Monday 30 July 2007

Congenital Adrenal Hyperplasia(Pathophysiology)
Ji Keon LOOI

Congenital Adrenal Hyperplasia
• an autosomal recessive diseases (mutation arises on chromosome six)
• lack of an enzyme needed by the adrenal gland to make the hormones cortisol and aldosterone
• pervert or impair development of primary or secondary sex characteristics in affected infants, children, and adults.
• 21-Hydroxylase enzyme deficiency, accounts for approximately 90-95% of all CAH disorders

Result of a 21-Hydroxylase Deficiency
• Accumulation of progesterone and 17-hydroxyprogesterone as a result of a 21-hydroxylase deficiency.

CAH results in 3 disturbances:
• Lack of Cortisol
• Lack of Aldosterone
• Too much Androgen

In Normal Babies
• When babies begin their development within the womb, it is impossible to distinguish male and female genitalia - the "undifferentiated" genitalia of males and females look alike.
• In boys, between approximately 12 to 15 weeks after conception, their testes start producing androgen, which drives the "undifferentiated" genitalia to develop the male structure and characteristics.
• As androgen is not normally produced in the female fetus, this "masculinization" does not occur.

In CAH Babies (female)
• In CAH, however, the adrenal glands of the female overproduce androgen – forcing the girl's genitalia to begin development in the male direction.
• The clitoris is enlarged with the urethral opening at the base and may resemble a small penis.
• In addition, the cleft between the labia or lips may be partly closed over, hiding the entrance to the vagina.
• Often only one opening can be seen, with the urinary passage and vagina both opening into this one entrance.
• Normal internal organs - the vagina, uterus (womb), fallopian tube and ovaries.

Males??
• No obvious problems in newborn males
• changes can be seen long before puberty normally occurs.
• The child becomes increasingly muscular, the penis enlarges, pubic hair appears, and the voice deepens.
• Boys may appear to enter puberty as early as 2-3 years of age.
• At puberty, the testes are small

21-hydroxylase enzyme deficiency
• In more severe forms - adrenal crisis in the newborn due to salt wasting (21-hydroxylase enzyme deficiency).
• severe symptoms shortly after birth- vomiting, dehydration , electrolyte changes, and cardiac arrhythmias .
• Untreated, lead to death within 1 to 6 weeks after birth.

Sources
http://www.emedicine.com/ped/topic48.htm
http://www.cah.org.au/index.php?option=com_content&task=view&id=12&Itemid=31
• http://www.umm.edu/ency/article/000411.htm
http://www.aafp.org/afp/990301ap/1190.html
http://en.wikipedia.org/wiki/Congenital_adrenal_hyperplasia

Investigations (CAH)

1. Plasma 17 OH Progesterone
  • should be elevated
  • couldn't be converted to 11-deoxycortisol
  • characteristics of 21 hydroxylase deficiency

2. Serum ACTH-elevated

3. urine test

  • presence of 17-ketosteroids(derived from androgens)
  • 10-15 times normal-Guyton Phiology Textbook

3. Renal function, electrolyte

  • may be associated with electrolyte and water disturbances
  • for e.g: in this case ' It's a Boy'- salt-wasting
  • hyponatreamia
  • hyperkaleamia`
  • metabolic acidosis (after birth, why?)

4. karyotyping (map out the genetic make up)

5. Pelvic or abdominal ultrasound scan

  • to determine pelvic structures and the presence/absence of gonads

prepared by:

SRI MURNIATI ROSLI

references:

Task List

Congenital Adrenal Hyperplasia (CAH)


  1. Epidemiology - Lawrence
  2. Definition, Aetiology and Differentials for ambigious genitalia - Madhura
  3. Pathophysiology (Inclusive of steroidogenesis pathway) - Ji Keon
  4. Signs and Symptoms - Shantz
  5. Investigations - Sri
  6. Management, Prognosis and Complications - Christine / John
  7. Psychosocial issues, Breaking bad news - support groups, website, referral, genetic counselling - Vivian / Chris

Updated by JI KEON on 30 Jul 2007

Thursday 26 July 2007

Side Effects of Oral Contraceptive Pills

Oral Contraceptive Pills

- contain estrogen and progesterone (composition may vary)

Side effects:

Most women have no side effects. Most side effects go away after the 1st 3-4 cycles.

- Bleeding between periods: spotting may occur while taking the first three weeks of hormone pills, but this is not serious. Usually occurs during the first 2-3 cycles. Becomes serious if bleeding becomes heavier or last a few days.

- Irregular periods

- Nausea: usually goes away if the pill is taken with a meal or a snack at bedtime (due to effects of estrogen..therefore if too severe, give pill with less estrogen)

- Headaches: also given lower dose of estrogen or taken off OCP if too severe

- Mood changes: exercise and a healthy diet may help, if not, change the type of pill

- Acne: usually helps cure acne, but a few women feel they get acne from taking OCP

- Appetite change: appetite increases, becomes bloated

- Weight gain (some claim they lose weight)

- Breast tenderness

- Blood clots: usually in women over 35 who smoke

Important:

  • Abdominal pain (severe)
  • Chest pain (severe), cough, shortness of breath
  • Headache (severe), dizziness, weakness, or numbness
  • Eye problems (vision loss or blurring), speech problems
  • Severe leg pain (calf or thigh)

Why do women use OCP?

