ENDOCRINE AND METABOLISM BLOCK

Case week 5: Ms. Kuchi Hotahai, Cushing’s syndrome

Case Objectives
1. Describe the pathophysiology, incidence/prevalence, and mortality/morbidity
associated with the disease/disorder/condition/syndrome being reviewed, along
with the race, sex, and age range of persons typically affected;
2. Recognize the typical clinical presentation, including common symptoms and
physical examination findings;
3. Generate an appropriate differential diagnosis;
4. Choose laboratory, imaging, and diagnostic studies, tests, and procedures helpful
in confirming the diagncsis and recognize associated histological findings and
staging classifications (if applicable);
5. Administer proper medical and recommend appropriate consultations, diets, and
activities;
6. List categories of medications useful in treatment and demonstrate familiarity
with dosage regimens of appropriate medications;
7. Provide suitable follow-up care;
8. Institute deterrence/prevention strategies;
9. Discuss potential complications and prognosis
Tutorial 1
Page 1

Kuchi Hotahai, a 44-yeardd woman, presented to the outpatientc linic in Siloam

Hospital with thief complaint of 12.5 kg weight gain over 6 months. She noticed that
her abdomen getting bigger and had some purple marks on it. She had also increased
hair growth and acne on her face. She complained of getting up two or three times a
night to urinate. Her menstrual period became irregular since 3 months ago. She had
history of asthma since 20 years ago and usually took Prednisone 3x5mg without
doctor’s prescription She did not smoke, take recreational drugs or alcohol.

1. What are the patient’s problems?

12.5 kg weight gain over 6 months, abdomen getting bigger and had some
purple marks on it, increased hair growth and acne on face, wake up two or three
times a night to urinate, irregular menstrual period since 3 months ago, history
of asthma.

2. What are the possible causes and explanations of the problems?

3. What are the possible explanations for the possible etiology?

Cushing’s syndrome or hypercortisolism is an endocrine disorder caused by
excessive levels of the endogenous corticosteroid and hormone cortisol. It may
also be induced iatrogenically by treatment with exogenous corticosteroids for
other medical conditions.
Cortisol is secreted by the adrenal glands under regulation by the pituitary gland
and hypothalamus. Strictly, Cushing’s syndrome refers to excess cortisol of any
etiology.

Guiding Questios:
1. Anatomy of adrenal gland
2. Histology of adrenal gland
3. Hormones secreted by adrenal glands: cortisol, androgens, aldosterone
Tutorial 1
Page 2

Dr. Krino was the physician who examined her. Upon physical examination it was
found that she had round, red, and full face with acne and thick facial hair. There was
collection of fat between her shoulders with purple marks around the shoulder girdle.
Purple marks were also found on abdomen, thighs, and breasts.

Body weight = 77kg, height = 166cm, abdominal circumference = 92cm

Vital signs: BP = 140/95 mmHg, RR = 16x/min, pulse = 80x/min, T = 36.9 °C

1. Does this information change your hypothesis? No

2. How do you explain each of the findings? See tutorial 1, page 1, question no .2
3. What further information do you want?
- Lab: routine blood test, RBS (diabetes mellitus?),
- Ro: cardiomegaly, mediastinal widening ← central fat accumulation,
vertebral fractures, rib fractures, renal calculi
- EKG
- Diagnostic: dexamethasone suppression test, urine free cortisol, serum
cortisol
Tutorial 1
Page 3

Dr. Krino requested some laboratory examinations and the results returned:
Hbg = 12 g/dL, WBC = 9,000/mm3, Platelets = 155,000/mm3
Random blood glucose = 242 mg/dL,
Serum cortisol at 8 a.m: 50 mcg/dL (N = 6-23 mcg/dL)2
4 hour Urine free cortisol: 110 mcg/day (N < 50 mcg/day)

Dr. Krino made a request for Dexamethasone suppression test

1. Does this information change your hypothesis

 24 h Urinary Free Cortisol
Suspect Cushing’s Normal No Further
and/ or Evaluation or
Observation
Late Night Salivary Cortisol

Abnormal

Normal/ Elevated Suppressed Adrenal Adenoma

Serum ACTH

ACTH – Pituitary
Overnight Response >1 cm Adenoma Adenoma
MRI Pituitary
DST Test
Normal or < 1cm Adenoma
Petrosal/ Peripheral ACTH – Pituitary
No Response Petrosal Sinus ACTH > 3 Adenoma
Catheterization
Petrosal/ Peripheral
ACTH < 3
Ectopic ACTH

