Transcript Adrenal Insufficiency Dr Jammah

Adrenal Month
21/5/2008
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
–
–
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–
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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
Norm TT4(5-12 microg/dl), TT3(70-195 ng/dl)
Among 255 Pts: TSH(<1.0 to 568
mU/L). FT4(20 to 100 pmol/L).
FT3(8.0 to 40.2 pmol/L)
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 ADDISON
1795-1860
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
Hypothyroidism
Nontoxic goiter
Thyrotoxicosis
Total
Incidence (%)
8
7
7
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.
106 nmol/l
275 nmol/l
469 nmol/l
ERDINC ERTURK J Clin Endocrinol Metab, 1998
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
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
Richard I Dorin. Ann Intern Med. 2003
570 nmol/L-highdose
500 nmol/L-low-dose
Mayenknecht J, J Clin Endocrinol Metab. 1998
Median duration of follow-up was 4.2
yr
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)
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
Blocks the conversion of 11deoxycortisol to cortisol by 11-betahydroxylase (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.
Normal response
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, 11deoxycortisol, 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 <[email protected]>
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
Hydrocortisone
Equivalent
Glucocorticoid
Dose (mg)
Half-Life
AntiInflammatory
MineralCorticoid
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
Methylpredniso
lone
4
5
0.5
180
12-36
Long Acting
Dexamethasone
0.75
30
0
200
36-54
Betamethasone
.6
30
0
300
36-54
Fludrocortisone
0
15
150
240
24-36
Aldosterone
0
0
400 +
20
--
Mineralocorticoid
Reference: Adrenal Cortical Steroids. In Drug Facts and Comparisons. 5th ed. St. Louis, Facts and
Comparisons, Inc.:122-128, 1997
-1
for each sign or symptom
+1
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
•
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).
Target upper normal range
• 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
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 with
Celiac Disease
Peter Elfstro¨m,
J Clin Endocrinol Metab 2007
Suri et al. • ACTH stimulation Test in Pregnancy. J Clin Endocrinol Metab,
October 2006
• 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 Thank
conductedyou
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?.