- Milder menstrual cramps: for girls who experience severe menstrual cramps and OTC medications do not help. Helps to decrease menstrual cramps.

- Lighter periods: reduce the amount and length of menstrual bleeding. For girls whose menstrual periods are irregular (too often, too late, or not at all), OCP help regulate the menstrual cycle to every 28 days and provide the body normal amounts of estrogen to help protect the bones

- Cure acne: for moderate to sever acne, which OTC and prescription medications can’t cure, OCPs may be used. Hormones help stop acne from forming. May take several months to work

- Protection from ovarian cancer and endometrial (lining of uterus) cancer

- Does not increase risk of breast cancer

- Protection from anemia: because less menstrual bleed

Resources:

http://womenshealth.about.com/od/thepill/f/pillsideeffects.htm

http://www.youngwomenshealth.org/med-uses-ocp.html

(Posted by: Vivian)

health guidelines for travellers

Protection for travellers to developing/tropical countries

Protection can be divided into 3 categories:

Personal protection
personal hygiene
insect repellent
bed netting
avoidance of animals
care with food and drink
safe sex

Chemoprophylaxis, eg. Antimalarials

Immunizations
yellow fever
hepatitis A and B
typhoid

more details in Oxford Handbook of Clinical Medicine handout which i will be giving out in class.

Management+Prognosis of Grave's Disease &/or Hyperthyroidism

Treatment for hyperthyroidism
Treatment of hyperthyroidism depends on the cause. In most cases, the problem causing hyperthyroidism can be cured, or the symptoms can be eliminated or greatly reduced. If left untreated, however, hyperthyroidism places undue stress on the heart and many other organs.

Beta-blockers such as propranolol help control many of the symptoms of hyperthyroidism. These drugs can slow a fast heart rate, reduce tremors, and control anxiety. Doctors therefore find beta-blockers particularly useful for people with extreme hyperthyroidism and for people with bothersome or dangerous symptoms that have not responded to other treatments.

However, beta-blockers do not control abnormal thyroid function. Therefore, they are given until other treatments bring hormone production to normal levels.
Propylthiouracil or methimazole are the drugs most commonly used to treat hyperthyroidism; they work by decreasing the gland's production of thyroid hormone. Each drug is taken by mouth, beginning with high doses that are later adjusted according to blood test results. These drugs can usually control thyroid function in 6 to 12 weeks. Larger doses of these drugs may work more quickly but increase the risk of side effects. Pregnant women who take propylthiouracil or methimazole are closely monitored, because these drugs cross the placenta and can induce goiter or hypothyroidism in the fetus. Carbimazole, a drug that is widely used in Europe, is converted into methimazole in the body.

Iodine, given by mouth, is sometimes used to treat hyperthyroidism. It is reserved for those in whom rapid treatment is needed. It may also be used to control hyperthyroidism until the person can have surgery to remove the thyroid. It is not used long-term.
Radioactive iodine may be given by mouth to destroy part of the thyroid gland. Very little radioactivity is introduced to the body as a whole but a great deal is delivered to the thyroid gland because the thyroid gland takes up the iodine and concentrates it. Hospitalization is rarely necessary. After treatment, the person should probably not be near infants and young children for 2 to 4 days. No special precautions are needed in the workplace. There are no precautions needed for sleeping with a partner. Pregnancy should be avoided for about 6 months.

Some doctors try to adjust the dose of radioactive iodine to destroy only enough of the thyroid gland to bring its hormone production back to normal, without reducing thyroid function too much; others use a larger dose to completely destroy the thyroid. Most of the time, people who undergo this treatment must take thyroid hormone replacement therapy for the rest of their lives (see Thyroid Gland Disorders: Treatment). Concern that radioactive iodine may cause cancer has never been confirmed. Radioactive iodine is not given to pregnant or nursing women, because it crosses the placenta and enters the milk and may destroy the fetus's or breastfed infant's thyroid gland.

Surgical removal of the thyroid gland, called thyroidectomy, is a treatment option for young people with hyperthyroidism. Surgery is also an option for people who have a very large goiter as well as for those who are allergic to or who develop severe side effects from the drugs used to treat hyperthyroidism. Hyperthyroidism is permanently controlled in more than 90% of those who choose this option. Hypothyroidism often occurs after surgery, and people then have to take replacement thyroid hormone for the rest of their lives. Rare complications of surgery include paralysis of the vocal cords and damage to the parathyroid glands (the tiny glands behind the thyroid gland that control calcium levels in the blood).



Additional Treatment for Grave's Disease
In Graves' disease, additional treatment may be needed for the eye and skin symptoms. Eye symptoms may be helped by elevating the head of the bed, by applying eye drops, by sleeping with the eyelids taped shut, and, occasionally, by taking diuretics (drugs that hasten fluid excretion). Double vision may be helped by using eyeglass prisms. Finally, corticosteroids taken by mouth, x-ray treatment to the orbits, or eye surgery may be needed if the eyes are severely affected. Corticosteroid creams or ointments can help relieve the itching and hardness of the abnormal skin. Often the problem disappears without treatment months or years later.





