Transcript High Prevalence of Renin-Aldosterone Axis Abnormalities in

Curso Internacional de Especialización
en Fibromialgia y
Síndrome de Fatiga Crónica - 2004
Reproducción permitida citando la procedencia y la autora.
Research Advances in
Chronic Fatigue Syndrome
2004
Nancy Klimas, MD
University of Miami CFS Research Center
Definition - CFS
• >6 mo. debilitating fatigue, unexplained by
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preexisting illness or psychiatric co morbidity,
and at least 4 of eight symptom criteria:
post exertional relapse
concentration and cognitive complaints
myalgia
arthralgia
sore throat
painful lymph nodes
new headaches
unrefreshing sleep
Limitations of the Case
Definition
1. Fails to define subsets for targeted
interventions
2. Research case definitions fail to
encompass broader group
CFS/ME Clinical Case Definition
• 1. Substantial reduction in activity level due to new
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onset, persistent fatigue
2. Post exertional malaise
3. Sleep dysfunction
4. Pain – myalgia, headaches
5. Neurologic/Cognitive Manifestations
6. At least one symptom from 2 of the following:
- Autonomic manifestations eg. OI, IBS
- Neuroendocrine manifestations eg. Temp
intolerance, weight change
- Immune manifestations eg. Tender lymph nodes,
sore throat, flu-like symptoms
Fibromyalgia
Based on the 1990 ACR
classification guidelines:
• Historical feature = widespread (axial)
pain
of 3 months or more
• Physical finding = pain in at least 3 of
the 4 body segments + a finding of at
least 11 tender points on digital
palpation of 18 designated tender
points
(Merskey et al, 1994; Portenoy et al, 1996; Wall et al, 1994; Wolk M, 2002)
Chronic or relapsing fatigue  6 months
but not lifelong
(Determined during initial patient interview)
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NO
 6 months: Provide supportive
treatment of symptoms and reevaluate later
Lifelong: Look for other causes,
including depression
Significantly affects lifestyle
or ability to work
YES
NO
Non-syndromic chronic
fatigue:Treat conservatively
and follow periodically
YES
1. History & Physical (including neurological
& psychiatric tests) 2. Exclusionary lab tests
NO
YES
CFS is excluded if another plausible cause for
symptoms is found. Treat confounding
condition, re-evaluate as appropriate.
Meets  4 of the 8 Symptom Criteria
a) impaired memory or concentration
b) sore throat
c) tender cervical or axillary
lymph nodes
d) muscle pain
YES
e) multi-joint pain
f) new headaches
g) unrefreshing sleep
h) post-exertional malaise
NO
NCF
Diagnosis:
Chronic Fatigue
Syndrome
CFS “Caseness”
• Subpopulations
CFS
Autonomic
Immune
HPA
CFS “Caseness”
• Subpopulations
CFS
Autonomic
Immune
HPA
Conditions that can
explain chronic fatigue
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Cancer
Narcolepsy
Sleep apnea
Severe obesity
Hypothyroidism
Alcohol or substance abuse
Chronic, active hepatitis B or C
HIV
Conditions That Can
Explain Chronic Fatigue
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Hypogammaglobulinemia
Tuberculosis
Lyme disease
Multiple sclerosis
Lupus
Rheumatoid arthritis
Iatrogenic, e.g., medication
side effects
Pain syndrome
Conditions That Can
Explain Chronic Fatigue
• Dementia
• Schizophrenia
• Bipolar disorder
• Bulimia nervosa
• Anorexia nervosa
• Major Depressive Disorder
Initial Laboratory Work-up
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Urinalysis
Complete blood count with differential
Chemistry panel
Thyroid function test
(TSH & free T4)
Alanine aminotransferase
Hepatitis B,C (HIV?)
