MECHANISMS OF HUMAN DISEASE
ENDO CASE-BASED SMALL GROUP DISCUSSION
SESSION 16
ADRENAL AND PITUITARY DISEASE
MONDAY, FEBRUARY 5, 2001
10:30AM – 12:30PM
Case 1
A 32-year-old Caucasian woman was seen because of a 40 pound weight gain over the last two years. Patient has been having headaches and has been emotionally labile. She complained of generalized weakness, irregular and infrequent menstrual periods and has noticed some hair growth on the face for the last year. Past and family history are non-contributory. She is a non-smoker, non-alcoholic and is on no medicines. Thyroid function tests and prolactin done by her private M.D. six months ago were normal.
On examination - P = 90/m reg, BP= 160/100 mm/Hg. Generalized obesity with slight centripetal distribution. Height= 5'6", weight = 185 pounds.
HEENT - Face slightly rounded and plethoric, dark hair present on the chin, upper lip and legs, acne marks present. Visual fields are normal.
No thyromegaly or adenopathy. Chest and CVS normal.
Abdomen - obese with violaceous striae on the lower abdomen and in the axillary region.
CNS - Depressed mood, power 4/5 in proximal muscles of upper and lower extremities with some wasting.
Extremities - some ecchymoses on arms and thighs.
Sodium = 140 mM/L (n = 136-146), potassium = 3.5 mM/L (n = 3.5-5.3), chloride = 98 mM/L (n = 98-108) carbon dioxide = 28 mM/L (n = 20-32), BUN = 14 mg/dl (n = 7-22), creatinine = 1 mg/dl (n = 0.7-1.5), glucose = 214 mg/dl (n = 70-110). CBC, urinalysis and chest x-ray was normal.
EDUCATIONAL OBJECTIVES
CASE 1
1. What is the clinical diagnosis? What clinical manifestations help to determine this diagnosis?
Cushing's syndrome.
The clinical features that help are weight gain (with centripetal fat distribution in the subcutaneous tissues of face and neck, mediastinum, peritoneum,) depression, mild hirsutism, muscle weakness, hypertension, hyperglycemia, skin changes, etc.
2. What initial test(s) can be done to assess this condition?
24-hour urine free cortisol (UFC) which assesses the integrated plasma free cortisol centrations during a 24-hour period that is filtered by the kidney. Normal is less than 100 mcg/24 hours (although in assays of greater specificity it is less than 50 mcg/24 hours). UFC is normal in the obese although it may slightly increased in <5%. False positives in alcoholism and severe depression (pseudo Cushing states).
Overnight 1 mg Dexamethasone suppression test whereby 1 mg DEXA given p.o. at 11 p.m. and an 8 a.m. plasma cortisol > 5 mcg/dl suggests Cushing's syndrome. Problems: false positives in intermittent Cushing's syndrome, intake of drugs which increase DEXA metabolism (phenytoin, rifampin, Phenobarbital), estrogen therapy (increased CBG), endogenous depression, obesity, non-compliance with taking DEXA, etc.
3. What is the differential diagnosis after the screening test(s) has confirmed your clinical diagnosis.
ACTH dependent Cushing's syndrome.
-Cushing's disease (pituitary)
-Ectopic ACTH syndrome (small cell lung carcinoma, carcinoids,
neuroendocrine tumors)
-Ectopic CRH syndrome (bronchial carcinoid)
ACTH independent Cushing's syndrome.
