High Yield USMLE
High Yield Notes made for USMLE STEP 1. So GET THEM and make life easier.
Sunday, August 25, 2013
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Friday, August 16, 2013
Wednesday, August 14, 2013
Tuesday, August 13, 2013
Monday, August 12, 2013
HY NOTES for ENDOCRINE SYSTEM!!
ENDOCRINE SYSTEM
Pitutary Gland
- Anterior lobe (adenohypophysis)
- Acidophills (GH and prolactin)
- Basophills (ACTh and TSH, FSH and LH)
- Chromophobes
- Posterior lobe
- Pituicytes
- ADH, Oxytocin
Five cell types
- Somatotrophs – GH (acidophilic cells)
- Lactotrophs – prolatin (acidophilic cells)
- Corticotrophs – ACTH, MSH, endorphins and lipotropin (basophilic cells)
- Thyrotrophs – TSH (basophilic)
- Gonadotrophs – FSH and LH (basophilic cells)
Pitutary Disorder
- Hyperpituitarism
- Excess of pituitary hormones
- Common reason – functional adenoma
- Pitutitary adenoma
- Mainly single hormone excess in the anterior lobe (GH or PRL)
- Adenomas associated with MEN type 1 (multiple endocrine neoplasia)
- Mass lesion present in the sella turcica in pituitary adenoma
- mass effects like visual problems from pressing on the optic chiasm and prdn of prolactin or ACTH
- Uniform polygonal cells
- G-protein mutations, G-protein play a critical role in signal transduction transmitting signals
- Alpha-subunit mutation that interferes with its intrinsic GTPase activity with therefore results in constitutive activation of Gs Alpha. The alpha-subunit of Gs is encoded by the GNAS1 gene, located on chromosome 20q13
- Pituitary apoplexy
- Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy.
- Sudden onset of excruciating headache, diplopia owing to pressure on the oculomotor nerves and hypopituitarism
- Cardiovascular collapse – emergency
- Prolactinoma
- Hyperfunctioning of pituitary adenoma – hyperprolactinemia
- Dystrophic calcification ranging from isolated psammoma bodies to extensive calcification of entire tumor mass
- Galactorrhea in young women
- Mainly due to damage to the dopaminergic neurons of the hypothalamus
- Dopamine receptor antagonist such as the neuroleptic drugs can cause hyperprolactinemia
- Bbitemporal hemianopsia – visual field abnormalities due to compression of fibers in the optic chiasm
- Increased levels of prolactin – cause amenorrhea, galactorrhea, loss of libido and infertility
- Rx – bromocriptine
- Growth Hormone excess
- Gigantism (childhood) – somatotrophic adenoma appears in children before the epiphyses have closed, the elevated levels of GH. Long bones are involved
- Acromegaly (adults) – increased levels of GH after the closure of the epiphysis. Bone density is increased (hyperostosis). Enlargement of the jaw results in protrusion (prognathism). Broad hands and feets or (ACRAL enlargement)
- Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor I (IGF-1 or somatomedin C) causes the clinical manifestation.
