L16-18 and 20: Endocrine and Nutritional Diseases Flashcards
Adult human skeleton is composed of ___ bones
106
Bone matrix composition
35% organic “osteoid” component (mainly type I collagen)
65% mineral component (extremely hard) - hydroxyapatite; repository for 99% Ca and 85% P
Which bone cell type is multi-nucleated?
Osteoclasts
Functions of osteoblasts
- Main Function of osteoblast: secretion of a complex
mixture of bone matrix proteins (osteoid) - Regulate differentiation and activity of osteoclasts
- Important in maintaining calcium homeostasis
T or F: 10% of adult skeleton is replaced annually.
True
Essential hormones involved in bone remodelling
GH produced by pituitary stimulates fat production and production of IGF-1 by the liver to stimulate bone remodelling.
Wnt, LRP5/6, β-catenin
LRP5/6 activation by Wnt results in migration of β-catenin from cytoplasm to nucleus where it results in transcription of genes important in bone formation
Sclerostin
Sclerostin production by osteocytes inhibit osteoblast activation via the Wnt pathway
Osteoclast mechanism
Cathepsin K (proteinase) production is responsible for degradation of type I collagen in osteoclast-mediated bone resorption. The osteoclast has a pH of 5, which promotes degradation of bone.
Define: Osteopaenia
General reduction in bone density
Define: Osteoporosis
Severe form of osteopaenia which increases risk of fracture in normal, autraumatic physical activities
Genetic factors involved in osteoporosis
- Single gene loss-of-function mutation in LRP5
2. Sequence variation in osteoclast regulatory genes RANK, RANKL: low Ca2+ intake increases risk,
Menopause pathophysiology in osteoporosis
Decreased serum oestrogen leads to increased levels of IL-1, IL-6 and TNF (proinflammatory), RANK, RANKL, and increased osteoclast activity
Ageing pathophysiology in osteoporosis
- Decreased replicative activity of osteoprogenitor cells
- Decreased synthetic activity of osteoblasts, increased death of osteoblasts
- Decreased activity of growth factors
- Reduced physical activity
Why is osteoporosis more common in women?
Oestrogen (E) attenuates osteoclast activity/number therefore resorption of bone, therefore reduction in E activates on osteoclasts & bone resorption. Unlike E, androgen equally affects osteoblast and osteocyte activity – balance retained
Paget Disease
Chronic disease characterised by lesions of bone from disordered remodeling, in which excessive bone resorption initially results in lytic lesions tobe followed by disorganized and excessive bone formation.
Diffuse Non-toxic (Simple) Goiter
Enlargement of the thyroid caused by impaired synthesis of thyroid hormone, most often the result of dietary iodine deficiency - degree of enlargement is proportional to level and duration. Impairment leads to compensatory ↑ in TSH levels → hypertrophy and hyperplasia of follicular cells → gross enlargement of gland
Grave’s Disease aetiology
Excessive production of two thyroid autoantibodies: Thyroid-stimulating Ab, Growth-stimulating Ab. These Ab bind to the TSH receptor and act as ligands, stimulating cell resulting in increased levels of thyroid hormones and hyperplasia of the thyroid gland
Diagnosis of hyperthyroidism
Measurement of serum TSH concentration, because its levels are decreased early. Confirmed by high free T4
Cretinism
Hypothyroidism that develops in infancy or early childhood. Impaired development of the skeletal system and central nervous system, manifested by severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia
Myxedema
Hypothyroidism developing in the older child or adult. Generalized fatigue, shortness of breath and mental sluggishness due to reduced cardiac output , which may mimic depression. Decreased sympathetic activity results in constipation and decreased sweating
Thyroiditis
Typically acute inflammation of the thyroid gland. Three most common and clinically significant subtypes:
- Hashimoto thyroiditis
- subacutelymphocytic thyroiditis
- granulomatous(de Quervain) thyroiditis
Hashimoto thyroiditis
Painless enlargement of the thyroid, low T4 & T3, sometimes preceded by thyrotoxicosis (high T3 & T4). CD8+ cytotoxic T cells destroy thyroid follicular cells via FasL receptor present on the T cell.
