Adrenal Problems

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    Introduction

    • 3 zones in adrenal glands:
    1. zona (inner) reticularis. 
    • DHEA
    • DHEAS (Sulfate)
    • Androstenedione
    1. zona (middle) fasciculata
    • Glucocorticoid Synthesis (i.e. cortisol)
    1. zona (outer) glomerulosa
    • Aldosterone

     

    • Hormone Produced By Regulation Effect
      Aldosterone

      zona glomerulosa

      (outer)

      Increases with K+

      Increases via aldo synthase (through RAAS)

      K+ wasting, Na+ retention

      Increases Intravascular Volume

      Increases BP

      Cortisol

      zona fasciculata

      (middle)

      Stimulated by ACTH (ant. pit)

      Varies with circadian rhythm

        (little overnight, peak early AM, smaller

         oscillations throughout day)

      Physical Stress (critical illness)

      Attenuates inflammatory response

      Glucose homeostasis

        (promotes lipolysis, hepatic

         gluconeogenesis, insulin resistance)

       

      In critical illness:

        - Enhances smooth muscle tone

          (incr BP)

      DHEA

      DHEAS

      zona reticularis

      (inner)

       

      - converted periphrally to testosterone

       and dihydrotestosterone (DHT)

     

     

     

     

    Adrenal Insufficiency

    • Clincal & Biochemical features --> loss of secretion of corticosteroids
    • Causes
      • Primary: Adrenal
        • Loss of ALL corticosteorids (aldosterone, cortisol, DHEA, DHEAS)
        • Causes:
          • Autoimmune Adrenalitis
          • Infection (TB, fungal, bacterial, HIV)
          • Metastatic Cancer
          • Adrenal Hemorrhage
          • Medications (Ketoconazole, Etomidate, Mitotane, Metyrapone)
      • Secondary (Pituitary)
        • Pituitary Corticotroph Cells Function Lost
      • Tertiary (Hypothalamic)
        • Hypothalamic Disease (Destroys cells secreting CRH)
        • Hard to distinguish from secondary
      • Secondary & Tertiary Causes:
        • Hypothalamic/Pituitary Disease or Surgery
        • Cranial Irradiation
        • Exogenous glucocorticoids (or drugs with steroid activity i.e. megestrol)
          • Chronic use suppresses CRH and ACTH secretion sentrally.
          • Zona Fasciculata and Reticularis atrophy --> do not secrete cortisol (esp under stress)
          • (Zona Glomerulosa not affected - stimualted by RAAS)

     

    • Clinical Manifestations

      • Fatigue & Malaise are most common!
      • Hormone Deficiency Symptoms/Signs
        Cortisol

        Symptoms: Fatigue, Nausea, Weight Loss, Abdo Pain, Low-Grade Fever

        Physical Exam: Hyperpigmentation (if primary), low BP

        Labs: Hyponatremia, Normak K+, anemia/leukopenia, hypoglycemia, azotemia

        Aldosterone

        Symptoms: Salt Craving, Postural Dizziness

        Physical Exam: Hypotension, Dehydration

        Labs: Hyponatremia, Hyperkalemia

         

        Adrenal Androgens

        (DHEA/DHEAS)

        Symptoms: Decreased Libido

        Physical Exam: Decreased Public/Axillary Hair (women only)

        Labs: None

     

     

    • Primary vs. Secondary
    •   Primary AI Secondary AI
      Skin/mucosa Dark (palmar crease, extensor surfaces) Pale
      K+ High Normal
      Sodium Low Normal/Low
      Metabolic acidosis Present (Type IV RTA) Absent
      Associated Diseases

      1°Hypothyroidism, Type I DM, vitiligo, 

      neuro deficits.

      Central hypogonadism, hypothyroidism, growth hormone deficiency, DM.etc.
      Symptoms

      Weakness, fatigue, wt loss, hypotension, salt craving, postural hypotension, myalgias, 

      GI: nausea,vomiting, abdo pain, diarrhea

      No salt craving, GI less common
      Diagnostic Test

      Cosyntropin Stim Test

      High morning plasma ACTH

      Insulin tolerance test

      Cosyntropin Stim Test

      Low morning plasma ACTH

    •  
    • Adrenal Crisis
      • Occurs mostly in Primary Adrenal Insufficiency - b/c mineralcorticoids & glucocorticoids are absent (vascular instability).
      • Less common in secondary, except under extreme circumstances b/c RAAS system is active.  However, can occur due to vasodilation due to cortisol absence.