- Diagnosis – elevated serum GH and IGH-1 levels
- Corticotroph cell adenomas
- Excess prodn of ACTH by the corticotroph adenoma leads to adrenal hypersecreation of cortisol and the results in hypercortisolism (Cushing syndrome)
- Posterior Pituitary disorder
- ADH and oxytocin
- Clinical relevant Posterior syndrome include Diabetes insipidus and increase high levels of ADH
- Diabetes insipidus
- ADH deficiency (Central Diabetes Insipidus)
- Inability of the kidney to reabsorb water
- Head trauma n tumors
- Inflammatory disorders of hypothalamus
- Rx - desmopressin
- Renal tubular unresponsiveness to circulation ADH (Nephrogenic Diabetes Insipidus)
- Causes for nephrogenic DI
- Drugs like lithium, hypokalemia (vascular nephropathy of collecting tubules, nephrocalcinosis (calcification of collecting tubules)
- Clinical – excessive thirst, polyuria, increased osmolality and serum Na+
- Test – WATER DEPRIVATION TEST
- CDI - UOsm increase more than 50%
- NDI – Uosm increase less than 50%
- Rx – Thiazides – Vol depletion increases proximal tubule reabsorption of water
- SIADH (Syndrome of inappropriate ADH)
- Excess ADH causes resorption of excessive amonts of free water – Hyponatremia
- Cause – secretion of ectopic ADH by neoplasm
- Clinical – hyponatremia (increase serum Na+), cerebral edema, total body water is increased
- Rx – restrict water
- Hypopituitarism
- Decreased secretion of pituitary hormones (disease of hypothalamus or pituitary)
- Causes
- Pituitary adenoma
- Sheehan’s postpartum necrosis
- Carniopharyngioma
- Pituitary apoplexy
- Lymphocytic hypophysitis
- Clinical – Gonadotropins (FSH, LH) deficiency [ delayed puberty, adult females have secondary amenorrhea, males have impotence]
- Growth hormone (GH) deficiency
- Decreased GH decreases synthesis and release of IGF-1
- Growth delay, delayed fusion of epiphyses, bone growth does not match the age of the child
- Hypoglycemia (decreased gluconeogenesis)
- Thyroid-stimulating hormone (TSH) deficiency
- Secondary hypothyroidism – decreased T4 and TSH
- Clinical – cold intolerance, constipation, weakness
- No increase in TSH after TRF stimulation
- ACTH deficiency
- Secondary hypocortisolism
- Decreased ACTH and cortisol
- Hypoglycemia, hyponatremia
- Rx –Metyrapone (inhibits adrenal 11-hydroxylase – causes a decrease in cortisol and increase in plasma ACTH and 11-deoxycortisol)
- Anterior pituitary tumor
- Sheehan syndrome [pituitary hemorrhage]
- Ischemic necrosis [postpartum]
- Happens during pregnancy
- Anterior pituitary become twice as normal size
- Lack of blood supply cause obstetric hemorrhage or shock
- No resumption of normal menstrual cycles, she become sluggish and tired
- Clinical – inability to breast feed a child, hyponatremia, hyperkalemia and hypoglycemia
- Empty sella syndrome
- Condition that destroys part or all of the pituitary gland
- Types
- Primary – defect in the diaphragm sella that allows arachnoid mater and CSF to herniated to sella. Clinicals – obese women, hyperprolactinemia, hypopituitarism
- Secondary – pituitary adenoma, enlarges the sella. Loss of pituitary function, hypopituitarism
- Hypothalamic suprasellar tumors
- Gliomas and
- Craniopharyngiomas – vestigial remnants of Rathke pouch (ectodermal derivative from oral cavity). Abnormality of the WNT signaling pathway including activating beta-catenin mutations, also visual disturbances
- Adamantinomatous carniopharyngioma – there is calcification, stratified squamous epithelium. Nests of squamous cells grandually merge into a layer of columnar cells. They contain a cholesterol-rich, thick brownish yellow fluid ‘ machinery oil’.
- Papillary craniopharyngioma - rarely calcified.
THYROID
Hypothalamus produces TRH then pituitary produces TSH which makes thyroid to make T3 n T4.
Disorders of Thyroid
Hyperthyroidism
- Thyrotoxicosis – elevated levels of free T3 n T4 [hypermetabolic state]. Reason – diffuse hyperplasia of the gland [Graves disease], hyperfunctional multinodular goiter and hyperfunctional adenoma of the thyroid. Also due to overactivity of the sympathetic nervous system.
- Rx – Methimazone, propyl
- Clinicals - diarrhea, weight loss, mennorrhegia, tremors, changes in the skin of tibia. Atrial fibrillation, sweating, proximal muscle weakness.
- Primary – the cause is within the gland. Most common
- Secondary – if the cause is outside the gland like pituitary
- Graves disease – exophthalamos, accumulation of loose connective tissue behind the eyeballs adds to the protuberant appearance of the eyes.
- Increase porosity of cortical bone and reduced volume of trabecular bone.
- Net effect – osteoporosis, increased risk of fractures.
- Acute elevation in catecholamine levels
- Febrile and present with tachycardia.
- Apathetic Hyperthyroidism
- Mainly in elderly
- Unexplained weight loss or worsening cardiovascular disease
- Diagnosis of Hyperthyroidism
- – measurement of serum TSH concentration using sensitive TSH assays provides the most useful single screening test for hyperthyroidism
- - Low TSH value with FREE T4.