-Adrenocortical neoplasm (benign or malignant)
-Nodular adrenal hyperplasia (micro-, macro-, PPNAD)
-Food dependent (gastric inhibitory polypeptide mediated)
-Factitious
Pseudo Cushing's syndrome
-Alcoholism
-Major depression, severe stress
-Anorexia/bulimia
4. Dexamethasone 0.5 mg PO Q 6 hours is given for 2 days and then 2.0 mg PO Q 6 hours for 2 days. Blood and urine samples are collected at baseline and daily for serum cortisol, urine free cortisol (UFC) and 17 (OH) corticosteroid [17 (OH) CS]. Results are shown in the following table:
DAYS
Baseline Low Dose High Dose
1 2 3 4 5 6
17 (OH) CS 28 32 30 28 11 8
(2.5-8 mg/24 hr)
UFC 200 160 146 128 52 20
(<100 mcg/24 hr)
8 AM cortisol 36 28 20 10 4 3
(6-25 mcg/dl)
4 PM cortisol 34
(2-18 mcg/dl)
ACTH 121
(9-52 pg/ml)
5. With this information what is the diagnosis in this patient?
After two days of high dose DEXA (this can also be performed by overnight 8 mg DEXA p.o.), suppression of 17/(OH)CS by > 64% of baseline and UFC by > 90% of baseline indicating pituitary dependent Cushing's disease. Results that are inconclusive may need further testing such as peripheral CRH stimulation test, inferior petrosal sinus sampling, etc.
In this patient, 17(OH)CS suppresses by 72% on day 4 and UFC suppresses by 90% on day 4. ACTH > 52 pg/ml suggests ACTH dependent Cushing's syndrome.
6. What therapeutic strategy would you recommend?
High resolution MRI of sella turcica with and without gadolinium enhancement. No tumor was identified (only 50% of the microadenomas that cause Cushing's
disease are detected). If there was no suppression with high-dose DEXA and ACTH was measurable, a chest +/- abdominal CT/MRI should be done to rule out ectopic ACTH-producing tumor. If ACTH was suppressed, a thin section CT/MRI of adrenals should be done to rule out adrenal adenoma/carcinoma.
b) treatment
Transsphenoidal hypophysectomy with 85% resection of anterior pituitary was done. Immmunostain were strongly positive for ACTH. Patient was placed on anterior pituitary replacement hormones.
Case 2
A 34-year old white female is admitted to the intensive care unit with fever, chills, dysuria, diarrhea, marked dizziness, anorexia, nausea, vomiting and abdominal pain for 4 days. On examination, she is ill-appearing, pulse = 98/minute and BP = 100/70 mm/Hg in the supine position. On sitting up, pulse = 110/minute, BP = 80/56 mm/Hg and Temperature = 39C. Skin pigmentation is normal. Abdominal exam shows mild diffuse tenderness.
Sodium = 139 mM/L (n = 136-146), potassium = 4 mM/L (N = 3.5-5.3), CHLORIDE = 96 mM/l (n = 98-108), carbon dioxide = 27 mM/L (n=20-32), BUN = 25 mg/dl (n= 7-22), creatinine = 1.2 mg/dl (n= 0.7-1.5), glucose = 60 mg/dl (n= 70-110). CBC, x-ray chest - normal. U/A - hazy, many WBC, RBC, bacteria
EDUCATIONAL OBJECTIVES
CASE 2
1. What are the clinical problems?
Fever, hypotension, hypovolemia, gastrointestinal complaints, urinary tract infection.
2. What is the differential diagnosis?
Urosepsis, gastroenteritis, other intra abdominal infections, acute adrenal insufficiency precipitated by an infection.
which have been taken for the past 3 days because of nausea. What may be the diagnosis now?
Acute adrenal insufficiency exacerbated by bacterial infection in a patient with secondary adrenal insufficiency following the cure of Cushing's syndrome (patient in Case 1). This occurred due to lack of education regarding the need to increase steroids for stress. If this was a patient with no previous history, a rapid
ACTH stimulation test should have been done for diagnosis of adrenal insufficiency.
4. How do you differentiate between primary and secondary insufficiency of this target gland?
Usual features of adrenal insufficiency are present in both. Some differences are:
Primary Secondary
Hyperpigmentation + -
Hyperkalemia + -
High ACTH + -
Low aldosterone + -
Hyponatremia + May be present
Other hormone May be present Present
deficiencies
5. What therapeutic strategy would you recommend?
a) Now
-I/V fluids, antibiotics, supportive care
-Intravenous infusion or I/M hydrocortisone 200-300 mg/24 hours to be
tapered down as stress resolves.