Prognosis

Up to 50% of people treated with 12 to 24 months of anti-thyroid drugs have prolonged remissions of their illness. Radioactive iodine also is an effective treatment, although most people will develop an underactive thyroid (hypothyroidism) following this treatment. However, this condition is easily treated with a single pill of thyroid replacement medication daily.

The prognosis for Graves’ disease patients is extremely favorable. Most patients respond well to treatment, but lifelong observation by a healthcare professional is important because possibly serious complications are associated with the disease. Antithyroid medications may also cause side effects. The more serious complications of prolonged, untreated, or improperly treated Graves’ disease include a weakened heart muscle, which can lead to heart failure, osteoporosis, or possible severe emotional disorders.


http://pubs.acs.org/subscribe/journals/mdd/v04/i02/html/disease.html
http://www.intelihealth.com/IH/ihtIH/WSIHW000/9339/9513.html

Chris.

Sign & Symptoms of Hyperthyroidism and Graves' disease

Signs and Symptoms of Hyperthyroidism

· Weight loss, increased appetite
· Recent onset of heat intolerance
· Agitation, nervousness
· Hot, sweaty palms
· Fine peripheral tremor
· Bounding (forceful) peripheral pulses
· Tachycardia, atrial fibrillation
· Lid retraction and lid lag
· Goitre, with or without overlying bruit
· Brisk tendon reflexes

Signs and symptoms are usually a result of increased basal metabolism rate and sympathetic activity. It is thought that the thyroid hormone increases the activity of the sympathetic system by increasing the body's sensitivity to catecholamines.
Autonomic overactivity causes increased tone and spasm of levator palpebrae superioris. This causes retraction of the upper lid as well as an abnormal following reflex where the upper lid lags well being the pupil during downward movement.

Signs and Symptoms of Graves’ disease

· Diffuse goitre with audible bruit
· Pretibial myxoedema (non-pitting oedema), finger clubbing
· Onycholysis (Plummer’s nails)
· Lid retraction, lid lag
· Proptosis, exophthalmos (a more severe form of proptosis)
· Conjuctival oedema (chemosis)

Signs and symptoms unique to Graves’ disease may be a result of antibody-mediated autoimmune reactions. It is thought that antibodies found in Graves’ disease react with antigens found in parts of the body e.g. the eye, (causing the eyes to swell and protrude) & the nails (causing separation of nail from its bed).


Comparison between Signs and Symptoms of Graves ’ disease and Toxic Nodular Goitre (another cause of hyperthyroidism)

Graves’ disease (GD) vs Nodular Goitre (NG)

Sex: Female >> Male(GD) Female = Male(NG)

EyeSigns: Very common, exophthalmos(GD) Less severe(NG)

Goitre: Smooth, diffuse, overlying bruit (GD) Uneven, may be multinodular(NG)

Heart: Tachycardia, atrial fibrillation(GD) Also angina, congestive heart failure(NG)

Weight: May lose weight(GD) Often profound weight loss(NG)

Contributed by John Lee

Source: Epstein, Clinical Examination 3rd Ed

Wednesday 25 July 2007

Investigations

(a) Screening Purposes

1. ECG – to rule out heart problem and anxiety (cheap, fast and most available)

2. Full blood count – The determination of the quantity of each type of blood cell in a given sample of blood, often including the amount of hemoglobin, the hematocrit, and the proportions of various white cells. Also called blood profile. The FBC is used for the following purposes:

· as a preoperative test to ensure both adequate oxygen carrying capacity and hemostasis

· to identify persons who may have an infection

· to diagnose anemia

· to identify acute and chronic illness, bleeding tendencies, and white blood cell disorders such as leukemia

· to monitor treatment for anemia and other blood diseases

· to determine the effects of chemotherapy and radiation therapy on blood cell production

· to rule out infections e.g HIV or other infectious diseases

  1. Fasting blood glucose/ urine test – to rule out Diabetes Mellitus

(b) Diagnostic Purposes

1. Thyroid Function Test – check for T3/T4 and TSH level

2. Radioisotope – for e.g diffuse uptake of isotope (Grave’s Disease) vs low patchy uptake of isotope ( multinodular goiter)

3. TSHr antibody – check for the proliferation of antibody to TSH receptor

Prepared by,

Sri Murniati Rosli


Tuesday 24 July 2007

Cause, Risk Factor and Complication of Grave's disease & Hyperthyroidism

Cause & Risk Factor of Graves' disease & Hyperthyroidism

cause of Grave's disease is still unknown as it is an autoimmune disease. However, there are several risk factors that are associated with Graves' disease:
  • Hereditary
  • Sex - susceptibility is increased in females. Hyperthyroidism due to Graves' disease has a female to male ratio of 7-8:1
  • Age - typically, Graves' disease is a disease of young women, but it may occur in persons of any age. The typical age range is 20-40 years. Most affected women are aged 30-60 years.
  • Stress
Causes of Hyperthyroidism

There are several causes of hyperthyroidism. Most often, the entire gland is overproducing thyroid hormone. This is called Graves' Disease. Less commonly, a single nodule is responsible for the excess hormone secretion ( 'hot' nodule).

Graves' disease
The most common underlying cause of hyperthyroidism is Graves' disease. In Graves' disease, patients' immune system mistakenly attack their thyroid gland, but instead of destroying the gland, an antibody called thyrotropin receptor antibody (TRAb) stimulates the thyroid to make excessive amounts of thyroid hormone.

