- Somatotroph --> 50% of cells --> Produce GH

- Lactotroph --> 15% of cells --> Produce prolactin

- Corticotroph --> 15% of cells --> Procude ACTH

- Thryotroph --> 10% of cells --> Produce TSH

- Gonadotroph --> 10% of cells --> Produce LH/FSH

- Protein hormones --> GH and prolactin

- Glycoprotein hormones --> LH, FSH, TSH, and hCG --> a subunit for all 4 hormones with independent b subunit

- TRH stimulates TSH production from pituitary

- TSH stimulates T4 and T3 secretion from the thryoid

- Somatostatin and Dopamine inhibit TSH production

- T3 and T4 negatively inhibit TRH and TSH production

- GHRH released from hypothalamus stimualtes GH secretion from pituitary

- GH stimulates IGF-1 secretion from liver and bone

- Somatostatin inhibits GH secretion from the pituitary

- IGF-1 negatively inhibits both GH and GHRH secretion

- ADH and CRH released from the hypothalamus stimulate ACTH release in the pituitary

- ACTH stimulates cortisol release from the adrenal gland

- Cortisol inhibits CRH and ACTH release from the hypothalamus and pituitary

- GnRH is released from the hypothalamus and stimulates FSH and LH release from the pituitary

- FSH stimulates mullerian inhibiting substance and inhibin release in the male and estrogen and inhibin release in the female

- LH stimulates progesterone and inhibin release in the female and testosterone in the male

- Testosterone, inhibin, estrogen and progesterone provide negative feedback on GnRH and FSH/LH release

- Dopamine from the hypothalamus and the rest of the brain inhibit prolactin release from the pituitary

- TRH stimulates prolactin release from the pituitary

- Prolactin preps the breast for lactation

- Estrogen stimulates prolactin release from the pituitary

- Pituitary adenoma --> Most common in adults

- Craniopharyngioma

- Benign sellar cyst

- Chordoma

- Meningioma

- Metastatic lesions

- Abscess

- Lymphocytic hypophysitis --> Sarcoid, TB, and amyloid

- Prevalence: 8.9/100,000

- 10-15% of all intracranial tumors

- Pituitary incidentaloma --> 15-27%

- Microadenoma (<1 cm) and macroadenoma (>1 cm)

1. Upward Growth

- Optic pathways --> Visual field cuts and blindness

- Hypothalamus --> Disturbed autoregulation

- Olfactory nerve compression --> Anosmia

- Dura --> Headache

2. Lateral Growth

- Cavernous sinus --> Proptosis, eyelid edema, and hemiplegia

- Internal carolid --> Altered LOC

- Oculomotor, abducens, trochlear and opthalmic nerves --> Opthalmoplegia, ptosis, pupils, facial pain, and corneal anesthesia

3. Downward Growth

- Epistaxis and CSF rhinorrhea

- Pituitary adenoma

- Craniopharyngioma

- Meningioma

- Optic glioma

- Rathke's cleft cyst

- Infections

- Apoplexy --> Sudden hemorrhage of pituitary adenoma --> Stroke, sudden headache and death

- Granulomatous disease, autoimmune hypophysitis, and hemochromatosis

- Traumatic stalk section

- Transsphenoidal surgery

- External radiation

- ACTH --> Adrenal crisis and death

- TSH --> Hypothyroidism and death

- LH/FSH --> Infertility, sexual dysfunciton and osteoporosis

- GH --> Short stature (children) and hyperlipidemia, adiposity, and osteoporosis (adult)

- Prolactin --> Deficient lactation

- Prolactinoma --> 50%

- Nonfunctioning --> 34% --> 90% secrete a-subunit, b-LH, or b-FSH --> No treatment for small tumors and transsphenoidal surgery for large tumors

- GH --> 10%

- ACTH --> 5%

- TSH --> 1%

- FSH/LH --> <1%

1. Physiologic causes

- Pregnancy

- Nursing

- Stress and nipple stimulation

2. Pharmacologic

- Dopamin antagonists --> Antipsychotics

- Estrogen

3. Pathologic

- Prolactinoma

- Primary hypothryoidism --> Increased TRH can overcome inhibitory effect of dopamin --> Increases prolactin

- Chronic renal failure

- Chest wall lesions --> Breast stimulation

- Polycystic ovary syndrome

- Hypothalamic/pituitary lesions

- Galactorrhea --> 30-80% female and <10% male

- Hypogonadism --> Anovulation, oligo/amenorrhea, reduced fertility, reduced libido, and impotence

- Osteopenia/osteoporosis

- Hirsuitism

- Dopamine agonist --> Bromocriptine and cabergoline (D2R agonist)

- Surgery --> High recurrence rate

- Observation --> Hypogonadal effects

- Radiation --> Not effective

- Somatotropes --> 50% of hormone producing cells in the pituitary

- Pulsatile release

- Stimulated by hypoglycemia and inhibited by glucose

- Also stimulated by exercise, arginine, and stress

- Levels also rise during pregnancy

- Effects: Increased protein synthesis and visceral organ growth, lipolytic effets, antagonist of insulin action with insulin resistance, decreased glucose uptake into muscle and adipose, and increased hepatic glucose production

- Stimulates the release of IGF-1 from liver and bone --> Increased bone, cartilage, and soft tissue growth

- GH excess before puberty --> Gigantism

- GH excess after puberty --> Acromegaly

1. Musculoskeletal

- Soft tissue growth

- Acral enlargement

- Arthralgia

- Prognathism --> Severe underbite

2. Cutaneous

- Increased sweating

- Skin tags

3. Cardio

- Cardiomyopathy

- Hypertension

4. Respiratory

- Tongue enlargement

- Sleep apnea

5. Metabolic

- Diabetes mellitus

- Hyperlipidemia

- Hypercalcuria

6. Gastrointestinal

- Colonic polyps

- Increased risk of colon CA

- 2-5 times increased in mortality due to cardio, respiratory, neoplastic, and diabetic complications

- Morbidity due to arthritis, nerve entrapment, sweating, skin tags, fatigue, acral changes, and dental malocclusion

- Treatment Goals: GH < 2 ng/mL after oral glucose tolerance test and normal IGF-1 levels

- Surgery --> Microadenoma (70-80% cure), macroadenoma (30% cure rate), and 6% recurrence rate

- Radiotherapy --> 5-42% normalization of IGF-1 levels but may take decades

- Medical therapy: Somatostatin analogs (ocretotide), dopamine agonists (bromocriptine/cabergoline), GH receptor antagonists (pegvisomant), and IGF-1 receptor antagonists (JB3 investigational drug)

- L-Arginine Vasopressin (AVP)/Anti-diuretic hormone (ADH) --> Binds renal V2 receptors --> Stimulates cAMP and results in the insertion of aquaporin 2 channels

- Supra-physiologic AVP binds V1 receptors on blood vessels --> Increases BP

- Released from the supraoptic and paraventricular nuclei of the hypothalamus --> Travels down the stalk and to the posterior pituitary

- Binding protein: Neurophysin --> No binding at physiologic serum pH

- Hormone stored in the axon terminals

- 5-10 day supply when hormone used to the max

- 1 month supply when hormone not maxed

1. Osmoregulators

- Located in the anterior hypothalamus

- Suppresses AVP release when plasma Osm <280

- Max urine output --> >16 L/day

- Max dilute urine --> 150 Osm

- AVP rises linearly with P Osm --> Max of 6 pg/mL

- Max release when P Osm >295

- Max conc. urine --> >800 Osm

2. Baroreceptors

- Located in the cardiac atria --> Reaches AVP neurons via CN IX and X

- AVP released when blood volume down 5-10%

- Sino-aortic baroreceptors cause a huge AVP release with a pressor effect

3. Nausea --> Potently and rapidly stimulates AVP release

4. Thirst --> Stimulated when P Osm >290

- Also stimulated by hypovolemia

- Central vs. Nephrogenic

- Urine volume > 50 mL/kg/day

- Urine Osm <300 and SG <1.010

1. Lack of AVP production and release (central)

2. Renal AVP insensitivity (Nephrogenic)

3. Increased water intake --> Schizophrenia, etc

4. Increased AVP clearance

- Requires a loss of >90% of secretory capacity in order to lose enough ADH to show symptoms

- Large hypothalamic or stalk lesion --> Pituitary lesions are insufficient

- 10% of AVP producing cells can keep the urine output <4 L/day

- Presentation: Abrupt onset of polyuria, polydipsia, thirst, nocturia, preference for "ice cold" water, normal exam, hypernatremia, and hyperosmolarity

- Hyperosmolarity --> Altered mental status, hyperthermia, coma, brain shrinkage and vessel rupture

- Causes: Neurosurgery, trauma, craniopharyngioma, hypothalamic glioma, germinoma, infiltrative diseases, and idiopathic (25-50%)

- Rare variant: Essential hypernatremia, loss of osmoreceptor input and excretion of dilute urine until hypovolemic --> Then ADH released

- Classic Triphasic Response: Acute loss of ADH due to initial insult (acute), cell death and damage to neurons leads to leakage of ADH (interphase), and finally progression back to having no ADH activity (permanent)

- Etiologies: Hypokalemia, hypercalcemia, and lithium --> cAMP inhibition

- Familial X-linked Disease: Defect in AVP V2 receptor --> Mother's disease can be mild since mom is XX

- Idiopathic or schizophrenia

- Schizophrenia --> "Water is healthy"

- Dipsogenic DI: Osmotic threshold for thirst is lower than that for ADH secretion --> Leads to chronic thirst, which precipitates polydipsia

1. Diagnosis

- Rule out osmotic diuresis with urine osmolality, serum osmolality, and serum chemistry (electrolytes, glucose, creatinine, and Ca)

- Polyuria reduces max urine Osm

- T1 weighted MRI --> Loss of bright spot 

2. Monitoring

- Withhold fluids --> Measure weight and urine osmolality hourly until 3 consecutive samples vary by <30 mOsm/L

- Check ADH levels

- DDAVP Trial: 1 ug SC --> Check urine Osm after 1 hour

- Placenta produces vasopressinase which rapidly degrades ADH

- 4-6x increased ADH clearance

- Polyuria during the 3rd trimester --> 2 weeks postpartum

- Plasma Osm and Na levels --> 5 mEq/L lower during pregnancy

1. Symptomatic hypernatremia

- Correct rapidly only if it appeared within hours

- Otherwise correct slowly to avoid cerebral edema

- H20-Deficit= 0.6 x wt x (1-140/[Na+])

2. DDAVP

- 1 spritz intranasally delivered in 10 ug doses

- Find lowest dose that prevents nocturia

- Some patients will also require an AM dose

- Routine breakthrough doses as well

3. Variations

- Parenteral DDAVP (SC, IM, or IV) --> 10x more potent

- Oral --> 1/10th as potent and has a shorter half life

- L-AVP and porcine AVP have shorter T1/2's 

- Considered with low [Na+] in euvolemic patients

- Etiologies: CNS disease, pulmonary processes, and malignancies

- Treatment: Fluid restriction

- Normalize fluid slowly to avoid any CNS side effects

- Smaller in women than in men

- Also smaller in men who think they are women

- Lots of barriers to access to care

- Many doctors are uncomfortable or don't know how to talk about the topic of transgender

- 99% of patients were satisfied with their gender change

- Refer to mental health provider --> Need to determine if patient is actually serious or if they suffer from a mental disorder

- Do not treat pre-pubertal children

- Discuss impact of treatment with the patient and their parents

- Discuss future fertility

- Goal of treatment is to get hormones within the normal gender range

- Review time-course of changes --> Things move over months to years not overnight

- Monitoring is necessary --> Monitor every 3 months then every 6, monitor prolactin, bone mass density, screen breasts/prostate, and consider surgery for cancer risk female to male patients

1. Female to male: Take estrogen and switch to testosterone --> Testosterone by various routes are OK

- Begin at half the dose and titrate up quickly

- 100 mg IM testosterone weekly

- Consider surgery as a cancer issue in female to male patients

- Goals: Absence of menses, facial hair, and acne

- Follow: Serum testosterone, CBC, and lipid profile

- Don't forget to continue pap smears and mammograms until surgery

2. Male to female: Take testosterone and switch to estrogen --> Anti-androgen and E2 supplementation

- Monitor levels every 3 months and then every 6-12 months

- Spironolactone --> May require high doses and other anti-androgens are OK

- Estrogen --> Conjugated estrogens --> Need high doses and must monitor for thrombosis risk

- Begin at 1/4 strength --> Keep serum E2 range between 50 and 200

- Goals: Absence of erections/ejaculations, loss of facial hair, reversal of baldness (only in young men), and breast development

- Pitfalls: Diminished libido

- Follow: Serum testosterone, estrogen, prolactin, potassium, and lipid profile

- Don't neglect prostate exams

- Only consider surgery when endocrinologist and psychiatrist agree the patient is ready --> At least after 1 year

- Female to male options: Mastectomy, hysterectomy, oopherectomy, and neophallus construction

- Male to female options: Breast augmentation, rhinoplasty, thyroid chondroplasty, orchiectomy, neocliteroplasty, and vaginoplasty

- Suppress puberty if patient is ready

- Suppress puberty at the time of first changes --> Use GnRH analogues to delay puberty

- Cross sex hormones about age 16

- Surgery only after age 18 and when patient is ready

- Avoid treatments that result in permanent characteristics

- The majority of children presenting as transgender are NOT so as adults

- Metabolism: Raises blood glucose, stimulates gluconeogenesis, lipolysis, and protein catabolism, blocks glucose uptake into tissues, and promotes glycogen synthesis

- Circulatory: Potentiates pressor effects on heart and vasculature

- Immune system: Anti-inflammatory effect on lymphocytes, monocytes, and eosinophils, and blunts the response to inflammatory cytokines and prostaglandins

- Renal sodium retention

- Potassium excretion

- Volume expansion

- Raises blood pressure

- Renin-angiotensin System: AII directly stimulates the zone glomerulosa cells

- Potassium: Increasing potassium directly stimulates aldosterone secretion

- ACTH: Directly stimulates aldosterone secretion --> Less effect than angiotensin and potassium

1. Primary --> Addison's disease

- Adrenal destruction and deficiency of all adrenal hormones

- Causes: Autoimmune adrenalitis, TB, AIDS, systemic fungal infetions, bilateral adrenal hemorrhage, metastatic carcinoma, isolated glucocorticoid deficiency, adrenomyeloneuropathy, and drugs

2. Secondary

- Due to lack of ACTH secretion from the pituitary

- Deficiency in just cortisol

- Causes: Sudden withdrawal of excess steroids, pituitary tumor, lymphocytic hypohysitis, infiltrative diseases, hypothalamic tumors, post-partum necrosis (Sheehan's syndrome), head trauma, and pituitary surgery

- Glucocorticoid lack: Weight loss, nausea, fatigue, weakness, and hypoglycemia

- Mineralocorticoid lack: Postural hypertension, hyperkalemia, and hyponatremia

- Elevated ACTH level: Hyperpigmentation due to MSH production and melanocyte stimulation

1. Rapid cortrosyn test --> ACTH test

- IV administration of 250 mcg ACTH

- Draw cortisol and aldo levels at 0,30, and 60 minutes

- Draw ACTH level at 0 minutes

- Interpretation: Normal cortisol peak >15 mcg/dL and >7 increase, normal aldo increases >5 and ACTH should be within normal range

- Addison's: Low cortisol and aldosterone with high ACTH levels

- Secondary: Low cortisol, normal aldo, and low ACTH

- Hydrocortisone (20-25 mg/day in divided doses), cortisone, or prednisone

- Florinef --> Synthetic aldosterone --> 0.05-0.2 mg.day

- With or without androgen replacement for women

- Patients must wear a steroid ID bracelet

- Increasing doses of supplementation needed during illnesses

- Glucocorticoid excess

- Causes: High-dose steroid use, ACTH-producing pituitary tumor, ectopic ATCH production, CRH production tumor, and primary adrenal excess due to adrenal adenoma or carcinoma