     

    • Diagnosis:

      • To diagnose must demonstrate low basal cortisol AND inability to stimulate with ACTH
      • NOTE: Numbers are from the Endocrine Society Guideline 2016 (PAI)
      • Plasma morning Cortisol (highest in AM 8-9am).
        • AM cortisol: 18-20mcg/dl (495-550 nmol/L) confirms sufficiency
        • (Normal, 5-25 µg/dL [138-690 nmol/L]) considered normal (MKSAP 16)
        • AM Cortisol Level < 140 nmol/L (5mcg/dL) --> Adrenal Insufficiency
        • AM ACTH Level, if > 2-fold ULN = Primary Adrenal Insufficiency
          • If low, then Central AI.
        • Must confirm with cosyntropin stim test eventually
      • Confirmatory Cosyntropin Stimulation Test (for primary adrenal insufficiency)
        • (From Endocrine Society Guidelines 2016)
        • Give Cosyntropin 250mcg IV (Adults & Children ≥ 2y) - ACTH Analogue
        • Then measure plasma cortisol levels at 0, 30, and 60min.
          • Normal: Stimulates cortisol of >500 nmol/L (>18 ug/dL) at 30 OR 60min
          • Inaproppriate: does not stimulate.
        • NOTE: 1mg cosyntropin only recommended if it is in short supply.
      • DHEA & DHEAS - low in both primary and central. (rarely done).
      • If Biochemically Central AI --> Must do head MRI for causes/
      • Insulin Tolerance Test (rarely used)
        • Inject insulin to induce hypoglycemia < 2.2 mmol/L (<40 mg/dl).  (cannot interpret unless hypoglycemia achieved).
        • ACTH and GH are released as part of stress mechanism.
        • ACTH also increases plasma cortisol  (>170 nmol/L rise above baseline, if not then Cushing's suspected).
        • Dangerous, MD must be present at all times.
    • In ICU Setting:
      • When acutely resuscitating patients, often very hard to say if they are adrenally insufficient. 
      • In critical care, low serum protein levels reduces bound cortisol, making total cortisol lower (free=active)
      • Random Cortisol 414 nmol/L (15mcg/dL) makes adrenal insufficiency unlikely
        • If hypoproteinemia (albumin < 25 g/L) use  > 331 nmol/L (12mcg/dL) 
      • Cosyntropin Stimulation test is NOT necessary b/c already stimulated from stress of critical illness. 
      • Study shows up to 60% of patients in septic shock are adrenally insufficient (and up to 30% of random ICU pts)
      • Hypotension that is refractory to vasopressors is the most common AI symptom in ICU (electrolyte and other features often unreliable)

     

    • Workup

    • Treatment:

    • In acute adrenal insufficiency (i.e. sepsis, or another stressed state)
      • Hydrocortisone (solu-cortef) 50mg IV q6h
        • Benefit: has both mineralcorticoid and glucocorticoid activity
        • Benefit: is preferred steroid for replacement
        • Will interfere with ACTH stim test (only start after stim test comleted)
        • When stressor is gone can drop dose to 20mg/day (basal steroid level produced by adrenals)
      • Can give dexamethasone 2mg IV bolus (equivalent to 54mg hydrocortisone) --> will not interfere with ACTH stim test (can do before, during or after stim test)
        • Often times dexamathasone is started, ACTH stim test is done, and switched to hydrocortisone. 
    • If NOT acute:

     

    Hormone Dosing Monitoring
    Cortisol Hydrocortisone 15-25mg or cortisone acetate 20-35mg (2-3 divided doses daily).
    • Highest dose should be given in AM.
    • Typical dose: Hydrocortisone 20mg qAM + 10mg qPM

    Alternative: Prednisolone: 3-5mg/day (OD or BID) - if poor compliance

    Dexamethasone --> NOT recommended (Cushingoid effects, hard to titrate - long acting).

    - NOT based on lab

    Clinical: 

    - Weight, fatigue

    Postural Sx, HTN

    Glucose

    Aldosterone

    (Only if Primary Adrenal Insufficiency)

    Fludrocortisone (Start 50-100mcg).

    • Do not restrict salt intake.

    - NOT based on lab

    Clinical:

    - Salt Craving,

    - Postural hypotension

    - Edema

    - Electrolytes

    DHEA

    NOT Essential for Survival

    Can replace if low libido, depression, low energy.