'Hot' nodule
Hyperthyroidism can also be caused by a single nodule within the thyroid instead of the entire thyroid. Thyroid nodules usually represent benign (non-cancerous) lumps or tumors in the gland. These nodules sometimes produce excessive amounts of thyroid hormones. This condition is called "toxic nodular goiter". This single nodule is comprised of thyroid cells which have lost their regulatory mechanism which dictates how much hormone to produce. Without this regulatory control, the cells in this nodule produce thyroid hormone at a dramatically increased rate causing the symptoms of hyperthyroidism.

Inflammation of thyroid gland (thyroiditis)
thyroiditis can lead to the release of excess amounts of thyroid hormones that are normally stored in the gland. In subacute thyroiditis, the painful inflammation of the gland is believed to be caused by a virus, and the hyperthyroidism lasts a few weeks.

A more common painless form of thyroiditis occurs in one out of 20 women, a few months after delivering a baby and is, therefore, known as postpartum thyroiditis.

Thyroiditis generally last only a few weeks until the thyroid hormone stored in the gland has been exhausted.

Thyroid medication
Hyperthyroidism can also occur in patients who take excessive doses of any of the available forms of thyroid hormone. This is a particular problem in patients who take forms of thyroid medication that contains T3, which is normally produced in relatively small amounts by the human thyroid gland.

Risk factors of Hyperthyroidism

It is possible to develop hyperthyroidism with or without the risk factors listed below. However, the more risk factors you have, the greater your likelihood of developing hyperthyroidism.

There are two medical conditions that may increase your risk of hyperthyroidism:

  • Certain viral infections
  • Pregnancy—Five to eight percent of women develop postpartum thyroiditis (hyperthyroidism followed by hypothyroidism).
Age
Risk is greatest between the ages of 30 and 40 years. Hyperthyrodism rarely occurs before age 10.

Gender
Women are more likely than men to develop hyperthyroidism by a ratio of 7:1.

Genetic Factors

A family history of Graves’ disease or other forms of hyperthyroidism increases your risk.

Ethnic Background
People of Japanese ancestry appear to be at greater risk of hyperthyroidism. This may be attributed to a diet high in saltwater fish, which are rich sources of iodine.

Other
Supplementating iodine to a previously iodine-deficient diet may precipitate hyperthyroidism.

Complications of Graves' disease

Graves ophthalmopathy
Thyroid eye disease is an inflammatory condition which affects the orbital contents including the extraocular muscles and orbital fat. It is almost always associated with Graves' disease but may rarely be seen in Hashimoto's thyroiditis, primary hypothyroidism, or thyroid cancer. The ocular manifestations include soft tissue inflammation, eyelid retraction, proptosis, corneal exposure, and optic nerve compression.

Heart problems
Some of the most serious complications of hyperthyroidism involve the heart. These include a rapid heart rate, a heart rhythm disorder called atrial fibrillation and congestive heart failure. These complications are generally reversible with appropriate treatment.

Bri
ttle Bones
Untreated hyperthyroidism can also lead to weak, brittle bones (osteoporosis). The strength of your bones depends, in part, on the amount of calcium and other minerals they contain. Too much thyroid hormone interferes with your body's ability to incorporate calcium into your bones.

Thyrotoxic crisis
Hyperthyroidism also places you at risk of thyrotoxic crisis — a sudden intensification of your signs and symptoms, leading to a fever, a rapid pulse and even delirium. This complication is rare, but if it occurs, seek immediate medical care.

Contributed by Lawrence Oh

References:
http://www.mayoclinic.com/health/graves-disease/DS00181/DSECTION=6
http://www.emedicine.com/med/byname/Graves-Disease.htm
http://healthgate.partners.org/browsing/browseContent.asp?fileName=19617.xml&title=Risk%20Factors%20for%20Hyperthyroidism
http://www.endocrineweb.com/pregnancy.html
http://en.wikipedia.org/wiki/Graves_disease

Effects of stress

Week 2 – The Wedding
Effects of stress
Presented by
Ji Keon LOOI

Acknowledgements
•Dr Craig Hassed’s Year 1 Lecture Notes
•Prof. Khalid’s Year 2 Endocrinology Notes
Visit http://pclgroupd.blogspot.com for more information.

Outline of presentation
After this presentation, you are expected:-
•To define stress and allostatic load
•To look at how the body reacts in presence of stress (endocrinology)
•To discuss the negative consequences as a result of chronic/prolonged stress, using our immune system as an example
•To appreciate different modalities available to help cope with stress

Stress? Allostatic Load? What are they?
Stress
•Perceived inability to cope
•Natural and essential physiological response to threat, to preserve life
•Will impose negative consequences if not switched off when is not necessary

Allostatic Load
•Prolonged stress leads to wear and tear on the body
•Mediated through the symphathetic nervous system

What happened when you are stressed !?!
*Refer to Prof Khalid’s Adrenal Gland Lecture

Craig Hassed’s Revision
Don’t worry
3 more slides to go ;-)

Effects of Stress on Immunity
•Lower immune markers
•Increase susceptibility to infections
•Increase severity and progression of infections
•Increase relapse of chronic and latent infections
Increase activity of inflammatory illnesses
•Increase activity of autoimmune conditions (in relation to this case)

•Poor response to immunisation
•Effect the activity of allergic conditions
•Impair immune response to some cancers

How to ease stress?
•Focus on the present
–One action at a time
•Clarify perception
–CBT, mindfulness, relaxation
•Learning from but letting go of the past
–Do not ruminate over past mistakes


Mindfulness Based Therapy
•Characterised by dispassionate, non evaluative, sustained moment-to-moment awareness of perceptible mental states and processes

MCQ
The followings are basic assumptions of mindfulness, EXCEPT:
•People generally operate on automatic pilot
•Development of mindfulness is gradual, and requires practise
•Awareness makes life richer and more vivid
•Awareness replaces conscious reactiveness
•It gives rise to veridicality of perceptions

Thank you!!!
Man is not disturbed by events, but by the view he takes of them
~ Epitectus.