- Cortisol excess symptoms --> Hyperglycemia, truncal obesity, thin skin, easy bruising, psych symptoms, depression, muscle weakness, purple stretch marks, full/red face, and hypertension

- ACTH excess symptoms --> Cortisol excess symptoms, hypertension, hypokalemia, acne, hirsuitism, and hyperpigmentation

- Adrenal adenoma symptoms --> Pure cortisol excess

- Adrenal cancer --> Any excess hormone combination, rapid progression, prominent hirsuitism and virilization, weakness, weight loss, and cachexia

1. Overnight dexamethasone suppression

- 1 mg dexamethasone at bedtime

- Measure cortisol levels the next morning

- Normal: Cortisol <1.8 mcg/dL

- False positives: Obese or alcoholic patients, and drugs that increase clearance --> Two-day low dose dex. suppression test to eliminate

2. 24-hour urine cortisol excretion

- Averages out the normal swings in cortisol levels

- Any level above normal is suspicious

- Levels >3 times upper limit of normal are rare except in Cushing's syndrome

- False positives: Depression and alcoholics

- False negatives: Incomplete urine collection

3. ACTH dependent vs. independent

- Measure 2 or 3 cortisol and ACTH levels

- Cortisol >15 mcg:

1. ACTH < 5 pg/mL --> ACTH independent

2. ACTH > 15 pg/mL --> ACTH dependent

3. ACTH 5-15 pg/mL --> Usually ACTH dependent

- Adrenal adenoma --> Surgical removal

- Adrenal carcinoma --> Surgical resection is rarely curative so medical therapy --> Ketoconazole, metyrapone, DDD, and aminoglutethamide for medical adrenalectomy

- Ectopic ACTH production: Treat underlying tumor and medical adrenalectomy

- Cushing's Disease: Resect pituitary tumor, pituitary irradiation, bilateral adrenalectomy, and medical adrenalectomy

- Cushing's syndrome

- Congenital steroid enzyme defect --> CAH -->11-OH or 17-OH deficit 

- Glucocorticoid Remediable Aldosteronism (GRA)

- Hyperaldosteronism

- Pheochromocytoma

- Adrenal cortical adenoma --> More severe

- Bilateral hyperplasia (Z. glomerulosa) --> Least severe --> Due to 17 alpha-hydroxylase deficiency --> Everything shunted to aldosterone production

- Adrenal carcinoma (rare) --> Most severe

- Need suspicion --> 30% reduction in potassium, BP resistant to standard treatment, and adrenal incidentaloma --> Screen with trial of thiazide diuretics and see if K falls

- Screening: Aldosterone level, PRA, and aldosterone:renin ratio

- Confirm diagnosis: Non-suppressible aldosterone production --> Give IV fluids which should turn of renin and aldo secretion

- Identify types: Adrenal imaging, venous sampling, and functional assays

- Aldo/PRA ratio: >30 suggests hyperaldo and plasma aldo should be >10 --> Ratio may be normal during treatment with diuretics and abnormal with beta-blockers --> Must stop interfering meds 2-6 weeks before

- When to screen? --> BP >160 systolic or >100 diastolic, low K, treatment-resistant hypertension, or adrenal incidentaloma on imagin

- Right and left adrenal vein sampling of aldo levels

- Helps determine if levels are coming from one or both adrenal gland

- Adrenal CT or MRI are not reliable

- Adenoma: Surgery often curative (50%) --> If not curative, surgery makes lesion more responsible to medical therapy

- Adenoma: Medical therapy with K-sparing diuretics (Spironolactone or amiloride)

- Bilateral hyperplasia: K-sparing diuretics, Ca-channel blockers, and ACE inhibitors --> Better to treat medically because surgical treatment would make patient adrenally insufficient

- Rare tumors of the adrenal and extra-adrenal sympathetic tissues --> Accounts for 1% of hypertension

- Most are symptomatic and hypertensive (90%) --> 67% have sustained hypertension and 33% have intermittent

- Biochemical screening should precede imaging

- Not rare in patients with incidentally discovered adrenal masses

- Symptoms: Palpitiations, hypertension, flushing/blanching, headaches, anxiety, and impending doom

- Hypertension

- Anxiety attacks

- Hyperthryoidism

- Intracranial lesions

- Diencephalic seizures

- Cocaine use

- Baroreflex failure

- Neurofibromatosis

- von-Hippel Lindau syndrome --> Retinal hemangiobastoma and renal cancer as well

- Familial Pheochromocytoma

- Multiple Endocrine Neoplasia 2B --> Hyperparathyroid, medullary thryoid cancer, and pheochromocytomas

- Urine catecholamines, metanephrines and VMA

- Plasma metanephrines --> Gold standard

- Plasma catecholamines

- Dynamic testing --> No longer used

- Imaging --> Right adrenal usually extends posteriorly from the IVC and left adrenal usually triangular and overlaps upper pole of left kidney

- Pheos are hyper-intense on T2 weighted MRIs

- Adrenal --> 90%

- Organ of Zukerkandl --> Only other place in the body where epinephrine can be produced (on top of abdominal aorta)

- Abdominal sympathetic ganglia

- Bladder

- Mediastinal sympathetic ganglia

- Heart

- Head and Neck

- 10% are extra-adrenal

- 10% are familial

- 10% are bilateral

- 10% are malignant

- Surgical intervention --> Needs an experienced surgeon and anesthesiologist

- Medical treatment pre-operative or palliative

- Treat with alpha blockers (phenoxybenzamine or prazosin) first until BP lowers

- HR will then go up due  to unopposed beta input

- Treat with beta blockers to slow heart rate

- Treat with calcium channel blockers (nifedipine)

- Seen in 2-4% of all abdominal CTs and MRIs

- About 10% make some hormone

- About 10% are malignant

- Want to know if it's secreting and if it's malignant!!

- 90% make nothing/non-functional

- 6% made cortisol

- 3% are pheochromocytomas

- 1% are aldosteronomas

- Types of masses: Cortical adenoma (52%), other (22%), Pheochromocytoma (11%), carcinoma (13%), and metastases (2%)

- Help answer if the mass is secreting a hormone

1. Overnight dexamethasone suppression --> Cortisol

- Normal <1.8 mcg/dL

2. Plasma free metanephrines --> Pheochromocytoma

- Normal normetanephrine <0.9 and metanephrine <0.5

3. Plasma aldo:renin ratio --> Aldosterone

- Normal is <20 with plasma aldo >15 ng/dL

- Benign masses --> Regular borders, homogenous appearance, and no invasion of surrounding structures

- Bigger is more worrisome

- Tumor contents --> Fat density=benign

- Perfusion differences --> Fast washout for benign

- >90% of <3 cm masses are bening

- 10% of masses >4 cm are malignant

- 15% of masses > 6cm are malignant

- Benign masses are generally lipid-rich and show fast washout

- Malignant masses are lipid poor and show slow washout

- 1-24% of masses with being secreting a hormone, 15-20% will get larger and 0.2-0.5% will transform into malignant masses

- Lung (42%)

- Breast (58%)

- Melanoma (50%)

- Gastric (16%)

- Colon

- Lymphoma (25%)

- Tumor

- Infection

- Hemorrhage

- Thyroid is stimulated by TSH --> Very slight changes in T4 result in large changes in TSH

- Thyroid hormones are 59-65% iodine

- Phenolic rings of thyroglobulin are iodinated form mono-iodotyrosine, di-iodotyrosine, T3 and T4

- T3 is 20-100x more biologically active than T4

- Reverse T3, MIT, and DIT are biologically inactive

- Thyroperoxidase: Forms thyroglobulin and iodinates phenolic rings

- 99.96% of T4 is bound in plasma --> Mostly bound to thyroxine binding globulin (TBG), transthyreitin, and albumin

- Nearly 100% of T3 is also bound in plasma --> Mostly bound to thyroxine binding globulin (TBG) and then albumin

- T3 acts on an intranuclear receptor --> Modifes RNA transcription and protein translation

- 80% of T3 is make in the periphery by D1 deiodinase

1. Increased protein

- Genetically associated --> 1 in 20,000 births

- Physiologic: Pregnancy and neonates

- Drug induced: Estrogen replacement therapy, birth control pills, FSH injections, methadone, heroin, clofibrate, and 5-FU

- Nonthyroidal illnesses: Active hepatitis, hepatoma, and acute intermittent porphyria

2. Decreased protein

- Genetically linked --> X-linked in 1 in 5,000 births

- Drug induced: Androgens, glucocorticoids, ASA, high dose IV furosemide, and Lupron

- Non-thyroidal diseases: Cirrhosis, nephrotic syndrome, protein losing enteropathies, protein malnutrition, and chronic illnesses

1. Primary Hypothyroidism: High TSH levels with low T3 and T4 levels --> Thyroid gland has been destroyed

2. Secondary Hypothyroidism: Low TSH with low T3 and T4 --> Thyroid gland is non-function because pituitary doesn't release TSH

3. Tertiary Hypothyroidism --> Low TRH, TSH, and T3/T4 levels --> Damage to the hypothalamus leads to shut down of the entire axis 

- Hashimoto's thyroiditis --> Autoimmune destruction of the thyroid gland

- Ablation --> I-131 therapy or surgical removal

- Subacute thyroiditis --> 90-95% will recover to normal function

- Drugs: Lithium (interferes with hormone synthesis) and high iodine levels (seaweed, SSKI, and amiodarone)

- Metastatic cancer or fibrotic disease --> Rare

- Dyshormonogenesis and neonatal hypothyroidism (ectopic production or absent thyroid gland)

- Iodine deficiency --> Most common world wide but very uncommon in the US

- Radioactive imaging --> Very low radioactive iodine uptake (RAIU)

- Autoimmune destruction of the thyroid gland

- Primary hypothyroidism

- Anti-thyroglobulin and anti-thyroperoxidase (anti-TPO) antibodies

- TPO antibodies are associated with hypothyroidism

- Developing Hashimotos --> Environmental factors, especially pregnancy can trigger or predispose patients --> Genetic factors also

- 1 in 1,600 births in Mass

- Causes cretinism --> Severe hypothyroidism and mental retardation

- All children are screened for hypothyroidism at birth

- Prompt treatment with T4/L-thyroxine can reverse symptoms

1. Dysgenesis or agenesis (90%) --> Thyroid begins forming at the base of the tongue but must migrate down into the neck --> If it doesn't, can become hypothyroid or could be removed and mistaken for a mass

2. Dyshormogenesis (10%) --> Huge goiter but there is an error in metabolism where T3 and T4 can't be produced

- Low TSH and T4 levels present

- Causes: Pituitary or parasellar tumor, surgery, or radiation

- Due to inability of the pituitary to make TSH

- Low TSH and T4 levels seen

- Due to an inability of the hypothalamus to make TRH

- Both the pituitary and thyroid are not stimulated so they do not produce their hormone

- Both pituitary and thyroid are function though

- Causes: Carcoidosis, histiocytosis X, tumors, and radiation

1. Iodine deficiency

- Worldwide problem in 3rd world countries

- Severe deficiency (<25 mcg/day) --> Most common cause of goiter and reversible mental retardation

- Causes hypothyroidism and cretinism

2. Peripheral resistance to thyroid hormone

- Very rare

- Mutation in the thyroid hormone receptor --> Usually binds DNA but not thyroid hormone

- No negative feedback to hypothalamus or pituitary --> Peripheral high levels but hypothyroid physiology

- Symptoms: Mental retardation, hearing loss, and short stature

1. Symptoms: Fatigue, dry and coarse skin, lethargy, eyelid edema, cold intolerance, decreased sweating, pallor of skin, memory impairment, constipation, weight gain, loss of hair, hoarsness, anorexia, and menstrual disturbance

2. Signs: Slow movements and speech, hoarsness, bradycardia, dry skin, nonpitting edema/myxedema, hyporeflexia, and delayed reflexation of reflexes

3. Disease assocations

- Goiter --> Chronic autoimmune thyroiditis and antithyroid substances or excess iodine

- Pituitary or hypothalamic tumor/apoplexy --> Headache, visual impairment, deficiency or excess pituitary hormone

- Dry and rough epidermis --> Poor growth and decreased sebaceous gland activity

- Nonpitting edema --> Water retention from accumulation of mucopolysaccharides, hyaluronic avid, and chondroitin sulfate --> Puffiness around the eyes and macroglossia

- Dry and brittle hair with variable hair loss

- Symptoms --> Dyspnea and decreased force of ventricular contraction

- Signs --> Cardiomegaly, pericardial effusion, hypertensio due to diastolic dysfunction, elevated LDL by 15-20%, and increased CAD

- ECG: Low voltage with globally flattened T waves and/or inverted T waves

- Total and LDL cholesterol are elevated --> Increase in atherosclerosis and CAD --> Independent risk for MI similar to diabetes, smoking, and hypertension

- Poor GI motility --> Abdominal distension, flatulence, constipation and megacolon possible

- Autoimmune atrophic gastritis --> Achlorhydria in 50% and parietal antibodies with B12 malabsorption/pernicious anemia in 12%

- Severe iodine deficiency and hypothyroidism --> Cretinism --> Most common cause of mental retardation in the world

- T3 and T4 are necessary for CNS development

- Psychomotor depression --> Fatigue, depressed affect, slowing of speech and movements, and weight gain

- Can be misinterpreted as normal aging or depression --> Need high index of suspicion and TSH level to diagnose

- Oral L-thyroxine (T4) --> Long half life of 7-14 days

- Dosage requires ~6 weeks to achieve stead state

- Check TSH every 4-6 weeks to monitor levels

- Titrate T4 dosage to achieve normal TSH levels

- TSH should be checked every 6-12 months at the steady state

- Dosage for <40 year old: Start with full 75 - 125 mcg/day

- Dosage for 40-60 year old: Start cautiously at 50 mcg/day and slowly titrate up by 2 mcg/day every 3-4 weeks

- Dosage for 40-60 with CAD or >60 year old: Start wt 25 mcg/day and slowly titrate up every 4 weeks by 25 mcg/day

- Age and weight --> ~1.6 ug/kg

- History of previous I-131 therapy

- Concurrent medications --> Estrogen replacement therapy and anti-seizure meds

- Concurrent conditions --> Pregnancy (25-50% increase in dose may be required)

- Interference with T4 absorption --> Iron, calcium, sulcrafate, malabsorption, and fatty foods --> Wait 20-30 minutes to eat after taking meds

- Depends on the manufacturer of L-thyroxine

- 50% mortality rate

- Decompensated state of severe hypothyroidism with mental status changes

- Often presents in elderly patients with untreated underlying thyroid conditions

- Predisposing factors: Cold exposure, infection, CVA/MI, trauma, surgery, and CNS depressants

- Signs and symptoms: Hypoventilation with CO2 retention, hyponatremia, low core body temperature, and altered mental status

- Treatment: IV levothryoxine  (100-500 mcg bolus and 50-75 mcg/day), IV glucose, and assisted ventilation

- Be careful when using narcotics and other CNS depressants

- Treat other precipitating factors such as infection, MI, and CVA

- Avoid external warmth --> Sudden vasodilation may lead to hypoventilation and vascular collapse

1. 21-hydroxylase deficiency: Presents with effects of low aldosterone and cortisol --> Hypotension, hyperkalemia, and increased renin activity

- All intermediates are shunted towards producing androgens

- Males --> Present with precocious puberty with growth spurts, axillary hair growth and body odor

- Females --> Ambiguous genitalia at birth

2. 17-hydroxylase deficiency: Presents with symptoms of low androgens and cortisol

- Males --> Ambiguous genitalia due to decreased DHT

- Females --> Lacks secondary sex characteristics

- Low cortisol --> Hypoglycemia, hypotension, etc

- High aldosterone --> Hypertension due to fluid expansion and hypokalemia due to excessive K loss

3. 11-hydroxylase deficiency --> Presents with low levels of aldosterone and cortisol

- Low aldosterone --> Hyponatremia, hyperkalemia and fluid loss

- High levels of 11-deoxycortisone --> Makes up for the loss of aldosterone --> Hypertension

