Sunday, August 25, 2013

Frequently asked MICROBIOLOGY Slides!!!!!!

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