Granulomatous Thyroiditis
Virus-initiated. Histologically distinct – presence of multinucleated ‘Giant Cells’
Mechanism of regulation of calcium homeostasis by the parathyroid glands
Decreased levels of Ca2+ stimulate the synthesis and secretion of PTH. PTH activates osteoclasts (Ca2+ and P released into the blood), increases calcium reabsorption from food, and promotes activation of Vit D, which further increases calcium absorption from food. Rising Ca2+ in the blood inhibits PTH release
Genetic polymorphism in hyperparathyroidism
Cyclin-D1 gene inversions leading to overexpression of cyclin-D1 in the parathyroid cells.
Composition of the adrenal gland
Medulla (inner part) constitutes 20% of the gland and the cortex (outer part) constitutes 80%. Cortex consists of three zones. The medulla and each of the zones in the cortex produce different hormones.
Zona glomerulosa
Outermost zone of the adrenal cortex that secretes mineralcorticosteroids, hormones important for fluid homeostasis, e.g. Aldosterone which regulates absorption/uptake of K+ and Na+ levels in the kidney
Zona fasciculata
Middle zone of the adrenal cortex that secretes glucocorticoids important for macronutrient metabolism, e.g. Cortisol which raises blood glucose and cellular synthesis of glycogen.
Zona reticularis
Innermost layer of the cortex, secretes sex hormones (androgens), and small amounts of glucocorticoids
Adrenal medulla
Composed of functional units - the chromaffin cell which functions as a neuroendocrine cell. In response to stimulation chromaffin cells secrete adrenaline and noradrenaline directly into blood.
ACTH is produced from which precursor
POMC
Initial precursor of glucocorticoids, mineralocorticoids, and androgens
Cholesterol
Glucocorticoid action
- Increasing glycogen synthesis in the liver and decreasing of glucose utilisation by peripheral tissues. Increase in gluconeogenesis.
- Increasing protein synthesis in the liver and decreasing of its synthesis in muscles and increasing of protein destruction in muscles.
- Increase in lipolysis.
- Anti-inflammatory function and immmunomodulation
- Cardiovascular regulation (increase in blood pressure)
Mineralocorticoid action
Regulation of electrolyte balance - mainly Na+:
Angiotensinogen (produced in the liver) is converted to angiotensin I by renin (produced by the kidney). ACE (released from the lungs) convertes angiotensin I to angiotensin II which acts on the adrenal gland to stimulate release of aldosterone, as well as directly on blood vessels to stimulate vasoconstriction. Aldosterone acts on the kidneys to stimulate reabsorption of salt and subsequently water.
Waterhouse-Friderichsen syndrome
Primary acute adrenocortical insufficiency - massive bacterial infections, rapid hypotension - shock, intravascular coagulation - seen in skin
Rapid adrenocortical failure
Addison disease
Primary chronic adrenocortical insufficiency caused by gradual destruction of the adrenal cortex mostly due to autoimmune adrenalitis (destruction of steroidogenic cells) - autoantibodies against steroidogenic enzymes 21/17-hydroxylase.
Can also be caused by metastatic neoplasia of adrenal, mainly from primary lung and breast cancer or infections such as TB.
Cushing syndrome
Constellation of signs and symptoms caused by prolonged excessive amounts of circulating glucocorticoid.
Aetiology: mostly result from exogenous administration of GCs “iatrogenic”. Endogenous aetiology can be ACTH-dependent or independent
In cases where endogenous GCs cause Cushing, bilateral cortical ____ occurs
hyperplasia
In patients where exogenous GCs cause Cushing,
suppression of ACTH occurs leading to bilateral
cortical _____
atrophy
Clinical features of Cushing
Obesity, thin and fragile skin with pinkish striae, hypertension, proximal muscular weakness affecting
predominantly the muscles of the pelvic girdle, acne, hirsutism, and menstrual irregularities, osteoporosis, compression fractures and persistent back pain, peripheral oedema, psychiatric manifestations, including anxiety, depression, rarely psychotic episodes
Treatment for Cushing
Surgery, pituitary irradiation, pharmocologic therapy
Define: Obesity
Pathological fat excess. BMI of 30 or higher