- Increased androgens --> Masculinization of females

- Hyperthyroidism --> Increased synthesis and secretion of thyroid hormones from the thyroid glands --> Circulating thyroid stimulators and autonomous thyroid functioning

- Destructive: Thyroid hormone antibodies

- Miscellaneous

1. Signs

- Tachycardia

- Tremors

- Stare

- Warm and moist skin

2. Symptoms

- Anxiety

- Weight loss

- Palpitations

- Perspiration

- Elevated total T3 and T4 levels

- TSH can either be high or low depending on the etiology of the hyperthyroidism

- Primary: Elevated T3/T4 with low TSH

- Secondary: Elevated T3/T4 with high TSH

- Subclinical: Low serum TSH but normal T3/T4 levels

- Helpful test to differentiate between types of thyrotoxicosis

- Tracer dose of I-123 is given to the patient

- Uptake scan obtained 4 and 24 hours after tracer dose

- Elevated RAIU causes

- Low RAIU causes

1. Grave's disease --> Circulating TSH receptor antibody

- Constitutively activates TSH receptor --> Increased T3/T4 production

2. Inappropriate TSH hypersecretion

- TSH-secreting pituitary tumor --> Specifically produces increased a-subunit

- Pituitary resistance to thyroid hormone negative feedback

3. Trophoblastic tumor, choriocarcinoma, and hyperemesis gravidarum --> Elevated levels of circulating hCG --> Binds TSH receptor

- D&C to remove the molar pregnancy reduces hCG levels and significantly reduces T4 levels

- Autoimmune disorder --> More common in females than males

- Most common cause of hyperthyroidism

- Mechanism: Circulating TSH-receptor antibody binds receptor --> Increased T3/T4 synthesis

- Diffusely increased RAIU seen on imaging

- Placental transfer of antibodies is possible --> Mom can make baby hyperthyroid --> VERY bad for baby but will disappear within 4-6 months of birth

- Goiter --> Enlargement of the thyroid gland

- Ophthalmopathy --> Exopthalamus --> Can progress to extreme inflammation and only seen in Grave's

- Dermopathy/Pretibial Myxedema

- Associated autoimmune diseases: Type I diabetes, vitiligo (~30%), premature grey hair, hypoparathyroidism, premature ovarian/testicular failure, hypophysitis, etc

1. Solitary hyperfunctioning adenoma --> Hot nodules producing excess T4 --> Low TSH

2. Multinodular goiter --> More common and called toxic multinodular goiter --> High T4 and low TSH

3. Non-autoimmune autosomal dominant hyperthyroidism

- Mutated TSH receptor gene leading to constitutive activation

4. Familial gestational hyperthyroidism

- Mutant TSH receptor that is hypersensitive to hCG

5. Lithium

1. Antithyroid drugs (ATD) --> Propylthiouriacin (PTU), methimazole (MMI), and iodide

2. Radioactive iodine --> I-131 is concentrated by the thyroid and destroys the hyperfunctioning gland

- This treatment may worsen Grave's disease --> Especially in patients who smoke

3. Thyroidectomy

- Especially useful in patients with a very large goiter or with severe Grave's eye disease

- Very rare cause

- Caused by a mutant TSH receptor that is hypersensitive to hCG --> Normally rise during pregnancy

- Thyrotoxicosis will resolve after delivery of the child and reduction of the hCG results

1. Inflammatory disease --> Release/leak of stored T3/T4

- Silent lymphocytic thyroiditis

- Subacute painful thyroiditis

- Drug-induced thyroiditis --> Amiodarone, IFN-a, and lithium

- High dose X-ray therapy

- Surgical manipulation

- Infarction of thyroid adenoma

- As the disease progresses the gland will become depleted of the stored hormone and will return to a euthyroid state

2. Thyrotoxicosis factitia --> Exogenous thyroid hormone

3. Metastatic thyroid cancer --> Foci of function autonomy

4. Iodine-induced hyperthyroidism --> Iodine excess plus goiter

5. Struma ovarri --> Ovarian teratoma/hyperthyroidism

- Thyrotoxicosis --> Elevated T3/T4 with depressed TSH that occurs 0-3 months after delivery

- No history of exogenous iodine or thyroid hormone

- Non-tender thyroid on exam

- Low RAIU

- Thyroid antibody (TPO) often positive

- High chance of recurrence with future pregnancies

- Lymphocytic infiltration seen by biopsy

- Treatment of thyrotoxic phase --> Symptomatic control with beta blockers

- Treatment of hypothyroid phase --> Hormone replacement

- Possibly of viral etiology

- Symptoms: Fever, viremia, tender thyroid, and symptoms of thyrotoxicosis

- Labs: Elevated T3/T4, low TSH, elevated serum thyroglobulin, low RAIU, elevated ESR (inflammation), and elevated CRP (inflammation)

- Treatment of Thyrotoxic Phase: Symptomatic control with beta-blockers or NSIADs and steroids

- Treatment of hypothyroid phase: No treatment required usually

1. IFN-a --> Used to treat chronic hep C

- Up to 15% elevation in TPO antibodies

- Thyroid dysfunction (1-35%) --> Hypothyroidism due to TPO antibodies (common) and hyperthyroidism (2-3%)

2. Amiodarone --> Rich in iodine --> Excessive iodine uptake leads to shutdown of the gland (hypothyroidism)

- Occurs in iodine-sufficient areas

- Antibodies are present in Type I but not type II

- Low RAIU

3. Lithium

- Exogenous thyroid hormone ingestion from medication or food

- Intentional or unintentional consumption

- Cases presented in the tri-state area of Iowa, Minnesotta, and Nebraska

- Due to local slaughter houses including cow thyroid in their ground beef

- Thyroid cancer most commonly metastasizes to the lung

- Relatively rare cause

- Excess ectopic production of thyroid hormone --> Inhibits TSH and reduces T3/T4 levels

- Commonly presents in patients with iodine deficiency being treated with iodine supplementation

- Can be seen in euthyroid Grave's disease during iodine administration

- Seen in patients with underlying thyroid disease --> Nontoxic nodular or diffuse goiter and autonomous nodules

- Seen in patients with no underlying disease --> Areas with mild to moderate iodine deficiency

- Also common in the US because we used iodine contrast for CT scans

- Can pre-treat with an iodine uptake inhibitor to eliminate the risk of post-CT hyperthyroidism

- Ovarian teratoma producing thyroid hormone

- Teratomas often include thyroid tissue --> Ectopic thyroid hormone production

- Normal thyroid uptake and function after teratoma removal

1. Well differenatiated

- Papillary --> 80% --> RET rearrangement mutation

- Follicular --> <10%

- Both papillary and follicular can undergo transformation to anaplastic due to p53 gene loss

- RET proto-oncogene: Membrane bound tyrosine kinase receptor for a growth factor --> Mutations of the extracellular and intracellular component are possible

2. Poorly-differentiated

- Anaplastic --> Very poor prognosis --> Death within 6 months even with treatment --> p53 gene loss

3. C-cells

- Medullary (rare)

4. Non-thryoid cells

- Lymphoma

- Metastasis from elsewhere

1. Activating mutations

- MEN IIa

- MEN IIb

- Familial medullary carcinoma

2. Rearrangement

- Papillary thyroid carcinoma

3. Inactivation

- Hirschsprung's disease: Congenital absence of parasympathetic ganglia in the gut

- 50% of patients over 60 years have one on ultrasound or autopsy --> Only 5% are clinically apparent nodules

- History: Must include symptoms of thyroid hormone excess or deficiency and family history of syndromes

- More concerning nodules --> Hard, immobile, >4 cm, and associated with lymphadenopathy --> Solitary or dominant nodule >1 cm but practically anything well palpated on exam

- Predisposing factors to concerning nodules --> Male patients, young patients, age >45 years, history of radiation exposure, and symptoms of rapid thyroid growth

- Simple office procedure --> Doesn't need advanced preparation

- Six passes with fine need

- Lidocaine anesthesia involved

- Several days of local bruising may result but no other morbidity from procedure

- Most nodules are benign

- 10% are suspicious

- 10% are insufficient for examination

- 5% are malignant

- Ultrasound --> Augments physical diagnosis

- Nuclear scan --> Useful to evaluate hyperthyroidism but is not necessary to evaluate nodules in euthyroid patients

- Commonly cold nodules on exam

1. Benign cytology

- Thyroidectomy if it grows despite appropraite TSH

2. Insufficient or fluid filled sample

- Repeat exam

3. Suspicious

- Microfollicular cytology

- With or without Hurthle cells

- Unable to make a clear malignant diagnosis --> Sometimes benign and malignant cells looks so similar, so need further testing

4. Malignant

- Evidence of carcinoma

- Papillary and follicular have indolent courses

- Medullary is indolent but fatal

- Anaplastic is extremely agressive and fatal even with treatment

- Near-total thyroidectomy --> Removal of the nodule --> Don't need to do catastrophic surgeries

- Radioactive iodine ablation of remnant --> Iodine treatment post surgery --> Well differentiated tumors are highly susceptible to iodine treatment

- Suppressive thyroid hormone dosing --> Suppresses TSH secretion and stops other thyroid nodules from growing

- Follow progress with thyroglobulin levels and I-131 full body scans

- Metastatic spread: Lungs, bones, and brain

- Rare thyroid malignancy

- Sporadic and familial types

- Cancer of the C-cells --> Calcitonin producing

- Associated with MEN IIa, MEN IIb, and familial MCT

- 5 year survival is 50%

- MEN IIb --> 2 year survival is 50%

- Treatment: Extensive surgery, prophylactic thyroidectomies (earliest is 7 months old), and regular surveillance for recurrence with serum calcitonin and CEA levels and imaging

- Screening: Screen for pheochromocytoma, preoperative staging of the tumor, identification of RET proto-oncogene mutation, and family screening for RET mutations

- Parathyroid hyperplasia

- Pancreatic tumors --> Gastrinoma, insulinoma, glucoagonoma, and VIPoma

- Pituitary tumors --> Non-functioning, GH, ACTH, PRL, and other

- Other tumors --> Adrenal adenoma, lipoma, carcinoid, and thyroid adenoma

- Medullary Carcinoma of the Thyroid --> Normally presenting feature --> Surgery is curative

- Pheochromocytoma --> Must diagnose pre-surgery to avoid hypertensive crisis

- Parathyroid hyperplasia

- Medullary Carcinoma of the Thyroid

- Pheochromocytoma

- Mucusal neuromas and ganglioneuromas --> Nastier disease course

- Marfinoid habitus

- Hyperparathyroidism (rare)

- Absorb 0.5-1.5 g a day in the gut --> Excrete 0.35-1.0 g daily

- Majority of calcium is located in bone --> 900-1400 g

- ECF: 1-2 g

- Kidney: 6-10 g transferred to kidney and 0.15-0.3g excreted daily

- 60% is bound to albumin in blood while 40% is free

- Must correct calcium levels is albumin is abnormal

- Serum Ca Correction= (4-Albumin level) x0.8

- Measured Ca + Ca correction --> Actual Ca value

- 0.6-2.0 absorbed daily by the gut and 0.2-0.6 excreted daily

- Majority of stores are in bone --> 500-800 g

- ECF: 0.8 g

- Kidney: Excretes 0.5-1.4g daily

- Vitamin D: Absorbs Ca from the gut

- PTH: Increases serum calcium but increasing reabsorption in the kidney and decreases phosphate by increasing phosphate excretion by the kidney

- Calcitonin: Decreases serum calcium levels

- PTHrP: Acts like PTH to raise calcium

- FGF23: Major hormone regulating phosphate levels --> Decreases phosphate levels 

- Major hormone regulating phosphate concentration

- Internalizes the Na/PO4 co-transporter in the kidneys

- Stimulates phosphaturia/phosphate excretion in the urine

- Produced by osteoblasts and osteocytes in bone

- 32 amino acid hormone

- Made by the C-cells of the thyroid

- Decreases/inhibits osteoclast activity

- Decreases bone resportion and serum calcium

- 84 amino acid protein hormone --> The first 34 amino acids are shared with PTHrP

- PTH increases Ca absorption and PO4 excretion in the kidney

- PTH increases the activity of 1 alpha-hydroxylase --> Increased 1,25(OH)2D

- PTH binds osteoblasts --> Stimulates RANK-L production

- RANK-L binds RANK receptor on immature monocytes

- Binding stimulates monocytes/macrophages to differentiate into osteocalsts --> Bone resorption and increased serum Ca levels

- There is a baseline secretion of PTH by the parathyroid gland --> Low Ca leads to higher PTH secretion and high Ca leads to lower PTH secretion

- Important ion for regulating the activity of enzymes

- High and low levels suppress PTH release

- Hypomagnesemia can be overshadowed by hypocalcemia

- Hypomagenesemia --> Prevents PTH from working on the skeleton

- Produced primarily by the skin via UV light exposure

- 7-DHC --> Pre-D3 via UVB radiation

- Pre-D3 --> Vitamin D3 via temperature change

- Any excess vitamin D made in the skin is destroyed --> Cannot become vitamin D toxic from sun exposure

- 25 hydroxylation occurs in the liver --> Major circulating form

- 1 hydroxylation occurs in the kidney --> 1,25(OH)2-D3

- 1,25(OH)2-D3 is transported to the intestine, binds vitamin D receptor, and increases Ca absorption

- Without vitamin D --> Intestine absorbs 10-15% of dietary calcium

- With vitamin D--> 30-80% of dietary calcium

- Stimulates mitochondria to make 1,25(OH)2-D3 in macrophages --> Stimulates phagocytosis of mycobacteria --> Crucial for mycobacterial infections

1. Fat malabsorption --> Chron's Disease, Ulcerative Colitis, cystic fibrosis, cholestyramine, and other meds decreasing fat absorption

2. Latitude, time, and season --> Amount of UV exposure

3. Skin pigmentation --> Darker skin produces less

4. Sunscreen --> Reduces production by ~98%

5. Aging

6. Clothing --> Reduces exposure

7. Obesity --> Associated with vitamin D deficiency due to decreased synthesis and absorption --> Need 2-3x the dose in supplements

8. Severe hepatic failure --> No production of 25(OH)D

- Commonly associated with malignancies --> Lung cancer

- 9 of the first 20 residues of PTH and PTHrP are identical

- Measured based on the 25(OH) D levels --> Best screening test

- Vit. D deficiency --> Decreased serum Ca levels --> Increased PTH --> Secondary hyperparathyroidism --> Raises serum Ca levels back to normal

- Rickets in children --> Square head, frontal bossing, Harrison's groove rachitic rosary, widened wrists and muscle weakness

- Osteomalacia in adults

- Increased PTH --> Leeches Ca and PO4 from bone and demineralizes bone

- Clinical manifestations caused by chronically low PO4 but NOT Ca

- Most people are vitamin D deficient --> 84% of black elderly, 32% of BMC residents and students, and 42% of health adolescents

- >150 ng/mL of 25(OH)-D --> Vitamin D toxicity

- >100 ng/mL of 25(OH)-D--> Excess

- 40-60 ng/ML and 100 ng/mL --> Safe range

- Increased PTH --> Secondary hyperparathyroidism

- Increased bone Ca mobilization

- Causes defects in bone mineralization and osteomalacia

- Increases the predisposition towards osteoporosis

- Symptoms: Generalized bone pain, isolated bone pain, and muscle aches

- Often misdiagnosed as fibromyalgia due to "trigger points"

- Diagnosis: Palpate the sternum, distal radius, and anterior tibia with the thumb/forefinger

- Vitamin D receptor is also present in skeletal muscle --> Muscle pain

- Increased neuromuscular irritability

- Paresthesias

- Laryngospasm --> Can be fatal

- Bronchospasm

- Tetany

- Seizures

- Chvostek sign --> Tapping on facial nerve

- Trousseau sign

- Prolonged QT interval on ECG

- Carpal spasm --> Very painful

- Hypoalbuminemia --> Albumin <4

- Hypomagnesemia --> Alcoholism or malnutrition

- PTH deficiency

- PTH resistance

- Hyperphosphatemia

- Vitamin D resistance

- Vitamin D deficiency

- Pancreatitis

- Rhabdomyalysis

- Sepsis

- Malignancy --> PTHrP

- Toxic shock

- High calcitonin

- Hepatic or renal failure --> Can't make 25(OH)-D or 1,25(OH)2-D3 to allow for proper Ca absorption in the gut

