7/6/2012
Patient cases
Fatigue
July 2012
Wendy Kohatsu MD
Director, Integrative Medicine Fellowship
Santa Rosa Family Medicine Residency
With thanks to Alan McDaniel, MD
Definitions
Clinical approach to fatigue
3 components
Differential Diagnosis
Psychologic
◦
◦
◦
◦
◦
Depression
Anxiety
Somatization d/o
Drug addiction/wd
Seasonal affective d/o
Hypnotics
Antihypertensives
Antidepressants
Antihistamines
Endocrine
◦
◦
◦
◦
◦
◦
Pharma
◦
◦
◦
◦
Tackle the low-hanging diagnostic “fruit”
first
1.
◦ Perception of generalized weakness --inability
to initiate activity, in the absence of objective
findings
◦ Easy fatiguability - reduced capacity to
maintain normal activity
◦ Mental fatigue - difficulty with concentration,
memory, and emotional stability
40 yo woman, c/o 6 weeks of debilitating fatigue,
memory lapses, mom of 3, 16 mo son “difficult”
sleeper, gets up 2-3x/night, h/o HTN since age
25 (before 1st child) – on labetalol 100 mg BID,
heavy menses. Husband laid off.
20 yo woman, h/o fatigue, since age 17, also dx’d
with cyclic vomiting d/o, for which she takes
vicodin and benzos, reports nl menses, BMI 17
33 yo male, typically high achiever, in stressful
residency, finds his energy, exercise tolerance,
concentration are not the same.
Hypothyroidism
DM
Pituitary insufficiency
Adrenal insufficiency
Chronic renal fx
Hepatic fx
Heme
◦ Anemia
◦ Iron deficiency
Standard tests to r/o known medical disease
Address psychologic factors
3. Difficult cases – keep climbing the tree..
2.
Adrenal
Thyroid function
Hormone balancing
Mitochondrial
Differential Diagnosis (cont.)
Cardiopulmonary
◦ CHF
◦ COPD
◦ Sleep apnea
Infectious
◦
◦
◦
◦
TB
HIV
Mononucleosis
CMV
Musculoskeletal
◦ Rheumatic dx
◦ Chronic pain
(inadequately treated)
◦ Dental disease
“Idiopathic”
◦ Chronic fatigue
◦ CFS
◦ Fibromyalgia
1
7/6/2012
Psychologic factors are important
to address
60-80 % of patients with chronic fatigue
have psychiatric diagnosis – depr, panic
attacks, somatization.
Recent study, only 46% co-presentation
Cognitive-behavioral therapy (CBT) most
effective therapy
Also internet-based CPT shown to be
effective in teens with CFS
Cognitive Behavioral Therapy
Basically, re-framing your thoughts.
◦ changing maladaptive thinking leads to change
in affect and in behavior.
• Replace overgeneralizing, magnifying negatives, and
catastrophizing (i.e. “every morning is horrible”)
• With more realistic and effective thoughts, thus
decreasing self-defeating feelings and behavior
• Resource: The Feeling Good Handbook, David
Burns, MD.
Ciba Found Symp. 1993;173:23
Psychol Med. 2012 May 9:1-6.
Clin Psychol Psychother. 2011 Oct 9
Lancet 2012; 379:1412-1418
Workup of patient with fatigue
History, history, history
◦ Including occupation, meds, OTCs, stressors
Don’t forget ROS
Gyn – menorrhagia, Endo- cold/hot intolerance
Pulm – snoring.
Basic labs
◦ CBC, CMP (glucose, lytes, LFTs), TSH
◦ Ferritin
◦ Vitamin D, 25-OH
BMJ. 2003;326(7399):1124.
Why ferritin?
Iron deficiency even w/o anemia can impair:
◦ Exercise tolerance
◦ School performance – kids with iron deficiency
had > 2x risk of scoring below average
8.7% iron deficient GIRLS age 12-16, BUT
ONLY 1.5% had abnormal RBC values
Supplement iron in fatigued, non-anemic pt?
◦ Study: 144 women , age 18 -55, low/borderline
ferritin/ nl RBC.
◦ 80 mg elemental FeS04 vs. placebo x 1 month
◦ 29 vs 13 pts had signif improvement
Peds 2001;107:1831
Am Fam Phys 2007;75: 671
BMJ. 2003;326(7399):1124.
