Adrenal Month21/5/2008

Anwar Ali Jammah

PGY5

• Case of hypothyroidism ???

• Diagnosis of adrenal insufficiency

• Treatment and Prognosis of AI

• Some updated subjects

Case

• A. Y. 63 years old gentleman admitted under medicine team. – Productive Cough for 3 weeks.– Wt. loss

Question to Endo consult. Service:

TSH: 20

FT4 :14

FT3 :5

Case

• More History– .– .– .

• Examination– In isolation ?TB.– BP 90/55 pulse 102– Cachectic.– Euthyroid – Skin and mucosa ?

Case

• DDx of high TSH and normal FT3 FT4:– Hypothyroidism (sub clinical TSH<15)– Recovery from non-thyroidal illness. – Adrenal insufficiency. – ?TSH-producing pituitary adenomas and ?

resistance to thyroid hormone, and ?rare mutations of the TSH receptor (neonate).

– Antiemetic Metoclopromide or domperidone

Among 255 Pts: TSH(<1.0 to 568 mU/L). FT4(20 to 100 pmol/L). FT3(8.0 to 40.2 pmol/L)

Norm TT4(5-12 microg/dl), TT3(70-195 ng/dl)

case

• PM Cortisol 59 nmol/l (85-459 3-5 PM).• PM ACTH 86.99 pmol/l (1.98-12.47 7-10 AM fasting sample).• AM Cortisol 80 nmol/l (119-618 7-9 AM)• AM ACTH 160.9 pmol/l.• Anti TPO -ve

Diagnosis

Treatment

• In 1855 Thomas Addison describes the clinical features and autopsy findings of 11 cases of diseases of the suprarenal capsules, 6 of which were tuberculous in origin.

Thomas ADDISON1795-1860

case

• TB confirmed in sputum sample AFB and Culture.

• He started on Anti TB medication:– INH– RIF– PZA– EMB

• Recovery of Adrenal gland may occur but usually does not.

Bhatia E. Clin Endocrinol 1998

Penrice J. Postgrad Med J 1992

TB treatment

• Rifampicin reduces effectiveness and bioavailability of steroid.

• Corticosteroids level may decrease the serum concentration of Isoniazid.

McAllister WA Br Med J, 1983.Sarma GR. Antimicrob Agents Chemother, 1980.

case

• Follow up TFT after steroid replacement– TSH 7.5– FT4 14– FT3 4

• INCIDENCE OF THYROID DISEASE IN PATIENTS WITH AUTOIMMUNE ADRENAL INSUFFICIENCY (N = 448)

Disease Incidence (%)Hypothyroidism 8 Nontoxic goiter 7 Thyrotoxicosis 7Total 22

Betterle C, et al: EndocrRev   2002; 23:327-364

Autoimmune polyglandular syndrome

• Type I consists mainly of:– Adrenal insufficiency. – Hypoparathyroidism. – Mucocutaneous candidiasis.

• Type II consists mainly of:– Adrenal insufficiency.– Autoimmune thyroid disease.– Insulin-dependent diabetes mellitus.

Diagnosis of Adrenal insufficiency

• Serum Cortisol

– 7 to 9 AM (275 to 555 nmol/L).

– Sensitivity and specificity mainly depend on the cut off level.

ERDINC ERTURK J Clin Endocrinol Metab, 1998

275 nmol/l106 nmol/l 469 nmol/l

Diagnosis

• Acute serum cortisol and plasma ACTH measurements.

– Provide immediate evaluation of the HPA axis in emergency cases.

Patient with AI (O)

Normal Subjects

Patients with Pituitary Disease with or without AI

Multiply by 0.22 (pmol/l)

Multiply by 27.6(nmol/l)

W. OELKERS, 1996 NEJM

Richard I Dorin. Ann Intern Med. 2003

Sensitivity and Specificity are 96.5% for the diagnosis of primary adrenal insufficiency. Positive likelihood ratio of 19.5 and a negative likelihood ratio of 0.026

Richard I Dorin. Ann Intern Med. 2003

Richard I Dorin. Ann Intern Med. 2003

Richard I Dorin. Ann Intern Med. 2003

570 nmol/L-highdose500 nmol/L-low-dose

Mayenknecht J, J Clin Endocrinol Metab. 1998

20 patients (missing case notes). None of them were on steroid replacement, and all were well.(Phone, family Dr, or hospital records). 10 patients (no evidence of hypothalamic-pituitary disease)

Median duration of follow-up was 4.2 yr

98 patients: >550

50 patients: 510-550 (advised to take stress doses of hydrocortisone in cases of stress).

