Liver Unit - Hadassah

Clinical Manifestations

Clinical Manifestations

of

of

Hepatitis C Virus Infection

Hepatitis C Virus Infection

Daniel Shouval

Daniel Shouval

Liver Unit

Liver Unit

Hadassah Hospital

Hadassah Hospital

Hebrew University

Hebrew University

Jerusalem

Jerusalem

Israel

Israel

Liver Unit - Hadassah

Clinical Manifestations of

Clinical Manifestations of

Hepatitis C Virus Infection

Hepatitis C Virus Infection

Key Concepts

Key Concepts



Disease is usually insidious and subclinical

Disease is usually insidious and subclinical



Persistent HCV infection may progress over decades

Persistent HCV infection may progress over decades

to chronic hepatitis with fibrosis, cirrhosis, portal

to chronic hepatitis with fibrosis, cirrhosis, portal

hypertension, encephalopathy and hepatocellular ca.

hypertension, encephalopathy and hepatocellular ca.



HCV is the main indication for liver transplantation

HCV 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, extra-

hepatic manifestations are common

hepatic manifestations are common



HCV may complicate the course of other diseases

HCV 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 transplantation

renal failure, organ transplantation

Liver Unit - Hadassah

Clinical Manifestations

Clinical Manifestations

of Hepatitis C Virus Infection

of 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 caused

inflammatory liver disease caused

by

by

hepato-

hepato-

tropic viruses

tropic viruses

•

The basic morphologic pattern of acute or

The 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 virus

causative virus

•

Despite of the above, there are unique

Despite of the above, there are unique

characteristic morphologic patterns in chronic

characteristic 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 Unit - Hadassah

Liver Biopsy in Chronic

Liver Biopsy in Chronic

Hepatitis C – is it still

Hepatitis C – is it still

necessary?

necessary?

Background:

Background:

Little correlation between the inflammatory process

Little correlation between the inflammatory process

observed by microscopy and the clinical or

observed by microscopy and the clinical or

laboratory manifestations

laboratory manifestations

The impact of clinical presentation on the

The impact of clinical presentation on the

rational for performing a biopsy:

rational for performing a biopsy:

•

Establish diagnosis

Establish diagnosis

•

Assess grade and stage (Metavir score etc)

Assess grade and stage (Metavir score etc)

•

Exclude other or additional conditions

Exclude other or additional conditions

(i.e alcohol, NASH, CLD, HBV )

(i.e alcohol, NASH, CLD, HBV )

•

Guide management

Guide management

•

Follow-up of therapy

Follow-up of therapy

Liver Unit - Hadassah

Clinical Manifestations

Clinical Manifestations

of Hepatitis C Virus

of Hepatitis C Virus

Infection

Infection

•

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

not

not

recognized

recognized

•

Clinical symptoms in patients with acute HCV when

Clinical symptoms in patients with acute HCV when

present, are usually

present, are usually

milder

milder

as compared to other

as compared to other

hepatitis viruses

hepatitis viruses

•

~80%

~80%

of patients who contract acute HCV infection

of patients who contract acute HCV infection

will develop

will develop

persistent

persistent

infection which often lasts

infection which often lasts

for decades

for decades

Liver Unit - Hadassah

Hepatitis C Virus Infection

Lab Markers

Hepatitis C Virus Infection

Lab Markers

Symptom

s (if any)

