Hypoadrenalism

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  • “ It will hardly be disputed that at the present moment, the functions of the supra renal capsules, and the influence they exercise in the general economy, are almost or altogether unknown. The large supply of blood which they receive from three separate sources; their numerous nerves, derived immediately from the semilunar ganglia and solar plexus; their early development in the fœtus; their unimpaired integrity to the latest period of life; and their peculiar gland-like structure; all point to the performance of some important office: nevertheless, beyond an ill-defined impression, found on a consideration of their ultimate organization, that, in common with the spleen, thymus and thyroid body, they in some way or other minister to the elaboration of the blood, I am not aware that any modern authority has ventured to assign to them any special function of influence whatever.”
  • Hypoadrenalism

    1. 1. Hypoadrenalism Gus Brooks Ali Chakera Angus Jones
    2. 2. Scope of today's talk <ul><li>Primary Hypoadrenalism (Addison’s disease) </li></ul><ul><ul><li>Symptoms & signs </li></ul></ul><ul><ul><li>Causes </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Treatment </li></ul></ul><ul><ul><li>Controversies </li></ul></ul><ul><ul><li>Evidence </li></ul></ul><ul><li>Genetic causes of hypoadrenalism </li></ul><ul><li>Secondary (pituitary) hypoadrenalism </li></ul><ul><li>Some questions </li></ul>
    3. 3. Primary hypoadrenalism Addison’s disease
    4. 4. A typical case <ul><li>26 year old, VE </li></ul><ul><ul><li>Nursery school teacher </li></ul></ul><ul><ul><ul><li>Gets lots of bugs </li></ul></ul></ul><ul><ul><li>D&V. Iv fluids, Δ gastroenteritis. Home </li></ul></ul><ul><ul><li>Begins to feel a bit dizzy and weak. </li></ul></ul><ul><ul><li>Five more admissions with the same. </li></ul></ul>
    5. 5. VE, 26♀ <ul><li>Diagnostics </li></ul><ul><ul><li>Eventually someone did a SST </li></ul></ul><ul><ul><ul><li>0 ΄ <20 </li></ul></ul></ul><ul><ul><ul><li>30 ΄ <20 </li></ul></ul></ul><ul><ul><ul><li>60 ΄ <20 </li></ul></ul></ul><ul><ul><li>Raised ACTH – Δ primary hypoadrenalism </li></ul></ul>
    6. 6. VE, 26♀ <ul><li>Rx: Hydrocortisone 10mg od Fludrocortisone 100mcg od </li></ul><ul><li>OPD: Noted she was on a low dose of hydrocortisone. </li></ul><ul><ul><li>BP was 128/62 sitting, 108/71 standing </li></ul></ul><ul><ul><li>A cortisol day curve was requested </li></ul></ul><ul><li>However, still having problems </li></ul><ul><ul><li>Turned up to A&E, vomiting </li></ul></ul><ul><ul><li>Waiting for 2 hours before being told to call Devon Docs! </li></ul></ul>
    7. 7. Issues highlighted by case <ul><li>Non-specific symptoms </li></ul><ul><li>Diagnosis </li></ul><ul><li>Optimum treatment </li></ul><ul><li>Optimum management and review </li></ul><ul><li>Treatment when unwell </li></ul>
    8. 8. Clinical questions <ul><li>Are there any symptoms and signs that are cardianal for Addison’s disease? </li></ul><ul><li>What is the best way to diagnose Addison’s disease? </li></ul><ul><li>What is the best treatment for Addison’s disease? </li></ul><ul><li>How should we follow-up patients with Addison’s disease? </li></ul><ul><li>How should we manage unwell patients with Addison’s disease? </li></ul>
    9. 9. What is primary hypoadrenalism?