One patient in >550 nmol/l group developed adrenal insufficiency at 2 yr, and one patient in 510-550 nmol/l group developed adrenal insufficiency at 6 months. The other two patients who were in group 2 had clinical diagnostic uncertainty.

The high-dose SST is reliable for the purpose of excluding clinically significant secondary adrenal insufficiency.

Two-day ACTH infusion test

• 250 µg cosyntropin is infused for eight hours on two consecutive days(3 to 5 days).

• In primary adrenal insufficiency:

– Little, or no increase in cortisol production.

• In secondary adrenal insufficiency :

– Cortisol should reach >550 nmol/L in 30 to 60 minutes after the ACTH infusion is begun and >690 nmol/L after six to eight hours.

– Urinary excretion of 17-OHCS should be >74 nmol during the first 24 hours of infusion and >130 nmol during the second 48 hours.

Thorn, GW. 1966,

CRH test

• CRH 1 mcg/kg body weight or 100 mcg total dose is injected IV. Blood samples for ACTH and cortisol at -15, 0, 5, 10, 15, 30, 45, 60, 90 and 120 minutes after CRH injection.

– Pats. w pituitary ACTH deficiency (secondary adrenal insufficiency) have decreased plasma ACTH and serum cortisol responses to CRH.

– Pats. with hypothalamic disease (CRH deficiency) have exaggerated and prolonged plasma ACTH responses; the plasma cortisol responses are subnormal.

– Patients with primary adrenal deficiency have high basal plasma ACTH and exaggerated responses to CRH, cortisol level is low before and after.

Metyrapone Test

Normal response

Blocks the conversion of 11-deoxycortisol to cortisol by 11-beta-hydroxylase (P-450c11), the last step in the synthesis of cortisol, and induces a rapid fall of cortisol and an increase of 11-deoxycortisol in serum.

ITT

80 patients (total), 19 patients with adrenal insufficiency, 7 with primary and 12 with secondary.

Conclusion:Following injection of 250 μg Cortrosyn. Stimulated levels of aldosterone, 11-deoxycortisol, dehydroepiandrosterone, provided additional discrimination between states of adrenal sufficiency and insufficiency.

Treatment

The average daily secretion rate of cortisol in normal subjects is 2.7 to 14 mg/M2/day. i.e. 6 - 26 mg of hydrocortisone/day

Average dose will be between 15 - 20 mg of hydrocortisone taking two-thirds of the in the morning and one-third in the afternoon.

JONATHAN Q. J Clin Endocrinol Metab 2004

E-mail from Dr Edmonds

Re: daily cortisol production From: Merrill Edmonds <medmonds@uwo.ca> Date: Wednesday, August 10, 2005 Time: 6:14 pm

• Hi

• I can't comment on which technique for measuring the cortisol production rate is the most accurate.  The main criticism they had of the traditional double isotope method was inaccurate collection of urine.  I'm sure there are problems with deconvolution analysis too but know very little of this technique.  Still, just to make it clear, the article in adults estimates the 24 hour production rate to be 9-11mg/m2 and NOT 9-11mg.  For someone like me with a surface area close to 1.9, that means the 24 hour production rate  will be close to 20mg of hydrocortisone per day.  In my experience, very few people with adrenal insufficiency due to complete destruction of their adrenals (i.e. surgical removal) feel okay on 20mg of hydrocortisone per day.   Some patients with Addison's still have some adrenocortical function and can do okay on this dose, at least until they wipe out the rest of their adrenal cortex.  The bigger doses are likely due to less than 100% absorption and inappropriate diurnal rhythm but they are still necessary to keep the patient feeling reasonably normal. I'm appending a review from JAMA for the information of the residents.

Merrill

 Potency relative to

HydrocortisoneHalf-Life

 Equivalent

Glucocorticoid Dose (mg)

Anti-Inflammatory

Mineral-Corticoid

Plasma(minutes)

Duration of Action (hours)

Short Acting

Hydrocortison (Cortef, Cortisol)

20 1 1 90 8-12

Cortisone Acetate 25 0.8 0.8 30 8-12

Intermediate Acting

Prednisone 5 4 0.8 60 12-36

Prednisolone 5 4 0.8 200 12-36

Triamcinolone 4 5 0 300 12-36

Methylprednisolone

4 5 0.5 180 12-36

Long Acting

Dexamethasone 0.75 30 0 200 36-54

Betamethasone .6 30 0 300 36-54

Mineralocorticoid          

Fludrocortisone 0 15 150 240 24-36

Aldosterone 0 0 400 + 20 - -

Reference: Adrenal Cortical Steroids. In Drug Facts and Comparisons. 5th ed. St. Louis, Facts and Comparisons, Inc.:122-128, 1997

Assessment of the adequacy of hydrocortisone therapy

Clinical assessment alone works equally well to the use of normative day-curve cortisol values.