- If there is normal elevation after the injection of TRH then secondary hyperthyroidism is excludes
- ****If there is diffusely increased uptake in the whole gland then its GRAVES DISEASE
- ****If there is increased uptake of radioactive iodine in a solitary nodule – toxic adenoma
- ****Decrease uptake of radioactive iodine by the thyroid gland– thyroiditis – hypothyroidism
GRAVES DISEASE
- Female, 20-40y
- Autoimmune
- Hyperthyroidism [hyperfunction, diffuse enlargement]
- Infiltrative opthalmopathy
- Pretibial myxedema
- Presence of MHC haplotypes, specifically HLA-B8 and DR3
- CTLA-4 = cytotoxic T-lymphocyte-associated-4 gene
- CTLA-4 is an inhibitory receptor that prevents T-cell response to self antigens
- Antibodies to the TSH receptor, thyroid peroxisomes and thyroglobulin are present in the serum
- Thyroid stimulating immunoglobulin [TSI] are specific for Graves disease
- There is infiltration of the retro-orbital space by mononuclear cells, edema and swelling of extraocular muscles, accumulation of extracellular matrix, GAGS and fatty infiltration
- Crowded number of cells, with meaty appearances
- HASHIMOTO DISEASE – eventually people become hypothyroidism.
HYPOTHYROIDISM
- decrease in adequate levels of thyroid hormone
- primary
- autoimmune hypothyroidism – Hasimoto thyroiditis
- iodine deficiency
- drugs – lithium
- Postablative – surgery, radioactive therapy or external irradiation
- Secondary
- Pituitary failure
- Hypothalamic failure – rare
- Primary
- Thyroprivic – due to absence or loss of thyroid parenchyma
- Goitrous – due to enlargement of the thyroid gland under the influence of TSH. Anto-TSH receptor autoantibodies circulating autoantibodies
- Dyshormonogenetic goiter
- Hormone synthesis defect
- Iodine transport into thyrocytes
- Iodine organification
- Iodotyrosine coupling
- Mutations in the thyroid peroxidase gene
- Pendred syndrome
- Mutation in the SLC2644 gene whose product is pendrin
- Problem in organification of iodine
- Isolated hypothyroidism
- Inactivating fermline mutation of the TSH receptor
- CLINICALS
- CRETINISM (60 slide)
- Develops in infancy
- Mentally retarded
- Short stature
- Coarse facial features, protruding tongue
- Reduction in maternal thyroid hormone later in pregnancy, after the fetal thyroid has developed, allows normal brain development.
- MYXEDEMA or GULL disease
- Slowing of physical and mental activity
- Mental sluggishness
- Depreseeion
- Speech and intellectual functions slowed
- Constipation and decreased sweating
- Skin – cool and pale
- Weight gain
- Accumulation of matrix substance [GAGS and hyaluronic acid]
- THYROIDITIS
- Acute illiness with severe thyroid pain
- Neck pain and tenderness
- Fever chills
- Painful cervival adenopathy
- Little inflammation and thyroid dysfunction
- HASHIMOTO THYROIDITIS
- Autreactive CD4+ Tcells to thyroid antigens appears to be initiating event
- Abnormal T cell activation and subsequent B cell stimulation
- Presence of circulating autoantibodies against thyroglobulin and thyroid peroxidase
- Mononuclear inflammatory infiltrate within germinal centers
- Hurthle cells – metaplastic response of normally low cuboidal follicular epithelium to in going injury
- Prone for Non-Hodgkins lymphoma
- There is painless enlargement of the thyroid
- REIDEL’S THYROIDITIS
- Associated with sclerosing conditions
- Extension of fibrosis into surrounding tissue
- Fibrous tissue replacement of the gland
- Tracheal obstruction
- GOITRE
- Enlargement of thyroid
- Raised TSH
- They can be hyperthyroid or hypothyroid
- Diffuse and multinodular goiters caused by dietary iodine deficiency
- Types
- Diffuse nontoxic – involves the entire gland without producing nodularity. Filled with colloid.
- Multinodular goiter – irregular enlargement of thyroid, cause compression of other organs like airway obstruction. There can be cancer of thyroid – papillary carcinoma. There is colloid rich follicles
NEOPLASM OF THYROID
Cold nodule – when the nodule is taking no radioactive
Hot nodule – toxic adenomas – takes radioactive
Follicular adenoma
- Multiple nodules
- Covered by a capsule
- There is uniform appearing follicle
- There is no vascular invasion but follicular carcinoma have invasion
- Capsule will be present
- No invasion
- **** incomplete
Papillary carcinoma thyroid contain psammoma bodies. Seen in later cases
Follicular carcinoma
- Present in women
- Increased in areas of dietary iodine deficiency
- Single nodules that may be well circumscribed or widely infiltrative
- Tumor cells resemble like follicles in thyroid but its less apparent.