Initial Laboratory Work-up
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Albumin
Globulin
Alkaline phosphatase
Calcium
Phosphorus
Glucose
Other studies as
indicated by health
assessment
CFS Epidemiology: CDC Studies
• National health survey estimated 1 in 9
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individuals report chronic fatigue(>6mo), and 2
in 100 would meet a phone survey based case
definition1
Wichita random digit dialing of 1/3 the
population of this city resulted in a confirmed
case prevalence of 235/100,000; 373/100,000
women2
85% UNDIAGNOSED
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1Bierl
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et al Population Health Met 2004 2(1):1
2 Reyes et al Arch Int Med 2003 163:1530-36
Epidemiology: DePaul University
• Latinos: 726 per 100,000
• African Americans: 337 per 100,000
• Caucasians: 224 per 100,000
• Women: 522 per 100,000
• Men:
291 per 100,000
Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63
Model of CFS Pathogenesis
Genetic Predisposition
Triggering event / infection
Mediators (Immune, endocrine,
neuroendocrine, psychosocial)
Health Outcome/Persistence
Genetic Predisposition - CFS
• HLA DR haplotypes in 112 South Florida CFS
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patients, compared to 5,000 regional and
national controls
4 to 6 fold increased relative risk for DR4, DR3
and DQ3. (Keller et al, 1992)
Seattle CFS Cooperative Research Center Twin
study - genetic predisposition, hereditability
estimate of 51% (2nd World Conf)
Evidence for Triggering
event/ infection - CFS
• 60 to 80% of CFS subjects date the onset of
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their illness to an acute viral-like illness
(Komaroff, Buchwald)
Lloyd and colleagues in Australia performed a
prospective study during and after acute EBV, Q
fever or Ross River Virus -Anergy during acute
infection predicted persistent CFS like symptoms
Evengard and colleagues reported at the 4th
AACFS meeting - 67% of CFS group and
controls had a negative life event in the
months preceding illness
Model of CFS Pathogenesis
Genetic Predisposition
Triggering event / infection
Mediators (Immune, endocrine,
neuroendocrine, psychosocial)
Health Outcome/Persistence
Immune cascade
Macrophage presents antigen
Natural Killer
Cells(Th1)
Helper CD4 cell
Th1 cytokines
IL-2, INF
activates CD8
Helper CD4 cell
Th2 cytokines
IL-6, IL-10
activates B cells
CD8 cells
kill virus
B cells
make antibody
prevent and help
clear infection
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Neuro/Endocrine/Immune
Balance
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CFS
endocrine
neurologic
Immune
Immune abnormalities in CFS
Immune Activation
Functional defects
• DR, CD26 expression
• TH2 cytokine shift
• Proinflammatory
NK Cell dysfunction
CD8 abnormalities
perphorins, granzymes
Macrophage abnormalities
Antibody production
cytokines expression
TNF-a, IL-1, IL6
Immunology What’s New?
• Exercise induced complement activation1
• NK phenotypes predict risk 2
• Gene expression patterns break
population into two groups, one with
increases in gene expression involved in
immune activation, another with lower
levels of gene expression in areas
reflecting metabolism3
1 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-403
2 Stewart et al Cytometry 2003 53(1)2633
3 Vernon, Suzanne, presentation CFS Regional Conference, Oct 2003
Immune cascade
Macrophage presents antigen
Natural Killer
Cells(Th1)
Helper CD4 cell
Th1 cytokines
IL-2, INF
activates CD8
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Helper CD4 cell
Th2 cytokines
IL-6, IL-10
activates B cells
CD8 cells
kill virus
B cells
make antibody
prevent and help
clear infection
Role of the Immune System
in Illness Persistence
Direct
• Contribution to
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Indirect
• Interaction with
symptom complex
Immune competence, •
role in preventing re•
activation of
infections
Long term outcomes
from Th2 shift
HPA axis
Impact on sleep
Neurotransmitter
interactions
Activation and Flu-like Symptoms
• CD2+26+% was positively associated with
reports of flu-like symptom (tender lymph
nodes & sore throat) frequency (r=.347, p=.056)
and severity (r=.463, p=.009)
• CD2+26+% was also associated with fatigue
(FSI-Intensity; r=.383, p=.028) and daily
disruption caused by fatigue (FSI-Disruption;
r=.400, p=.021)
• These findings corroborate earlier work (Cruess
et al., 2000) showing a relationship between
CD2+26+ and lymph node symptoms
LYMPHOCYTE PROLIFERATION IN RESPONSE TO PHA: MEAN (+/- S.D.) NET CPM
IN CFS PATIENTS ABOVE OR BELOW THE MEAN ON COGNITIVE DIFFICULTIES SCALE
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P = .O3
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LOW CDS
HIGH CDS
Other CFS Symptoms
• Low NKCC
participants reported
more cognitive
difficulties
(Multidimensional
Fatigue Symptoms
Inventory – Mental);
p=.001
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Low
NKCC
Normal
NKCC
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MFSI-Mental
The Immune System Influences
the Brain
Neurotransmitters
within the brain, and
in the periphery
Cytokines
Type 1
Type 2
Pro-inflammatory
Neuroendocrine
hormones,
promote
antiinflammatory
response
Viral Persistence/Reactivation
HHV6 virus is present in 22 to 54% of patients in
cross sectional studies (Ablashi, Krueger, Knox),
HHV6 virus is present in 79% of CFS patients in
longitudinal studies (HHV6 PCR assay, Knox)
HHV6 virus is present in the spinal fluid of 28 of
120 CFS patients (Peterson), and 7 of 35 CFS
samples (Knox).
