol, NASH, CLD, HBV )• Guide management Guide management • Follow-up of therapyFollow-up of therapy



• Incubation period: Incubation period: Acute hepatitis C 15-150 days (M 50d)Acute hepatitis C 15-150 days (M 50d)

• Most cases of acute HCV infection (~75%) are Most cases of acute HCV infection (~75%) are notnot recognized recognized

• Clinical symptoms in patients with acute HCV whenClinical symptoms in patients with acute HCV when present, are usually present, are usually mildermilder as compared to other as compared to other hepatitis viruseshepatitis viruses

• ~80%~80% of patients who contract acute HCV infection of patients who contract acute HCV infection will develop will develop persistentpersistent infection which often lasts infection which often lasts for decadesfor decades


Hepatitis C Virus InfectionLab Markers

Hepatitis C Virus InfectionLab Markers

Symptoms (if any)

Time after ExposureTime after Exposure

Tit

er

Tit

er

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4YearsYearsMonth

sMonths

HCV - RNAHCV - RNAIIIIIIII IIIIIIIIIIIIIIIIIIII


Clinical Presentation of Chronic Clinical Presentation of Chronic HCV InfectionHCV Infection**

Clinical presentation may vary depending on the host Clinical presentation may vary depending on the host Immune status, the source and duration of infectionImmune status, the source and duration of infection

• Often asymptomaticOften asymptomatic

• Frequently detected during routine lab testingFrequently detected during routine lab testing or blood donationor blood donation

Non specific signals: Non specific signals: -- mild to moderate fatigue mild to moderate fatigue -- fluctuating ALT levels are fluctuating ALT levels are *Sharara AL et al. Hepatitis c. Review Ann Int Med 1996; 125:658*Sharara AL et al. Hepatitis c. Review Ann Int Med 1996; 125:658



Symptoms *Symptoms * FatigueFatigue MalaiseMalaise NauseaNausea Abdominal discomfortAbdominal discomfort** Dark urine and acholic stoolsDark urine and acholic stools VomittingVomitting JaundiceJaundice PruritusPruritus ArthralgiaArthralgia FeverFever

* May be present in acute as well as in chronic hepatitis* May be present in acute as well as in chronic hepatitis


Clinical Manifestations of HCVClinical Manifestations of HCV

o FatigueFatigue

o MalaiseMalaise

o MyalgiaMyalgia

o DepressionDepression

o Cognitive Cognitive dysfunctiondysfunction


Musculoskeletal Pain and Fatigue Musculoskeletal Pain and Fatigue in HCVin HCV**

239 patients; age M 46.7y; Males 52%239 patients; age M 46.7y; Males 52%Results:Results: Musculoskeletal pain – 70% for M of 7yMusculoskeletal pain – 70% for M of 7y Fatigue – 56% for a M 3.3yFatigue – 56% for a M 3.3y Backache - 54%Backache - 54% Morning stiffness – 45%Morning stiffness – 45% Arthralgia – 42%Arthralgia – 42% Myalgia – 38%Myalgia – 38% Neck pain – 33%Neck pain – 33%

* Barhuizen A et al. Am J Gastroenterology 1999;94:1355* Barhuizen A et al. Am J Gastroenterology 1999;94:1355


Hepatitis C and Cognitive Impairment Hepatitis C and Cognitive Impairment of Patients with Mild Disease I*of Patients with Mild Disease I*

*Forton DM et al. Hepatology 2002;35:433*Forton DM et al. Hepatology 2002;35:433

Material and MethodsMaterial and Methods 27 HCV patients with biopsy proven mild HCV27 HCV patients with biopsy proven mild HCV 17 control patients with resolved HCV17 control patients with resolved HCV

Testing through computor based cognitiveTesting through computor based cognitive assessment batteryassessment battery

Completing depression, fatigue and qualityCompleting depression, fatigue and quality of life questionnairsof life questionnairs


Hepatitis C and Cognitive Impairment Hepatitis C and Cognitive Impairment of Patients with Mild Disease II*of Patients with Mild Disease II*

*Forton DM et al. Hepatology 2002;35:433*Forton DM et al. Hepatology 2002;35:433

RESULTSRESULTS HCV patients wereimpaired on moreHCV patients wereimpaired on more cognitive tasks than patients who cognitive tasks than patients who cleared HCv ( P < 0.02)cleared HCv ( P < 0.02) HCV patients showed impairment in:HCV patients showed impairment in: - concentration power- concentration power - speed of working memory- speed of working memory (irrespective of fatigue or depression)(irrespective of fatigue or depression) Cerebral proton magnetic resonance spectro-Cerebral proton magnetic resonance spectro- scopy showed elevated choline/creatine ratiosscopy showed elevated choline/creatine ratios suggesting a possible organic etiology for suggesting a possible organic etiology for cognitive impairment in HCV infectioncognitive impairment in HCV infection