Friday 20 July 2007

Investigations of Cushing Syndrome

1. Lab Studies

Biochemical evaluation of Cushing syndrome

The diagnosis of Cushing syndrome due to endogenous overproduction of cortisol requires the demonstration of inappropriately high serum or urine cortisol levels.

Currently, 4 methods are accepted for the diagnosis of Cushing syndrome: urinary free cortisol level, low-dose dexamethasone suppression test, evening serum and salivary cortisol level, and dexamethasone–corticotropin-releasing hormone test.

- Urinary free cortisol (UFC) determination provides measurement of cortisol over a 24-hour period. Urine free cortisol values higher than 3-4 times the upper limit of normal are highly suggestive of Cushing syndrome.

- Dexamethasone suppression tests mimic the physiology of the pituitary, which in the presence of steroids decreases the release of ACTH causing a fall in plasma and urine cortisol. In Cushing syndrome, a loss of sensitivity to glucocorticoids occurs and ACTH is therefore not suppressed and adrenal production of cortisol is not affected. The overnight 1-mg dexamethasone suppression test requires administration of 1 mg of dexamethasone at 11 pm with subsequent measurement of cortisol level at 8 am. In healthy individuals, the serum cortisol level should be less than 2-3 mcg/dL. A cutoff value of less than 1.8 mcg/dL (50 nmol/L) excludes Cushing syndrome. Its ease of administration makes the 1-mg dexamethasone suppression test a widely used screening tool.
- Late night serum and salivary cortisol levels take advantage of the alterations in circadian rhythm of cortisol secretion in patients with Cushing syndrome. Normally, nighttime cortisol values are at their lowest level; in patients with Cushing syndrome, elevated nighttime cortisol can be an early but not definitive finding. This test requires hospitalization with blood samples obtained within 5-10 minutes of waking a patient and is not a practical test.

- Measuring salivary cortisol level is a simple and convenient way of obtaining a nighttime sample. This measurement allows patients to collect their own samples at home. With repeated measurements, levels less than 1.3 ng/mL (radioimmunoassay) or 1.5 ng/mL (competitive protein-binding assay) exclude Cushing syndrome. Less experience has been gathered for this assay, and it is expensive. Readings are obtained over several evenings to increase accuracy.

- The dexamethasone-CRH test is intended to distinguish patients with Cushing syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg every 6 hours) is given 8 times, CRH is then administered intravenously and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. A cortisol value greater than 50 nmol/L (1.4 mcg/dL) identifies Cushing syndrome. This test is reserved for patients with high clinical suspicion for Cushing syndrome but equivocal results on other diagnostic tests.

Unfortunately, mild Cushing syndrome is often difficult to distinguish from normal cortisol secretion or pseudo-Cushing states. The aforementioned tests can produce both false-positive and false-negative results. False-positive results are associated with obesity, alcoholism, chronic renal failure, affective disorders, strenuous exercise, or eating disorders. Other potential confounders in the interpretation of tests include the following:

Medications that increase corticosteroid-binding globulin, such as estrogen and tamoxifen, may cause appropriate increases in serum cortisol levels.
Medications that facilitate the metabolism of dexamethasone, such as phenobarbital, phenytoin, and rifampin, may cause false-positive results with the dexamethasone suppression test.

Acute illness activates the Hypothalamic- Pituitary- Adrenal (HPA) axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill.

Other laboratory abnormalities seen in Cushing syndrome include the following:
Elevated white blood cell count greater than 11,000/mm3
Hypokalemic metabolic alkalosis may occur in patients with urinary free cortisol levels higher than 1500 mcg/24 h.

Once the diagnosis is established, the next step requires determining the etiology of Cushing syndrome. This first involves identifying if the hypercortisolism is an ACTH-dependent or ACTH-independent disorder.

· A plasma ACTH level that is undetectable is diagnostic of ACTH-independent Cushing syndrome. There are patients with cortisol-producing adrenal adenomas, where the ACTH may be undetectable; therefore, several collections should be obtained.
· A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor.
· An ACTH level greater than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome.
· For ACTH-dependent disease, the high dose (8-mg) overnight dexamethasone suppression test and the 48-hour high-dose dexamethasone test determine whether a patient who has pituitary-dependent or ectopic ACTH disease.

8-mg overnight dexamethasone suppression test: Individuals ingest 8 mg dexamethasone orally at 11 pm, with measurement of an 8 am cortisol level the next day. Suppression of serum cortisol level to less than 50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH.