- With or without colloid
- Capsular and Vascular Invasion
Medullary carcinoma
- Derived from parafollicular cells or C cells of the thyroid
- Secrete calcitonin
- they are going to have amyloid stroma with Congo red staining
- polygonal to spindle-shaped cells
- Acellular amyloid deposits [ produced from altered calcitonin]
Anaplastic carcinomas of thyroid
- High mortality rate 100%
- Older people
- Undifferentiated – giants cells, spindle cells, mixed of those
Increased up take of radioactive iodine is seen in Graves and toxic nodular goitre
Decrease uptake of radioactive iodine – thyroiditis, and for people who takes thyroid hormone
PARATHYROID
- Parathyroid gland has chief cells and oxyphills cells
- PTH
- Increase Ca+ reabsorption in early DT
- Decreases HCO-3 reclamation in the PT
- Decreases phosphorus reabsorption in the PT
- Hypocalcemia stimulate the release of Ca+ from PTH
- Antagonizes CALCITONIN
- PTH binds to osteoblasts receptor. (SLIDES 7)
- Components of total serum Ca+ [albumin, phosphorus n citrate]
- Hypoalbuminemia
- Decreased total serum Ca+ [ due to decrease in Ca+ bound to albumin]
- Normal PTH
- Metabolic alkalosis
- Increases –ve charge on albumin
- Normal serum calcium
- Decreased ionized Ca+, incrased PTH
- Tetany development
- Carpopedal spasm [ thumbs flexes into the palm[
- Chvosteck’s sign [ facial twitch after tapping]
Parathyroid Disorder
Primary Hyperparathyroidism
- Adenoma
- Caused by sporadic parathyroid adenomas or sporadic hyperplasia
- Parathyroid adenoma 1 [PRAD1] gene defect
- Sporadic adenomas – MEN1, type 2An2B
- Osteitis fibrosa cystic
- Cortex is grossly thinned
- Increased amount of fibrous tissue in the marrow
- Bone turn soft and become deformed
- Bone pain, fractures
- Nephrolithiasis
- Constipation, ulcers, gallstones
- Cardiac valve calcification
- hypercalcemia
- Nephrocalcinosis – causes polyuria and renal failure
- Calcium deposit in the limbus of the eye [ band keratopathy]
- In EKG – shortened QT interval and prolonged PR interval
Secondary Hperparathyroidism
- Renal failure
- Glands are hyperplastic
- Hypercalcermia
- Increased Ca+ reabsorption in the jejunum n kidney
- Sarcoidosis – macrophages in granulomas synthesize 1-alpha hydroxylase causes hypervitamin D
- Multiple myeloma – increased secretion of osteoclast activating factor(IL-1) by malignant cells
- Thiazides – vol depletion increases renal tubule reabsorption of calcium
Hypoparathyroidism
- Hypofunction lead to hypocalcemia [tetany], circumoral numbness or paresthesias [ tingling]
- Neuromuscular irritability due to decreased serum ionized calcium concentration. Chvostek sign and Trousseau sign.