Food sources of iron
RDA: Adult women = 18 mg/day
Adult men and postmenopausal = 8 mg/day
Heme-source
Mg Iron
NON-heme
Mg Iron
Chicken liver 3 oz
11.0
18.0
Oysters
5.7
Iron-fortified cereal or
oatmeal
Lean chuck beef, 3
oz
3.1
Soybeans, boiled, 1 c
8.8
Lentils, boiled 1 c
6.6
Turkey – dark, 3 oz
2.0
*Blackstrap molasses, 1 T
3.6
Tuna canned light, 3
oz
1.3
Black beans, boiled 1 c
3.6
Cooked spinach, ½ c
3.2
15-35% absorption
Tomato paste, ¼ c
2.0
Raisins, ½ c
1.6
2-20% absorption
Improved with vitamin C and meat proteins
2
7/6/2012
Outside the allopathic box…
Nutrition
◦ Food insecurity
◦ Malabsorption (consider effect of acid
suppression)
◦ Avoid caffeine energy swings
◦ Glycemic index/load
◦ Adequate intake of B6, B12, magnesium, EFA’s
14
Outside the allopathic box…
box… (cont.)
Exercise
Functional Medicine – to address “high“highhanging” fruit
◦ Ask about Post-workout fatigue
◦ LACK of exercise induces symptoms common
to chronic fatigue syndrome
◦
◦
◦
◦
Depression, fatigue, pain
Reduced cortisol and reduced NK cell activity
Adrenal Insufficiency
Hypothyroidism ~ functional approach*
Estrogen/Progesterone/Testosterone
Mitochondrial dysfunction
One of few proven therapies for CFS –(start with
walking to tolerance and increase prn)
J Behav Ther Exp Psych 2002; 33:203
Med J Aust 2004; 180:444
J Psychsom Res 2004; 57(4):391
Hypothalamic dysfunction– address first
◦
◦
◦
◦
Teitelbaum J. in Integrative Medicine, 3rd Ed. 2012 Rakel D, editor
Hypothalamic dysfunction
Disordered Sleep
Hormonal insufficiency
Low body temperature
Neural-mediated hypotension
Adrenal Insufficiency
Hypothyroidism ~ functional approach*
Estrogen/Progesterone/Testosterone
Mitochondrial dysfunction
4 major functions
Sleep/Circadian rhythm
Hunger & thirst
Body temperature
Neurohormones via pituitary
– H.P.A. axis
Disordered Sleep
Hormonal insufficiency
Low body temperature
Neural-mediated hypotension
◦ Graded exercise therapy
Functional Medicine
Hypothalamic dysfunction– address this first
Premise: hypothalamus requires proportionally
more energy for its function.
Proper sleep is critical to ‘resetting’
hypothalamus
Teitelbaum J. in Integrative Medicine, 3rd Ed. 2012 Rakel D, editor
3
7/6/2012
SLEEP
Sleep Rx
◦ *Sleep history:
Include shift work
Hours of sleep,Time to bed/ awakening time
Trouble going to sleep, or staying asleep
◦ L-theanine 50 -200 mg
Induces alpha brainwave activity
◦ Valerian 300 -600 mg
Improves sleep quality
Can take 1 -2 weeks
Comparable efx to some benzos
◦ Sleep Rx tips
7 -9 hours
“Early to bed, early to rise”
BEST SLEEP from 10 pm – 2 am
Avoid benzos
Herbal
◦ Passionflower 90 mg
Supplements
◦ Magnesium 500 – 1000 mg (clinical trials)/day
Am J Med Sci 1962;243:758
J Am Coll Nutr 1990; 9:48
Bharadvaj D, 2008, Natural Treatments for Chronic Fatigue Syndrome
◦ Sleep resources
www.srfmr.org “Sleep Well” sleep hygiene
Biol Psychol 2007; 74:39
Hadley S., Petry J.J.:Valerian. Am Fam Physician 2003; 67:1755-1758.
(Passionflower) Altern Complement Ther 2003.89-92.