    10. 10. A bit of history <ul><li>Thomas Addison first described the disease over 150 years ago </li></ul><ul><li>“ The disease presented in every instance the same general character, pursued a similar course, and, with scarcely a single exception, was followed, after a variable period, by the same fatal result. </li></ul><ul><li>“ It occurs in both sexes, generally, beyond the middle period of life </li></ul><ul><li>“ The leading and characteristic features of the morbid state to which I would direct attention, are… </li></ul><ul><li>“ anæmia, general languor and debility, remarkable feebleness of the heart’s action, irritability of the stomach, and a peculiar change of colour in the skin…” </li></ul>
    11. 11. 1 º hypoadrenalism <ul><ul><li>Glomerulosa </li></ul></ul><ul><ul><li>Fasiculata </li></ul></ul><ul><ul><li>Reticularis </li></ul></ul><ul><ul><li>Mineralocorticoids </li></ul></ul><ul><ul><li>Glucocorticoids </li></ul></ul><ul><ul><li>Androgens </li></ul></ul><ul><li>Failure of the adrenal cortex </li></ul><ul><li>Symptoms as a result of above failure </li></ul>
    12. 12. Epidemiology <ul><li>Primary Hypoadrenalism </li></ul><ul><ul><li>Prevalence: 90-140 per million </li></ul></ul><ul><ul><li>Incidence: 6 per million per year (Western pop.) </li></ul></ul><ul><li>Secondary hypoadrenalism </li></ul><ul><ul><li>Prevalence: 250 per million </li></ul></ul><ul><ul><li>Accounts for 2/3 cases of hypoadrenalism </li></ul></ul><ul><li>Morbidity & Mortality </li></ul><ul><ul><li>Decreased health-related QoL </li></ul></ul><ul><ul><li>Decreased life expectancy - particularly those diagnosed < 40 years old </li></ul></ul><ul><ul><li>Lovas K et al. Health status in …Addison's disease. Clin Endocrinol (Oxf) 2002;56(5):581-8. </li></ul></ul><ul><ul><li>Bergthorsdottir R et al. Premature mortality in Addison’s. J Clin Endocrinol Metab 2006;91(12):4849-53. </li></ul></ul>
    13. 13. Are there any cardinal symptoms and signs of primary hypoadrenalism?
    14. 14. A typical case <ul><li>26 year old, VE </li></ul><ul><ul><li>Nursery school teacher </li></ul></ul><ul><ul><ul><li>Gets lots of bugs </li></ul></ul></ul><ul><ul><li>D&V. Iv fluids, Δ gastroenteritis. Home </li></ul></ul><ul><ul><li>Begins to feel a bit dizzy and weak. </li></ul></ul><ul><ul><li>Five more admissions with the same. </li></ul></ul>
    15. 15. Clinical Suspicion Symptoms Signs Laboratory results <ul><li>Fatigue </li></ul><ul><li>Malaise </li></ul><ul><li>Loss of appetite </li></ul><ul><li>Nausea & vomiting </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Weight loss </li></ul><ul><li>Postural dizziness </li></ul><ul><li>Myalgia </li></ul><ul><li>Joint pain </li></ul><ul><li>Salt craving </li></ul><ul><li>Loss of libido (women) </li></ul><ul><li>Hyperpigmentation of skin & mucous membrane </li></ul><ul><li>Low blood pressure </li></ul><ul><li>Postural hypotension </li></ul><ul><li>Hyponatraemia </li></ul><ul><li>Hyperkalaemia </li></ul><ul><li>Hypoglycaemia </li></ul><ul><li>Raised urea </li></ul><ul><li>Metabolic acidosis </li></ul><ul><li>Hypercalcaemia </li></ul><ul><li>Raised thyroid stimulating hormone </li></ul><ul><li>Normocytic anaemia </li></ul>
    16. 16. Clinical Suspicion Symptoms Signs Laboratory results <ul><li>Fatigue </li></ul><ul><li>Malaise </li></ul><ul><li>Loss of appetite </li></ul><ul><li>Nausea & vomiting </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Weight loss </li></ul><ul><li>Postural dizziness </li></ul><ul><li>Myalgia </li></ul><ul><li>Joint pain </li></ul><ul><li>Salt craving </li></ul><ul><li>Loss of libido (women) </li></ul><ul><li>Hyperpigmentation of skin & mucous membrane </li></ul><ul><li>Low blood pressure </li></ul><ul><li>Postural hypotension </li></ul><ul><li>Hyponatraemia </li></ul><ul><li>Hyperkalaemia </li></ul><ul><li>Hypoglycaemia </li></ul><ul><li>Raised urea </li></ul><ul><li>Metabolic acidosis </li></ul><ul><li>Hypercalcaemia </li></ul><ul><li>Raised thyroid stimulating hormone </li></ul><ul><li>Normocytic anaemia </li></ul>
    17. 17. Pitfalls in diagnosis <ul><li>Symptoms may mimic other illnesses </li></ul><ul><ul><li>Anorexia </li></ul></ul><ul><ul><li>GI disorder </li></ul></ul><ul><li>Patient may have another autoimmune disorder to which symptoms are attributed </li></ul><ul><li>60% patients consulted 2 or more physicians before diagnosis made. </li></ul>
    18. 18. Other associations <ul><li>T1DM </li></ul><ul><ul><li>Unexplained hypos / decrease in insulin requirement </li></ul></ul><ul><li>Hypothyroidism </li></ul><ul><ul><li>Raised TSH can oocur in hypoadrenalism </li></ul></ul><ul><ul><li>Patient gets worse despite starting thyroxine </li></ul></ul><ul><li>Electrolyte disturbance </li></ul><ul><ul><li>Low Na, high K, high Ca </li></ul></ul>
    19. 19. How do we diagnose Addison’s disease?