-Replacement doses of glucocorticoid (cortisone acetate 37.5 mg/day or hydrocortisone 30 mg/day or prednisone 7.5 mg/day). Patients with primary adrenal insufficiency will also require mineralocorticoid e.g., fludrocortisone 100 mcg/day.
-Double the dose for minor stress (fever > 100ºF, vomiting, diarrhea, dental procedures, locat anesthesia).
-10x usual dose for major stress (surgery, major trauma, infection, etc.).
-Parenteral steroids if patient not eating.
-Medic Alert bracelet/chain.
-Regular physician follow up.
Case 3
The patient is an 18 year old male who noted the onset of severe headache and markedly increased urination about 4 years prior to admission. He stated that the onset of the increased urination had been dramatic and abrupt and he could recall the exact day it had begun. He said that he would urinate 10-12 times during the waking hours and would have to get up 5-6 times per night for further urination. He said he had an intense thirst with the craving for ice cold beverages and consequently during the last few months had been consuming vast quantities of water, but he seemed quite sure that the increase in urinary frequency preceded the increase in drinking. As an outpatient he, on the advice of his doctor, made a 24-hour urine collection and the volume of that collection was 5 liters.
He further stated that he never developed body or facial hair and had never shaved. He felt embarrassed that while the voices of many of his friends were deepening, he was still a soprano. Although he tried to involve himself in vigorous body building activity, he felt that his muscular development was lacking. He also lacked libido and had been unable to have an erection for about one year.
He said that he had been growing until the age of 14 years when his growth simply ceased. Over the time course of all these symptoms, he felt generally tired and depressed.
PAST MEDICAL HISTORY
Although the patient has been generally healthy prior to the onset of the current symptoms, it is notable that 6 months ago he was involved in an automobile accident. His car was hit in the rear when he was switching from the center to the left lane and did not see the care coming up beside him.
PHYSICAL EXAMINATION
The patient was alert and oriented to person, time and place. Pulse - 56/min; blood pressure - 110/70 mmHg; respiratory rate 16/min; temperature - 96 F; height - 65 inches; weight - 135 pounds.
HEENT Examination was unremarkable, except that on gross confrontation his temporal visual fields were constricted bilaterally.
Neck Thyroid not palpable.
Chest Bilateral white liquid was expressed with forcible squeezing from his nipples.
Lungs Clear
Heart S1 and S2 were normal. There was no S3, S4 or murmurs.
Abdomen Unremarkable
Genitalia The penis was small, measuring about 4-6 cm in length. The scrotal sack lacked rugation, pigmentation or a median raphe. The testes were soft and small, measuring about 1.5 cm in longest diameter.
Extremities Within normal limits
Skin Cool, dry, pale.
Neurologic The neurologic examination was normal, except for generalized muscle weakness and "hung-up" deep tendon reflexes.
Hair Very little hair was found on the face or in the axillary or pubic areas.
LABORATORY DATA
Glucose = 100 mg% (nl 70-110); sodium = 145 mEg/L (nl 135-145); potassium = 4 mEg/L (nl 3.5-4.5); chloride = 100 mEg/L (nl 98-108); CO2 = 24 mEg/L (nl 20-32); calcium = 9.4 gm% (nl 8.9-10.3); BUN = 30 mg/dl (nl 7-22); creatinine = 0.9 mg/dl (nl 0.7-1.5). Urinalysis was negative with a s.g. of 1.001
WATER DEPRIVATION TEST
Time Weight B.P. Pulse Urine Osm. Plasma Osm. Urine
(hrs) (lbs) (mmHg) (bts/min) (mOsm/Kg) (mOsm/Kg) Output
0 135 110/80 58 75 305 300
1 135 110/80 58 75 350
2 134 110/80 54 70 350
3 133 108/70 54 78 310 300
4(5 U AVP) 133 108/70 54 200 100
5 133 110/80 54 400 50
6 133 110/80 54 800 280 50
Serum AVP unmeasurable just before exogenous AVP was given.