48-hour high-dose dexamethasone suppression test: Patients ingest 2 mg dexamethasone every 6 hours for 8 doses. A decrease in urinary free cortisol of greater than 50% is suggestive of an anterior pituitary adenoma rather than ectopic ACTH.

· Testing with CRH is also used in the differential diagnosis of ACTH-dependent Cushing syndrome. In most patients with pituitary ACTH secretion, the intravenous administration of CRH causes a rise in plasma ACTH and cortisol levels. In patients with ectopic secretion of ACTH, CRH does not affect ACTH or cortisol levels. ACTH and cortisol samples are obtained before administration of ovine CRH (oCRH), and subsequently at 15, 30, 45, 60, 90, and 120 minutes after administration of 1 mcg/kg of CRH.

· If concern for adrenal carcinoma exists, measurement of 17-ketosteroid or other cortisol precursors (eg, serum dehydroepiandrosterone sulfate [DHEAS]) is useful.

2. Imaging Studies:

Imaging studies for Cushing syndrome should be performed after the biochemical evaluation has been performed. The rationale for this is that unguided imaging of the pituitary or adrenal glands may yield a 10% incidence of incidental nonfunctioning pituitary or adrenal adenomas, which may mislead one from proper therapy and surgery. Ideally, the biochemical abnormalities should reconcile with the anatomic abnormalities before definitive therapy is offered.

- An abdominal CT scan is recommended if a primary adrenal problem is suspected. The presence of an adrenal mass larger than 4-6 cm raises the possibility that the mass is an adrenal carcinoma.
- If a pituitary source of excess ACTH is suspected, patients should undergo a contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary.
- Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH production.

Contributed by John Lee

Source: http://www.emedicine.com/emerg/topic117.htm

Treatment and Prognosis of Cushing's Syndrome

Treatment
  • Treatment depends on the specific reason for cortisol excess and may include surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs.
  • If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will gradually reduce the dosage to the lowest dose adequate for control of that disorder.
  • Once control is established, the daily dose of glucocorticoid hormones may be doubled and given on alternate days to lessen side effects.
Pituitary Adenomas
  • The most widely used treatment is surgical removal of the tumor, known as transsphenoidal adenomectomy.Using a special microscope and very fine instruments, the surgeon approaches the pituitary gland through a nostril or an opening made below the upper lip.
  • The success, or cure, rate of this procedure is over 80 percent when performed by a surgeon with extensive experience.
  • After curative pituitary surgery, the production of ACTH drops two levels below normal. This is a natural, but temporary, drop in ACTH production, and patients are given a synthetic form of cortisol (such as hydrocortisone or prednisone). Most patients can stop this replacement therapy in less than a year.
  • For patients in whom transsphenoidal surgery has failed or who are not suitable candidates for surgery, radiotherapy is another possible treatment.
  • Radiation to the pituitary gland is given over a 6-week period, with improvement occurring in 40 to 50 percent of adults and up to 80 percent of children.
  • However, the combination of radiation and the drug mitotane (Lysodren®) can help speed recovery. Mitotane suppresses cortisol production and lowers plasma and urine hormone levels.
Ectopic ACTH Syndrome
  • To cure the overproduction of cortisol caused by ectopic ACTH syndrome, it is necessary to eliminate all of the cancerous tissue that is secreting ACTH.
  • The choice of cancer treatment—surgery, radiotherapy, chemotherapy, immunotherapy, or a combination of these treatments—depends on the type of cancer and how far it has spread.
  • Since ACTH-secreting tumors (for example, small cell lung cancer) may be very small or widespread at the time of diagnosis, cortisol-inhibiting drugs, like mitotane, are an important part of treatment.
  • In some cases, if pituitary surgery is not successful, surgical removal of the adrenal glands (bilateral adrenalectomy) may take the place of drug therapy.
Adrenal Tumors
  • Surgery is the mainstay of treatment for benign as well as cancerous tumors of the adrenal glands. In Primary Pigmented Micronodular Adrenal Disease and the familial Carney's complex, surgical removal of the adrenal glands is required.
Prognosis
  • Prognosis depends on the source of the problem. When pituitary adenomas are identified as the source of increased ACTH leading to cortisol excess, about 80% of patients are cured by surgery. When cortisol excess is due to some other form of cancer, the prognosis depends on the type of cancer and the extent of its spread.

Source:

http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm
http://www.healthatoz.com/healthatoz/Atoz/common/standard/transform.jsp?requestURI=/healthatoz/Atoz/ency/cushings_syndrome.jsp