- Causes
- Previous surgery
- Digeorge syndrome – failure of descent of 3rd n 4th pharyngeal pouches. Absence of PT gland. Absent thymus [ Tcell deficiency]
- Hypomagnesemia – Mg low, which is cofactor of adenylate cyclase, causes diarrhea, diuretics, alcoholism
- Familial hypoparathyroidism
- autoimmuneHP
- Widened QT interval
- Lens calcification
- Intracranial calcification
Pseudohypoparathyroidism
- X-linked dominant disease
- Mental retardation
- Short 4th n 5th metacarpals [knuckle-knuckle-dimple-dimple sign]
- Hypocalcemia, normal increased PTH
Type 1a Pseudohypoparathyroidism
- Bone resorption with blunting of the 4th and 5th knuckles of the hand
- Knuckle knuckle dimple dimple sign
- Turner syndrome is characterized by blunting of only the fourth knuckle
- Associated with multihormone resistance
- Characterized by skeletal and developmental defects
- Clinical
- Short stature
- Obesity
- Short metacarpal n metatarsal bone
Pseudopeusohypoparathyroidism
- Mutation is inherited on the paternal allele
- No hypocalcemia or hyperphosphatemia
Secondary Hyperparathyroidism
- Chronic renal insufficiency – due to decreased phosphate excretion – hyperphosphate
- Elevated PO4 decreases Ca+ and thus stimulate parathyroid gland
- There is a reduction in availability of alpha-1-hydroxylase
ADRENAL GLAND
Adrenal Cortex
Synthesis
- Glucocorticouds by Zona fasciculata
- Mineralocorticoids by Zona glomerulosa
- Sex steroids by Zona reticularis
Adrenal Medulla
- Composed of Chromaffin cells
- Synthesize n secrete catecholamines (epinephrine)
- Product of epinephrine n NOR epinephrione – metanephrine and VMA
- Metabolic product of dopamine 0 Homovanillic acid
Cushing disease
- Dude to pituitary adenoma[excess growth of pituitary gland]
- Primary hypersecretion of ACTH with cortisol
- Mainly in women
- Clinical
- Upper body obese with thin arm and legs
Cushing syndrome
- Crooke hyaline change
- Main cause pituitary adenoma
- There is diffuse hyperplasia [ glands become bigger]
- Adrenal cortex is thickened and yellow
- Clinicals
- Central obesity
- Moon facies
- Weakness
- Hirsutism
- Hypertension
- Diabetes
- Hyper insulinism
- Buffalo hump
- Loss of collagen and resorption of bones
- Hyperglycemia, glucosuria and polydipsia
- In this syndrome there is 24hr urine free cortisol level [increased]
- High dose of dexamethasone, reduce the secretion of ACTH.
- In Ectopic tumor[outside the gland], ACTH levels are elevated[ higher than pituitary adenoma] and in adrenal tumors the ACTH levels are low
- High dose of dexamethasone difference pituitary CS from Adrenal and ectopic
Primary Aldosteronism
- Suppression of the rennin-angiotensin system
- Decreased plasmaSLIDE 41*****************
Adrenal Insufficiency
Primary
Acute
- Adrenal crisis
- A patient who has chronic or addison disease and now he has a source of stress
- Patients on exogenous corticosteroids with rapid withdrawal result is stress to adrenal crisis
- Waterhouse Friderichsen’s Syndrome
- Catastrophic syndrome
- Massive bilateral adrenal hemorrhage
- Hypotension shock
- Bacterial infection like Neisseria meningitides, Pseudomonas, H.influenza
- Meningococcemia is the usual cause with hemorrhafe and adrenal failure
- Develops over less than 2 days
- Skin lesion
Chronic
- Addison disease
- Destruction of adrenal cortex
- Autoimmune
- Clinical –
- Weakness
- Fatigability
- Hormones from cortex is decreased
- Increase production of ACTh from anterior pituitary and also produces melanocytes with hyperpigmentation of skin
- Hyperkalemia
- Hyponatremia
- Volume depletion
- Hypotension
- Hypoglycemia due to decrease in cortisol
- Autoimmune adrenalitis
- Autoimmune polyendocrine syndrome type1(APSI)
- Abnormalities of skin, dental n nail
- Organ specific autoimmune disorders [ hypogonadism. hypoPTD]
- Mutation in AIRE gene on 21q22
- AIRE protein is in thymus, function as a transcription factor that promotes expression of many self-antigens
- Autoimmune polyendocrine syndrome type 2 (APS2)
- Early adulthood
- Thyroiditis or Diabetes type 1
Secondary adrenocortical Insufficiency
- Disorder of the hypothalamus n pituitary