Wiebke Arlt. Clinical Endocrinology 2006

-1 for each sign or symptom +1

• Open label, placebo-uncontrolled design pilot study.

• All had ACTH,TSH, and gonadotropin deficiency. GH deficiency was documented in all subjects, by low plasma IGF-1 and 3 patients underwent insulin hypoglycemia.

• All patients received replacement therapy with L-thyroxine 0.075–0.15 mg/day, testosterone in men 250 mg IM per 2 weeks or estrogen/progesterone in women. NO GH replacement.

• Patients were on Glucocorticoid replacement in form of Hydrocortisone 15–20 mg in the morning, 5–10 mg in the afternoon. The total daily dose was 20–30 mg/day.

• The subjects were instructed to decrease their hydrocortisone replacement dose to 5–10 mg in the morning and 5 mg in the afternoon. The total daily dose 10–15 mg/day.

•A decrease in the hydrocortisone replacement was not accompanied by any symptoms or signs of adrenocortical failure. No subject reported fatigue, weakness, tiredness, low energy, or orthostatic lightheadedness.

•The blood pressure remained normal in 9/11. Two persisted with mild hypertension.

•8/10 subjects had UFC above the upper limit of the normal. In 5 subjects (1.5–2.5-fold of ULN).

•The decrease in dose led to the normalization of UFC in all subjects.

Two points

• Decreasing the glucocorticoid replacement dose to <15 mg/day over 6 and 12 months is safe, and beneficial in term of:– body composition.– lipid profile.– quality of life.

• These benefits occurred in the absence of concomitant GH replacement therapy. – speculate that the metabolic and neuropsychiatric abnormalities of

panhypopituitarism may be due not only to GH deficiency as such, but rather to overzealous replacement of glucocorticoids.

Both Issues need to be addressed in a double-blind, placebo controlled design.

Mineralocorticoid replacement ‘Fludrocortisone’

• Usual dose: 0.1 mg/day. – 0.05 – 0.1 mg/day if patient on hydrocortisone. – 0.1-0.2 mg/d if patient on prednisone or dexamethasone.

• Assessment of the adequacy of mineralocorticoid : – Symptoms of postural hypotension and edema.– Measuring supine and upright blood pressure, pulse, and edema.– Serum sodium and potassium.

– Measuring Plasma renin activity (PRA).

• Initially on diagnosis.• If it is difficult to assess the adequacy of replacement clinically• Routinely Once a year.

Oelkers W. Clin Endocrinol Metab 1992

Smith SJ. Lancet 1984 Jan

Target upper normal range

1675 patients (995 women and 680 men) diagnosed with primary adrenal insufficiency, followed for 6.5 years (average).

Compared with the background population, RR for death was more than two-fold higher in patients with Addison’s disease. Cardiovascular, malignant and infectious diseases were responsible for the higher mortality rate

Decreased bone mineral density occurred in more than 30% of male patients receiving long-term glucocorticoid replacement therapy for Addison disease.

The daily hydrocortisone dose per kg of body weight was higher in the patients with low BMD.(~30mg hydrocortisone/day)

BMD of the lumbar spine was inversely correlated with glucocorticoid dose in the entire group.

P.Zelissen, Ann Intern Med February 1994

New stuff

Skin lightening and its complications among African people living in Paris

Antoine Petit MD, Cécile Cohen-Ludmann MD, Philippe Clevenbergh MD, Jean-François Bergmann MD, PhD and Louis Dubertret MD

From the Dermatology Service, Hôpital Saint LouisInternal Medicine Service, Hôpital Lariboisière

Paris, France.  Available online 28 August 2006.

Forty-six patients from various African countries (39 women, 7 men) presented with skin changes suggestive of side effects from skin lightening practices .

2 patients diagnosed with 2ndry Adrenal insufficiency.

Risk of Primary Adrenal Insufficiency in Patients withCeliac DiseasePeter Elfstro¨m,J Clin Endocrinol Metab 2007

Suri et al. • ACTH stimulation Test in Pregnancy. J Clin Endocrinol Metab, October 2006

Thank you

• Patient with Adrenal Insufficiency may presents with atypical findings.

• Diagnosis of AI may be easy and straightforward but it can be difficult and challenging. 250 mcg test is reliable and easer to perform than 1 mcg.

• Treatment of AI should be conducted with minimum dose of steroid and dose assessment during follow up is necessary.

• AI associated with higher mortality and morbidity. ?dose related.

• Celiac disease and skin lightening preparations and AI.

• Pregnancy?.