Endocrine

Hypothyroidism symptoms

* Fatigue, constipation, dry skin and weight gain. * Cold intolerance. * Slowed movement and loss of energy. * Decreased sweating. * Mild nerve deafness. * Peripheral neuropathy. * Menstrual irregularities (typically menorrhagia). * Depression, dementia and memory loss. * Hair loss from an autoimmune process

What is the Primary carrier of Thyroid hormones?

*TBG (thyroxine-binding- globulin-) primary carrier of TH. TBG is synthesized in the liver.

What is the CP of De Quervain Thyroiditis?

*TENDER* thyroid with *transient hyperthyroidism* that does NOT progress to hypothyroidism

Describe Hormone Transport and Thyroid Hormone Transport Portiens

*• Thyroid hormones are poorly soluble in water, and more than 99% of the T3 and T4 circulating in blood is bound to carrier proteins. *Thyroxine-Binding Globulin is the Primary Carrier. 80% bound, and has a very HIGH affinity. Cannot be used. *Only Free Thyroid hormone can enter target tissues and have effect.

Pathophysiology of hashimoto (1A)

- T-cell mediated autoimmune -Th2 create anti-TSH-R abs which block TSH receptors (20%) - also have anti-TPO and anti TBG abs

Ix for hypothyroidism

- TSH inc -Low T4 - inc. TPO abs

aetiology of graves

- high iodine intake -smoking -stress -infections : e.coli & other gram -ve bacteria -autoimmune diseases -traume to thyroid gland -HAART

subacute thyroiditis

- painful De Quervain's (granulomatous thyroiditis) -caused by viral infection or post viral infection : including mumps, coxsackie, in uenza, adenoviruses, and echoviruses -damages follicular cells--> released of stored t3/4 -does not increase synthesis -lasts 2-6 wks

Hypothyrdoidism (1A)

- reduce production of thyroid hormones due to destruction of thyroid gland -includes hashimoto thyroditis -common in women aged 40-60

medullary thyroid cancer

-4% thyroid cancers -don't uptake iodine. arise from neuroendocrine parafollicular c-cells in the thyroid. -arise in MEN type 2. - produces calcitonin -may occur spontaneously -calcitonin lowers serum Ca+ and Phosphate levels . -serum calcium is normal because the high level of calcitonin ultimately down-regulates its receptors. - X-rays may show a dense, homogenous, conglomerate calcification. can also secrete prostaglandins, ACTH, serotonin, kallikrein, orbradykinin

Rx for myxedema coma

-ABC: ICU -hydrocortisone -thyroxine

Rx for thyroid storm

-IV fluids -b-blockers -large dose of thionamides -dexamethasone (8mg OD) or hydrocortisone

what is hashitoxicosis

-Inflammatory process in Hashimoto thyroiditis causes severe apoptosis resulting in thyroid hormone release and transient hyperthyroidism

Lab findings in TNG

-Low TSH and high T3/4

what is grave's disease?

-T-cell mediated autoimmune disorver resulting in thyrotoxicosis -Th2 cells stimulate production if autoAbs to TSH-R on thyroid follicular cells --> Abs bind to TSH-Rs --> increase thyroid hormone synthesis

Ix for thyroid storm

-TFT- inc. T3&4, undetectable TSH -ECG-arrythmias LFTs- elevated -hyper glycameia, hyperkalaemia

what is a thyroid storm (1b)

-acute exacerbations of hyperthyroidism symptoms -affects 1-2% with graves or people not treated properly -· precipitatedby infection, trauma, surgical emergency or radiation thyroiditis, DKA

thyroditis (1b)

-acute inflammatory disorder of the thyroid gland characterized by an initial thyrotoxic state followed by hypothyroidism eventually followed by euthyroidism in most cases - common in females ages 20-40 -subacute thyroditis -drug induced

drugs that cause thyroid disorders

-amiodarone : increases sytnthesis (type1) or destroys follicular cells (type 2) -lithium -ITFN-a : Hep c ppx -kinase inhibitors

treatment options/methods for graves

-block and replace (highdose c arbomazole + levothyroxine -titration

SE of thionamides

-carbimazole, PTU -agranularcytosis --> rash and sore throat o Thrombocytopaenia,toxic psychoses, enlargement of lymph nodes o Hepaticnecrosis with PTU, 3rd most common cause of drug-related liverfailure. R

cretinism

-congenital hypothyroidism -presents with mental retardation and short stature -impaired motor development -protuberant

what is hyperthyroidism

-excess amounts of thydroid hormone -common in women

eye changes

-exophthalmos due to due to abnormal connective tissue deposition in the orbit and extraocular muscles. -Ophthalmoplgeia paralysis of muscles surrounding eyes -conjuctival oedema -papillodema optic swelling Keratopathy -eyelid lag & retraction

DDX for hashimoto

-grave's -TMN -Struma ovarii -subacute thyroiditis -iodine induced hyper

atrophic hashi hypo

-hypothyroid from the beginning. - associated with thyroid lymphoma -Abs block TSH receptors --> not used , they shrink

What is hashimoto thyroiditis ?

