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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