Complications of Acute HCV Complications of Acute HCV Infection (I)Infection (I)

• Fulminant hepatitis – rareFulminant hepatitis – rare• Chronic hepatitis - ~80%Chronic hepatitis - ~80%• CirrhosisCirrhosis** ~20-35% ~20-35%• Hepatocellular carcinomHepatocellular carcinom**** - ` 1-4% - ` 1-4% annually, after prolonged infectionannually, after prolonged infection

* * Maybe clinically silent but eventuallyMaybe clinically silent but eventually may lead to portal hypertension, ascites, may lead to portal hypertension, ascites, esophageal and gastric varices which may bleed,esophageal and gastric varices which may bleed, or hepatic encephalopathyor hepatic encephalopathy

** ** As * with additional extra hepatic manifestationsAs * with additional extra hepatic manifestations


Complications of Acute HCV Complications of Acute HCV Infection (II)Infection (II)**

average time between acute hepatitis caverage time between acute hepatitis candand

“ “Clinically significant” liver disease Clinically significant” liver disease ~10 years~10 years

Cirrhosis Cirrhosis ~ 21.2 years~ 21.2 years

Hepatocellular carcinoma Hepatocellular carcinoma ~ 29 years~ 29 years

*Sharara AL et al. Hepatitis c. Review Ann Int Med 1996; 125:658*Sharara AL et al. Hepatitis c. Review Ann Int Med 1996; 125:658


Association of HCV infection with Association of HCV infection with other Diseases and Conditionsother Diseases and Conditions

and Impact on Clinical Presentationand Impact on Clinical Presentation

• Infection with other viruses: HIV, HBV,Infection with other viruses: HIV, HBV, HTLV, HerpesHTLV, Herpes• Infection of patients with schistosomiasisInfection of patients with schistosomiasis• IVDAIVDA• Hemophilia, Thalassemia, Sickle cell anemia etc.Hemophilia, Thalassemia, Sickle cell anemia etc.• Hemodialysis and kidney transplantationHemodialysis and kidney transplantation• Iron overloadIron overload• Alcoholic liver diseaseAlcoholic liver disease• Autoimmune hepatitis. PBC, PSCAutoimmune hepatitis. PBC, PSC


Extrahepatic Manifestations of Extrahepatic Manifestations of Hepatitis C Virus InfectionHepatitis C Virus Infection**

EndocrineEndocrine Salivary Glands (sialadenitis)Salivary Glands (sialadenitis) Ophtalmic ( uveitis, ulcers) Ophtalmic ( uveitis, ulcers) Hematologic/lymphoid organsHematologic/lymphoid organs SkinSkin RenalRenal Autoimmune diseasesAutoimmune diseases Neurologic and Cognitive impairmentNeurologic and Cognitive impairment MiscellaneousMiscellaneous**S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9


Extrahepatic Manifestations of Extrahepatic Manifestations of Hepatitis CHepatitis CEndocrineEndocrine

HyperthyroidismHyperthyroidism

HypothyroidismHypothyroidism

Hashimoto’s Disease and ThyroiditisHashimoto’s Disease and Thyroiditis

Thyroid antibodiesThyroid antibodies**

Diabetes MellitusDiabetes Mellitus •Higher prevalence of anti-thyroid antibodies; also induced Higher prevalence of anti-thyroid antibodies; also induced

through interferon Rx and leading to hyper and hypothyroidismthrough interferon Rx and leading to hyper and hypothyroidism


Extrahepatic Manifestations of Hepatitis CExtrahepatic Manifestations of Hepatitis CThyroid dysfunction Anti-thyroid Antibodies and Thyroid dysfunction Anti-thyroid Antibodies and

Interferon TreatmentInterferon Treatment

AuthorAuthor

% % PatientsPatients

< < InterferonInterferon

> > InterferonInterferon

DiBiscegli DiBiscegli (USA)(USA) 9.59.5 00 00Lisker-MelmanLisker-Melman

(USA)(USA)7.07.0 11 22

Berris (Canada)Berris (Canada) 5.55.5 00 33Pateron Pateron (France)(France) 9.09.0 22 22Baudin Baudin (France)(France) 1212 11 44KodamaKodama (Japan)(Japan) 1212 44 66Deutsch (Greece)Deutsch (Greece) 10.910.9 1919 3131


Extrahepatic Manifestations of Extrahepatic Manifestations of Hepatitis CHepatitis C