- Cholestyramine --> Bile acid binding resins

- Anti-seizure meds

- AIDS meds

- Prednisone and other glucocorticoids

- Last 3 meds all cause increased catabolism of 25(OH)D before it can be converted to active vitamin D

- Renal dsyfunction --> Reduced production of 1,25(OH)2-D --> Decreased Ca absorption by the gut

- Increased PTH levels due to low Ca levels --> Secondary hyperparathyroidism

- Increased PTH levels lead to low PO4 levels

- Kidney dysfunction --> Decreased PO4 clearance --> FGF23 release from  bone as an attempt to lower PO4

- FGF23 --> Inhibits 1 alpha hydroxylase --> Further reduces production of active vitamin D

- Severe disease when GFR <30 --> Severe Renal Failure

- Exogenous forms of vitamin D 

- Active vitamin D analogs that can be incorporated into the gut --> Calcitrol as needed

- 25(OH)D supplementation --> Decreased PTH levels

- Want to maintain 25(OH)D > 30 ng/mL

- Pseudovitamin D Deficiency Rickets

- Cannot make 1,25(OH)2-D3 in the kidney

- Mutation that inactivates 1 alpha-hydroxylase

- Not actually vitamin D deficient --> Can't make active vitamin D

- Labs: Increased 25(OH)D but no 1,25(OH)2-D3

- Vitamin D resistant rickets

- Mutation in the vitamin D receptor

- Associated symptoms: Alopecia

- Normal synthesis and conversion of vitamin D in the body but cannot be incorporated into the gut and other tissues like normal

- Reduced active vitamin D production

- Reduced bone Ca and PO4 mobilization

- Decreased Ca absorption --> Hypocalcemia

- Decreased PO4 excretion --> Hyperphosphatemia

- Causes: Deficiency PTH secretion, inability to make active PTH, and inability of kindeys or bone to respond to PTH

- Signs and symptoms: Tingling legs, fingers, and toes, muscle cramps, pain in the face, legs, and feet, abdominal pain, dry hair, brittle nails, dry and scaly skin, cataracts, convusions, and muscle spasms (tetany)

- Most signs and symptoms due to hypocalcemia

- Labs: Calcium, albumin and PTH levels

- Hereditary --> Absent parathyroid glands

- Acquired: Accidental damage due to thryoid surgery

1. Isolated

- Autosomal dominant --> PTH gene mutation

- Autosomal recessive --> PTH gene mutation

- X-linked

2. Congenital multi-system syndromes

- DiGeorge & Velocardiofacial --> 22q11 chromosome mutation

- Barakat/HDR

- Kenny-Caffey and Sanjad-Sakati

3. Metabolic Disease

- Mitochondrial neuromyophathies

- Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

- Heave-metal storage disorders

4. Autoimmune disease --> Polyendocrine syndrome type I

5. Parathyroid resistance syndromes

- Pseudohypoparathyroidism --> Can't recognize receptor

- Blomstrand chondrodysplasia and related PTH receptor defects

- Hypomagnesemia and other metabolic disorders

- Normal PTH production

- PTH receptor mutation --> Can't recognize PTH

- Type Ia --> Inactivation mutation of GNAS gene

- Type Ib --> Selective resistance to PTH due to imprinting defect of GNAS gene

- Diagnosis: Examine MCP joints --> 4th and 5th metacarpals are shortened --> Knuckle, knuckle, dimple, dimple

- Evidence seen in the brain as well

- Type 2 --> Normal cAMP but no phosphaturia after PTH stimulation

- Vitamin D supplementation --> If due to vitamin D deficiency

- Vitamin D active analogs --> Helps raise Ca levels

- IV CaGluconate --> Immediate Ca repletion

- IV magnesium --> If due to hypomagnesemia too

- PO Ca and Mg --> Requires prolonged supplementation

- Initially --> Supplementation of 50,000 IU vitamin D2 every week --> 6600 IU/day --> Can be continued every week for 5-6 years without any issues

- Then --> 50,000 IU vitamin D2 every 2 weeks --> 3,300 IU/day

- Vitamin D2 and vitamin D3 are just as effective

- 100 IU of vitamin D3 raises 25(OH)D2 by only 1 ng/mL

- Goal: 25(OH)D2 >30 ng/mL

- Sun exposure too!! --> SPF 30 on your face but not on your arms and legs to allow synthesis

- Cancer risk and mortality

- Autoimmune disease

- Type I diabetes

- Hypertension

- Type II diabetes

- 0-1 years --> 400-1000 IU/day --> 2,000 IU/day safe upper limit

- 1-18 years --> 600-1000 IU/day --> 4,000 IU/day safe upper limit (1-12 years)

- >18 years --> 1500-2000 IU/day --> 10,000 IU/day safe upper limit (>13 years)

- Obesity --> 2-3x more for age range

- X-linked and autosomal disease

- Due to mutation in FGF23 binding site for neuraminidase or neuraminidase mutation

- Leads to inability to inactivate FGF23 --> Hypophosphatemia

- Incrased FGF23 --> Inactivation of 1 alpha hydroxylase --> Reduced 1,25(OH)2-D3 production --> Reduced Ca absorption

- Ca leeched from bone to normalize serum Ca --> Hypocalcemia only results after all the Ca has been leeched out of the bone

- Produces PTHrP

- Leads to hypophosphatemia

- Often due to benign lesions of the bone marrow --> Often very hard to find

- Normal 1,25(OH)2-D3 levels with hypophosphatemia and hypercalcemia

- PTHrP initially works in a paracrine fashion but can work in an endocrine fashion when levels are high enough

- Diagnostic Labs: Mg, PO4, TSH, repeat calcium, albumin, PTH, PTHrP, 25(OH)D levels, and 1,25(OH)2 levels

- If albumin is abnormal --> Need to calculate the corrected Ca level

- Symptoms: Weakness, bone pain, osteoporosis, polyuria, polydypsia, kidney stones, anorexia, nausea, constipation, and confusion/altered mental

1. PTH-Mediated

- Primary hyperparathyroidism

- MEN I and IIa

- Familial Hypercalcemic Hypocalciuria (FHH) --> Low 24 hour calcium excretion

- Tertiary hyperparathyroidism

2. PTH-Independent

- Malignancy --> PTHrP

- Vitamin D intoxication

- Granulomatous disease

- Medications

- Other: Thyrotoxicosis, pheochromocytoma, adrenal insufficiency, and total parenteral nutrition

- 85% due to parathyroid adenoma

- 15% due to parathyroid hyperplasia

- <1% due to parathyroid carcinoma

- Signs: Osteitis fibrosa cystica --> Increased bone swelling

- Vitamin D deficiency makes things worse --> Must replete if low

- Labs: High calcium, low phosphorous, and low bone density --> Osteomalacia or osteoporosis

- 20-30% of malignancy cases

- Associated cancers: Breast, lung, and multiple myeloma

- Poor prognostic sign for cancer

- Most common cause of hypercalcemia in hospitalized patients

1. Humoral hypercalcemia (80%)--> Due to increased PTHrP levels --> Works like PTH so skeletal Ca release and decreased Ca excretion

- Labs: Increased calcium, decreased PTH, and increased PTHrP

2. Osteolytic metastases (20%) --> Increased skeletal Ca release --> Cytokines and interleukins can stimulate osteoclast formation and activation --> Bone breakdown

- Labs: Increased calcium, decreased PTH, and decreased PTHrP

- Granulomatous disease

- Unregulated excessed of vitamin D

- Classically presents in early fall (September)

- Labs: Increased calcium, decreased PTH and PTHrP, and increased 1,25(OH)2-D3

- Increased gut absorption of Ca due to excess vitamin D production

1. PTH-mediated

- MEN I and IIa --> Much lower penetrance of hyperparathyroidism

- Tertiary hyperparathyroidism --> Due to chronic kidney disease --> Low PTH levels and bone doesn't properly respond to Ca and PO4

2. PTH-independent

- Vitamin D intoxication --> Pretty rare --> Has to ingest huge quantities through creams and meds

- Medications: Lithium (chronic ingestion), thiazides, vitamin A (high doses), theophyline toxicity, and teriparitide

- Milk-alkali syndrome: Severe peptic ulcer disease or ingestion of HUGE quantities of calcium

- Pheochromocytoma: PTHrP release by abnormal chromaffin cells

- Miscellaneous: Increased 1,25(OH)2D due to lymphoma, immobilization, adrenal insufficiency, hyperthyroidism, and TPN acromegaly

- Jansen-type Metaphyseal condrodysplasia

- Tonic activation of PTH receptor

- Results in skeletal abnormalities

- Normal PTH levels but PTH receptor mutation

- Can be asymptomatic or can present with hypercalcemia or hypophosphatemia

- Depends on the symptoms and the Ca level

- Asymptomatic or mild symptoms (Ca <12 mg/dL) --> Doesn't require immediate treatment

- Marked hypercalcemia (12-14 mg/dL) --> Well-tolerated if chronic

- Always treat if neurological symptoms are present or Ca >14 mg/dL --> Medical emergency 

1. Isotonic saline hydration --> Hydrate patients first, helps get kidneys working --> Works within hours and only active during infusion

2. Loop diuretics/furosemide --> Inhibits renal Ca resorption --> Works within hours

3. Calcitonin --> Inhibits bone resportion and promotes urine calcium excretion --> Takes 4-6 hours to work and lasts for 48 hours

4. Bisphosphonates --> Inhibits bone resportion --> Takes 24-72 hours to take effect and lasts 2-4 weeks

5. Glucocorticoids --> Inhibits intestinal Ca absorption and decreases 1,25(OH)2D production in granulomatous cells of the kidney --> Takes 2-5 days to take effect and lasts days to week

6. Dialysis --> Only required if Ca is extremely high --> Brings Ca down acutely and only for a limited time

7. Denosumab --> Monoclonal antibody that inhibits osteoclasts

8. Calcimimetics --> Acute treatment modality

- ~ 200 million women worldwide are affected --> 1/3 of women 60-70 years old and 2/3 of women >80 years old

- Approximately 30-50% of women over the age of 50 have one or more vertebral facturs

- Approximately 1 in 5 men over the age of 50 will have an osteoporosis related fracture in their remaining lifetime

- Osteoporotic fractures are associated with high rates of morbidity and 20% mortality within 1 year

- 20% die within 1 year

- 30% have permanent disability

- 40% are unable to walk independently

- 80% are unable to carry out at least one independent activity of daily living

- Back pain

- Loss of height

- Deformity --> Kyphosis and protuberant abdomen

- Reduced pulmonary function due to inability to expland rib cage

- Diminished quality of life --> Loss of self esteem, distorted body image, depedence on narcotics, sleep disorders, depression, and loss of independence

- Skeletal disorder characterized by compromised bone strength

- Predisposes to an increased risk of fracture

- Silent condition

- T-score >-2.5

- Diagnosis: Dual energy X-ray absorptiometry (DEXA) scans --> Gives T and Z scores

- Symptoms: Bone pain before fracture

- Labs: Abnormalities in serum calcium, phosphorous, alkaline phosphatase, and urine calcium

- Family history of hip fracture

- personal history of fracture in adulthood

- Current cigarette smoking

- High daily intake of alcohol

- Low body weight (<127 lb)

- Glucocorticoid therapy

- Rheumatoid arthritis

- Hyperparathyroidism

- Vitamin D insufficiency

- Hyperthyroidism

- Cushing's syndrome

- Renal insufficiency

- Multiple myeloma

- Celiac disease

- Origination: Signal activates osteoblasts to become activated --> Release of RANK-L to bind and activate osteoclasts

- Activation: Osteoclast activation --> Begin resorption

- Resorption: Osteoclasts resorb bone

- Formation: Osteoblasts come in and fill resorbed pit with osteoid

- Mineralization: Osteoid is mineralized and new bone formed

- Takes 4 years to completely replace bone

- Familial mutation leading to extremely high bone density

- Very thickened bones seen on x-ray

- LRP-5 binds to Wnt in the Wnt signaling pathway involved with bone density and increases bone formation

- Sclerosin binds and inhibits the interaction between LRP-5 and Wnt

- LRP-5 mutation inhibits Dkk inhibition of the pathway --> Constitutive activation of Wnt signaling pathway

- Inhibition of osteoclast formation and activation

- Cathepsin K inhibitors

- Selective estrogen regulation --> Helps modulate osteoclast activity

- Life-style changes --> Moderate alcohol use and stop smoking

- Adequate calcium intake --> 1200-1500 mg daily

- Adequate vitamin D intake --> 800-1000 IU daily

- Weight bearing exercise

- Fall prevention techniques 

1. Anti-resorptive

- Estrogens

- Selective Estrogen Receptor Modulators (raloxifene)

- Calcitonin

- Bisphosphonates --> Alendronate, risedronate, ibandronate, and zoledronic acid

- Denosumab: Monoclonal antibody that binds and inhibits RANK-L binding

- Strontium ranelate --> Cathepsin K inhibitor --> Not approved yet

2. Anabolic --> Increased bone formation

- Teriparatide

- Fluoride --> Not used anymore --> Causes dishevelled bone architecture

- Strontium ranelate

- Other monoclonal antibodies are available for this too

- Approved to prevent osteoporosis

- Available in various oral and transdermal forms

- Binds nuclear estrogen receptors

- Oral --> High hepatic first pass effect

- Adverse effects --> Hypercoagulability, breast cancer, and cholestasis

- Black box warning for CV disease

- Approved for osteoporosis therapy

- Subcutaneous and intranasal forms

- Binds to calcitonin receptors on osteoclast and renal cells

- Suppresses bone resportion and increases calciuria

- Onset --> 15-30 minutes

- Duration --> 8-24 hours

- Adverse effects --> Rhinitis, GI upset, and itch

- Some increased risk of developing cancer

- Zoledronic acid, risedronate, alendronate, and ibandronate

- Can be taken orally or IV --> Daily, weekly and monthly dosing for PO and every 3 or every 12 months for IV dosing

- Used for prevention and treatment of osteoporosis

- Binds hydroxyapatite released by osteoclasts

- Interferes with the mevalonate pathway --> involved in cholesterol synthesis

- Suppresses bone resorption

- Long half life --> 10 years

- Poorly absorbed orally --> Must be taken on an empty stomach

- Improvement of periodontal health too

- Adverse effects --> Hypocalcemia, esophagitis, and jaw osteonecrosis

- Exposed bone after tooth extraction

- 94% of patients were treated with zoledronic acid or pamidronate or both

- 85% of patients have multiple myeloma or metastatic breast cancer

- Prevalence in patients with cancer is 6-10%

- 60% occurs after dentoalveolar surgery for infections

- Prevention --> Treatment for dental infections before starting bisphosphonates

- Monoclonal antibody that binds RANK-L and mimics osteoprotegerin

- Decreases bone resorption and increases bone density at the spine, wrist and hip

- Reduces vertebral, hip and non-vertebral fractures

- Contraindicated in hypocalcemia

- Adverse effects --> Cellulitis, eczema, and jaw osteonecrosis

- Not approved in the US yet

- Given orally

- Binds to hydroxyapatite released by osteoclasts

- Decreases the number and function of osteoclasts

- Increases the number of pre-osteoblasts

- Simultaneously decresaes bone resorption and increases bone formation

- Decreases vertebral, hip and non-vertebral fractures

- Adverse effects --> Diarrhea

- Approved for high risk patients

- Daily subcutaneous injections

- Binds to PTH-1 receptors on osteoblasts to stimulate bone formation

- First 34 amino acids are the same as PTH

- Peaks in 30 minutes and is gone in 3 hours

- Adverse effects --> Hypercalcemia, headache, and leg cramping

- Contraindications --> Paget's disease, metastasis to bone, radiation therapy, and open epiphyses

