Cardiovascular & Metabolic Complications of Cushing’s Syndrome Presented by: Saeed Behradmanesh,...
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Transcript of Cardiovascular & Metabolic Complications of Cushing’s Syndrome Presented by: Saeed Behradmanesh,...
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Cardiovascular & Metabolic Complications of Cushing’s
Syndrome
Presented by:Saeed Behradmanesh, MD
Internist, Endocrinologist
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Effects of Glucocorticoids
Carbohydrate, Protein, and Lipid Metabolism
► In the liver: – cortisol stimulates glycogen deposition– inhibits glycogenolysis – activates gluconeogenesis
► In peripheral tissues (muscle, fat):– inhibits glucose uptake and utilization
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► Stimulate adipocyte differentiation & promote adipogenesis.
► Long-term effects upon adipose tissue: – deposition of visceral or central adipose
tissue.– catabolic effect on subcutaneous adipose
tissue.
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►In adipose tissue, lipolysis is activated > ═release of FFAs into the circulation.
►↑Total chol. & ↑TGs, but ↓HDL-chol.
►Permissive effect upon other hormones (CCAs & glucagon).
►Insulin resistance & increase in BG.
►Protein and lipid catabolism.
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• The explanation for the predilection
for visceral obesity may relate to the
increased expression of both the GR
and 11β-HSD1 in omental compared
with subcutaneous adipose tissue.
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Skin, Muscle, and Connective Tissue
► Catabolic changes in muscle, skin, and connective tissue.
► In the skin and connective tissue:▬ inhibit epidermal cell division
▬ inhibit DNA synthesis
▬ reduce collagen synthesis and production
► In muscles: ▬ cause atrophy (but not necrosis)
▬ reduce muscle protein synthesis
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Bone and Calcium Metabolism
■ Inhibit osteoblast function
■ Cause osteopenia and osteoporosis
■ Osteoporosis affecting 50% of patients treated with GCSts for > 12 months.
■ Cause osteonecrosis (avascular necrosis)
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Osteonecrosis (avascular necrosis):• Rapid and focal deterioration in bone quality.
• Primarily affects the femoral head.
• Leading to pain and ultimately collapse of the bone.
• It can affect individuals of all ages.
• May occur with relatively low doses of GCSts (e.g., during replacement therapy for adrenal failure).
• No explanation for individual susceptibility.
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• Recent data implicate:
– glucocorticoid-induced osteocyte
apoptosis in the pathogenesis of the
condition, and
– the lack of a direct role for an
interrupted blood supply.
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► Induce negative calcium balance by:
▬ inhibiting intestinal calcium absorption
▬ increasing renal calcium excretion
► PTH secretion is usually increased.
► In children, GCSts suppress growth but the increases in BMI are thought to offset a deleterious effect on BMD.
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Salt and Water Homeostasis& BP Control
► GCSts increase BP. ► Mechanisms: effect on the kidney &
vasculature.► In vascular smooth muscle:
▬ Increase sensitivity to pressor agents such as CCAs & ATII
▬ Reduce NO-mediated endothelial dilatation.
► Increase Angiotensinogen synthesis.
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• On the distal nephron cause Na+ retention & K+ loss (mediated via the MR).
• Elsewhere across the nephron increase: – GFR – proximal tubular epithelial Na+ transport– free water clearance
• Antagonism of the action of AVP• Dilutional hyponatremia in glucocorticoid
deficiency.
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Gut
► Long-term but not acute administ. of GCSts ═˃ ↑ risk of developing PUD.
► Pancreatitis with fat necrosis.
► The GR is expressed throughout the GI.
► MR is expressed in the distal colon.
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Growth and Development
► Stimulate GH gene transcription in vitro.
► In excess, inhibit linear skeletal growth.
► Catabolic effects on connective tissue, muscle, & bone.
► Inhibition of the effects of IGF-1.
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► Stimulate lung maturation through the synthesis of surfactant proteins (SP-A, SP-B, SP-C).
► Stimulate phenylethanolamine N-methyltransferase (PNMT):
Noradrenaline → Adrenaline
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