    20. 20. VE, 26 ♀ <ul><li>Diagnostics </li></ul><ul><ul><li>Eventually someone did a SST </li></ul></ul><ul><ul><ul><li>0 ΄ <20 </li></ul></ul></ul><ul><ul><ul><li>30 ΄ <20 </li></ul></ul></ul><ul><ul><ul><li>60 ΄ <20 </li></ul></ul></ul><ul><ul><li>Raised ACTH – Δ primary hypoadrenalism </li></ul></ul>
    21. 21. Diagnosis <ul><li>Short-synacthen test </li></ul><ul><ul><li>250mcg vs 1mcg synacthen test </li></ul></ul><ul><li>Insulin tolerance test </li></ul><ul><li>Anitbodies </li></ul><ul><li>Other tests </li></ul><ul><li>Imaging </li></ul>
    22. 22. Short-synacthen test (SST) <ul><li>Ideally performed in the morning </li></ul><ul><li>Inject 250 µg of synacthen (im or iv) </li></ul><ul><li>Blood for cortisol at 0, 30 and 60 minutes </li></ul><ul><li>Normal response is a rise in serum cortisol 30 or 60 minutes after the synacthen injection to above 500 nmol/l </li></ul><ul><li>If the cortisol response is inadequate (less than 500 nmol/l), you should measure plasma ACTH </li></ul>
    23. 23. Underlying cause <ul><li>ACTH </li></ul><ul><li>(Renin) </li></ul><ul><li>Antibodies </li></ul><ul><ul><li>Adrenal </li></ul></ul><ul><ul><li>21-hydroxylase antibodies </li></ul></ul><ul><li>Very long chain fatty acids (VLCFA) </li></ul><ul><li>CT Adrenals </li></ul><ul><li>Differentiate primary from secondary </li></ul><ul><li>To highlight autoimmune disease </li></ul><ul><li>To diagnose adrenoleucodystrophy </li></ul><ul><li>If other tests are negative </li></ul>
    24. 24. Causes of Addison’s disease <ul><li>Autoimmune adrenalitis </li></ul><ul><ul><li>Isolated adrenal insufficiency </li></ul></ul><ul><ul><li>Autoimmune polyglandular syndromes (APS) – type 1 and type 2 </li></ul></ul>Infective <ul><ul><li>Tuberculosis </li></ul></ul><ul><ul><li>Fungal (histoplasmosis, Cryptococcosis) </li></ul></ul><ul><ul><li>HIV </li></ul></ul>Bilateral adrenalectomy Haemorrhage / infarction Infiltration <ul><ul><li>Malignant – mets, lympoma </li></ul></ul><ul><ul><li>Non-malignant - sarcoid, haemochromotosis, amyloid </li></ul></ul>Drugs <ul><ul><li>ketaconazole, etomidate, aminoglutethimide, mitotane </li></ul></ul><ul><li>Genetic </li></ul><ul><ul><li>Adrenoleucodystrophy </li></ul></ul><ul><ul><li>Congenital Adrenal hyperplasia </li></ul></ul><ul><ul><li>Familial ACTH resistance syndromes </li></ul></ul><ul><ul><li>Adrenal hypoplasia congenita </li></ul></ul><ul><ul><li>Kearns-Sayre syndrome (Mitochondrial cytopathy) </li></ul></ul>
    25. 25. Causes of primary hypoadrenalism <ul><li>APS 1 </li></ul><ul><ul><li>Also known as APECED (autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy) </li></ul></ul><ul><ul><li>Rare. Autosomal recessive. AIRE-1 gene </li></ul></ul><ul><ul><li>Associated with mucosal candidiasis, hypoparathyroidism, T1DM, chronic hepatitis </li></ul></ul><ul><li>APS 2 </li></ul><ul><ul><li>T1DM </li></ul></ul><ul><ul><li>Autoimmune hypothyroidism </li></ul></ul><ul><ul><li>Primary gonadal failure </li></ul></ul><ul><ul><li>Other autoimmune conditions - vitiligo </li></ul></ul>
    26. 26. Management of hypoadrenalism
    27. 27. Management of hypoadrenalism +ve +ve -ve -ve
    28. 28. How do we treat primary hypoadrenalism?