    - Discontinue DHEA if no improvement in symptoms at 6mo.

     

     

     

    Stress Dosing Steroids

    • Educate on stress dosing for "sick days"
      • Double daily dose if fever/illness requiring bed rest, requiring antibiotics, or dental work.
      • See Chart below
    • Source: MKSAP 16 (please cross-reference dosing)
    • Condition

      Hydrocortisone

      Prednisone

      Dexamethasone

      Physiologic daily dosing

      15-25 mg/d orally in three divided doses at 8 AM (7.5-12.5 mg), 12 PM (5-7.5 mg) and 6 PM (2.5-5 mg)

      3-5 mg/d orally in two divided doses at 8 AM (2-3 mg) and 3 PM (1-2 mg)

      0.375 to 0.75 mg/d orally in one dose or preferably as two divided doses

      Minor stress (such as cold symptoms)

      (Double Dose x2-3 days)

      30-50 mg/d orally in three doses for 2-3 days

      8-15 mg/d orally in two divided doses for 2-3 days

      1-2 mg/d orally in two divided doses for 2-3 days

      Moderate stress (such as a minor/moderate surgical procedure)

      (Triple Dose x2-3 days)

      45-75 mg/d orally or IV in three to four divided doses for 2-3 days

      15-20 mg/d orally or IV (as prednisolone) in two or three divided doses for 2-3 days; hydrocortisone can be used instead

      2-3 mg/d orally in two divided doses for 2-3 days; hydrocortisone can be used instead

      Severe stress (such as a major surgical procedure, sepsis)

      100-150 mg/d IV in four divided doses for 1 day; taper to physiologic dose over 3-5 days

      See hydrocortisone regimen

      See hydrocortisone regimen

      Septic shock, severe inflammatory process

      150-200 mg/d IV in four divided doses; taper as clinically tolerated

      See hydrocortisone regimen

      See hydrocortisone regimen

     

    Stress Dosing - Glycemic Control  

    • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765115/  (see Hyperglycemia and Diabetes)
    • Generally can use oral hypoglycemic agents if glucose < 15.
    • If Glucose is > 15 mmol/L --> Usually need to initiate insulin
      • If moderate-acting steroid is used (i.e. prednisone) --> use intermediate acting insulin (i.e. NPH) in AM, because prednisone only causes hyperglycemia in daytime. 
      • If long-acting steroid (i.e. dexamethasone) or multiple doses of short-acting (i.e. hydocortisone q8h) are used --> use long-acting insulin like detemir and lantus. 

    Hyperaldosteronism

    • Hallmark is hypertension and hypokalemia

     

    HyperadosteronismSmall.png

     

    Causes

    • Primary hyperaldosteronism
      • Adrenal Adenoma (40-50%)
      • Bilateral/idiopathic adrenal hyperplasia (50-60%)
      • Unilateral adrenal hyperplasia (or carcinoma) (rare)
    • Secondary hyperaldosteronism
      • Extra-adrenal cause (RAAS stimulation)

    Clinical Features

    • Hypertension (refractory to tx), Hypokalemia (50% eukalemic) (mild hypernatremia), metabolic acidosis
    • If Secondary: can have normal K+, low Na+, low circulating volume increases ADH --> edema.
      • See above diagram to diagnose
    • Cardiac:
      • Atrial Fibrillation
      • LV hypertrophy
      • Stroke
      • MI
    • General
      • Weakness, fatigue, parasthesia, headache... if severe.. tetany, paralysis.
    • NOTE:
      • Look for Cushing's features --> mineralcorticoid activity of cortisol becomes pominent.
      • Look for Pheochromocytoma Features (flushing, headaches, etc..) --> can send plasma catecholamines

    Diagnosis

    • Plasma aldosterone to renin ratio (TEST OF CHOICE, do even if on anti-HTN drugs)
      • Cannot do if on:
        • Eplerenone or Spironolactone (must dc x6wks)
      • ARR normal values vary per institution (genreally >25 = abnormal).
      • Alone is not diagnostic for hyperaldosteronism.  Can confirm with one of two:
        • Nonsuppressable. (see below)
          OR
        • Autonomous aldosterone excess (urine aldosterone of >33.2 nmol/24hr with correction of hyperkalemia and absence of high sodium diet x3 days).
    • Primary Hyperaldosteronism: Aldosterone suppression test
      • Give fluids - 500 mL/h IV NS for 4h --> then measure Aldo levels
        • Plasma aldo >277 pmol/L (>10 ng/dL) consistent with primary hyperaldosteronism.
        • Plasma aldo < 140 pmol/L (< 5ng/dL) is normal suppression.
      • Give oral salt load--> inappropriately high urine and plasma aldosterone.
    • Imaging: CT adrenals