Time after Exposure

Time after Exposure

T

it

e

r

T

it

e

r

anti-

HCV

ALT

Norma

l

0

1

2

3

4

5

6

1

2

3

4

Years

Years

Month

s

Month

s

HCV - RNA

HCV - RNA

IIIIIIII

IIIIIIIIIIIIIIIIIIII

Liver Unit - Hadassah

Clinical Presentation of

Clinical Presentation of

Chronic HCV Infection

Chronic HCV Infection

*

*

Clinical presentation may vary depending on the host

Clinical presentation may vary depending on the host

Immune status, the source and duration of infection

Immune status, the source and duration of infection

•

Often asymptomatic

Often asymptomatic

•

Frequently detected during routine lab testing

Frequently detected during routine lab testing

or blood donation

or 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

Liver Unit - Hadassah

Clinical Manifestations

Clinical Manifestations

of Hepatitis C Virus Infection

of Hepatitis C Virus Infection

Symptoms *

Symptoms *



Fatigue

Fatigue



Malaise

Malaise



Nausea

Nausea



Abdominal discomfort

Abdominal discomfort

*

*



Dark urine and acholic stools

Dark urine and acholic stools



Vomitting

Vomitting



Jaundice

Jaundice



Pruritus

Pruritus



Arthralgia

Arthralgia



Fever

Fever

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

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

Liver Unit - Hadassah

Clinical Manifestations of

Clinical Manifestations of

HCV

HCV

o

Fatigue

Fatigue

o

Malaise

Malaise

o

Myalgia

Myalgia

o

Depression

Depression

o

Cognitive

Cognitive

dysfunction

dysfunction

Liver Unit - Hadassah

Musculoskeletal Pain and

Musculoskeletal Pain and

Fatigue in HCV

Fatigue in 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 7y

Musculoskeletal pain – 70% for M of 7y



Fatigue – 56% for a M 3.3y

Fatigue – 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

Liver Unit - Hadassah

Hepatitis C and Cognitive

Hepatitis C and Cognitive

Impairment of Patients with Mild

Impairment of Patients with Mild

Disease I*

Disease I*

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

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

Material and Methods

Material and Methods



27 HCV patients with biopsy proven mild HCV

27 HCV patients with biopsy proven mild HCV

17 control patients with resolved HCV

17 control patients with resolved HCV



Testing through computor based cognitive

Testing through computor based cognitive

assessment battery

assessment battery



Completing depression, fatigue and quality

Completing depression, fatigue and quality

of life questionnairs

of life questionnairs

Liver Unit - Hadassah

Hepatitis C and Cognitive

Hepatitis C and Cognitive

Impairment of Patients with Mild

Impairment of Patients with Mild

Disease II*

Disease II*

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

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

RESULTS

RESULTS



HCV patients were

HCV patients were

impaired on more

impaired 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 ratios

scopy showed elevated choline/creatine ratios

suggesting a possible organic etiology for

suggesting a possible organic etiology for

cognitive impairment in HCV infection

cognitive impairment in HCV infection

Liver Unit - Hadassah

Complications of Acute HCV

Complications of Acute HCV

Infection (I)

Infection (I)

•

Fulminant hepatitis – rare

Fulminant hepatitis – rare

•

Chronic hepatitis - ~80%

Chronic hepatitis - ~80%

•

Cirrhosis

Cirrhosis

*

*

~20-35%

~20-35%

•

Hepatocellular carcinom

Hepatocellular carcinom

**

**

- ` 1-4%

- ` 1-4%

annually, after prolonged infection

annually, after prolonged infection

*

*

Maybe clinically silent but eventually

Maybe 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 encephalopathy

or hepatic encephalopathy

**

**

As * with additional extra hepatic manifestations

As * with additional extra hepatic manifestations

Liver Unit - Hadassah

Complications of Acute HCV

Complications of Acute HCV

Infection (II)

Infection (II)

*

*

average time between acute

average time between acute

hepatitis c

hepatitis c

and

and



“

“

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

Liver Unit - Hadassah

Association of HCV infection

Association of HCV infection

with other Diseases and

with other Diseases and

Conditions

Conditions

and Impact on Clinical

and Impact on Clinical

Presentation

Presentation

•

Infection with other viruses: HIV, HBV,

Infection with other viruses: HIV, HBV,

HTLV, Herpes

HTLV, Herpes

•

Infection of patients with schistosomiasis

Infection of patients with schistosomiasis

•

IVDA

IVDA

•

Hemophilia, Thalassemia, Sickle cell anemia etc.

Hemophilia, Thalassemia, Sickle cell anemia etc.

•

Hemodialysis and kidney transplantation

Hemodialysis and kidney transplantation

•

Iron overload

Iron overload

•

Alcoholic liver disease

Alcoholic liver disease

•

Autoimmune hepatitis. PBC, PSC

Autoimmune hepatitis. PBC, PSC

Liver Unit - Hadassah

Extrahepatic Manifestations

Extrahepatic Manifestations

of Hepatitis C Virus

of Hepatitis C Virus

Infection

Infection

*

*



Endocrine

Endocrine



Salivary Glands (sialadenitis)

Salivary Glands (sialadenitis)



Ophtalmic ( uveitis, ulcers)

Ophtalmic ( uveitis, ulcers)



Hematologic/lymphoid organs

Hematologic/lymphoid organs



Skin

Skin



Renal

Renal



Autoimmune diseases

Autoimmune diseases



Neurologic and Cognitive impairment

Neurologic and Cognitive impairment



Miscellaneous

Miscellaneous

*

*

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

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

Liver Unit - Hadassah

Extrahepatic Manifestations

Extrahepatic Manifestations

of Hepatitis C

of Hepatitis C

Endocrine

Endocrine



Hyperthyroidism

Hyperthyroidism



Hypothyroidism

Hypothyroidism



Hashimoto’s Disease and Thyroiditis

Hashimoto’s Disease and Thyroiditis



Thyroid antibodies

Thyroid antibodies

*

*



Diabetes Mellitus

Diabetes 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 hypothyroidism

through interferon Rx and leading to hyper and hypothyroidism

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

Hepatitis C

Hepatitis C

Thyroid dysfunction Anti-thyroid

Thyroid dysfunction Anti-thyroid

Antibodies and Interferon Treatment

Antibodies and Interferon Treatment

Author

Author

%

%

Patients

Patients

<

<

Interfer

Interfer

on

on

>

>

Interfer

Interfer

on

on

DiBiscegli

DiBiscegli

(USA)