Diabetes MellitusDiabetes Mellitus

• High prevalence reported in USA, UK, TurkeyHigh prevalence reported in USA, UK, Turkey

• UK : DM in 17/34 (50%) in HCV cirrhosis patientsUK : DM in 17/34 (50%) in HCV cirrhosis patients

• Reports on Reports on de-novode-novo appearance of DM post IFN Rx appearance of DM post IFN Rx

• Putative mechanism linked to destruction of Putative mechanism linked to destruction of pancreatic islet cells directly by HCV or indirectlypancreatic islet cells directly by HCV or indirectly via immune response to HCVvia immune response to HCV


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVSalivary GlandsSalivary Glands

Mild lymphocytic sialadenitis reported inMild lymphocytic sialadenitis reported in 3 studies in 14-57% patients3 studies in 14-57% patients

Lymphocytic “capillaritis” reported by Pawlotsky Lymphocytic “capillaritis” reported by Pawlotsky in ~50% of patients while symptomatic in ~50% of patients while symptomatic lymphocytic sialadenitis reported in 7/49 patients lymphocytic sialadenitis reported in 7/49 patients

Clinical presentation - Sjoegren syndr.-rare;Clinical presentation - Sjoegren syndr.-rare; antinuclear SSA antibodies are absentantinuclear SSA antibodies are absent

Lacrimal dysfunction reported in 17/34Lacrimal dysfunction reported in 17/34 asymptomatic patients without xerophtalmiaasymptomatic patients without xerophtalmia


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVOcular InvolvementOcular Involvement

Peripheral ulcerative keratitis Peripheral ulcerative keratitis (Mooren ulcers) reported during Interferon(Mooren ulcers) reported during Interferon therapy and also during post Rx relapsetherapy and also during post Rx relapse

Challenge with interferon may lead toChallenge with interferon may lead to exacerbation of ulcersexacerbation of ulcers

A few cases of Uveitis have been reportedA few cases of Uveitis have been reported


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVRenal InvolvementRenal Involvement

• Mild to moderate proteinuria detected in up to Mild to moderate proteinuria detected in up to 27% of patients with microscopic hematuria27% of patients with microscopic hematuria

• Glomerular deposition of IgG, IgM and C3 Glomerular deposition of IgG, IgM and C3 have been reported in cryoprecipitate conaininghave been reported in cryoprecipitate conaining HCV-RNA and anti-HCv antibodiesHCV-RNA and anti-HCv antibodies • Membrano-proliferative glomerulonephritisMembrano-proliferative glomerulonephritis reported in association with HCV and reported in association with HCV and cryoglobulinemiacryoglobulinemia


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCV

Hematological and Lymphoid DisordersHematological and Lymphoid Disorders** Mixed cryoglobulinemia Mixed cryoglobulinemia

Non-Hodgkin B-cell lymphoma (NHL)Non-Hodgkin B-cell lymphoma (NHL)

Aplastic anemia ( association ????)Aplastic anemia ( association ????)

Idiopathic thrombocytopenic purpuraIdiopathic thrombocytopenic purpura

**Linked to lymphotropism of HCV to PBLs, dendritic cells, Linked to lymphotropism of HCV to PBLs, dendritic cells, BM,megacariocyte,vascular endotheliumBM,megacariocyte,vascular endothelium and/or chronic antigenic stimulation and/or chronic antigenic stimulation


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVCryoglobulinemia with or without Cryoglobulinemia with or without

Vasculitis*Vasculitis* Association between HCV and MixedAssociation between HCV and Mixed Cryoglobulinemia (MCG) establishedCryoglobulinemia (MCG) established through HCV-RNA testing in cryoprecipitatethrough HCV-RNA testing in cryoprecipitate Often missed due to inadequate handlingOften missed due to inadequate handling of blood specimenof blood specimen Cryoglobulinemia may signal a pre-malignantCryoglobulinemia may signal a pre-malignant statestate Affects up to 40% of HCV patients withAffects up to 40% of HCV patients with cirrhosis (mean cryocrit >2%) but only ~10%cirrhosis (mean cryocrit >2%) but only ~10% have symptoms of vasculitishave symptoms of vasculitis

**S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9 Dammacco F et al. The cryoglobulins:an overview.Dammacco F et al. The cryoglobulins:an overview. Eur J Clin Invest. 2001;31:628Eur J Clin Invest. 2001;31:628


HCV Associated ArthritisHCV Associated Arthritis** Commonly presents as rheumatoid arthritis likeCommonly presents as rheumatoid arthritis like symptoms ( severe morning stiffness and pain)symptoms ( severe morning stiffness and pain) with symmetrical arthritis of small joints with symmetrical arthritis of small joints

