Post on 12-Mar-2018
7/6/2012
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FatigueFatigue
July 2012
Wendy Kohatsu MD
Director, Integrative Medicine Fellowship
Santa Rosa Family Medicine Residency
With thanks to Alan McDaniel, MD
Patient casesPatient 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’dwith 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.
DefinitionsDefinitions
� 3 components
◦ 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
Clinical approach to fatigueClinical approach to fatigue
1. Tackle the low-hanging diagnostic “fruit” first� Standard tests to r/o known medical disease
2. Address psychologic factors
3. Difficult cases – keep climbing the tree..� Adrenal
� Thyroid function
� Hormone balancing
� Mitochondrial
Differential DiagnosisDifferential Diagnosis
� Psychologic
◦ Depression
◦ Anxiety
◦ Somatization d/o
◦ Drug addiction/wd
◦ Seasonal affective d/o
� Pharma
◦ Hypnotics
◦ Antihypertensives
◦ Antidepressants
◦ Antihistamines
� Endocrine
◦ Hypothyroidism
◦ DM
◦ Pituitary insufficiency
◦ Adrenal insufficiency
◦ Chronic renal fx
◦ Hepatic fx
� Heme
◦ Anemia
◦ Iron deficiency
Differential Diagnosis (cont.)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
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PsychologicPsychologic factors are important factors are important to addressto 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
Ciba Found Symp. 1993;173:23Psychol Med. 2012 May 9:1-6.Clin Psychol Psychother. 2011 Oct 9Lancet 2012; 379:1412-1418
Cognitive Behavioral TherapyCognitive 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.
Workup of patient with fatigueWorkup 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?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;107:1831Am Fam Phys 2007;75: 671BMJ. 2003;326(7399):1124.
Food sources of ironFood sources of iron
Heme-source Mg Iron
Chicken liver 3 oz 11.0
Oysters 5.7
Lean chuck beef, 3 oz
3.1
Turkey – dark, 3 oz 2.0
Tuna canned light, 3 oz
1.3
NON-heme Mg Iron
Iron-fortified cereal or oatmeal
18.0
Soybeans, boiled, 1 c 8.8
Lentils, boiled 1 c 6.6
*Blackstrap molasses, 1 T 3.6
Black beans, boiled 1 c 3.6
Cooked spinach, ½ c 3.2
Tomato paste, ¼ c 2.0
Raisins, ½ c 1.615-35% absorption
2-20% absorptionImproved with vitamin C and meat proteins
RDA: Adult women = 18 mg/dayAdult men and postmenopausal = 8 mg/day
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Outside the allopathic box…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
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Outside the allopathic boxOutside the allopathic box… (cont.)… (cont.)
� Exercise
◦ 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
◦ Graded exercise therapy
� One of few proven therapies for CFS –(start with walking to tolerance and increase prn)
J BehavTher Exp Psych 2002; 33:203Med J Aust 2004; 180:444J Psychsom Res 2004; 57(4):391
Functional Medicine Functional Medicine –– to address “highto address “high--
hanging” fruithanging” fruit
� Hypothalamic dysfunction– address this first
◦ Disordered Sleep
◦ Hormonal insufficiency
◦ Low body temperature
◦ Neural-mediated hypotension
� Adrenal Insufficiency
� Hypothyroidism ~ functional approach*
� Estrogen/Progesterone/Testosterone
� Mitochondrial dysfunction
Teitelbaum J. in Integrative Medicine, 3rd Ed. 2012 Rakel D, editor
Functional MedicineFunctional Medicine
� Hypothalamic dysfunction– address first◦ Disordered Sleep
◦ Hormonal insufficiency
◦ Low body temperature
◦ Neural-mediated hypotension
� Adrenal Insufficiency
� Hypothyroidism ~ functional approach*
� Estrogen/Progesterone/Testosterone
� Mitochondrial dysfunction
Teitelbaum J. in Integrative Medicine, 3rd Ed. 2012 Rakel D, editor
Hypothalamic dysfunctionHypothalamic dysfunction
� 4 major functions� Sleep/Circadian rhythm
� Hunger & thirst
� Body temperature
� Neurohormones via pituitary
– H.P.A. axis
� Premise: hypothalamus requires proportionally more energy for its function.
� Proper sleep is critical to ‘resetting’ hypothalamus
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SLEEPSLEEP
◦ *Sleep history:
� Include shift work
� Hours of sleep, Time to bed/ awakening time
� Trouble going to sleep, or staying asleep
◦ Sleep Rx tips
� 7 -9 hours
� “Early to bed, early to rise”
� BEST SLEEP from 10 pm – 2 am
◦ Sleep resources
� www.srfmr.org� “Sleep Well” sleep hygiene
Sleep RxSleep Rx
� Avoid benzos� Herbal◦ 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
◦ 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
Biol Psychol 2007; 74:39Hadley S., Petry J.J.:Valerian. Am Fam Physician 2003; 67:1755-1758.(Passionflower) Altern Complement Ther 2003.89-92.
Sleep Rx: Sleep Rx: PharmaPharma
� 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
Role of Adrenal glandsRole of Adrenal glands
� Regulate:
◦ 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.
2011 AAEM McDaniel - Adrenal
Maladaptive adrenal Maladaptive adrenal stress responsesstress responses
Chronic Stress:
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 (over-trained athlete syndrome).
Psychoneuroendocrinology. 2000 Jan; 25(1):1-35
Adrenal “Fatigue”Adrenal “Fatigue”
� Stuck in vast gray zone between◦ Addison’s disease (adrenal depletion)
◦ Cushing’s Syndrome (adrenal excess)
�When is “normal”, not normal?◦ Postulate there is spectrum of manifestations
� Adaptation to chronic stress (Hans Selye)◦ Phases: Alarm �Resistance �Exhaustion
◦ Sx: Decreased ability to deal with stress, cortisol depletion, early aging
◦ Affects adrenal cortex-
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2011 AAEM McDaniel - Adrenal
The Adrenal Gland: Normal function 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
•promptly, miraculously restored.
•Oral replacement dose for Addison's disease is 25–30 mg cortisol daily.
Adrenal testingAdrenal 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)
Adrenal Rx: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; 65:251Altern Med Review 2009; 14(2):114-140 **excellent reviewNutrition 2005;21:705
Adrenal Rx Adrenal Rx -- AdaptogenicAdaptogenic herbsherbs
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 well-being
Med Physiol 1987;40:85Altern Med Review 2009; 14(2):114-140 **excellent reviewJ Altern Complement Med 2008;14:175Phytomedicine 2000; 7:85
Adrenal Rx Adrenal Rx -- AdaptogenicAdaptogenic herbsherbs
◦ 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;1:156-215Drugs Exp Clin Red 1996;22:323Endocrinol Jpn 1967;14:39
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Adrenal RxAdrenal Rx
� Also LAUGHTER
Adrenal glandular RxAdrenal 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: ◦ MetagenicsAdrenogen®� raw bovine adrenal concentrate + B6+pantothenic acid
� 1-3 tabs q am
◦ CytozymeAD, Biotics
Even more radical… or sane?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
JefferiesW.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 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, - heart rate,
- cardiovascular tone - blood pressure
• Sharpens brain function:
- aroused and more vigilant
• Enhances normal immune function
2011 AAEM McDaniel - Adrenal
The Adrenal Gland: Treatment 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**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
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Patient casesPatient 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’dwith 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.
Patient casesPatient cases
� 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’dwith 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.
Another case…Another case… Mitochondrial dysfunctionMitochondrial dysfunction� 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 dysfunctionMitochondrial 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