- Most common disease of bone after osteoporosis

- 2% of the population >55 years old

- 15-30% have positive family histories

- Most common in people of Northern European descent

- Chronic and progressive skeletal disorder

- Increased size and number of osteoclasts

- Localized areas of excessive bone resorption and formation --> Lots of formation but really disorganized structure

- Pagetic bone is weaker than normal bone

- Physical exam: Skeletal deformity, abnormal gait, elevated temp, erythema, or tenderness, hearing loss, dilated scalp veins, bowing of the lower extremities high-output cardiac failure, and neuro findings

- All PE findings due to excessive and abnormal bone growth

- Diagnosis: Hot spots seen on radioactive scans

- Bisphosphonates

- Subcutaneous calcitonin

- NSAIDs, COX2 inhibitors, analgesics, and opioids --> For pain relief

- Surgery --> To repair fractures and fix bone deformities

- Other IV agents are available too --> More commonly used than PO agents and stronger therapy

- 70% of the population is either overweight or obese

- 19.8% of the US has 3 comorbidities

- 88% of the US has at least 1 weight related comorbidity

- Defined as BMI >30

- Pulmonary disease --> Obstructive sleep apnea and hypoventilation syndrome

- Nonalcoholic fatty liver disease --> Steatohepatitis and cirrhosis

- Gallbladder disease

- Gynecological abnormalities --> Abnormal menses, infertility, and PCOS

- Osteoarthritis

- Skin

- Gout

- Idiopathic intracranial hypertension

- Stroke

- Cataracts

- Coronary artery disease

- Diabetes

- Hypertension

- Severe pancreatitis

- Cancer --> Breast, uterus, cervix, colon, esophagus, pancreas, kidney, and prostate

- Phlebitis --> Venous stasis

- Defined as BMI >30 --> Morbidly obese when BMI >40 and super obese when BMI >50

- BMI: (weight (lb)x703)/(Height(in)2)

- Waist circumference: Increased risk when >35" for women and >40" for men --> Measured from the top of the iliac crest

- More people are becoming obese and people are becoming more obese

- Increase of BMI by 5 points --> ~30% higher mortality

- Moderate weight loss (~7%) reduces metabolic syndrome by 41%

- Weight loss of 5-10% is the goal

- Increased life expectancy

- Improved glycemic control

- Lower blood pressure

- Improved serum lipid profile

- May decrease cancer risk

- Improves lower back pain, reflux, lower extremitiy arthralgias, and sleep apnea

- Can decrease the need of drugs for obesity-related conditions --> Some meds can actually cause weight gain

- BMI of 25-26.9 --> Diet, exercise and life-style changes

- BMI of 27-29.9 --> Diet, exercise, life-style changes, and pharmacotherapy if patient has other co-morbidities

- BMI of 30-34.9 --> Diet/exercise and pharmacotherapy

- BMI of 35-39.9 --> Diet/exercise, pharmacotherapy and surgery if patient has other co-morbidities

- BMI of >40 --> Diet/exercise, pharmacotherapy and surgery

- Most effective at helping people achieve substantial weight loss

- 30 minutes of moderate-intensity activity most days of the week --> Reduces the risk of chronic disease

- 60 minutes of moderate/vigorous activity most days of the week --> Manage weight and prevent weight gain

- 60-90 minutes of moderate activity most days of the week --> Sustain weight loss

- Patients with a BMI >27 with comorbidities or patient with BMI >30

- Only implemented after diet and exercise has been tried for 6 months

- Current drugs primarily target appetite centers in the hypothalamus --> Reduce appetite

- Sympathomimetic

- Controls appetite --> Reduces appetite and decreases food consumption

- IV injections for short term use

- Formulated for immediate release

- 15 mg or 37.5 mg daily or twice daily injections

- Side effects: Dry mouth, constipation, insomnia, and palpitations

- Monitor BP and HR while on med

- Combination of phentermine and topiramate (extended release)

- Approved in July of 2012

- Once a day combination pill --> Once a day dosing

- Combination allows for smaller dosages of both drugs which helps to alleviate the side effects of both

- Phentermine: Appetite suppressant

- Topiramate --> Augments GABA activity, modulates voltage-gated ion channels, inhibits AMPA/excitatory glutamate receptors, and inhibits carbonic anhydrase

- 13.2% of weight loss over 1 year for full dose

- 10.5% of weight loss over 1 year for mid-dose

- Lorcaserin

- Approved June 2012

- Selective 5-HT2c receptor agonist (11x higher affinity for other receptors) --> Similar target as fenphen

- Fenphen was taken off the market because of its effect on the 5-HT2b receptor in the cardiovascular system

- 10 mg dosing BID --> No titration necessary

- Side effects --> Dry mouth, constipation, fatigue, and headache

- 8% weight loss after 1 year compared to 3.7% with placebo

- Most effective treatment for obesity

- Greatest weight loss and duration of weight loss

- Dramatic improvement or resolution of co-morbidities --> Especially diabetes

- Improved quality of life

- Indications: BMI >40 or BMI 35-39.9 with co-morbidities

- Contraindications: Non-compliance with meds and psychiatric illness

- Roux-en-Y procedure --> 48-74% weight loss and remission of diabetes usually occurs within 48 hours post-op

- Sleeve gastrectomy --> 50-60% weight loss without the same effect on diabetes

- Adjustable gastric banding --> 36% weight loss

- Maximum weight loss occurs 10-24 months post-op

- Average weight loss is 61.2%

- Mortality --> 0.1-1.1%

- Diabetes resolved --> 76.8%

- Hypertension resolved --> 61.7%

- Sleep apnea resolved --> 85.7%

- Self monitoring --> Recording food intake and weighing yourself at least once a week

- Low calorie and low fat diet --> 1300-1400 kcal/day intake with 20-25% fat intake

- Eat breakfast daily

- Regular physical activity --> 2500-3000 kcal/week --> Walk 4 miles a day

- Continued follow up with physician

- Inadequate or imbalanced nutritional status

- Includes both undernutrition and overnutrition

- Improper or insufficient diet

- Etiology: Diminished intake, malabsorption/maldigestion, increased utilization, excessive losses, and altered metabolism

- Classification: Starvation related, chronic disease related, and acute diseaes related

- Insufficient energy intake

- Weight loss --> Must always consider state of hydration

- Loss of muscle mass

- Loss of subcutaneous fat

- Localized or generalized fluid accumulation that may mask weight loss --> Hypoalbuminemia

- Diminished functional status as measured by handgrip strength

- Inflammation induced --> Chronic or acute disease related

1. Hypometabolic non-stressed patient/Starvation Related

- Decreased cytokines, catecholamines, glucagon, cortisol and insulin

- Decreased metabolic rate

- Decreased proteolysis and gluconeogenesis

- Decreased urea excretion

- Increased fat catabolism and fatty acid utilization

- Normal starvation adaptation

2. Hypermetabolic stressed patients

- Increased cytokines, catecholamines, glucagon, cortisol, and insulin levels

- Increased metabolic rate

- Increased proteolysis and gluconeogenesis

- Increased urea excretion

- Increased fat catabolism and fatty acid utilization

- Abnormal adaptation to starvation

- Bloating of the stomach due to edema --> Fluid leakage into the body

- Associated with chronic or acute disease related starvation --> Inflammatory mediated

- Muscle wasting and deterioration of tissues

- Antibodies degraded to provide protein to the body --> Increased risk for infection and death

- Associated with starvation

- Calorie deficiency due to lack of food, poverty, or being a neglected child/infant

- Protein is used for energy --> Huge muscle wasting and tissue deterioration

- Brain development is impaired

- Results in blindness for 500,000 children a year --> Xerophthalmia

- Primarily due to a rice diet lacking green vegetables

- Vitamin supplements help --> $3 a year

- Golden rice also could help

- Best source is cod liver

- Immune function deficiency

- Antioxidant activity

- Neuromuscular problems

- pre-existing vitamin E deficiency has been reported in up to 23% of patients who underwent roux-en-y gastric bypass procedures

- Neuropathy --> Vitamin E deficiency after gastrectomy from gastric cancer

- Affects 740 million people worldwide

- Single greatest cause of preventable brain damage in babies

- Causes goiter, stillbirth, miscarriages, and mental retardation

- Prevented by iodized salt --> In the US

- Best sources --> Seaweed and sea food

- Alpha-linolenic acid (omega-3 fatty acid)

- Linolenic Acid (Omega-6 fatty acid)

- Symptoms: Hemorrhagic dermatitis, skin atrohy, scaly dermatitis, dry skin, and folliculitis

- Most common in patients with a history of steatorrhea

- Can give IV injections of omega-3 and omega-6 fatty acids

- Can also do oil massages for supplementation

- Poor wound healing

- Growth retardation

- Delayed sexual maturation

- Skin and eye lesions

- Hair loss after gastric bypass surgery

- Vitamin B3

- Pellagra: Dermatitis, diarrhea, and dementia

- Often leads to death

- Causes wet or dry beriberi

- Due to a diet high in polished rice

- Polishing rice takes the shell off brown rice

- Shell contains lots of niacin

- Thiamine is integrally involved in the pyruvate dehydrogenase reaction

- Without thymine --> Decreased acetyl-CoA production --> Decreased ATP production because pyruvate can't enter Kreb's cycle

- Slower wound healing

- More complications

- Higher morality and morbidity

- Longer length of stay

- Higher health care costs

- Serum albumin --> Low levels leads to edema

- Serum trasferrin

- Prealbumin

- Retinol binding protein

- C-reactive protein --> Marker for inflammation

1. Decreased synthesis

- Protein malnutrition and defective synthesis due to liver failure

- Inflammation --> Activating TNF-a leading to decreased albumin

- Increased serum oncotic pressure

2. Increased catabolism

- Inflammation --> Increased fractional catabolism

3. Increased protein loss

- Nephrotic syndrome

- Protein losing enteropathy

- Burns

- Lymphatic blockage

4. Redistribution

- Ascites, CHF, and hemodilution/dialysis

- Sepsis --> No decrease in albumin synthesis, just redistribution

- Serum and CSF carrier of thyroid hormone (T4)

- Also carries retinol throughout the body

- Half life is 2-3 days --> Half life of albumin is 15-20 days

- Decreased levels in liver failure and acute stress

- Response to nutritional support

- Prealbumin was a significant predictor of nutritional status

- Not a marker for nutritional status anymore though

- Patients don't need massive caloric loads

- Energy requirements can be estimated

- 25-30 kcal/kg/day --> Reasonable estimate

- Equations may overestimate the needs of ventilated, sedated, or paralyzed patients

- More accurately determined via an indirect calorimeter --> Gold standard for determining caloric need --> Based on VO2 and VCO2

- Should be considered when patient has been unable to eat for 5-7 days after admission

- Try to have patient eat on their own before implementing nutritional support

- Still ineffective at preventing muscle wasting associated with sepsis and chronic disease

- Administration: Oral, nasogastric tube, nasoduodenal tube, nasojejunal tube, gastrostomy tube, jejunostomy tube, peripheral parenteral nutrition (PPN) and total parenteral nutrition (TPN)

- Preferred over PPN or TPN because it uses the natural GI tract to absorb

- Contraindications: Ileus, bowel obstruction, high output fistulas, and severe sepsis

- PPN uses a peripheral line --> Higher risk of infection

- TPN uses a central line --> Also risk of infection

- Indications: Post-bowel resection, short bowel syndrome, severe and untreatable steatorrhea, diarrhea or malabsorption, complete bowel obstruction, intestinal pseudo-obstruction, prolonged acute abdomen and ileus

- Used when enteral feeding is not feasible --> Not adequate or not tolerated

- High output fistula of >500 mL and no distal enteral access possible

- Other possible uses: IBD, hyperemesis gravidarum (>5-7 days), partial bowel obstruction, intense chemotherapy, major surgery, chylous ascities, chylothorax, and severe pancreatitis

- Contraindications: Functioning GI Tract, treatment anticipated for <7 days, inability to obtain venous access, poor prognosis not warranting agressive nutrition, and when risks>benefits for PN

- Starvation leads to depletion of ATP due to loss of phosphate groups

- After feeding --> Not LOTS of phosphate available --> Phosphate is sucked into cells due to increased insulin levels

- Insulin is crucial for the pathogenesis

- Leads to electrolyte imbalances and heart arrhythmias

- Electrolyte imbalances --> Hypophosphatemia, hypomagnesemia, and hypokalemia

- Complications: Cardiac dysfunction, rhabdomyolysis, hemolysis, and respiratory failure

- Caloric intake should be limited to 10 kcal/kg/day

- Extreme cases --> 5 kcal/kg/day and continuous telemetry monitoring

- Replete electrolytes --> Phosphate, potassium, and magnesium

- Thiamine replacement --> Reduces the likelihood for patient to develop Wernicke's encephalopathy or Korsakoff's syndrome

- No sign of suffering attributable to starvation and dehydration

- Nutrition therapy generally not recommended

- Dehydration --> Helps decrease pulmonary secretions, urine output, GI fluid, and peripheral edema

- Lack of nutritional or fluid supplementation leads to relief of choking/drowing feeling, less coughing, fewer bedwetting episodes, and less vomitting, bloating, and diarrhea

- Overall leads to a more comfortable death in the end

- Obesity, genetics and inactivity work together to cause a pre-metabolic syndrome state

- Hyperinsulinemia, insulin resistance, and metabolic abnormalities result

- Metabolic syndrome results in type II diabetes, arteriosclerotic cardiovascular disease (ASCVD), hypertension, hyperlipidemia, and others

- Need 3 out of 5

1. Abdominal obesity/waist circumference

- Men >102 cm/40 in

- Women >88 cm/35 in

- Waist/Hip ratio --> >0.95 in men and >0.85 in women

- Any weight gain in adulthood --> Increased risk of diabetes, CHD, and gallstones

2. Triglycerides >150

3. HDL cholesterol

- Men <40 mg/dL

- Women <50 mg/dL

4. Blood pressure >130/85 mmHg

5. Fasting glucose >100 mg/dL

- 30% reduction in the prevalence of heart attacks with just a little bit of exercise a week

- Significant reduction in blood glucose and insulin levels after 12 months of intense endurance exercise training --> 3 times a week of 60 minute exercise sessions

- Benefits of exercise from each individual session --> Lasts 2-3 days

- If you stop exercising --> levels go right back up to where they were before

- Really need to watch your weight and make sure you don't become obese --> Much higher morbidity for just about everything

- Decreased AMP kinase activity in patients with metabolic syndrome

- SIRT1 also decreased --> Histone deacetylase that helps increase the transcription of genes --> Reduced activity leads to reduced transcription

- Pathogenic changes: Hyperinsulinemia, insulin resistance, ectopic lipid, inflammation, oxidative and ER stress, and mitochondrial dysfunction

- Leads to manifestations of metabolic syndrome

- Also predisposes patients to cancer (breast, liver, pancreas, and colon), Alzheimer's and aging

- Integrally involved with metabolic syndrome

- Initially: AMP replaces ATP on AMP kinase

- This AMP replacement allows the Thr 172 residue to be phosphorylated --> Activated enzyme

- SIRT is involved in the activity of AMPK too

- Factors activating: Exercise, hypoxia, adiponectin, metformin, glucose deprivation, LKB1 (tumor suppressor), and CAMKK (Calcium dependent kinase)

- AMPK increases ATP generation

- AMPK reduces ATP usage --> Reduces fatty acid, TG, cholesterol, and protein synthesis and reduces ion transport

- Stimulates: Glucose transport, fatty acid oxidation, mitochondrial function, and SIRT1 synthesis

- Reduces: Chemokines, ER stress, oxidative stress, inflammation (via NFkB reduction), mTORC1, and lipogenesis

- Activators: Caloric restriction, exercise, metformin, adiponectin, a-lipoic acid, estrogen, resveratrol, fenofibrate, statins, and HDL