Confirm by CT,
MRI or
Octreoscan

2. How do you explain each of the findings?

Hyperglicemia

Urine-free cortisol: the most useful clinical study in the confirmation of

Cushing's syndrome. It's accurate and specific. Urinary free cortisol is usually
less than 50 ug/24 h. The test is used to evaluate for increased or decreased
cortisol production.
Cortisol levels rise and fall during the day. Highest levels occur at about 6 a.m.
to 8 a.m. and lowest levels at about midnight.
Increased levels of urine cortisol may indicate:
 - Cushing syndrome — pituitary-independent
- Cushing's disease — pituitary-dependent
- Pseudo-Cushing’s
- Tumor that releases ACTH
Decreased levels of urine cortisol may indicate:
- Addison’s disease
- Hypopituitarism
- Congenital adrenal hyperplasia
The test may also be done in cases of exogenous Cushing syndrome.
Factors that interfere with this test are:
- Medications, including glucocorticoids, lithium, diuretics, ketoconazole,
estrogens and tricyclic antidepressants
- Severe emotional or physical stress
Note: Due to these interfering factors, the urine cortisol is often tested on three
or more separate occasions to get a more accurate picture of average cortisol
production.

3. What is dexamethasone suppression test? How is it performed?

Dexarnethasone suppression test measures the response of the adrenal glands to
ACTH.
During this test, you will receive dexamethasone, and the health care provider
will measure your cortisol levels.
There are two different types of dexamethasone suppression tests:
- the low-dose test and
- the high-dose test.
Each type can either be done in an overnight or standard (3-day) way.
1. Low-dose overnight method — you will get 1 mg of dexamethasone at 11
p.m., and a health care provider will draw your blood at 8 a.m. for a cortisol
measurement. Standard bow-dose method urine is collected over 3 days
(stored in 24-hour collection containers) to measure cortisol. On da y 2, you
will get a low dose (0.5 mg) of dexamethasone by mouth every 6 hours for
48 hours.
 2. High-dose overnight method the health care provider will measure your
cortisol on the morning of the test. Then you will receive 8 mg of
dexamethasone at 11 p.m. Your blood is drawn at 8 a.m. for a cortisol
measurement. Standard high- ill receive a high dose (2 mg) of
dexamethasone by mouth every 6 hours for 48 hours.

Blood is typical dose test urine is collected over 3 days (stored in 24-hour
collection containers) for measurement of cortisol.

4. What is your next step?

24 h Urinary Free Cortisol

Suspect Cushing’s Normal No Further
and/ or Evaluation or
Observation
Late Night Salivary Cortisol

Abnormal

Normal/ Elevated Suppressed Adrenal Adenoma

Serum ACTH

ACTH – Pituitary
Overnight Response >1 cm Adenoma Adenoma
MRI Pituitary
DST Test
Normal or < 1cm Adenoma
Petrosal/ Peripheral ACTH – Pituitary
No Response Petrosal Sinus ACTH > 3 Adenoma
Catheterization
Petrosal/ Peripheral
ACTH < 3
Ectopic ACTH

Confirm by CT,
MRI or
Octreoscan
Tutorial 2
Page 1

The dexamethasone suppression test result showed that:

Overnight 8 a.m serum cortisol = 1,3 mcg/dL (N < 1.8 mcg/dL)
Urinary free cortisol on day 3 = 9 mcg/day (N < 10 mcg/day)

1. Does his informationc hange your hypothesis?

Normal Values:
Cortisol levels should decrease after you receive dexatnethasone.
Low dose:
Ovemight: 8 a.m. plasma cortisol < 1.8 mcg/dl
Standard: Urinary free cortisol on day 3 < 10 mcg/day
Hiqh dose:
Ovemight: > 50% reductioni n plasma cortisol
Standard: > 90% reduction in unnary free cortisol

An abnormal response to the Iowadose test may mean there is abnortnal release
of cortisol (Cushing syndrome). This could be due to:
 Adrenal tumor that produces cortisol
 Pituitary tumor that produces ACTH
 Tumor in the body that produces ACTH

The high-dose test can help tell a pituitary cause (Cushing's disease) from other
causes. Abnormal results vary based on the condition causing the problem:
Cushing syndrome caused by an adrenal tumor:
Low-dose test: no change
High-dose test: no change
Cushing syndrome related to an ectopic ACTH-producing tumor:
Low-dose test: no change
High-dose test: no change
Cushing syndrome caused by a pituitary tumor (Cushing's disease)
 Low-dose test: no change
High-dose test: normal suppression