(USA)

9.5

9.5

0

0

0

0

Lisker-Melman

Lisker-Melman

(USA)

(USA)

7.0

7.0

1

1

2

2

Berris

Berris

(Canada)

(Canada)

5.5

5.5

0

0

3

3

Pateron

Pateron

(France)

(France)

9.0

9.0

2

2

2

2

Baudin

Baudin

(France)

(France)

12

12

1

1

4

4

Kodama

Kodama

(Japan)

(Japan)

12

12

4

4

6

6

Deutsch

Deutsch

(Greece)

(Greece)

10.9

10.9

19

19

31

31

Liver Unit - Hadassah

Extrahepatic Manifestations

Extrahepatic Manifestations

of Hepatitis C

of Hepatitis C

Diabetes Mellitus

Diabetes Mellitus

•

High prevalence reported in USA, UK, Turkey

High prevalence reported in USA, UK, Turkey

•

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

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

•

Reports on

Reports on

de-novo

de-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 indirectly

pancreatic islet cells directly by HCV or indirectly

via immune response to HCV

via immune response to HCV

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Salivary Glands

Salivary Glands



Mild lymphocytic sialadenitis reported in

Mild lymphocytic sialadenitis reported in

3 studies in 14-57% patients

3 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 absent

antinuclear SSA antibodies are absent



Lacrimal dysfunction reported in 17/34

Lacrimal dysfunction reported in 17/34

asymptomatic patients without xerophtalmia

asymptomatic patients without xerophtalmia

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Ocular Involvement

Ocular Involvement



Peripheral ulcerative keratitis

Peripheral ulcerative keratitis

(Mooren ulcers) reported during Interferon

(Mooren ulcers) reported during Interferon

therapy and also during post Rx relapse

therapy and also during post Rx relapse



Challenge with interferon may lead to

Challenge with interferon may lead to

exacerbation of ulcers

exacerbation of ulcers



A few cases of Uveitis have been reported

A few cases of Uveitis have been reported

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Renal Involvement

Renal Involvement

•

Mild to moderate proteinuria detected in up to

Mild to moderate proteinuria detected in up to

27% of patients with microscopic hematuria

27% of patients with microscopic hematuria

•

Glomerular deposition of IgG, IgM and C3

Glomerular deposition of IgG, IgM and C3

have been reported in cryoprecipitate conaining

have been reported in cryoprecipitate conaining

HCV-RNA and anti-HCv antibodies

HCV-RNA and anti-HCv antibodies

•

Membrano-proliferative glomerulonephritis

Membrano-proliferative glomerulonephritis

reported in association with HCV and

reported in association with HCV and

cryoglobulinemia

cryoglobulinemia

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Hematological and Lymphoid

Hematological and Lymphoid

Disorders

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 purpura

Idiopathic thrombocytopenic purpura

*

*

Linked to lymphotropism of HCV to PBLs, dendritic cells,

Linked to lymphotropism of HCV to PBLs, dendritic cells,

BM,megacariocyte,vascular endothelium

BM,megacariocyte,vascular endothelium

and/or chronic antigenic stimulation

and/or chronic antigenic stimulation

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Cryoglobulinemia with or

Cryoglobulinemia with or

without Vasculitis*

without Vasculitis*



Association between HCV and Mixed

Association between HCV and Mixed

Cryoglobulinemia (MCG) established

Cryoglobulinemia (MCG) established

through HCV-RNA testing in cryoprecipitate

through HCV-RNA testing in cryoprecipitate



Often missed due to inadequate handling

Often missed due to inadequate handling

of blood specimen

of blood specimen



Cryoglobulinemia may signal a pre-malignant

Cryoglobulinemia may signal a pre-malignant

state

state



Affects up to 40% of HCV patients with

Affects up to 40% of HCV patients with

cirrhosis (mean cryocrit >2%) but only ~10%

cirrhosis (mean cryocrit >2%) but only ~10%

have symptoms of vasculitis

have symptoms of vasculitis

*

*

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

S.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;31:628

Eur J Clin Invest. 2001;31:628

Liver Unit - Hadassah

HCV Associated Arthritis

HCV Associated Arthritis

*

*



Commonly presents as rheumatoid arthritis like

Commonly 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 common

Mono or oligo-arthritis less common



Clinical course usually benign without deformities

Clinical course usually benign without deformities