    29. 29. VE, 26♀ <ul><li>Rx: Hydrocortisone 10mg od Fludrocortisone 100mcg od </li></ul><ul><li>What do people think of this regime? </li></ul><ul><li>How would you determine if it is adequate? </li></ul>
    30. 30. Glucocorticoids <ul><li>The evidence is weak: </li></ul><ul><ul><li>Small non-randomised study: Bd hydrocortisone - very low levels of cortisol late afternoon, could be prevented by tds hydrocortisone. </li></ul></ul><ul><ul><li>Retrospective study in favour of thrice-daily regime of hydrocortisone </li></ul></ul><ul><ul><li>Suggestion that a normal requirement is as little as 15mg/day </li></ul></ul><ul><li>Groves RW, Toms GC, Houghton BJ, Monson JP. Corticosteroid replacement therapy: twice or thrice daily? J R Soc Med 1988;81(9):514-6. </li></ul><ul><li>Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf) 1997;46(3):263-8. </li></ul><ul><li>Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endo. 2005;63:483-492 </li></ul>
    31. 31. Glucocorticoid <ul><li>Overtreatment </li></ul><ul><ul><li>Cushingoid </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Weight gain </li></ul></ul><ul><ul><li>Thin skin </li></ul></ul><ul><ul><li>Raised glucose </li></ul></ul><ul><li>Undertreatment </li></ul><ul><ul><li>Symptoms of hypoadrenalism </li></ul></ul><ul><li>Clinical monitoring </li></ul>
    32. 32. The problem patient… <ul><li>What should you do about the patient who does not feel quite right and is always putting up their dose? </li></ul>
    33. 33. <ul><li>Overtreatment </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Oedema </li></ul></ul><ul><ul><li>Low renin </li></ul></ul>Mineralocorticoids <ul><li>Undertreatment </li></ul><ul><ul><li>Postural hypotension </li></ul></ul><ul><ul><li>Dizzy spells </li></ul></ul><ul><ul><li>High renin </li></ul></ul><ul><li>Fludrocortisone </li></ul><ul><ul><li>50-200mcg Fludrocortisone </li></ul></ul>
    34. 34. What about the androgens? <ul><li>The adrenal cortex also makes DHEA/DHEAS which are weak androgens – not relevant in men, but are they relevant in women? </li></ul><ul><ul><li>Some studies suggest improved well-being, some suggest adverse lipid profile </li></ul></ul><ul><li>Gurnell EM, et al. Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial. J Clin Endocrinol Metab 2008;93(2):400-9. </li></ul><ul><li>Lovas K, et al. Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 2003;88(3):1112-8. </li></ul><ul><li>Srinivasan M, et al. Effect of Dehydroepiandrosterone Replacement on Lipoprotein profile in Hypoadrenal Women. J Clin Endocrinol Metab 2008 </li></ul>
    35. 35. How should we monitor patients with primary hypoadrenalism?