2. How do you explain the finding? See above

3. What is your next step?

The suggested treatment is to slowly stop taking any corticosteroids. Slowly
withdrawing the drug causing the condition can help reverse the effects of
adrenal gland shrinkage (atrophy), although this may take as long as a year.
Tutorial 2
Page 2

Dr. Krino made the diagnosis of Cushing’s syndrome and discusses with Mrs. Kuchi the
importance of careful control of her prednisone intake. Dr. Krino started tappering off
the prednisone dose gradually every 3 days, started from 2x5mg/day, followed by 1x
5mg/day.

1. How cortisol hormone should be regulated?

2. What factors could give the influences to the cortisol level?

Normally, cortisol levels rise and fall during the day, repeating on a 24-hour
cycle (diurnal variation). Highest levels are at about 6 - 8 a.m. and lowest
levels are at about midnight.

Physical and emotional stress can increase cortisol levels, because during the
normal stress response, the pituitary gland increases its release of ACTH.

Higher than normal cortisol levels are expected in women who take estrogen
or birth control pills.
Tutorial 2
Page 3

Dr. Krino prescribed Mitotane 3x2g/day and asked Mrs. Kuchi to do regular follow up
every month.

1. What is the role of medication in controlling cortisol level?

Medical Therapy for Cushing’s Disease

Drug Mechanism of Action
Antifungal agent; blocks cholesterol side-chain cleavage
Ketoconazole to reduce cortisol. May have independent inhibitory
actions directly on ACTH secretion
Inhibits 1 lß-hydroxylase to reduce cortisol. May also
cause hypertension and hypokalemia due to increase in
Metyrapone
11-deoxycorticosterone, and hirsutism due to increased
androgens.
Often used together with metyrapone to reduce side
effects. Inhibits cholesterol side-chain cleavage and
Aminoglutethimid
1lß/118-hydroxylation. May cause hypothyroidism by
e
interfering with iodine incorporation into thyroid
hormone.
Destructive to adrenal cortex. Frequent adverse
Mitotane reactions. May cause hypercholesterolemia due to
activation of HMG coenzyme reductase.
Trilostane Glucocorticoid antagonist. Not approved in U.S.

2. What factors should be monitored in follow up of Cushing's syndrome?

The level of cortisol serum → adrenal crisis in mitotane prescription
Tutorial 3
Page 1

1 week later, Mrs. Kuchi was carried to the emergency department at Siloam Hospital
with severe pain on her right hip after she bumped to a table at home. The physical
examination showed that her right hip was swelling, red, and painful. There was
tenderness to palpation over injured hip.

1. What are Mrs. Kuchi’s problems now?

Severe pain on her right hip after she bumped to a table at home. The right hip
was swelling, red, and painful. There was tenderness to palpation over injured
hip.

2. What are the possible causes?

Pathologic hip fracture

3. What are the explanations of these problems?

Osteoporosis

4. What are your next steps?

Right hip x-ray
Tutorial 3
Page 2

The X-ray examination of Mrs. Kuchi right hip was shown below:

1. Does this information change your hypothesis?

Right femoral neck fracture

2. What are complications that usually occur in Cushing's syndrome?

Patients with CS have a mortality rate four times higher than age- and gender-
matched subjects; this is due to the complications of the syndrome. The majority
of the complications are correlated with direct and/or indirect effects of
glucocorticoid excess, and therefore, the primary goal in the prevention and
treatment of complications is the correction of hypercortisolism.

Common complication:
 Cardiovascular risk factors and complications
  Hypertension.
 Impaired glucose tolerance and diabetes.
 Obesity.
 Hyperlipidemia.
 Coagulopathy.
 Metabolic syndrome.
 Osteoporosis
 Psychological and cognitive alteration
 Glucocorticoids affect behavior, mood, neural activity, and a number of
specific biochemical processes in the central nervous system.

3. What is the pathogenesis of complications in Cushing's syndrome? See

tutorial 1, page 1, question no. 2

4. What is your conclusion about Mrs. Kuchi's case?

Cushing's syndrome with pathologic right femoral neck fracture

5. What is her prognosis?

Ad malam

Epilogue
Mrs. Kuchi was referred to an orthopedist to get treatment for her hip injury. She got a
hip replacement with satisfied result. She continued to follow the management plan and
no other complications were reported.