Sleep Rx: Pharma
Role of Adrenal glands
As temporary ‘crutch’
Slippery slope to chronic use…
Least disruptive to stage 3-4 sleep:
◦
◦
◦
◦
Zolpidem 5-10 mg qhs
Gabapentin 300 mg 1-2 tabs qhs
Trazodone, 50 mg (esp if + anxiety)
Amitriptyline – low dose, 10 – 50 mg
Maladaptive adrenal stress responses
Chronic Stress:
◦ Energy production – controls carb, protein, and
fate conversion to blood glucose
◦ Fluid and electrolyte balance
◦ Fat storage
◦ Sex hormone production – esp after
menopause/andropause
ANY major stressor can trigger adrenal
fatigue – long period of mental stress, one
severe stress, serious illness/infection.
Adrenal “Fatigue”
After weeks of severe situational stress,
pituitary gonadotropin production is
inhibited:
• Women stop menstruating and
• Men’s testosterone drops.
• PTSD patients have the same low cortisol
as over-trained marathon runners (overtrained athlete syndrome).
Regulate:
Stuck in vast gray zone between
◦ Addison’s disease (adrenal depletion)
◦ Cushing’s Syndrome (adrenal excess)
When is “normal”, not normal?
Adaptation to chronic stress (Hans Selye)
◦ Postulate there is spectrum of manifestations
◦ Phases: Alarm Resistance Exhaustion
◦ Sx: Decreased ability to deal with stress,
cortisol depletion, early aging
◦ Affects adrenal cortex-
Psychoneuroendocrinology. 2000 Jan; 25(1):1-35
2011 AAEM McDaniel - Adrenal
4
7/6/2012
The Adrenal Gland: Normal function
Cortisol is the top priority hormone.
• Every human cell has a cortisol receptor.
• The adrenal gland makes a lot of cortisol
- one of the few truly essential hormones.
- 100 to 1,000 times more than
aldosterone
•Available
to physicians in the early ‘50s.
• First for patients dying of Addison’s disease
Adrenal testing
Plasma free cortisol
◦ 8:00 am [15-22 mg/dL] usu 2-25
◦ 4:00 pm [10-14 mg/dL]
Salivary cortisol testing
◦ Four point on graph: 8 am, noon, 4 pm, 10 pm
24-hour urinary cortisol
◦ Suspect adrenal dysfunction if in lower1/3 of
normal
◦ Expanded profile can detect metabolism
errors (but costs ~ $212)
•promptly, miraculously restored.
•Oral replacement dose for Addison's disease is
25–30 mg cortisol daily.
2011 AAEM McDaniel - Adrenal
Adrenal Rx:
Proper nutrition
◦ No caffiene, high quality carbs,
◦ Eat regular meals
Supplements:
◦
◦
◦
◦
Vitamin C – 2000 gm
B-complex – thiamine, B3, B5, B6, B12
Magnesium – 500 -1000 mg
Omega 3 fish oils – 1-3 gm
Clin Clim Acta 1975; 65:251
Altern Med Review 2009; 14(2):114-140 **excellent review
Nutrition 2005;21:705
Adrenal Rx - Adaptogenic herbs
Rhodiola rosea
Demonstrated effects in cortex and
hypothalamus
Seems to prevent depletion of adrenal
catecholamines.
Signif improvement in HAM-A, decreased
stress-related fatigue, and salivary cortisol
Physicians on night-duty
50 mg bid of standardized extract – improved
psychomotor fxn, mental performance and wellbeing
Med Physiol 1987;40:85
Altern Med Review 2009; 14(2):114-140 **excellent review
J Altern Complement Med 2008;14:175
Phytomedicine 2000; 7:85
Adrenal Rx - Adaptogenic herbs
◦ Siberian Ginseng (Eleutherococcus senticosis)
Most extensively used in Russia
Review of >2000 pts shows better tolerance to physical
and mental stress, and preserved work fxn
◦ Korean ginseng (Panax ginseng spp.)
Animal studies support effect on HPA axis
Limited human studies
◦ Licorice (Glycyrrhiza glabra)
Binds to glucocorticoid and mineralocorticoid
receptors, weak mimick
Can spare cortisol by extending its half-life
Dose: 0.7 g/day glycyrrhizic acid
Econ Med Plant Res 1985;1:156-215
Drugs Exp Clin Red 1996;22:323
Endocrinol Jpn 1967;14:39
5
7/6/2012
Adrenal Rx
Adrenal glandular Rx
Subject of controversy…
Give adrenal extracts – dried bovine, or
porcine adrenal glands (w/o adrenaline =
banned substance)
Why? Theory: give back building blocks
needed for repair
Brands:
Also LAUGHTER
◦ Metagenics Adrenogen®
raw bovine adrenal concentrate + B6+pantothenic acid
1-3 tabs q am
◦ Cytozyme AD, Biotics
Even more radical… or sane?