- Reduction in ACTH causes hypoadrenalism
- Hyperpigmentation is lacking
Adrenogenital syndromes
- Exess androgens due to gonadal disorders or adrenal
- DHEA & Androstenedione converted to testosterone
- Androgen excess is secondary to cushing disease
- 11 hydroxlase
- Hypertension****
- Hypokalemia
- Increase in 11 deoxycorticosterone has same property as aldosterone
- Ambiguous genitalia in females
- 17-hydrozylase deficiency –
- only mineralocorticoids are found –
- more Na retention-
- K+excretion –
- Hypertension****
- No androgens – phenotypically female****
- When there is 21 hyrdroxylase enzyme deficient [congenital adrenal hyperplasia]
- Gene is present in short arm of chromosome 6
- there is no cortisol n
- no aldosterone[mineralocorticords] –
- hypotension
- ambiguous genitalia [ small penis, scrotal development]
- salt wasting*****
- low BP, low Na, high K
- adrenal hyperplasia [decrease in feedback inhibition causes secretion of adrenocorticotropic hormone]
- Female pseudohermaphroditism [female with male phenotypes]
Adrenal Medulla
- Derived from neural crest, chromaffin cells
- Synthesize and secrete catecholamines
- Cells are modified sympathetic postganglionic neurons
- Disease
- Neuronal tumors
- Ganglion cell tumors
- Chromaffin cell tumors
- Pheochromocytoma
- Excess synthesize of catecholamines
- Hypertension
- Benign or malignant
- Color – yellow tan, incubation with potassium dichromate (Zenker’s fixative) Dark brown color [due to oxidation of stored catecholamines]
- “Zellballen” pattern
- Episodic hypertension
- Tachychardia, palpitation, headache, drenching sweats, tremor
- Cardiac complications – catecholamine cardiomyopathy
- Lab – 24hrs urine for VMA and metanephrine
- Hyperglycemia
- Neuroblastoma
- Under 5 years old
- Located adrenal medulla
- Amplification of N-MYC oncogene
- Small cell tumor
- Presence of Homer-Wright rosettes
- Lab – similar to pheochromocytoma
- MEN type 1
- 3Ps (pancreastic, pituitary, parathyroidism)
- Pancreatic – gastrinomas (ulcers)
- Pituitary – prolactinomas
- Mutation MEN 1 Gene
- MEN 2A [sipple’s syndrome]
- RET gene
- Medullary thyroid carcinoma
- Parathyroid hyperplasia (hypercalcemia)
- Pheochromocytoma
- MEN2B[William syndrome]
- Medullary thyroid carcinoma
- RET gene
- No parathyroid hyperplasia
- Marfanoid habitus
- Ganglioneuromas of GIT, Lips and tongue
- Familial medullary thyroid cancer
- Only thyroid cancer nothing else
- Von Hippel-Lindau
- Pheochromocytoma
- Paraganglioma
- Renal cell carcinoma
- Hemangioblastoma
- Pancreatic endocrine neoplasm
Pancreatic Endocrine Neoplasm
Islet cell Tumors
- Rare
HYPERINSULISISM
- Tumor from beta cells of langerhans
- Hypoglycemic shock [confusion, tumor, loss of consciousness]
- 80% have MEN1
- Lab – high insulin levels, high C-peptide levels [ endogenous marker of insulin produced in Beta-islet cells]
- If patient is in sulphonyl urea[can increaseinsulin level too] – urine will contain it – for weight loss
- Zollinger-Ellsion syndrome –
- gastrin producing tumor
- hypergastrinemia [ peptic ulcer]
- ulcer in unusual locations
- [NOT TEST USMLE}Glucagonoma
- High glugagon secretion
- Mild diabetes
- Necrolytic migratory erythema rash
- [NOT TEST USMLE]Somatostatinoma
- High somatostatin
- Mild diabetes
- Cholelithiasis
- Steatorrhea
- Hypochlorhydria
- VIPoma
- Watery diarrhea
- Hypokalemia
- Hypotension
- Periorbital edema
DIABETES
3Ps
- Polyuria
- Polydypsia
- Catabolic state
- Reduction in glucose level
- Insulin requiring cells –striated and cardiac muscle, fibroblast, fat
- Non-insulin requiring – BV, nerves, kidney, eyelens
- GLUT 4 [in muscle n adipose tissue]
- In pancreatic cell – GLUT 2 mediators [ in beta cells]
- Sulfonylurea drugs make the beta cells to release insulin
- Low glucose inside cell
- High glucose outside
- TYPE 1 Diabetes Mellitus
- Autoimmune
- Pancreatic beta-cell destruction
- You will find lymphocytic infiltrate in pancrease
- Patients improve with insulin administration
- Insulitis
- Autoimmune occurs against these antigens
- Insulin
- Beta cell enzyme glutamic acid decarboxylase
- Islet cell autoantigen 512