- Plasma glucose <70 mg/dL

- Abnormally low plasma glucose that exposes a patient to harm

- Glycemic thresholds for symptoms of hypoglycemia can shift

- Patients taking sulfonylurea, glinide, or insulin are at high risk of developing hypoglycemia --> Hypoglycemic and glucose independent hypoglycemia

- Metformin

- Thiazolidinediones --> Increases adiponectin

- Alpha-glucosidase inhibitors

- Incretin-based therapies

- SGLT2 inhibitors

- Glucose dependent mechanisms

- Do not usually cause hypoglycemia

- Medicines: Sulfonylureas/glyburide, meglitinides, insulin, elderly patients, renal and liver disease, poor nutrition/erratic meals, weight loss, and variable physical activity

- Predictors of hypoglycemia: Advanced age, recent hospitalization, and use of lots of meds

- Severe hypoglycemia: Requires assistance of another person to administer carbohydrates and glucagon --> <40 mg/dL leads to impaired action and judgement and <10 mg/dL results in neurons being essentially electrically silent

- Documented symptomatic hypoglycemia: Typical symptoms are accompanied by PG <70 mg/dL --> Due to autonomic dysfunction and too tight glycemic control

- Asympatomatic hypoglycemia: PG <70 mg/dl without symptoms

- Probably symptomatic hypoglycemia: Typical symptoms not accompanied by PG determination

- Pseudohypoglycemia: Reports of typical symptoms with PG >70 mg/dL --> Occurs in patients with very poorly controlled diabetes

1. Adrenergic --> Can be alleviated with B-blockers except sweating

- Shakiness and anxiety

- Sweating

- Pallor --> Feeling cold and clammy

- Palpitations

- Tachycardia

- Mydriasis

- Paresthesias

2. Glucagon Mediated

- Hunger

- Nausea and vomiting

- Abdominal pain

- Headache

- Borborygmus

3. Neuroglycopenic

- Mental status change

- Impaired judgement

- Dysphoria and mood changes

- Fatigue and weakness

- Confusion and amnesia

- Double/blurred vision

- Difficulty speaking

- Ataxia/motor deficit

- Coma

- Generalized or focal seizures

- Brain is the first organ affected

- Glycogenolysis --> Liver stores ~75g of glycogen in the liver and can avert hypoglycemia for a short period of time (8-10 hours)

- Gluconeogenesis --> Production of glucose from non-carbohydrate sources --> Lactate, glycerol, glucogenic amino acids (alanine) --> Takes place in the liver and the cortex of the kidney

- Whipple's Triad: Hypoglycemic symptoms, low glucose reading, and reversal or improvement of symptoms

1. Type I Diabetes

- 10% of the day glucose is between 50-60 mg/dL

- 2 symptomatic episodes per week

- 1 severe episode per year

- 3x more frequent when HbA1c <6%

2. Type II diabetes

- Rates are unknown

- Probbaly about 30-40% of the frequency for type I diabetics

- More frequent with increased duration of disease

- 6-10% of deaths in patients with DM1 may be due to hypoglycemia

- Type II diabetics attempting to achieve low A1c targets are also at high risk for hypoglycemia and mortality

- Most deaths due to arrhythmias --> Hypokalemia, sympathoadrenal activation, and prolonged QT interval

- Frequent episodes of hypoglycemia result in attenuated sympathoadrenal responses and loss of "warning signs" 

- Severe illness --> Sepsis

- Prolonged fasting

- Exercise

- Alcohol --> Reduces NADH stores needed for gluconeogenesis

- Growth hormone deficiency

- Hypopituitarism

- Addison's disease, adrenal insufficiency, and other autoimmune disease

- Medications: Salicylates, bactrim/spectra, beta blockers, quinine, and pentamidine

1. Mild to moderate

- Ingest 15 g of glucose or quick acting carb

- Recheck PG in 15 minutes

- Repeat if needed

- Quick acting carbs --> Glucose tablets/gels, hard candies, raisins, soda, fruit juice, and milk

- Avoid high fat carbs --> Fat delays absorption of carbs

2. Severe --> Inability to self treat

- Glucagon injection --> SC or IM injection

- IV dextrose

- Evaluate HbA1c targets --> Tailor to patient

- Evaluate meds and insulin regimen

- Temporarily raise BG targets

- Discuss effects with exercise and alcohol

- Consider changing meds --> Change to metformin, TZDs, DDP-4 inhibitors, and GLP-1 based therapies if possible

- Avoid regular insulin with meals

- Be very careful of sulfonylurea in elderly patients

- Associated conditions: Renal failure, heart failure, infection, sepsis, decreased glucocorticoid taper, and decreased oral intake

- Responsive patients: Administer oral glucose and check PG after 15 minutes

- NPO responsive patients: Give 10-20 g IV 50% dextrose or 1g glucagon IM

- Nonresponsive patients: Give 25 g of IV 50% dextrose or 1g glucagon IM

- Prevention: Frequent glucose monitoring, adjust prandial insulin to account for change in oral intake, and adjust basal and prandial TDD during high dose glucocorticoid therapy

- 30% of basal insulin and 70% of prandial insulin are required when glucocorticoids are given

- Rapid acting --> 5-15 minute onset, peaks 0.5-1.5 hours, and lasts <5 hours

- Regular --> 30-60 min onset, peaks in 2-3 hours, and lasts 5-8 hours

- NPH --> 2-4 hour onset, peaks in 5-10 hours, and lasts 10-16 hours

- Long acting --> 2-8 hour onset, no peak and lasts ~1 day --> Doesn't do a great job at altering levels at meals

- Must add prandial insulin if taking a long acting insulin

- All have varied effect on glucose levels

- Most lead to nocturnal hypoglycemia --> Highest risk in regular and NPH insulin

- With respect to mealtime sugars --> Rapid acting is best but requires 4 doses a day

- Educate the patient --> Discuss risks facotrs and remediation for taking insulin, educate on hypoglycemia and meds

- Diet --> Long-acting secretagogues and fixed insulin regimens need to follow a predictable meal plan (can't miss meal)

- Exercise --> Carefully monitor PG before, during and after exercise

- Glucose monitoring --> Essential for good health in diabetic patients

- Medication adustment --> Depending on PG patterns, risk for hypoglycemia, and HbA1c targets

- Clinical surveillance --> Necessary for all patients on insulin

- Megaloblastic anemia assocaited with atrophic gastritis, complete achlorhydria, malabsorption of vit B12, and deficiency of intrinsic factor

- Autoimmune disorder leading to destruction of parietal cells

- 90% have antibodies to parietal cells

- 70% have antibodies to intrinsic factor

- 50% have antibodies to thyroid tissue

- 30% of patients with chronic  thyroiditis have anti-gastric antibodies as well

- More prevalent in Northern Europeans with blond hair and blue eyes

- Presentation: Desquamation of the tongue, atrophic gastritis, megaloblastic anemia, leukopenia, thrombocytopenia, subacute combined system disease, and dementia

- Bone marrow effects: Hypercellular marrow, erythroid hyperplasia, megaloblastosis, giant metamyelocytes, and N/C asynchronism

- Peripheral smear effects: Macro-ovalocytes, hypersegmented polys, and giant platelets

- Neurological effects: Symmetric numbness and tingling of extremities, impaired vibratory and position sense, and degeneration of posterior and lateral columns of the spinal cord --> Present in 75% of untreated patients

- Diagnosis: Serum B12 and folate levels, gastric achlorhydria, Schillings test, and urinary excretion of methylmalonic acid

- Cobalamin

- Complex organometallic compound

- Microorganisms are the ultimate source

- Daily requirement --> 2-3 ug/day

- Body stores --> 2-3 g

- Absorption: Requires R-binders, intrinsic factor (IF), and IF receptors

- Enzyme reactions: Methyltransferase in the conversion of homocysteine to methionine and isomerization of methyl malonyl CoA to succinyl CoA

- Dietary lack of vitamin B12

- Lack of IF --> Pernicious anemia and gastrectomy

- Competition for vitamin B12 --> D.latum and blind loop syndrome

- Impaired ileal absorption of vit B12 --> CD or ileal resection

- Congenital deficiency of TC II

- Megaloblastic anemia similar to vitamin B12 deficiency but lacks the neuro findings

- Folic acid is essential for one carbon transfer reactions

- Humans are entirely dependent on dietary sources --> Modest body reserve

- Very sensitive to boiling

- Daily requirement: 50-200 mg

- Dietary folates/polyglutamates are split by the intestinal conjugases into monoglutamates

- Absorbed by the proximal jejunum

- Causes: Decreased intake, inflammation or infiltration, drugs (phenytoin and OCPs), increased requirement, and antagonists (MTX)

- Most common form of nutritional deficiency

- Total body iron --> 2g for women and 6 g for men

- 80% of iron is present in Hb

- Transportation via transferrin

- Normal serum Fe --> 100 ug/dL in women and 120 ug/dL in men

- Absorbed in the duodenum --> Some to transferrin and the rest to ferritin

- Normal diet --> 10-20 mg but only 20% is absorbed

- Dialy loss of 1-2 mg/day of iron

- Causes: Low dietary intake, malabsorption, increased demand, and chronic blood loss

- Retinol (transport form), retinol ester (storage form), retinal (visual pigment), and retinoic acid

- Animal derived foods (liver, fish, eggs, milk and butter) and vegetables (carrots, squash, and spinach)

- Vegetables supply provitamins (beta-carotene and carotenoids)

- Bile, pancreatic enzymes, and antioxidant activity in the food is required for absorption

- More then 90% of vitamin A is stored in the liver (Ito cells) as retinyl ester

- Functions: Maintains normal vision, stimulates differentiation of mucus-secreting epithelium, and enhances immunity to infections

- Used to treat severe acne, certain forms of psoriasis, acute promyelocytic leukemia, and undifferentiated neuroblastoma in children

- Impaired vision --> Nigh blindness and xerophthalmia (dry eye) --> Forms debris in the eye which can lead to ulceration of the cornea

- Pulmonary infections

- Renal and urinary bladder stones --> Dryness in the urinary tract too

- Follicular or papular dermatosis

- Impairment of immunity

Acute effects: Headache, dizziness, vomiting, stupor, and blurred vision --> Pseudotumor cerebri

- Acute cases associated with eating the liver of polar bears, whales, sharks, and even tuna

- High risk of spontaneous abortion and birth defects --> Cleft palates and cardiac abnormalities

- Chronic toxicity --> Fatigue, skin changes, sore throat, alopecia, weight loss, anorexia, nausea, vomiting, and bone pain (arthralgias)

- Synthetic retinoids are used for treatment of acne 

- Ascorbic acid

- Not synthesized endogenously

- Entirely dependent on the diet for this nutrient --> From milk and some animal products

- Abundant in a variety and fruits and vegetables too

- Participates in the hydroxylation of procollagen

- Antioxidant properties --> Scavenges free radicals directly and can act indirectly by regenerating antioxidant form of vitamin E

- Scurvy

- Common in elderly patients, patients who live alone, chronic alcoholics, patients on peritoneal dialysis and hemodialysis patients, food faddists, and infants maintained on formulas and not supplemented with vitamin C

- Leads to impaired collagen formation --> Poor vessel support and inadequate synthesis of osteoid

- Impaired wound healing

- Symptoms: Nausea, vomiting, diarrhea, fatigue, and sleep problems

- Protection against the common cold with megadoses --> No clinical studies

- Slight relief may be experienced during colds --> Slight antihistamine actions

1. Fasting plasma glucose --> >126 mg/dL on at least two occassions --> Fasting defined as no caloric intake for at least 8 hours

2. 2 hour plasma glucose --> >200 mg/dL during oral glucose tolerance test (OGTT) --> Glucose load containing the equivalent of 75 g anyhdrous glucose in water

3. Patients with classic symptoms of hyperglycemia or hyperglycemic crisis --> Random glucose >200 mg/dL

4. Hemoglobin A1c > 6.5% --> Doesn't require fasting

- Only need 1 of the 4 to diagnose

- Diabetes results due to failure of the Beta cell to meet insulin demand --> Either due to inability to produce insulin or the body's inability to respond

- Affects 25.8 million people of all ages

- 8.3% of the US population --> Really about 9% and 11% at BMC

- 7 million people have undiagnosed diabetes

- Age: 26.9% of americans >65 years

- 215,000 people <20 have type I or type II diabetes

- Preventability: Type II diabetes is entirely preventable --> 35% of adults >20 have pre-diabetes and 50% of >65 year olds have pre-diabetes

- Adults >45 years old

- Adults <45 who are pregnant or obese --> Also women with a history of gestational diabetes or who gave birth to a baby >9 pounds (macrosomia)

- Children who are overweight with one of the following risk factors --> Hypertension, low HDL, high triglycerides, family history, belonging to a high risk ethnicity, and signs of insulin resistance

1. Type I

- Normal weight or underweight

- <35 years old at onset

- 0.5% prevalence

- Diminished or absent insulin secretion

- High risk of DKA

- Higher risk of microvascular complications than in type II

- Risk for both macro and micro vascular complications

- ~50% heritability for monozygotic twins --> Associated with HLA-B8,BW-15, DW-3, and DW-4

- Islet cell antibodies are present

- Predisposing factors: Viral infection and autoimmunity

- Histology: Infiltration of CD8 T-cells --> Insulitis

2. Type II

- Overweight or obese

- Variable age of onset --> Usually preceeded by pre-diabetes (preventable)

- 7.0% prevalence --> Closer to 9%

- Moderately diminished or increased insulin secretion

- Not at high risk for DKA --> Possible though

- Higher risk for macrovascular complications

- Microvascular complications are less common

- 100% heritability between monozygotic twins --> No HLA type association

-  No islet antibodies

- Predisposing factors are obesity and stress

- Histology: Amyloid islet deposition --> Proinsulin/insulin secretion

- Lack of insulin --> Starvation state --> Occurs once 90% of Beta islet cells are lost --> >200 mg/dL of glucose

- Hyperglycemia --> Polyuria, polydipsia, and polyphagia

- Impaired lipid and protein metabolism --> Increased lipid and protein breakdown --> Muscle wasting

- Hyperglycemia and impaired lipid and protein metabolism --> Infection, weight loss, and ketoacidosis --> High risk for DKA

- All associated with poor glycemic control

- DKA

- Microangiopathy --> Nephropathy, retinopathy, and others

- Neuropathy --> Demyelination

- Macroangiopathy --> Accelerated atherosclerosis --> Occurs later in Type I than in type II

- High and rising prevalence --> Nearly 10%

- Highest risk in obesity --> Especially abdominal obesity

- Increased risk of ischemic heart disease at the time of diagnosis --> Present in 20-50% of patients already

- Glucose tolerance impaired 8-10 years before diagnosis with diabetes

- Beta cell function down to ~50% at the time of diagnosis

- Insulin production rarely drops to 0% in classical type II diabetes

- Pancreas works overtime to compensate for the increased need due to impaired glucose tolerance and building insulin resistance

- Glucagon abnormality: Increased glucagon --> Further increases glucose level in the blood --> Starvation state due to insulin resistance leads to glucagon release

- State of impaired glucose tolerance

- Almost always precedes overt type II diabetes by >5 years

- Associated with insulin resistance and accelerated atherosclerosis

- Development of diabetes is preventable at this stage

- Majority never develop diabetes

- Need intensive lifestyle intervention and may possibly need meds to help prevent --> Metformin and thiazolidinediones

- Oral glucose tolerance test --> 140-199 mg/dL 

- Fasting plasma glucose --> 100-125 mg/dL

- HbA1c --> 5.7-6.4%

- "Ticking clock hypothesis" --> Macrovascular complications start before diagnosis of type II diabetes while microvascular complications develop after diagnosis with type II diabetes

- Growing in prevalence

- Associated with obesity

- Accounts for as much as 30-40% of childhood diabetes in some ethnic groups --> More prevalent in blacks, Hispanics, and Asians

- Increased risk for future CAD

- First appears during pregnancy

- Affects 3-15% of pregnant women

- 15-75% of women with gestational diabetes will ultimately develop type II diabetes