Enterovirus is present in 13% of CFS muscle
samples (Douche-Aourik, 2003)
EBV? Still a maybe
CNS
• Viral encephalitis?
• Neuroendocrine Dysfunction
• Autonomic Nervous System
• Sleep Physiology
• Blood Flow
• Neurotransmitter Imbalance
Endocrinology
Reduced Cortisol output via several mechanisms
A) heightened negative feedback
B) heightened receptor function
C) impaired ACTH and cortisol responses to challenge
DHEA functional abnormality (early data)
Abnormal seritonin function
IL-6 increase associates with low cortisol CRH mediated
Many confounding factors (deconditioning, sleep,
comorbid depression, stress, medication)
Cleare AJ Endocr Rev 2003 24(2):236-52
Papanicolau Neuroimmunomodulation 2004 11(2)65-74
HPA Axis dysregulation
• Demitrack low basal cortisols in CFS subjects,
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hypothalamic dysfunctionDinan and colleagues - evidence of deficiency
of hypothalamus, pituitary, and adrenal
hypofunction.
Small adrenal gland in depressed and non
depressed CFS subjects, enlarged adrenal in
depressed control group.
Bennett et al studied 500 FM patients with
basal IGF-I levels which were significantly
lower than controls.
Renin Aldosterone Axis
• High Prevalence of Renin-Aldosterone Axis Abnormalities
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in Patients with Chronic Fatigue Syndrome (CFS)
30 of the 33 patients had at least one value of supine or
upright PRA or supine or upright serum AL outside of the
95% Tolerance Interval (TI) for normal volunteers
16 patients had low serum AL and low or normal PRA,
consistent with Hyporeninemic Hypoaldosteronism (HH)
• The underlying defect may be autonomic nervous
system dysfunction and/or a primary adrenal defect.
Zuckerbraun, E, Kim, HS, Daigle, K, Lee, ML, Friedman, TC, Charles R. Drew University
Autonomic Dysfunction
• Neurally mediated hypotension (Rowe)
• Orthostatic hypotension (Streeten)
• Parasympathetic dysfunction(Sisto)
• Sympathetic over activation (Pagini, De
Becker)
• Study in adolescents mirrored that of
adults
Balancing Act
sympathetic
parasympathetic
Autonomic Nervous System
• Haemodynamic Instability Score taken during tilt
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table testing predicts CFS with 90% sensitivity. 1
Heart Rate variability as a predictor of CFS 2
Blood flow volume of the middle cerebral artery
during tilt showed no difference between cases
and controls 3 (Prior studies supine have shown
reduced regional blood flow in response to task)
1 Naschitz QJ Med 2003 96(133-142)
2 Yamamoto Exp Biol Med 2003 228(2):167-74
3 Razumovsky J Neuroimmun 2003 13(1)57-67
Autonomic Dysfunction
• Drops in BP followed by CFS relapse
• Exhaustive treadmill testing results in
cognitive function decline (LaManca et al)
• Perfusion abnormalities of brain stem,
cerebellum (Costa et al)
• Mid cerebral reduced perfusion (Schwartz
et al)
Sleep Physiology
• Circadian Sleep - Wake neuroendocrine and
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immune functions in CFS (Modolfsky)
altered diurnal patterns in cortisol, prolactin
altered diurnal patterns of NK cell function
alpha wave intrusion on sleep EEG , reduced
stage III and IV
Higher %REM (Twin study, 22 discordent twins)1
1 Watson et al Sleep 2003 26(3):32-8
Muscle
• Cardiac muscle – cardiac output related to
severity,and predicted exercise induced relapse1
Exercise testing in 189 CFS subjects resulted in
clinically significant subgroups 50% showing
moderate to severe functional impairment.