Give body back cortisol (hydrocortisone)
NOT prednisone
1 mg prednisone = 5 mg hydrocortisone
Start with LOW DOSE hydrocortisone
◦ 2.5 mg in am
◦ 2.5 mg at noon
The adrenal cortex responds with
cortisol.
•Increases available
energy
- increases blood sugar production
- reduces conversion of amino acids to protein
- mobilizes free fatty acids;
• Increases the metabolism, including
- respiratory rate,
- cardiovascular tone
- heart rate,
- blood pressure
Sharpens brain function:
- aroused and more vigilant
• Enhances normal immune function
•
Jefferies W.M.: Safe Uses of Cortisol. 2nd ed.. Springfield, IL, Charles C Thomas, 1996.
Arch Intern Med. 1967;119(3):265-278.
2011 AAEM McDaniel - Adrenal
The Adrenal Gland: Treatment
Criticism of cortisol therapy:
Prior studies of “low-dose” treatment for
CFS gave more than physiological dose:
• We
make 25–30 mg hydrocortisone daily.
- this equals 5 mg Prednisone.
• “Low-dose” studies gave Prednisone ≥7.5 mg
- That is not a low dose!
Resulting adrenal suppression in 12 of 30.
Functional hypothyroidism**
Pt with fatigue, weight gain, thinning hair,
menstrual irregularity, dry skin, mood
swings, but “normal” TSH of 2.9.
Hint:
◦ If classic sx present, treat to low normal TSH
range 0.5 – 1.4
◦ Check also free T4, total T3/reverse T3 ratio
2011 AAEM McDaniel - Adrenal
6
7/6/2012
Patient cases
Patient cases
40 yo woman, c/o 6 weeks of debilitating fatigue,
memory lapses, mom of 3, 16 mo son “difficult”
sleeper, gets up 2-3x/night, h/o HTN since age
25 (before 1st child) – on labetalol 100 mg BID,
heavy menses. Husband laid off.
20 yo woman, h/o fatigue, since age 17, also dx’d
with cyclic vomiting d/o, for which she takes
vicodin and benzos, reports nl menses, BMI 17
33 yo male, typically high achiever, in stressful
residency, finds energy, exercise tolerance,
concentration not the same.
Another case…
Mitochondrial dysfunction
40 yo mom –Rx: cognitive reframing (CBT),
reassured with normal labs, TSH 1.03, Hgb 14,
24 urine cortisol – 27 [4 -50 mcg/24º] Still on
labetalol, office BP 106-120/60-80.
20 yo woman, h/o fatigue, since age 17, also dx’d
with cyclic vomiting d/o… workup in progress.
33 yo male, high achieving resident. Started
adrenal supplements, did very well with return
of energy and function.
Classic sx: Post-exercise fatigue
◦ Up to 24 hours after exercise
Mitochrondrial support – “magic 4” co-factors
1. D-ribose –
Krebs cycle metabolites: ATP, NADP = needs ribose
Rate-limiting compound of ATP production is ribose
Uncontrolled study – showed signif sx improvement
Dose: 5 grams tid to bid
2. Acetyl L-cartinine
Low in patients with CFS
Dose: 1000 mg/day
(body can make carnitine from lysine + vit C + B’s
Controlled study – for fibromyalgia
J Altern Complement Med. 2006 Nov;12(9):857-62.
Clin Exp Rheumatol. 2007 Mar-Apr;25(2):182-8.
Mitochondrial dysfunction
Mitochrondrial support – “magic 4”
3. Co-enzyme Q10
Critical mitochondrial and myocardium substrate
Dose: 100 -200 mg/day
Ubiquinol better absorbed than ubiquinone
4. Magnesium
Critical co-factor for over 200 enzymatic
functions in the body, incl. NT synthesis
Dose: 150 – 500 mg/day
Chelated form
7