- Risk depends on the need for insulin to control glucose during pregnancy

- Results in both maternal and fetal problems during pregnancy

- Type I diabetes that presents in adults

- Anti-GAD antibodies

- Patients are generally thinner than typical type II diabetic patients

- May account for 10-15% of type II patients

- Requires insulin treatment within a few years --> Much faster progression than normal type II

- Resembles type II diabetes but present in younger patients

- Much less common

- Appears in patients 10-30 years old

- Accounts for 2-3% of type II diabetes

- Autosomal dominant interference

- Various genetic defects in B-cell --> Alterations in glucokinase activity in some families and mitochondrial DNA and HNF 1a and 4a mutations in other patients

- Relapsing and remitting beta cell function with slow deterioration over time

- Presents with ketoacidosis requiring insulin but regains beta cell function and comes off insulin

- Cycle recurs with unknown triggers

- More common in non-white, African or Afrocaribbean patients

- Most common in men and menopasual, low-estrogen state women

- Most commonly presents in patients <40 years old

- Patients may have a history of obesity or may just be overweight at presentation

- Post-pancreatic disease or resection --> Cystic fibrosis, etc

- Chronic excessive corticosteroid exposure/Cushing's syndrome

- Glucoagonoma --> Increased glucagon secretion leading to severe hyperglycemia

- Acromegaly

- Other rare genetic disorders --> Mitochondrial diabetes --> MELAS

- Rare autoimmune disorders --> Type A and B insulin resistance syndromes

- FPG --> <100 is normal, goal of 90-130 for ADA but <110 AACE goal

- PPG --> <140 is normal, ADA goal of <180, and AACE goal of <140

- A1c --> 4-6% is normal, ADA goal of <7%, and AACE goal of <6.5%

- Set glycemic goals a little bit higher for elderly --> Too tight glycemic control leads to higher likelihood of developing hypoglycemia

- Blood pressure: <140 mmHg systolic and <120 with renal disease

- LDL <100 mg/dL and <70 mg/dL with coronary disease or cardiac event/stroke

- Nephropathy prevention: Monitory BP, lipid and glycemic control

- Retionpathy prevention: Yearly retinal exam

- Foot protection/care --> Self exam, and provider exams multiple times per year

- CAD primary and secondary prevention --> HMG Co-A reductase inhibitor for patients >40 without contraindication and daily baby aspirin

- Only applies for type II

- Diet an excercise is the best

- ~30% greater results than meds for diet and exercise

1. Increased intracellular non-esterified fatty acids --> Intracellular signaling leading to insulin resistance

2. Adipokine release --> Cytokines released by adipocytes leading to insulin resistance

3. Inflammation of adipose tissue --> Activates cell signaling leading to insulin resistance

4. Peroxisome proliferator activated receptor gamma (PPAR-G) mediated pathways

1. Formation of advanced glycosylation end products

- Hyperglycemia leads to advanced glycosylation end products --> Act on extracellular matrix compnents, endothelial cells, and proteins within cells and in circulating plasma

2. Activation of Protein Kinase C

- Intracellular hyperglycemia stimualtes several intracellular pathways

- Leads to formation of VEGF (proangiogenic), TGF-b (profibrotic), and PAI-1 (procoagulant)

3. Disturbances in polyol pathways

- Certain tissues don't require insulin for glucose uptake --> Uptake via GLUT2 instead of GLUT4 --> Nerves, lenses, kidneys, and blood vessels

- Intracellular hyperglycemia is dealt with by conversion of glucose to fructose via aldolase reductase

- Aldolase reductase utilizes NADPH and glutathione reductase

- Depletes cells of an important antioxidant --> Oxidative damage

4. Macrovascular disease

- Accelerated atherosclerosis

- Gangrene

- Hyaline arteriosclerosis --> More common and more severe in diabetics

5. Microvascular disease

- Diffuse thickening of the basement membrane --> Makes the vessels leaky and plasma proteins start to escape out of the blood vessels --> Deposited into tissues

- Affects the small vessels of the skin, skeletal muscle, retina, renal glomeruli (KW nodules), and renal medulla

6. Glomerular/Kidney Changes

- Thickening of glomerular capillary basement membranes

- Diffuse mesangial sclerosis and nodular glomerulosclerosis (KW lesion)

- Pyelonephritis --> Necrotizing papillitis --> Infections are more common in diabetics

7. Ocular Complications

- Diabetic retinopathy --> Thickening of the BM of the ciliary body

- Pre-proliferative/background retinopathy --> Thickening of BM, microaneurysms of vasculature, retinal microhemorrhage, macular edema, and exudates

- Proliferative retinopathy --> New vessel grwoth from existing vessels on the optic disc

- Cataracts --> Develop quicker than normal --> Due to sorbitol accumulation and cell death

8. Neuropathy

- Axonal neuropathy --> Areas of demyelination and loss of myelinated fibers

- Present in 50-80% of diabetics

- Distal and symmetric sensorimotor loss

- Thickening of BM also

- Insulin sensitivity: Ability of insulin to lower circulating glucose concentration --> Stimulates glucose utilization in muscle and fat, suppresses glucose production in the liver, and suppresses lypolysis in adipocytes

- Insulin resistance --> Occurs when above responses don't occur

- Condition of low insulin sensitivity

- Associated signs: Abdominal obesity, glucose intolerance, FHx, Hx of gestational diabetes, dyslipidemia, hypertension, increased PAI-1 and platelet levels, and acanthosis nigricans

- Hepatic glucose output is elevated --> Increased gluconeogenesis

- Glucose uptake in the muscle and adipose tissue is diminished

- Increased lipolysis --> Increased circulating FFAs

- Increased fatty oxidation in muscle --> Decreased insulin-mediated glucose uptake and disposal

- Increased gluconeogenesis and hepatic glucose output

- Increased triglycerides, VLDL, and small dense LDL-cholesterol

- Decreased HDL levels

- Low cholesterol content of LDL particles --> Increased particle number for a given LDL level

- Associated with increased triglycerides and decreased HDL levels

- Common genetic train associated with increased risk of coronary disease

- Increased atherogenicity due to greater arterial uptake, increased particle uptake by macrophages, and increased particle oxidation

- Presence of these LDL particles increases the likelihood of fatty streaks developing and atherosclerosis occuring

- Increase in FFAs and triglycerides

- Intramyocellular lipids --> Impair glucose uptake/metabolism in muscle

- Diet induced lower of tissue TG levels helps to improve insulin sensitivity

- Hepatic insulin resistance contributes to gluconeogenesis and hypertriglyceridemia

- Lipotoxicity impairs beta cell function --> Actually toxic to B-cells

- Abnormal fatty acid metabolism --> Can be a cause and a consequence of insulin resistance

1. Inherited --> Rare

- Insulin receptor --> Leproconism

- Glucose transporter

- Signaling proteins

- Common forms --> Largely unidentified

2. Acquired

- Inactivity

- Overating

- Aging

- Medications

- Hyperglycemia

- Elevated FFAs

- Must be an evolutionary advantage since obesity is so common

- People who are obese are particularly effective at storing energy

- This might allow them to survive longer in times of famine

- We don't live in a time of famine anymore --> Not actually necesssary

- Comorbidities manifest themselves in times of plenty

- Low birth weight babies are at increased risk of developing this thrifty gene and are more likely to develop type II diabetes 

1. Adiponectin --> Secretory protein that is specific to adipose tissue --> Increases insulin selectivity

- Obesity and insulin resistance --> Decreased adiponectin and decreased action with visceral adiposity

- Chronic caloric restriction --> Increased adiponectin and insulin sensitivity

- Increased levels --> Decreased risk of developing type II diabetes

- Thiozolidinediones --> Increase PPARg receptor binding --> Increased adiponectin levels

2. Leptin --> Secreted by adipose tissue --> Suppresses appetite, increases glucose uptake, and increses the ability of insulin to inhibit hepatic gluconeogenesis

- Increased leptin --> Decreased visceral adiposity and reduced triglyceride accumulation in muscle

- Obesity --> Increased levels but leptin resistance occurs

- Leptin resistance often coincides with insulin resistance

3. Resistin --> Adipose tissue-specific hormone --> Increases insulin resistance by acting directly on the liver

- Role unknown in type II diabetes

- Levels can either be elevated or reduced in insulin resistant patients

4. Pro-inflammatory cytokines --> TNF-a often increased in insulin resistance and type II diabetes

5. Phosphorylation of insulin receptor --> Induces resistance and inability of the receptor to respond properly

- Loss of first phase insulin release by B-cells --> GI releases incretins (GLP-1 and GIP) once glucose hits the GI tract and stimulates first phase

- Disruptions in the normal pulsatile nature of insulin secretion

- Patients with early diabetes and pre-diabetes have increased insulin resistance to compensate

- Accumulation of amloid deposits in the islets --> Increased proinsulin/insulin secretion

- Glucose toxicity --> Toxic to B-cells and impairs insulin secretion

- Progressive dysfunction --> Viscious cycle between insulin resistance which leads to hyperglycemia, which leads to glucose toxicity to B cells, which leads to further B-cell failure, and further hyperglycemia

- Strong correlation between inflammatory markers and insulin resistance

- Pro-inflammatory state

- TNF-a is increased in obesity and T2DM --> Increases FFAs, insulin resistance, and other cytokines through activation of NF-kB pathway

- IL-6 --> Increases FFAs by stimulation of lipolysis --> 3x risk of converting to diabetes with high IL-6

- CRP --> Marker of inflammation

- Some anti-inflammatory drugs (salicylates) can be used to reduce insulin resistance, improve glucose levels, and decrease FFA levels

1. Thrombosis

- Endothelial dysfunction due to oxidative stress --> Incresaes levels of TNF-a, tissue factor, and fibrinogen

- Platelet hyperaggregability

- Decreased concentration and activity of antithrombotic factors

2. Fibrinolysis --> Decreased clot breakdown

- Decreased t-PA activity

- Increased PAI-1 --> Inhibits plasminogen

- Decreased concentrations of a2-antiplasmin

- Blood glucose >250 mg/dL

- Metabolic acidosis with pH <7.3 or serum bicarbonate <15 mM

- Dehydration --> 3-5 L

- Mild --> bicarb 15-18

- Moderate --> Bicarb 15 or more with pH >7.0

- Severe --> Bicarb <15 with pH of 7.0 or lower

- Early --> Any bicarb deficit in the setting of insulin deficiency

- Ketonemia --> Most patients with ketonemia have + urine ketones or ketonuria

- More common in type I diabetes

- Develops over 2-6 days --> Due to increased glucagon, lipolysis, and ketoacidosis

- Patients feel sicker faster so they present earlier and with less dehydration

- <5% mortality

- Blood glucose >1,000 mg/dL

- Arterial pH >7.3

- Bicarbonate >15

- Serum osmolality >320 mOsm/kg H2O --> 2Na + glucose/18 (normal 280-290) --> Sodium drops when glucose increases to try and keep osmolality normal

- Mild ketonuria or ketonemia

- Dehydration usually ~9L --> Much more severe than DKA

- Much more common in type II diabetics

- Most commonly presents in 57-69 year olds

- Develops over 2-6 weeks --> Results in hyperosmolality and confusion --> High stress state

- Patients don't tend to feel sick until very late

- 15% mortality rate

- >75% mortality when hyperthermia, rhabdomyolysis and HHS in young African American adults

- Hormone sensitive lipase is inhibited in adipocytes --> Lypolysis is inhibited

- Glucose and amino acids are actively transported into cells

- Normal K and phosph transport

- Insulin inhibits glycogen breakdown in the liver

- Lipogenesis and glycogenesis are activated

- 

- Muscle: Can't use glucose and amino acids, K and phosph normally transported

- Liver: Gluconeogenesis stimulated and fatty acids are utilized for ATP since glucose can't be transported into cells

- Adipocyte: Lipolysis goes unchecked --> FFAs flood the bloodstream

- Acyl-CoA --> Lots of Acetyl-CoA --> TCA cycle overwhelmed

- Excess Acetyl-CoA shuttled over to make ketones (acetoacetate and D-B-hydroxybutyrate)

- D-B-hydroxybutyrate is increased when patients are really acidotic and DKA is really bad

- Initiated by illness and stress --> GH, Epinephrine, and cortisol

- Increased glucagon and decreased insulin levels

- Activation of hormone sensitive lipase in adipocytes --> Increased lipolysis that goes unchecked

- FFAs flood the bloodstream and overwhelm TCA --> Ketone bodies produced

- Increased glucagon --> Stimulates gluconeogenesis

- Acidemia reduces O2 binding capacity of Hb --> Higher pO2 levels needed for the same Hb binding

- Acidosis with an anion gap --> (Na) - (Cl+HCO3) - (unmeasurable anions) --> Normal may be as low as 5

- Polyuria and polydipsia

- Fatigue

- Nausea and vomiting

- Abdominal pain

- Increased respiratory rate/dyspnea --> Kausmal breathing

- Dry membranes

- + ketones on the breath --> Unreliable though

- Infection with or without fever --> Can be precipitating factor

- Complicating factors: Pancreatitis, toxic ingestion/withdrawal, renal dysfunction, MI, PE, and secondary causes of acidosis

- ABG --> With stat electrolytes including phosph and Ca

- Chem 7 with anion gap --> Normal <10 --> Monitor gap throughout treatment

- CBC with differential

- Urine analysis, gram stain, and culture

- ECG --> Possibly troponin

- Serum and urine tox

- Serum and calculated osmolality

- Serum acetone and/or B-hydroxybutyrate

- Lipid panel

- Amylase/lipase --> Rule out pancreatitis

1. Start IV fluids immediately!!! --> 0.9% saline 1L/hour

- Restore plasma volume until: urine output 30 cc/hour, mental status improvement, and blood pressure and pulse normalize

- Continuing fluids --> Depends on Na level --> High Na (0.45% NaCl), normal Na (0.45% NaCl), and low Na (0.9% NaCl)

- Once serum glucose reaches 250 --> Change fluid to D5 1/2 normal saline --> Continue insulin drip to keep glucose 150-200 mg/dL --> May need to give glucose back to continue insulin drip

- Hypothetical risk of repleting fluids too fast and causing cerebral edema --> However must sources say there is more risk at under repleting

2. Potassium --> Measure K level BEFORE giving any insulin

- Insulin causes a massive rush of K into cells --> Can cause severe hypokalemia leading to heart arrhythmias and death

- If K <3.3 mEq/L --> Hold insulin and give 40 mEq K until K >3.3

- If K >5.5 --> Start insulin and check K in 2 hours

- If K 3.3-5.5 --> Give 20-30 mEq in each liter of fluids

- Check chem 7 ever 2-4 hours

3. Insulin Drip

- Regular bolus 0.15 ug/kg

- 0.1 ug/kg/hour IV infusion

- Check serum glucose hourly --> If it doesn't fall by 50-70 mg/dL in the first hour then double hourly insulin until it does

- NEVER stop the insulin drip without SC insulin on board --> Overlap or transition patient

- Transition once glucose is in goal range on insulin drip

- Outpatient coaching with diabetes nurse

- Sick day guidelines --> Review

- Inpatient diabetes education

- Early outpatient treatment of infections

- Know about meds that impair glucose control --> Switch meds if necessary! 