Contributed by Lawrence Oh

Psychosocial Issues

Issues relating to Cushing's:
  • Loss of energy, a decreased level of activity and fitness
  • Loss of libido, infertility, low sex drive, impotence
  • Lack of self-esteem/confidence (body image issues) due to altered body image/physical changes/imbalance of hormones
  • Feelings of loss of control
  • Depression**/mood swings
    • restlessness, agitation
    • memory affected
    • sleep patterns affected
  • "Something is wrong with me"
  • History of being treated for other stress/mood related disorders. Doctors tend to imply to patients that they suffer from psychological disorders rather than physical disorders.
Because of the above factors:
  • strain on relationships
    • unmarried? divorced? - could this be an underlying reason?
    • family/relatives - unable to cope with the change in personality/mood swings etc.
    • snide or unkind comments from family/relatives/co-workers/friends regarding inability to lose weight/other physical changes or mood changes
  • strain on employment
    • unable to carry out normal duties due to depressive personality
    • unable to cope with stresses
Treatment/Management issues:
  • "Uncertainty is worse than reality" - therefore important for patient to learn all about the condition to reduce uncertainty and perhaps aid in alleviating depression
  • Cortisol replacement:
    • worries regarding the ups and downs of cortisol replacement
    • financial issues: able to pay for drugs? insurance?
    • forgetting to take medication daily?
    • stress!
  • Surgery:
    • distress regarding the procedures/risks
  • Managing depression*:
    • moderate alcohol/caffeine intake
    • have hormone levels checked
    • anti-depressants?
    • talk with others (cognitive behaviour therapy/mindful meditation/support group)
    • adequate sleep (reduced alcohol and caffeine intake helps)
    • proper diet and exercise routine - even after surgery, may take a while for body to go back to 'normal'
    • stressful life? change it! Or change reaction to stresses
Sources:
http://www.pituitary.org.uk/content/view/69/80/
http://www.pituitary.org.uk/content/view/278/157/

Thursday 19 July 2007

Definition and Causes of Cushing's Syndrome

Cushing’s Syndrome

Definition: Cushing’s Syndrome (also known as hypercorticolism) is a hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol, either produced excessively by the body or through excessive intake of cortisol or other steroid hormones.

What Causes Cushing’s Syndrome?

  1. Pituitary Adenomas

- most common cause (also known as Cushing’s Disease)

- benign tumors or hyperplasia of the pituitary gland, secreting increase amounts of ACTH

- affects women five times more frequently than men, and usually as a single adenoma

  1. Ectopic ACTH Syndrome

- benign or malignant tumors that arise outside the pituitary gland producing ACTH

- most common is lung tumors ( >50% of ectopic cases), usually by small cell lung cancer

- thyromas, pancreatic islet cell tumors, medullary carcinomas of the thyroid (C cells)

  1. Adrenal Tumors

- more commonly Adrenal Adenomas which releases excess cortisol

- Adrenocortical carcinomas, least common cause, secrete excess levels of several adrenal cortical hormones including cortisol and adrenal androgens. Cause very high hormone levels and rapid development of symptoms

  1. Intake Of Glucocorticoid Hormones

- also known as Exogenous Cushing’s Syndrome

- due to intake of glucocorticoids such as prednisone or dexamethasone for treatment purposes

- for asthma, rheumatoid arthritis, lupus, inflammatory diseases, immunosuppression after transplantation

  1. Familial Cushing’s Syndrome

- very rare; due to inherited tendency to develop tumors of one or more endocrine glands

- Primary Pigmented Micronodular Adrenal Disease: children or young adults develop small cortisol-producing tumors of the adrenal glands

- Multiple Endocrine Neoplasia Type I (MEN I): due to pituitary, ectopic or adrenal tumors


References

http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm

http://www.nlm.nih.gov/medlineplus/ency/article/000410.htm

Cortisol

Cortisol / Glucocortisol
Ji Keon LOOI

Outline of presentation
This presentation will cover:
•Site of production
•Site of release
•Target organ
•Means of transport
•Action
•Feedback Loop
Of cortisol

To clear things up before we start
•Two major types of adenocorticol hormones – mineralocorticoids and glucocorticoids
•Mineralocorticoids affect the electrolytes (minerals) of the ECF Na+ and K+ in particular
•Glucocorticoids increase blood glucose concentration, effects on CHO, protein and fat metabolism

The glucocorticoids
•Cortisol
•Corticosterones
•Cortisone
•Prednisone
•Methylprednisone
•Dexamethasone

Introduction to CORTISOL
•Principal glucocorticoid, 95% of all GC activity
•Secretion stimulated by ACTH, which in turn is controlled by CRF.
–What are sites of production?
•Produced by adrenal cortex
–Which layers?
•A.k.a stress hormone
•Hydrocortisone (synthetic)

Secretion of adrenocortical hormones by the different zones of the adrenal cortex and secretion of catecholamines by the adrenal medulla. (Diagram from Guyton)

Means of transport & Action
•Cortisol (hydrophobic) travels through the body in the blood via serum globulin.
•It diffuses through the cell membrane.

•Inside the cell, cortisol binds with its protein receptor in the cytoplasm, and the hormone-receptor complex (HRC) then interacts with specific regulatory DNA sequences, called glucocorticoid response elements, to induce or repress gene transcription. (Interaction facilitated by Transcription factors)
•It increases or decreases transcription of many genes to alter synthesis of mRNA for the proteins that mediate their multiple physiologic effects.
•Thus, most of the metabolic effects of cortisol are not immediate but require 45 to 60 minutes for proteins to be synthesized, and up to several hours or days to fully develop.
•N.B.: steroid hormones, exerts its effects by first interacting with intracellular receptors in target cells.