ENDOCRINE INVESTIGATIONS
|
NORMAL |
||
|
Testosterone |
0.1 ug% |
0.4-1 ug% |
|
LH |
3 mU/ml |
2-20 mU/ml |
|
FSH |
2 mU/ml |
2-20 mU/ml |
|
GH |
Undetectable |
< 5 ng/ml |
|
T4 |
2 ug% |
6-15 ug% |
|
T3 |
40 ng% |
70-170 ng% |
|
TSH |
0.05 uU/ml |
0.2-3 uU/ml |
|
Prolactin |
85 ng/ml |
5-15 ng/ml |
MRI scan - large mass with supra sella extension.
EDUCATIONAL OBJECTIVES
CASE 3
The cause of this patient's polyuria is diabetes insipidus. This patient is unable to concentrate his urine due to a lack of AVP. His renal collecting system is intrinsically normal, but the responsible hormone to make this system operative is lacking. The discussion of this should include the differential of polyuria (> 3 liters per day), including diabetes mellitus, hypokalemia, hypercalcemia, and an inability of the renal tubular system to respond to AVP or nephrogenic DI, in addition to psychogenic water drinking.
Causes of polyuria include diabetes mellitus (ruled out by a normal glucose), hypokalemia (ruled out by a normal potassium), hypercalcemia (ruled out by a normal calcium), excessive water ingestion (ruled out by borderline elevated BUN, serum sodium, and elevated serum osmolality), nephrogenic diabetes insipidus (ruled out by an absent ADH level during maximum dehydration and the normal response to DDAVP administration) and central diabetes insipidus, which was the correct diagnosis.
The disease process began 18 months prior to his presentation. The case should be expanded to include the patient's presentation of acute onset polyuria, which is characteristic of DI and the lack of any obvious etiology for this problem.
During the water deprivation test, the patient was unable to concentrate his urine osmolality and continued to be polyuric after three hours of dehydration. Once the patient was given AVP, he was immediately able to diminish his urine output and concentrate his urine successfully. His dehydration is clearly manifest by his plasma osmolality of approximately 305.
The signs and symptoms which reflect other hormone deficiencies include loss of body hair in the axilla, chest and pubic areas, reflecting loss of adrenal androgens; inability to shave and a soprano voice, in addition to his inability to develop muscles and lack of libido, all indicating lack of testosterone. His inability to perform sexually could be attributable to a high prolactin and low gonadotropins. The cessation of his growth would reflect growth hormone deficiency and his non-specific symptoms of tiredness and depression would be attributable to lack of
cortisol and lack of thyroid hormone. His past history of an automobile accident when switching lanes could reflect his visual field deficiency.
On physical exam, his bradycardia, depressed respiratory rate, and cool body temperature could be reflective of hypothyroidism. His height of 65" may reflect growth hormone deficiency; however, this would need to be taken in context of his family height history. His constricted visual fields reflect optic chiasm involvement from his enlarging pituitary mass. His non-palpable thyroid would be indicative of lack of TSH stimulation. The galactorrhea would reflect an elevated prolactin value. His genitalia exam is abnormal due to lack of gonadotropins. His cool, pale skin could be attributable to his hypothyroidism, as would be his delayed deep tendon reflexes. Finally, lack of axillary and pubic hair would reflect low adrenal androgens and low testosterone.
Craniopharyngioma
The hypothalamus and/or stalk
The elevated prolactin value could be secondary to stalk compression from his pituitary tumor, interfering with dopamine release from the hypothalamus. Thus, he would have disregulated prolactin synthesis and secretion.
The point should be enforced that DI invokes hypothalamic involvement rather than a pure pituitary problem. While AVP is stored in the posterior pituitary, it is synthesized in the PVN and SO areas of the hypothalamus. While transient DI can be seen with a pituitary problem, permanent DI, as this patient has, would invoke hypothalamic or stalk involvement.
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