Unexpected blunted HR and BP responses noted. 2
• Sarcoplasmic reticulum defect – conduction and
calcium transport abnormalities3
• Oxidative stress study, measuring protein carbonyls
suggested higher levels of protein oxidation than
controls 4
1 Peckerman et al AJ Med Sci 2003 326(2)55
2 Vaness Med Sci Sports Exerc 2003 35(6):908-13
3 Fulle et al Neuromuscul Disord 2003 13(6):479-84
4 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-5
Model of CFS Pathogenesis
Genetic Predisposition
Triggering event / infection
Mediators (Immune, endocrine,
neuroendocrine, psychosocial)
Health Outcome/Persistence
Management of CFS
Develop Individualized Plan
• Supportive
• Symptomatic
• Pathogenesis Models
Pathogenesis Directed
Interventions
• Immune - Ampligen, future
immunomodulators
• HPA axis interventions - Growth hormone,
cortisol
• NMH treatments (plasma expansion,
sympathetic and parasympathetic
stimulants/inhibitors);
• Sleep - pharmacologic and nonpharmacologic
Immune modulatory approaches
Ampligen, a immune modulator and antiviral
(Phase 3 recently completed)
Allergy immunotherapy to down regulate
allergic drive
 Future immunomodulators (trials underway):
Isoprinosine, thalidomide, anti- TNFa
monoclonal Ab
Proof of concept: Autologous lymphocyte
study
Implications for treatment NMH
• “Pipes and a pump”, wired by the
autonomic nervous system
• Fill the space - fluid vs. cells
• compress the space - alpha 1 agonists
• regulate the pump - beta blockers
HPA axis interventions • Growth hormone – phase 1 (Antwerp
study)
• Cortisol – conflicting phase 2 study results
(London, NIH)
• Restoration of sleep cycle (circadian
rhythm)
Autonomic Interventions
Fill the intravascular space
• Water and salt
• Fludrocortisone - retains sodium, at the
expense of potassium - need to monitor
potassium levels
• Precaution - supine hypertension
• Cells - rule out anemia, consider blood
volume studies
Autonomic Interventions
• Compress the veins: Alpha 1 agonists
- Midodrine (Proamitine) 2.5 to 10 mg
(q4h, upright)
– Less specific agents: pseudophedrine,
ephedrine, caffeine, other stimulants (may
worsen POTS)
Precaution - supine hypertension
- Compression hose
• Increase fill time: Highly selective beta blockers
Sleep
• Re-establish circadian rhythm
• Conditioned response to bed - avoid bed
for resting, reading, use bed for sleeping.
Establish “bedtime”.
• Avoid short acting hypnotics
• tricyclics, doxepan are longer acting, and
don’t trap in alpha wave
• mirtazapine (Remeron) – stage 4 inducer
University of Miami CFS
Research and Clinical Center–
Research Protocols
 SMART Energy Study (CBT)
 Erythropoetin (Procrit) phase 2 protocol
 Pathogenesis of NK cell defect in CFS
 Thalidomide Phase 1 protocol
 Isoprinosine Phase 2 protocol
 Natural history study
RATIO OF TYPE 1 TO TYPE 2 CYTOKINES
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BASELINE
P = .03
WEEK 1
200
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100
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Proportion of IFN-gamma to IL-5 in PHA-stimulated cultures
for CFS patients in immunomodulation trial.
What do we need to know?
• What is the nature and cause of the fatigue?
• What is the incidence (new cases each year) of
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this illness?
Sequence of events at onset – what puts a
person at risk?
What are the mediators that take this from “self
limited” to “chronic” illness?
What is its natural history? Are CFS patients at
a higher risk for other illnesses?
What do we need to know?
• Relevant subgroups – “lumping” has
slowed us down
• Once the illness is established, can its
course be changed by “adjusting” the
immune, neuroendocrine or autonomic
nervous system?
What do we need to know?
• Is there a subgroup with a chronic
infection driving the entire illness?
• Is there a subgroup with an autoimmune
process driving the entire illness?
• Is there a subgroup with primarily a CNS
driven illness?
• Are there available biologic markers that
define these subgroups?
What do we need to know?
• More effective treatments based on the
underlying pathophysiology of the illness.
• Could there be an effective method to
prevent this illness?
How do we get there from
here? Research
• Longitudinal studies, comparing subgroups to
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established illnesses and controls
Clinical intervention studies, to teach us about
effective therapies and underlying processes.
Single interventions that are proven to be
partially effective, then need to be studied in
combination.
Rehab studies, to make standard long term
rehabilitative approaches.
How do we get there from
here? Research
• International collaborative studies,
building bridges
• Developing networks of clinicians to work
together with the pharmaceutical industry
to recruit and implement intervention
protocols
• NIH sponsored research protocols
• CDC studies
Conclusion
• There has been significant progress in our
understanding of CFS .
• The neuroendocrine, immune, and central
nervous system are linked, and can’t be
considered separately.
• More effective therapies, based on this
new understanding are available, with
others under study.
All CFS patients can
experience a better quality of
life with compassionate care
and a multidisciplinary
approach.
Thank You!
Professional links:
AACFS on line: www.aacfs.org
CDC on line: www.cdc.gov
NIH on line: www.nih.gov
Advocacy organizations:
CFIDS Association of America
On-line: www.cfids.org Information: [email protected]
American Fibromyalgia Syndrome Assn.
Online: www.afsafund.org
National Gulf War Resource Center online:
www.ngwrc.org