BY Sami El-Sabbahy and Kamal Al-Azawi
What is It ?
• Cushing's Syndrome (Hyercortisolism) is a disorder caused by: • Excess production of Cortisol over a long period of time. • Excess production or OTHER similar Steroid (Glucocorticoid) Hormones. • Cortisol is a hormone which is produced in the adrenal CORTEX (outer portion of the adrenal gland), which is located at the top of each kidney. • The normal functions of cortisol is to stimulates an Anti-Inflammatory response, the catabolism of peripheral fat and protein to provide substrates for Hepatic Gluconeogensis, vascular tone, and bone metabolism.
Classification of Cushing's Syndrome.
• ACTH Dependant
1. Cushing's Disease 2. Ectopic ACTH syndrome 3. Ectopic CRH syndrome
• ACTH Independant
1. Iatrogenic Adrenal Adenoma 2. Micronodular Hyperplasia 3. Macronodular Hyperplasia
What Causes It ??
• When a person undertakes hormone (Steroid) treatment for a long period of time, like a steriodal anti-inflammatory drug/hormone for ARTHRITIS.... (IATROGENIC Cushing's Syndrome). When the body produces too much Cortisol, when either the Adrenal or the Pituitary gland are not working properly. Due to:
A tumour in the Pituitary Gland, though increased production of ACTH, which in turn stimulates over production of Cortisol. This FORM of Cushing's Syndrome is know as "CUSHING'S DISEASE". A tumour in the Adrenal Gland, which may cause the adrenal gland's to produce excess cortisol.
A tumour somewhere else in the body which initiates over production of ACTH which then causes over production of Coritsol, known as Ectopic ACTH Syndrome. But there is another state which is similar to Cushing's Syndrome which can cause confusion in diagnosis, such Alcohol and depression this is know as "Pseudo Cushing's".
• • • •
The Hypothalamus which secrets CRH. This stimulates the Pituitary Gland to secrete ACTH. Which stimulates the adrenal glands to produce Cortisol and is released into the blood stream. This acts as a biological feedback loop, in which the hypothalamus and pituitary release less CRH and ACTH, when Cortisol reaches adequate levels in the blood stream. The Adrenal Gland produces Cortisol by:
Transforming cholesterol in to pregnenolone or Progesterone. In Which C-17 and then C21, are Hydrolysed, by Dehydrogenase. Then C3 is Oxidised. The isomerization of the C-5 double bond to C-4, to produce 11-Deoxycortisol. (At this point to inhibit the synthesis of cortisol by using the drug Metyrapone) Deoxycortisol is hydrolized to Corisol
1. 2. 3. 4. 5. 6.
But when the feedback loop of Cortisol is disrupted, this results in excess Cortisol production. To inhibit the synthesis of cortisol the drug Metyrapone is used to inhibit 11β-Hydroxlase.
• Cortisol production is regulated by Adrenocorticotrophic Hormone (ACTH), which is produced in the Pituitary gland where it is located just below the Brain. • When cortisol is over produced by the adrenal gland, significant changes occur in all of the tissues and organs of the body... • The collective effects of the changes are called "CUSHING'S SYNDROME". • Cushing's syndrome can be stimulated by over production of ACTH. • This disease was named Cushing's Syndrome after Dr. Harvey Cushing, described the symptoms and signs of this disease in 1912 and 1932.
What Are The Symptoms ???
Symptoms in Children and Teenagers
1. Extreme Weight Gain in the centripetal (trancal). 2. Growth Retardation. 3. Absence of Menstrual Cycle. 4. Excess of Hair Growth. 5. Reddish Blue Steaks on the Abdomen or Proximal extremities (Virtually diagnostic of this Condition). 6. ACNE. 7. High Blood Pressure. 8. Tiredness and Weakness. 9. Very EARLY or LATE puberty.
Symptoms in Adults
Muscle and Bone weakness. Moodiness, Irritability or Depression. Sleep Disturbances. High Blood Pressure. Menstrual Disorders and (women). Lower Fertility in (Men). Fat deposits in the Dorsocervical Area (Buffalo Hump). Fat Deposits in the Supraclavicular Area. Fat Deposits on the cheeks (moon face).
What are the effects of Over Production of Cortisol ??
• It causes the amount of amino acids to increase to make glucose through a process called gluconeogenesis. This results in an overall increase of hepatic glycogen stores that will increase glucose levels. The glucose is then produced by the liver but is stopped from entering cells by the cortisol. Therefore the glucose remains in the blood which starves cells of energy. The liver then absorbes more and more amino acids, where they are made into glucose or other proteins. Muscle wastage and weak bones occurs due to the constant breakdown of amino acids. It initiates the breakdown of fat and mobilizes it from storage to be used for energy. In chronic use of glucocorticoids, fat is redistributed to the liver and abdominal area, whic gives the pot-bellied appearance in animals with hyperadrenocorticism.
• • • • • •
How Does It Effect Metabolism? • Gluconeogenesis
• Induces Lipid Catabolism
• Induces Protein Catabolism
• Cortisol initiates the carboxylation of pyruvate to form oxaloacetate at the expense of ATP. which is catalyzed by pyruvate carboxylase. • Phosphoenolpyruvate is then produced when Oxaloacetate is decarboxylated and phosphorylated by phosphoenolpyruvate carboxykinase. • Oxaloacetate has to be transformed into malate. • Phosphoglucose isomerase transforms fructose-6-phosphate into glucose-6-phosphate. • glucose-6-phosphate is then hydrolysed to form glucose by glucose6-phosphatase.
Lipids are broken down by a process called Lipolysis, which is the process in which:
Lipids are broken down, to make pyruvate, which enter into the Citric Acid Cycle. Triglycerides are broken into glycerol enters the Citric Acid Cycle and into Fatty Acids are broken down by β-Oxidation to form Acetyl CoA which also enter into the Citric Acid Cyle.
• Deamination: is the removal of the amino groups from amino acids, which is catalysed by transaminase enzymes, to form a carbon skeleton. • Ammonia which is produced as a byproduct is transformed into urea. • The amino acid carbon skeleton is catalysed to acetyl CoA, which is either oxidised via the citric acid cycle or converted to ketone bodies. • If oxidised in the citric acid cycle then any intermediate could be used to form glucose via Gluconeogenesis.
• The skeleton acts as a protective cage which prevent vital organs from getting damaged. • Amongst other things it acts like a support frame for our muscles and connective tissues, also it act like a reservoir of calcium and other ions. • Bone is made up by Bone forming cells, called Osteoblasts (OBs). • Cortisol stimulates the Osteoblasts to reabsorb, since high levels of steroids catabolic effects. • Which is due to higher levels of collagenase expression and lower levels of collagen expression. • Cortisol also interacts with IL-1 and IL-6 (cytokines), are involved in Bone remodelling.
How to Diagnose It ?
• 24 – Hour Urinary Free Cortisol Level. • Dexamethane Suppression Test. • CRH Stimulation Test. • Direct Visualisation of the Endocrine Glands (Radiological Imaging). • Petrosal Sinus Sampling. • The Dexamethasone – CRH Test.
How To Treat It ?
• For Pituitary Tumours, Surgical Removal is the usual treatment. Ectopic ACTH Syndrome, the tumorous tissue would be one of several Treatments.
Surgery Radiotherapy Chemotherapy Immunotherapy Or a Combination of these treatments
1. 2. 3. 4. 5.
Adrenal Tumours, Surgical Removal of Adrenal Glands is Required.