    Treatment

    • Inhibit Aldosterone
      • Spironolactone
      • Eplerenone
      • Triamterene
      • Amiloride
    • Surgical Adenoma Excision
    • Secondary Hyperaldosteronism
      • Treat underlying cause

     

    Cushing's Syndrome

    • Signs and symptoms after prolongued exposure to high doses of corticosteroids
    • Diagnosis is important due to high morbidity and mortality
    • In healthy persons serum cortisol levels vary greatly (nadir late at night, peak early in AM)
    • Clinical Features:
      • MANY features of cushing's syndrome, but ones that raise concern for cushing's syndrome:
        • MSK: Proximal Muscle weakness
        • Skin: Ecchymoses, Prominent supraclavicular fat pads, Violaceous striae
        • Metabolic: Hypokalemia, Diabetes Mellitus
        • Bones: Osteoporosis
        • CV: Hypertension
    • Causes:
      • Type of Cushing Syndrome

        Cause

        Endogenous

           ACTH dependent  

           (75%-80% of patients)

        ACTH-secreting pituitary adenoma (60%-65% of patients

        Ectopic ACTH secretion by tumors, i.e.

             carcinoid tumors (10%-15% of patients)

        CRH-secreting tumors (rare)

        Endogenous:

           ACTH independent    

          (20%-25% of patients)

        Adrenal adenoma (10%-15% of patients)

        Adrenal carcinoma (5%-10% of patients)

        Exogenous

        Prolonged administration of high doses of steroid therapy

        Administration of drugs with glucocorticoid activity

             (progestational agents, such as megestrol)

    • Workup:
      • Three ways to prove hypercortisolism
        • 1.  24-hr Urine Free Cortisol (Gold Standard)
          • Need >3-4 fold increase of ULN is diagnostic of Cushing's Syndrome
          • NO other tests needed.
        • 2.  Overnight Dexamethasone Suppression Test: (Shows loss of feedback inhibition of cortisol on HPA axis )
          • Give 1mg dexamethasone @11pm, and measure AM cortisol at 8-9am
          • Normal: < 2mcg/dL  (>5mcg/dL = diagnostic), 2-5mcg/dL need more tests
          • < 2mcg/dL NORMAL
            2-5 mcg/dL  Need more testing
            > 5mcg/dL DIAGNOSTIC
          • Less accurate in:
            • Estrogen therapy and pregnancy (Increase in corticosteroid binding levels - falsely increase levels)
            • Cyp 450 (phenytoin phenobarbital) increase metabolism of dexamethasone.
        • 3.  Midnight salivary cortisol (Loss of normal diurnal variation of cortisol secretion)
          • Loss of diurnal variation
          • Salivary cortisol in equilibrium with serum cortisol
          • If increased on two occasions = diagnostic
      • Confirmatory Testing:
        • 24-hr Urine free cortisol is gold standard confirmatory test
        • Low dose dexamethasone suppression test 
          • 0.5mg dexamethasone given q6h x48hrs --> suppresses serum cortisol to < 2mcg/dL
          • 24-hr urine free cortisol to > 20 mcg/24hrs = cushings
      • CRH + Desmopressin Stimulation Test can be helpful if many studies equivocal
        • Very expensive, not routine. 
      • Cause:
        • Adrenal? Pituitary? Ectopic?
        • Plasma ACTH level
          • ACTH-Dependent (adrenal neoplasms) vs. ACTH-Independent (ACTH < 5 mcg/mL)
          • Measure ACTH simultaneous with cortisol levels 
        • Imaging (only after biochemistry established)
          • ACTH-Dependent: MRI of sella turcica  (normal in 40-50% of pts - many small size)
            • Hard to distinguish ACTH adenomas vs. ectopic ACTH
            • Can give contrast to enhance
        • Bilateral Inferior Petrosal Sinus Catheterization
          • Central + peripheral measurements of plasma ACTH levels before/after CRH testing
          • Technically difficult
      • Treatment:
        • Exogenous: Discontinue glucocorticoid.
          • Smallest dose possible (once daily or every other day)
        • Endogenous - Central
          • ACTH-secreting pituitary adenoma (Actual Cushing's Disease) --> piuitary adenomectomy
          • Must replace glucocorticoid daily until endogenous production increased (up to 1yr)
          • Residual Disease Post-Op -->
            • Radiation therapy
            • Glucocorticoid Synthesis inhibitors (Ketoconazole, metyrapone, Mitotane)
        • Endogenous - Adrenal
          • Surgical resection (laparoscopic) - can curable. (carcinomas may not)
          • Must replace steroids after
        • Endogenous - Ectopic
          • Possible secreting from malignant tumor (i.e. carcinoid)

