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