- HLA locus on chromosome 6
- Genetic factor –occurs with transcription factor 7 like 2 [TCF7L2]
- Ketoacidosis
- TYPE 2 Diabetes Mellitus
- Peripheral resistance to insulin action
- Inadequate secretory response
- Loss of insulin sensitivity in the hepatocytes [ abdominal obesity][fat on the liver]
- No HLA association
- Under microscope you will find amyloid
- Decreased levels of adiponextin [ in obesity]
- TZDs [thiazolidinediones] activates peroxisome proliferator activated receptor gamma – it increase the adiponectin- decrease resistance
- Metformin – improves insulin sentivity – only drug – enhance the activity of the AMP-activated protein kinase (AMPK)
- Leptin improves insulin sensitivity
- Hyperosmolarnonketotic coma
- Rx – weight loss, upregulate insulin receptor synthesis
- Amyloid deposits can be seen islet of langerhans
Complications of Diabetes Mellitus
- Short term
- Hypoglycemia
- DK
- Non ketotic hyperosmolar diabetic coma
- Lactic acidosis
- Long term
- Microangiopathy
- Smaller BVs are damaged
- Excess deposition of protein
- Macroangiopathy
- Factors
- Insulin resistance
- Obesity
- Persistent hyperglycemia
- Recommended HbA1C be maintained below 7%
- Mechanism
- Formation of advanced glycation end products [AGEs]
- Its complex enzymatic reaction b/w glucose derived dicarbonyl precursor with amino group
- They gets deposited in the basement membrane
- It cross links the type 4 collagen which increases fluid filtration
- AGEs trap LDL particules and cause cardio vascular diseases
- Damages intracellular, extracellular and plasma proteins
- Activation of Protein Kinase C(PKC)
- Increase intracellular glucose increases DAG PKC activation
- Produces profibrogenic molecules. TGF-beta
- Increases plasminogen activator inhibitor 1
- Intracellular hyperglycemia with disturbance in polyol pathways
- Leads to an increase in intracellular glucose that is then metabolized but the enzyme aldose reductase to sorbital
- NADPH is used as a cofactor- for the enzyme glutathione reductase
- Increases cellular susceptibility
- Thickening of the basement membranes of small vessels, kidneys, retina, nerves
- Peripheral neuropathy
- Bilateral
- Tingling and numbness in the extremities
- Loss of pain sensation can result in the development of ulcers that heal poorly - diffuse vascular injury – morbidity
- Neuropathic ulcers – painless, callus, at pressure points
- Renal failure
- Lesions
- Glomerular lesions
- Capillary basement membrane thickening
- Diffuse mesangial sclerosis
- Nodular glomerulosclerosis
- Renal vascular lesion
- Pyelonephritis
- Nephropathy
- Morbidity
- Deposition of AGE {Advanced Glycosylation End-products as nodules}
- Nephritic syndrome
- End stage renal failure
- Kimmelstiel Wilson Sy
- Retinopathy
- Increased risk of cataracts and glaucoma
- Increased risk for retinal detachment and blindness
- Thickening of the basement membrane of the epithelium of the pars plicata of the ciliary body – histological marker of DB in the eye
- Basement membrane of retinal blood vessels is thickened
- Proliferative
- Retinal detachment
- Up-regulation of VEGF
- Retinal angiogenesis
- Non Proliferative
- Microaneurysms
- Cotton wool - infarcts
- Macular edema
- Elevated levels of PAI-1
- Diabetic patients you want to reduce the LDL levels less than 70
- Diabetic Dyslipidemia
- Hepatic production of atherogenic lipoproteins
- Suppress the uptake of circulating lipids in peripheral tissues
- Prone for Candidiasis infections [FUNGAL]
- Newborn Risks
- Hyperglycemia – causes increase in release of insulin – result in muscle mass and fat
- Caudal regression syndrome [SACRRAL AGENESIS] -
- Respiratory distress syndrome
- Macrosomia
- Gestational Diabetes
- Increased placental size and anti-insulin effect of human placental lactogen
- Acanthosis Nigricans – Hyperpigmentation in axis area – insulin resistance
- Diagnosis – Estimation of blood glucose, HbA1c should be less than 7%, fructose amine – reflects for 2 weeks
- Patients with DB
- Random glucose>200 mg/dl
- Fasting glucose?126mg/dl more than one occasion
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