    Adrenal Incidentalomas

    • Common now due to a large number of CT scans. 
    • Approach:
      • Is it functional? 10%
      • Is it malignant?
    • Must rule out malignancy
    • Imaging Characteristics for Malignancy Risk
      • Imaging Characteristic  
        Size

        < 4cm = 2% risk malignancy

        > 6cm = 25% risk

        CT Attenuation

        < 10 HU = low risk

        > 20 HU = high risk 

        Contrast Washout

        > 50% in 10min = low risk

        < 50% in 10min = high risk

        MRI (if done)

        Isointense to Liver = Low Risk

        Hyperintense to Liver = High Risk 

    • History/Physical:
      • Malignant Features?
      • Hormone Hypersecretion
    • Workup - identify functional tumors
      • Pheochromocytoma:
        • Catecholamines  (Urine Catecholamine metabolites & Fractionated Metanephrines)
      • Cortisol
        • Cortisol
          • Urine free cortisol OR
          • Dexamethasone suppression test (1mg)  [≥ 5mg/dL = abnormal]
          • +/- ACTH
        • Plasma Aldosterone + Renin Activity
          • Only if Hypertensive, Hypokalemia
      • Plasma DHEA + DHEAS
        • Only if symptoms (low libido, low mood, etc)
    • Management
      • Depends on risk of malignancy and function.
      • Consider for surgical removal if:
        • >6cm in size
        • Functional
        • High risk imaging features
        • (Except aldosterone secreting adenomas - can treat with aldo antagonists)
      • Conservative Mgmt if: non-functional, <4cm, favourable imaging features
        • Follow (unclear how frequent to repeat labs and imaging)
        • CT scans preferred for f/u - at least 6-12mo after initial visit. (some say 6, 12, and 24 mo)
        • Some say repeat labs annually for 3-4 years, others say only if symptomatic. (at least re-evaluate in clinic for features of hypersecretion). 

    Sheehan Syndrome

    • Pituitary infarction or hemorrhage often after a complicated delivery (particularly one associated with significant blood loss and hypotension).
    • Signs: Subacute, progressive:
      • Hypopituitarism;
      • Inability to lactate because of prolactin deficiency
      • Amenorrhea.
      • Central adrenal insufficiency is the primary cause of mortality in Sheehan syndrome.
    • Treatment:
      • Hydrocortisone to replace adrenal insufficiency.
      • Treat other insufficiencies as needed (thyroid etc..)

    Pheochromocytoma

    INCOMPLETE< TODO

    • Imaging
      • Contrast-Enhanced adrenal CT
    • Management
      • Initiate alpha-adrenoreceptor antagonist (such as phenoxybenzamine)
        • Avoid Beta-blockers  (can add once alpha-blockade achieved)
        • Options:
          • Phenoxybenzamine (causes orthostasis, nasal stuffiness, fatigue, retrograde ejaculation)
          • Prazosin
          • Doxazosin
          • Terazosin
        • Target BP < 130/80 seated and sBP > 90 standing  
        • Labetalol (combined alpha/beta blockade) can be used (esp if tachyarrhythmias)  (target HR 60-70 seated, 70-80 standing)

     

    Incidental Adrenal Mass

    • 10-15% of adrenal incidentalomas are functional
    • Clincal evaluation required (I.e. subclinical cushing's is common with no symptoms, but pts can have osteoporosis, obesity, diabetes).
    • Must test for secretion of:
      • Catecholamines (24-hr urine fractionated metanephrines and catecholamines)
      • Cortisol: Low-Dose dexamethasone overnight suppression test
      • Aldosterone --> If no hypertension, do not screen.  (Otherwise measure renin/aldosterone)
    • Needs radiologic surveillance:
      • At 3-6mo then annually for 1-2yrs.
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