- Acute infection --> 32-60%

- CVA

- MI

- Pancreatitis

- Pulmonary embolus

- Intestinal obstruction

- Renal failure

- Heat stroke

- Hypothermia

- Subdural hematoma

- Severe burns

- Endocrine --> Acromegaly, thyrotoxicosis and Cushing's syndrome

- 33% of patients don't have a history of diabetes

- <10% present with true coma

- Marked dehydration

- Multifactorial acidosis results

- ~40% on these drugs now --> Not used as much anymore

- High initial response rate but wears out after ~8 years --> Tachyphylaxis reaction

- Binds K ATPase channel --> Depolarizes cell and causes insulin release

- No lag period before response

- Lowers fasting plasma glucose 50-65 mg/dL

- Lowers HbA1c 1-2%

- Disadvantages: Can cause severe hypoglycemia, sulfa drug (allergic reactions), limited postprandial effect, weight gain, and drug interactions are common

1. Glyburide: 10 hour half life and lasts 12-24 hours --> 50:50 excretion by liver and kidney

2. Glipizide: 2-4 hour half life and lasts 12-14 hours --> Primarily excreted by the liver

3. Glipizide GIT: 8-10 hour half life and lasts 24 hours --> Liver and kidney excretion

4. Glimepiride: 9 hour half life and lasts 16-24 hours --> Liver and kidney excretion

- Contraindications: Pregnancy, type I DM, major surgery, and sulfa allergies

- Cardiovascular black box warning 

- Acarbose and miglitol

- Binds brush border enzymes and competitively inhibits

- Inhibits conversion of oligosaccharides to monosaccharides

- Undigested carbs travel distally for eventual digestion

- Prolonges the absorption of glucose --> Reduces the initial surge and allows B-cells to respond over time

- Decreases postprandial glucose ~50 mg/dL

- Decreases HbA1c 0.5-0.75%

- Doesn't cause hypoglycemia unless used in combination with SUs or insulin --> Treat by giving glucose, fructose or lactose NOT sucrose or starches

- Side effects: Flatulence (40%), abdominal cramping (12%), and diarrhea (28%)

- Needs to be taken with the first bite of the meal

- Increases prandial insulin release --> Binds K-ATP ion channel to close and cause depolarization

- Repaglinide (Benzoic acid derivative) --> HbA1c down ~1.5% --> Similar to SUs

- Nateglinide (Phenylalanine derivative) --> HbA1c down ~0.8%

- Helps restore 1st phase insulin release

- More effective in decreasing postprandial glucose excursion than stimulating muscle glucose uptake

- Best way to control post-prandial hyperglycemia --> Shuts off liver gluconeogenesis instead of shuttling glucose to muscle
- Mild improvement of FBGs --> Reduces glucotoxicity and lipotoxicity

- Metabolism: 100% hepatic

- Dose adjustment: Hepatic and renal failure

- Repaglinide is available in combination with metformin

- AKA biguanide

- Most common 1st line oral agent

- Mechanism: Sensitizes the liver and muscle to insulin, reduces hepatic glucose output, suppresses appetite, induces weight loss (4-6 lbs), and potentiates GLP-1 release from the gut

- May act by activating AMP kinase

- Anti-hyperglycemic --> Doesn't cause hypoglycemia

- Reduces FPG ~65 mg/dL and HbA1c 1.5-2% --> Synergistic with SUs

- Reduces post-prandial glucose --> Decreases premeal glucose and increases GLP-1 release

- May require 4-6 weeks to take full effect

- Combinations with: Glyburide/glipizide, repaglinide, and TZDs

- Effective with bedtime NPH or glarginie (long acting)

- Side effects: Lactic acidosis --> Rare but more common in patients with renal insufficiency, CHF, hypovolemia, and liver disease, and GI --> Abdominal cramping and diarrhea

- Contraindications: Pregnancy, T1DM, renal insufficiency (GFR <60 or Cr >1.5 for men and Cr >1.4 in women), liver failure, and active CHF

- Precautions: >80 years old, debilitated, people who don't eat well (<1000 cals), and vit B12 deficiency

- Discontinue before getting IV contrast

- Monitor B12 levels

- Pioglitazone and rosiglitazone

- Mechanism: Binds nuclear PPAR-g and -a receptors --> Increases GLUT4 expression and increases glucose uptake in fat and slight decrease in liver gluconeogenesis

- Improves insulin sensitivity and no direct stimulation on insulin secretion

- Results: Decreases FBG ~30-50 mg/dL, HbA1c 0.5-1.5%, insulin levels, and TGs, and provides vasculoprotective effects

- Metabolism: Hepatic P450 metabolism

- Excretion: 85% fecal and 3% urinary --> Can be used in renal insufficiency

- Delayed action --> Onset in 3 weeks and takes full effect in 10-12 weeks

- Combination with metformin or glimepiride

- Side effects: LFT elevation, rare hypoglycemia, fluid retention (especially with insulin), weight gain, anemia, and fractures of long bones in women

- Contraindications: Pregnancy, T1DM, liver disease, and <18 year olds

- Pramlintide --> Amylinomimetic --> Injectable synthetic amylin

- Restors B-cell amylin --> Neuroendocrine effect

- Amylin is absent in T1DM and deficiency in T2DM

- Amylin --> Early satiety, reduces gastric emptying, and inhibits glucagon release

- Patients eat 20-30% less when exposed to amylin

- Indications: Adjunct mealtime treatment in T2DM on oral agents and T1DM, inadequate prandial control, and not approved without insulin

- Dosing: Mealtime insulin reduced by 50%, 60-120 mcg TID in T2DM and 15-60 mcg TID in T1DM

- Efficacy: Significant reduction in FPG, PPG, and A1c and ~6 lb weight loss

- Adverse Effects: Nausea, anorexia, vomiting, fatigue, and dizziness

- Incretin effects and levels are decreased in hyperglycemia

- GLP-1 level may be reduced ~30% but sensitivity remains near normal

- GIP levels are normal but there is a loss of action

- 50% of B-cell insulin release is due to incretin release by the GI tract

1. Exenatide --> Binds GLP-1 receptor and activates

- Injectable replacement

- Resistant to DPP-4 (normal inhibitor) inactivation

- Measurable levels for up to 10 hours --> Long acting

- Increases insulin secretion, decreases glucagon secretion, decreases gastric emptying, decreases food intak, and decreases plasma glucose

- Adjunct therapy at mealtime --> 2x/day

- Contraindication: Gastroparesis and hypersensitivity

- Efficacy: Reduces FPG, PPG, A1c, and weight --> ~12 lb weight loss after 2 years

- Adverse Effects: Hypoglycemia (only with SU), nausea, vomiting, diarrhea, jitteriness, dizziness, headache, and dyspepsia

- Once weekly injections --> 2mg SC every 7 days

- Black box warning --> Risk of medullary thyroid carcinoma

2. Liraglutide --> GLP-1 receptor agonist --> 97% homology to GLP-1

- Injected SC once daily

- Endogenously metabolized

- Precautions: Medullary carcinoma of the thyroid (black box warning)

- Incretin enhancers --> Inhibits the inactivation of incretins (GLP-1 and GIP)

- Sitagliptin, saxagliptin, linagliptin, alogliptin

1. Sitagliptin --> Taken orally --> Lasts for 24 hours

- 2-3 fold increase in circulating levels of active GLP-1 levels

- Decreases glucagon concentration and increases responsiveness of insulin release to glucose

- Decreases fasting glucose and glucose excursion

- Monotherapy as an adjunct to diet and exercise and combination therapy with metformin, TZD, etc

- Efficacy: Decreased FPG by 17 mg/dL, PPG by 47 mg/dL, A1c 0.6-0.8% as monotherapy and A1c 0.6-0.9% as combination therapy

- Limitations: Not in T1DM, dose reduction in renal insufficiency, and 79% urinary excretion

- Adverse reactions: Hypoglycemia if used with SUs or insulin, low incidence of URI symptoms (sniffles), abdominal pain, nausea, diarrhea, angioedema and Steven's Johnson (rare), and acute pancreatitis

2. Saxagliptin

- Mono or add-on therapy

- Efficacy similar to sitagliptin

- Renal and hepatic excretions

- Adverse effects: Headache, nasopharyngitis, very rare urticaria/angioedema, and acute pancreatitis

3. Linagliptin

- Monotherapy or add-on therapy

- 90% excreted unchanged

- No dose adjustment for renal or hepatic impairment

- Little drug interactions

- Adverse reactions: Headache, nasopharyngitis, rare urticaria/angioedema and acute pancreatitis

4. Alogliptin

- Monotherapy or combination therapy

- No extensive metabolism

- Excretion: 60-70% renal and 13% feces

- Adverse reactions: Headache, nasopharyngitis, rare urticaria/angioedema, Stevens Johnson and pancreatitis

1. Colsevelam --> Bile acid sequestrant --> 625 mg tablets --> 6 tab QD or 3 tab BID --> Take with meals

- Greater bile acid binding

- Adjunct therapy for T2DM

- Mechanisms not fully understood

- Alteration in bile acid pool may reduce gluconeogenesis and induce GLP-1 secretion (G-protein receptor activation)

2. Bromocriptine --> Quick release --> D2-dopamine receptor agonist

- Mechanisms of action unkonwn

- Resets morning dopaminergic and sympathetic tone

- Modest effects on A1c reduction (0.6-0.9%) 

- Limited recognition and use in clinical practice

- 0.8 mg tablet --> Taken within 2 hours of waking in the AM

- Side effect: Nausea --> Usually lasts <2 weeks

- Canagliflozin

- Increases glucose excretion

- Reduces glycemia and HbA1c levels

- Loss of calories --> Weight loss

- Increased sodium excretion --> Blood pressure reduction

- Need to monitor K levels too --> Hypokalemia possible

- Benefits: Insulin-independent action, low hypoglycemic risk, and can be used regardless of diabetes duration

- Side effects: Repeated UTIs, genital infections, increased HCT, and decrased blood pressure

- Requires dose adjustment with decreased GFRs

- Inhibition of hepatic glucose production

- Increased uptake of glucose in the liver, muscle, and fat

- Suppression of lipolysis, proteolysis, and intrahepatic ketogenesis

- Inhibition of pancreatic glucagon release

- Anabolism and gene transcription

- Advantages: Controls all patients, flexible, immediate response, and multiple preparations are available

- Disadvantages: Hypoglycemia, weight gain, injections, and patient and physician non-acceptance

- Short acting: Aspart, lispro, and glulisine

- Regular insulin

- NPH insulin

- Long-acting insulin: Glargine and detemir  --> Slow disaggregation from hexamers to monomers --> ~24 hour effect

1. Split-Mixed Regimen: Done for simplicity

- Initial injection of NPH or regular before breakfast

- Short acting insulin covers breakfast

- NPH peaks to cover lunch

- Another injection before dinner --> Short acting for dinner and NPH for overnight

2. NPH/Regular insulins --> Not really done anymore

- Combined formulation at breakfast

- NPH covers lunch

3. Basal-Bolus Insulin --> Requires 4 shots a day

- Long acting in the morning for basal insulin levels

- short acting to cover each meal

- Some patients will need 2 basal injections a day --> 5 injections a day

- Syringe, pen and pump all available now

- Pump is the best for physiological matching --> Requires alot of glucose testing throughout the day and requires careful monitoring of the equipment

- Pump advantages: Programing of basal and bolus rates and flexible

- Pump disadvantages: Complex, DKA risk with equipment malfunctions and can be expensive

- Inhaled and buccal --> Under investigation --> May be great in the future

- Diabetic retinopathy

- Diabetic nephropathy

- Diabetic focal or proximal neuropathy --> Large nerves

- Diabetic peripheral neuropathy --> Metabolic perturbations of small nerves

- Can be reduced with strict glycemic control

- Cerebral circulation and carotid arteries --> TIAs and stroke

- Coronary circulation --> Angina and MI

- Lower limb circulation --> Claudication, ulceration, and gangrene

1. Damage to endothelial cells --> GLUT1 transport of glucose into cells cause glucotoxicity

2. Chronic hyperglycemia --> Increases in reactive oxygen species and increased oxidative stress --> Endothelial damage

- Increased H+ gradient with hyperglycemia --> Short circuits the ETC and causes production of superoxide

3. Direct tissue damage

4. Activation of oxidative stress sensitive pathways --> Require antioxidants to function properly --> Polyol, hexosamine, PKC, and AGE pathways

- Superoxide formation inhibits GAPDH --> Reduced usage of glycolysis and TCA cycle pathways

- Increased usage of antioxidant sensitive pathways --> Substrate shunting

- Aldose reductase --> Cytosolic enzyme that reduces the toxic aldehydes generated by ROS --> Produces inactive alcohols (sorbitol)

- Hyperglycemia increases pathway use by ~30%

- Glucose is reduced to sorbitol in the retinal, renal papillae, Schwann cells and aorta

- Sorbitol is oxidized to fructose by sorbitol dehydrogenase --> Some tissues don't have this though

- Sorbitol cannot diffuse out of cells so build up causes cell damage

- Pathway uses up NADH and reduces antioxidant protection

- Increased levels of sorbitol --> Osmotic stress, Na/K ATPase inhibition, depletion of myoinositol, loss of intracellular antioxidants, and increases in other pathways

- Potential treatment target --> Aldose reductase inhibitors

- Hyperglycemia shunts glucose into hexosamine pathway

- Increases N-acetylglucosamine production --> Competes with O-linked glycosylation and phosphorylation on target sites

- N-acetylglucosamine --> Modifies nuclear transcription --> Increases in PAI-1, TGF-b, and MMP and decreased NO

- Interference with insulin signaling --> Decreased muscle uptake of glucose

- Exacerbates hyperglycemia and oxidative stress

- Increases insulin resistance and glucotoxicity

- Composed of cell signaling enzymes that control cell growth, differentiation, apoptosis, and protein trafficking --> 11 isoforms

- Hyperglycemia --> Increased DAG --> Directly stimulates PKC

- Increases in hydrostatic pressure, vascular permeability, filtration of abnormal proteins, macromolecules, and immune complex accumulation in blood vessels and the mesangium of glomerulus

- Enhances angiogenic factors and stimulates pro-inflammatory gene expression 

- Hyperglycemia accelerates irreversible non-enzymatic protein glycation

- Increases advanced glycation end products within the body

- Binds to ECM proteins --> Stiff collagen

- Glycosylation of proteins with slow turnover --> Hb, albumin, lipoproteins, lens, mesangial matrix, glomerular BM, nucleic acids, arterial walls, and nerves

- AGEs activate macrophages --> Interference with integrins and causes protein overproduction that are further glycosylated

- Macrophages produce cytokines that stimulate cell and ECM growth --> Increase atherosclerosis and increase the formation of fatty streaks and plaques

- Leading cause of blindness in the working-age population

- 10,000 new cases a year

1. Background retinopathy --> Pericyte and endothelial cell loss --> Acellular capillaries

- Micoraneurysms and vascular BM thickening result

- Cells are lost by apoptosis

- Retinal blood flow and permeability is increased

- Capillary closure results --> Non-perfusion

- Angiogenic growth factors are produced --> VEGF, FGF, IGF, and TGF-B --> Most potent angiogenic factor is VEGF

2. Proliferative Retinopathy

- Neovascularization and uncontrolled angiogenesis

- Vision becomes cloudy/blurry and patchy

- Vessels begin to form around and through the fovea --> Blurry vision

- Histology: Soft exudates, neovascularization, vessel occlusion, and hemorrhages

- Macular edema results

- An eye disorder where the optic nerve becomes damaged

- Results in the loss of retinal ganglion cells --> Vision loss --> Tunnel vision results

- Second leading cause of blindness in the US

- Increased IOP --> Fluid pressure inside the eye increases causing irreversible retinal damage

1. Open angle --> Increased production of aqueous humor (90%)

- Progressive open-angle --> Increased intraocular pressure leading to optic cupping

2. Closed angle --> Narrowing of Canal of Schlemm

- Fluid is produced by the ciliary body, flows from the posterior to anterior chamber and then drains

- Hyperglycemia --> Induces excessive ECM production --> Narrows canal of Schlemm --> Closed-angle

3. Treatment: B-blockers (timolol) and muscarinic agonists (pilocarpine and dorzolamide)

- Causes blurred and misty vision --> Lens becomes cloudy

- 3-4x incidence in diabetics

- Excess buildup of sorbitol within the lens --> Disruption of osmotic balance --> Hydropic lens, cell damage, and apoptosis

- Non-enzymatic glycosylation of lens proteins --> Premature occurence of cataracts

- Increased free radical production in the lens

- Treatment: Surgery --> Remove lens and replace with plastic implant

- Basement membrane thickening occurs too