    36. 36. VE, 26♀ <ul><li>Rx: Hydrocortisone 10mg od Fludrocortisone 100mcg od </li></ul><ul><li>OPD: Noted she was on a low dose of hydrocortisone. </li></ul><ul><ul><li>BP was 128/62 sitting, 108/71 standing </li></ul></ul><ul><ul><li>A cortisol day curve was requested </li></ul></ul><ul><li>However, still having problems </li></ul><ul><ul><li>Turned up to A&E, vomiting </li></ul></ul><ul><ul><li>Waiting for 2 hours before being told to call Devon Docs! </li></ul></ul>
    37. 37. Patient Education <ul><li>Life-long condition requiring daily treatment. </li></ul><ul><li>Hydrocortisone replacement not associated with complications of excess steroid. </li></ul><ul><li>Concurrent illness, the dose of glucocorticoid should be increased. </li></ul><ul><li>Seek immediate medical help in case of repeated vomiting and being unable to keep glucocorticoid tablets down. </li></ul><ul><li>Carry a steroid card and a medic alert bracelet or necklace. </li></ul>
    38. 38. Routine review <ul><li>Assessment of general wellbeing </li></ul><ul><li>Measurement of postural blood pressure </li></ul><ul><li>Re-inforcement of ‘sick day rules’ </li></ul><ul><li>Monitoring </li></ul><ul><ul><li>Postural BP </li></ul></ul><ul><ul><li>Bloods – renin, TSH, fasting glu, FBC, coeliac screen (at baseline), testosterone/regular periods. </li></ul></ul>
    39. 39. Other tests <ul><li>Cortisol Day Curve </li></ul><ul><ul><li>Limited value in routine practice </li></ul></ul><ul><ul><li>You get a peak with cortisol soon after administration which then drops down before the next dose. </li></ul></ul><ul><li>24 hour urinary cortisols </li></ul><ul><ul><li>Maybe useful if you want to check compliance </li></ul></ul>
    40. 40. How do you manage primary hypogonadism in an unwell patient
    41. 41. VE, 26♀ <ul><li>Rx: Hydrocortisone 10mg od Fludrocortisone 100mcg od </li></ul><ul><li>OPD: Noted she was on a low dose of hydrocortisone. </li></ul><ul><ul><li>BP was 128/62 sitting, 108/71 standing </li></ul></ul><ul><ul><li>A cortisol day curve was requested </li></ul></ul><ul><li>However, still having problems </li></ul><ul><ul><li>Turned up to A&E, vomiting </li></ul></ul><ul><ul><li>Waiting for 2 hours before being told to call Devon Docs! </li></ul></ul>
    42. 42. Recognising a crisis <ul><li>Dehydration </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Vomiting </li></ul><ul><li>Obtunded </li></ul><ul><li>Systemic shock minimally responsive to ionotropes </li></ul>
    43. 43. Managing a crisis <ul><li>Fluids and parenteral hydrocortisone </li></ul><ul><li>In a previously undiagnosed patient </li></ul><ul><ul><li>As you take bloods – send a cortisol and ACTH </li></ul></ul><ul><ul><li>Fluids – normal saline </li></ul></ul><ul><ul><li>Hydrocortisone 100mg iv stat </li></ul></ul><ul><li>Reconsider the diagnosis once the patient is well </li></ul>
    44. 44. Management of physiologically unwell patients <ul><li>We probably overestimate the amount of steroid that we need to give </li></ul><ul><li>Grade severity of illness and increase steroids appropriately </li></ul><ul><li>75-150mg steroid secreted in a normal patient during surgery. </li></ul>
    45. 46. Exeter surgical guidelines
    46. 47. Other situations
    47. 48. Pregnancy <ul><li>No consensus </li></ul><ul><li>Often do not need extra steroid </li></ul><ul><li>Some authors suggest a </li></ul><ul><ul><li>increase in dose in third trimester and </li></ul></ul><ul><ul><li>double of dose in labour </li></ul></ul>
    48. 49. Exercise <ul><li>No consensus </li></ul><ul><ul><li>Extra 5-10mg before strenuous exercise </li></ul></ul>
    49. 51. Questions?
    50. 52. <ul><li>http://www.wehner.org/addison/p4.htm </li></ul>

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