Mono or oligo-arthritis less commonMono or oligo-arthritis less common

Clinical course usually benign without deformitiesClinical course usually benign without deformities

Absence of subcutaneous nodulesAbsence of subcutaneous nodules

>70% of patients complain of fatigue>70% of patients complain of fatigue

* Zuckerman E et al. BioDrugs 2001;15:573Zuckerman E et al. BioDrugs 2001;15:573


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVNon-Hodgkin LymphomaNon-Hodgkin Lymphoma **

Some evidence suggests that persistent HCVSome evidence suggests that persistent HCV infection leading to lymphoproliferation andinfection leading to lymphoproliferation and cryoglobulinemia may switch over to lymphomacryoglobulinemia may switch over to lymphoma HCV-RNA has repeatedly been demonstratedHCV-RNA has repeatedly been demonstrated in lymphoid and BM cellsin lymphoid and BM cells HCV viremia reported in up to 35% of patientsHCV viremia reported in up to 35% of patients with B cell lymphoma and almost with B cell lymphoma and almost 90% of90% of non-Hodgkin lymphoma patients withnon-Hodgkin lymphoma patients with cryoglobulinemiacryoglobulinemia Diagnosis sometime overlooked due to occultDiagnosis sometime overlooked due to occult presentation and /or similarity of symptomspresentation and /or similarity of symptoms to chronic HCV infection to chronic HCV infection

* Dammacco F. et al. Seminars in Liver-Disease. 2000;20:143


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVNeurological and Musculoskeletal Neurological and Musculoskeletal

InvolvementInvolvement Peripheral neuropathy reported but rarePeripheral neuropathy reported but rare Muscle weakness and myopathy areMuscle weakness and myopathy are frequent complaints in fatigued HCVfrequent complaints in fatigued HCV patients , often with cryoglobulinemiapatients , often with cryoglobulinemia

Some rare .latent muscle disorders maySome rare .latent muscle disorders may exacerbate in HCV patients receivingexacerbate in HCV patients receiving interferon treatmentinterferon treatment

Myasthenia Gravis rarely observed in Myasthenia Gravis rarely observed in interfeon treated patientsinterfeon treated patients


Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCVDermatologic Involvement*Dermatologic Involvement*

• Pruritus – Non specificPruritus – Non specific

• Leukocytoclastic-cutaneous necrotizing vasculitisLeukocytoclastic-cutaneous necrotizing vasculitis with cryoglobulinemiawith cryoglobulinemia

• Lichen PlanusLichen Planus• Erythema MultiformeErythema Multiforme• Erythema NodosumErythema Nodosum• UrticariaUrticaria• Porphyria Cutanea TardaPorphyria Cutanea Tarda• MalaplakiaMalaplakia

**S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9


Rare (anecdotal?) AssociationRare (anecdotal?) Associationwith HCVwith HCV

Behcet SyndromeBehcet Syndrome

Generalized vasculitis in polyarteritis nodosaGeneralized vasculitis in polyarteritis nodosa

Interstitial pulmonary fibrosis and vasculitisInterstitial pulmonary fibrosis and vasculitis

Anti-phospholipid syndromeAnti-phospholipid syndrome

Auto-antibodies in autoimmune hepatitisAuto-antibodies in autoimmune hepatitis


Effect of Interferon-alpha Treatment on Effect of Interferon-alpha Treatment on Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCV

CONDITIONCONDITION Improve.Improve. No No ChangeChange

WorseWorse

CryoglobulinemiaCryoglobulinemia ++++ ++ ++GlomerulonephritisGlomerulonephritis ++++ ++ ++Autoimmune MarkersAutoimmune Markers ++ ++ ++Muscular distrophyMuscular distrophy ++Lichen PlanusLichen Planus ++Corneal ulcerCorneal ulcer ++Porphyria CTPorphyria CT ++ITPITP ++ ++Thyroid DiseaseThyroid Disease ++ ++


Clinical Presentation of Hepatitis C Virus Clinical Presentation of Hepatitis C Virus InfectionInfection

SummarySummary The liver is the primary targetThe liver is the primary target for the hepatotropic HCVfor the hepatotropic HCV Yet infection with HCV is a Yet infection with HCV is a systemic diseasesystemic disease and can and can involve most organsinvolve most organs Clinicians taking care of patientsClinicians taking care of patients with HCV must pay attention to with HCV must pay attention to the multisystemic nature of the the multisystemic nature of the disease including the effects on disease including the effects on general well being and qualitygeneral well being and quality of lifeof life

Documents

Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Daniel Shouval Liver Unit Hadassah Hospital Hebrew University JerusalemIsrael