More about the stress hormone…
•Secretion in accordance with circadian rhythm. High in the early morning, low in late evening. Changes in sleeping habits alter the cycles.
–Clinical application: - measurement of blood cortisol only meaningful when expressed in terms of the time in the cycle at which the measurements are made
•Physical/Mental stress enhances secretion of ACTH and consequently cortisol.
•Negative feedback mechanism to decrease CRF and ACTH formation

Effects of Cortisol (1)
CHO metabolism
•Stimulates gluconeogenesis
•Decreases glusoce utilisation by cells
•Elevates blood glucose concentration and “adrenal diabetes”

Protein metabolism
•Reduces cellular protein
•Increases liver and plasma protein
•Increases blood aa, diminishes transport of aa into extrahepatic cells and enhances transport into hepatic cells

Fat Metabolism
•Mobilisation of FACs
•Excess results in obesity

Effects of Cortisol (2)
•Resists stress and inflammation ( )
•Blocks inflammatory response to allergic reactions
Mechanism for regulation of glucocorticoid secretion. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor.


THE DISORDERS OF CORTISOL SECRETION
Plasma Cortisol Plasma ACTH

Primary Hypercortisolism ↑ ↓
(Cushing Syndrome)

Secondary Hypercortisolism ↑ ↑
(pituitary, Cushing's disease)

Primary Hypocortisolism ↓ ↑
(Addison's disease)

Secondary Hypocortisolism ↓ ↓
(pituitary)

Thank you!!!
Sources
•Guyton, Textbook of Medical Physiology 11th Edn
•Prof. Khalid’s lecture *Components of the Endocrine System*
•http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Adrenals.html

Risk Factors (Cushing's Syndrome)

Overview: Cushing syndrome is a disease that occurs when your body produces too much of the hormone cortisol. It may also occur if you use take too much cortisol or other steroid hormones.

RISK FACTORS

Risk factors for Cushing syndrome are adrenal or pituitary tumors, long-term therapy with corticosteroids, and being female.

1.Cushing Syndrome caused by adrenal tumors: -caused by too much production of cortisol ( stress hormone) due to an adrenal gland tumor.

*Benign for eg. Adrenal adenomas or micronodular hypeplasia
*Malignant for eg. Adrenal carcinomas

2.Cushing Syndrome caused by corticosteroids – long term use of steroids/ drugs.
Drugs commonly used to treat conditions such as rheumatoid arthritis and asthma.

3.Cushing Syndrome caused by pituitary tumor

*pituitary gland releases too much adrenocorticotropic hormone (ATCH).
*ACTH stimulates adrenal , increasing the production and release of cortisol.

Reference:
MedLinePlus
http://www.nlm.nih.gov/medlineplus/ency/article/000410.htm

Prepared by:

SRI MURNIATI ROSLI

List of symptoms of Cushing's syndrome

The list of signs and symptoms mentioned in various sources for Cushing's syndrome includes the 81 symptoms listed below:


Specific childhood or adolescent Cushing's symptoms:

Extreme weight gain
Growth retardation
Missed periods - in teenage girls
Excess hair growth
Body hair growth
Facial hair growth
Acne
Reddish-blue streaks on the skin
High blood pressure
Tiredness
Muscle weakness
Very early puberty
Very late puberty





Adult Cushing's symptoms

Extreme weight gain
Upper body obesity
Rounded face
Increased neck fat
Excess hair growth
High blood pressure
Sleep disturbances
High blood sugar
Diabetes-like symptoms
Hyperadrenocorticism
Bruising easily
Skin problems
Thin skin
Fragile skin
Poor healing
Stretch marks
Abdominal stretch marks
Mood changes
Irritability
Anxiety
Depression
Moodiness
Fatigue
Mental disturbances
Weak muscles
Backaches
Thinning arms
Thinning legs
Weak bones
Rib fractures
Spinal column fractures
Sexual and fertility problems
Irregular menstrual periods
Absent menstrual periods
Reduced libido
Reduced male fertility
Virilisation
Deepening voice
Balding
Loss of scalp hair
Hirsutism
Increased facial hair
Increased body hair
Increased weight
Rounded face
Obesity around trunk
Slender limbs
Red face
Thin skin
Fragile skin
Slow-healing skin
Weakened connective tissue
Reddish-blue stretch marks
Excessive hair thickness in women
Menstrual disorders
Impaired male fertility
Reduced male sex drive
Absent male sex drive
Hypertension
Brittle bones
Fractures
Osteoporosis
Hyperglycemia
Severe weakness
Fatigue
Psychiatric disturbances

Note that Cushing's syndrome symptoms usually refers to various symptoms known to a patient, but the phrase Cushing's syndrome signs may refer to those signs only noticable by a doctor.

By Chris
source: http://www.wrongdiagnosis.com/c/cushings_syndrome/symptoms.htm

Labelling our posts

To avoid confusion to differentiate between pcl materials from MED2031 and MED2042 since we start with Week 1 again this semester, I would suggest that we label our work according to the title of the week.

I have entered all the pcl titles under this post and they should appear when you type in the first letter into the label slot. Alternatively, click on Show all to display all the pcl title.

Thanks.

Ji Keon

Monday 16 July 2007

Tasks for Week 1

Definition of Cushing Syndrome+Causes - Vivian
Signs & Symptoms - Chris
Risk Factors - Sri
Pathophysiology- Christine
Overview of Cortisol Pathway & Effects - Looi
Investigations+Differentials (Compare with Obesity & Menopause) - John
Management & Prognosis - Lawrence
Alternative Treatment (Green Tea etc.) - Shantz
Psychosocial Issues - Maddie :P

All the best for the exam....

chris