Absence of subcutaneous nodules

Absence of subcutaneous nodules



>70% of patients complain of fatigue

>70% of patients complain of fatigue

*

Zuckerman E et al. BioDrugs 2001;15:573

Zuckerman E et al. BioDrugs 2001;15:573

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Non-Hodgkin Lymphoma

Non-Hodgkin Lymphoma

*

*



Some evidence suggests that persistent HCV

Some evidence suggests that persistent HCV

infection leading to lymphoproliferation and

infection leading to lymphoproliferation and

cryoglobulinemia may switch over to lymphoma

cryoglobulinemia may switch over to lymphoma



HCV-RNA has repeatedly been demonstrated

HCV-RNA has repeatedly been demonstrated

in lymphoid and BM cells

in lymphoid and BM cells



HCV viremia reported in up to 35% of patients

HCV viremia reported in up to 35% of patients

with B cell lymphoma and almost

with B cell lymphoma and almost

90% of

90% of

non-Hodgkin lymphoma patients with

non-Hodgkin lymphoma patients with

cryoglobulinemia

cryoglobulinemia



Diagnosis sometime overlooked due to occult

Diagnosis sometime overlooked due to occult

presentation and /or similarity of symptoms

presentation and /or similarity of symptoms

to chronic HCV infection

to chronic HCV infection

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

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Neurological and

Neurological and

Musculoskeletal Involvement

Musculoskeletal Involvement



Peripheral neuropathy reported but rare

Peripheral neuropathy reported but rare



Muscle weakness and myopathy are

Muscle weakness and myopathy are

frequent complaints in fatigued HCV

frequent complaints in fatigued HCV

patients , often with cryoglobulinemia

patients , often with cryoglobulinemia



Some rare .latent muscle disorders may

Some rare .latent muscle disorders may

exacerbate in HCV patients receiving

exacerbate in HCV patients receiving

interferon treatment

interferon treatment



Myasthenia Gravis rarely observed in

Myasthenia Gravis rarely observed in

interfeon treated patients

interfeon treated patients

Liver Unit - Hadassah

Extrahepatic Manifestations of

Extrahepatic Manifestations of

HCV

HCV

Dermatologic Involvement*

Dermatologic Involvement*

•

Pruritus – Non specific

Pruritus – Non specific

•

Leukocytoclastic-cutaneous necrotizing vasculitis

Leukocytoclastic-cutaneous necrotizing vasculitis

with cryoglobulinemia

with cryoglobulinemia

•

Lichen Planus

Lichen Planus

•

Erythema Multiforme

Erythema Multiforme

•

Erythema Nodosum

Erythema Nodosum

•

Urticaria

Urticaria

•

Porphyria Cutanea Tarda

Porphyria Cutanea Tarda

•

Malaplakia

Malaplakia

*

*

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

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

Liver Unit - Hadassah

Rare (anecdotal?)

Rare (anecdotal?)

Association

Association

with HCV

with HCV



Behcet Syndrome

Behcet Syndrome



Generalized vasculitis in polyarteritis nodosa

Generalized vasculitis in polyarteritis nodosa



Interstitial pulmonary fibrosis and vasculitis

Interstitial pulmonary fibrosis and vasculitis



Anti-phospholipid syndrome

Anti-phospholipid syndrome



Auto-antibodies in autoimmune hepatitis

Auto-antibodies in autoimmune hepatitis

Liver Unit - Hadassah

Effect of Interferon-alpha

Effect of Interferon-alpha

Treatment on Extrahepatic

Treatment on Extrahepatic

Manifestations of HCV

Manifestations of HCV

CONDITION

CONDITION

Improv

Improv

e.

e.

No

No

Change

Change

Worse

Worse

Cryoglobulinemia

Cryoglobulinemia

++

++

+

+

+

+

Glomerulonephritis

Glomerulonephritis

++

++

+

+

+

+

Autoimmune

Autoimmune

Markers

Markers

+

+

+

+

+

+

Muscular distrophy

Muscular distrophy

+

+

Lichen Planus

Lichen Planus

+

+

Corneal ulcer

Corneal ulcer

+

+

Porphyria CT

Porphyria CT

+

+

ITP

ITP

+

+

+

+

Thyroid Disease

Thyroid Disease

+

+

+

+

Liver Unit - Hadassah

Clinical Presentation of Hepatitis C

Clinical Presentation of Hepatitis C

Virus Infection

Virus Infection

Summary

Summary



The liver is the primary target

The liver is the primary target

for the hepatotropic HCV

for the hepatotropic HCV



Yet infection with HCV is a

Yet infection with HCV is a

systemic disease

systemic disease

and can

and can

involve most organs

involve most organs



Clinicians taking care of patients

Clinicians 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 quality

general well being and quality

of life

of life