-hypothyroidism due to autoimmune destruction of thyroid. There is infiltration of T lymphocytes which result in the formation of autoantibodies which inhibit the production of thyroid hormones - two types goitous and atrophic --> same pathophysiology but different extent of lymphocytic infiltration, fibrosis, and thyroid follicular cell hyperplasia

why does graves result in diffuse goitre ?

-increased stimulation of folicular cells by TSH-R Abs --> hyperplasia F cells --> cells scallop --> reduced colloid space --> goitre

aetiology of hyperthyroidism generally

-most cases instrinsic (99%) Primary -graves is the most common cause -1% seondary due to TSH secreting tumour, Thy horm. resistance and gonadotrophin-secreting tumour --thyroiditis -toxic nodular goiter -exogenous iodine excess -pituitary tumors -thyroid cancer -toxic adenoma

goitrous hasi hypothyroidism

-rubbery goitre -euthyroid -followed by hypothyroidism (compesation ) -infiltration of immune cells cause enlargement of thyroid gland, follicular cells disapear , goitre

Anaplastic thyroid cancer

1%, no effective therapy, fatal. elderly and women. rapid painful enlargement of the goitre

What laboratory findings are present in Hashimoto?

1). decreased T4 and increased TSH 2). Anti-thyroglobulin & Anti-thyroid peroxidase Ab's are often present (sign of thyroid damage, they do *NOT* mediate disease)

Effects of TH on Lipid Metabolism

1. Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. 2. Enhance oxidation of fatty acids in many tissues 3. Plasma cholesteroal and triglycerides are inversley related with TH levels.

Describe Hypothalamic Pituitary Thyroid axis and the General Principles of Thyroid Hormone Production

1. Signals sent to the Hypothalamus (such as heat, or Leptin from adipose tissue) can signal a need to activate the axis. 2. parts of the hypothalamus (paraventricular & arcuate nuclei for leptin) begin to secrete TRH. 3. TRH that reaches the Anterior Pituitary and Produces Thyrotropin (Thyroid Stimulating Hormone). 4. Thyrotropin stimulates the Production of two Varieties of Thyroid Hormone. T4 and T3 (which increase metabolism, etc). 5. Long loop negative feedback by Thyroid Hormone reduces activity in the Hypothalamus and Pituitary Gland (and adipose tissue when that was the original stimulus).

Thyroid Hormone effect on White and brown Adipose tissue

1. Stimulates adipose cell differentiation. 2. Regulates rates of lipolysis and lipogenesis. 3. Increases responsiveness to β-adrenergic receptors. 4. May regulate leptin production/release. Starts a futile cycle of building and removing heat in order to stimulate THERMOGENESIS.

follicular thyroid cancer

10%, common in elderly in regions of iodine deff.

Thyroid cancers

4 types -Papillary: -follicular -medullary -anaplastic:

papillay thyroid cancer

80-90% of thyroid cancers. more common in females 30-60. spreads via lymphatics and mets to lungs

What is the classic CP of a patient with Riedel Fibrosing Thyroiditis?

A young, 35-40 y/o woman comes in presenting with a "hard as wood", non-tender thyroid gland with some issues with airway b/c of invasion into local structures

What is the classic CP of a patient with Anaplastic Carcinoma? *HY*

An older, 70-80 y/o woman comes in presenting with a "hard as wood", non-tender thyroid gland.

Rx for graves

B-blocker i.e. propranolol or calcium channel blockers if intolerant to b-blockers o Beta-blockers also weakly decrease peripheral conversion of T4 to T3. Reduces symptoms such as Tachycardia, Dysrhythmias, Tremor, Agitation while titrating antithyroid treatments Thionamides: Carbimazole, Propylthyrouracil (PTUU, good in pregnancy, potent), thiamazole limit action of TPO take 3-4 week to titrate Radioiodine preffered in teens Lithium

Effect of Thyroid Hormone

Check picture

What are the histological features of Hashimoto? *HY*

Chronic inflammation with *germinal centers* & *Hurthle cells* (eosinophilic metaplasia of cells that line follicles)

What is Riedel Fibrosing Thyroiditis?

Chronic inflammation with extensive fibrosis of the thyroid gland

What other disease does Riedel Fibrosing Thyroiditis mimic?

Clinically mimics *anaplastic carcinoma*, however with Riedel the patients are younger & malignant cells are absent on histology

What is a Deiodinase?

Deiodinase (or iodide peroxidase or "Monodeiodinase") is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

Hyptherthyroidism

Excess metabolism • Clinical Features of the "Hyperthyroid State" (Thyrotoxicosis) ↑ temperature, ↑ heart rate, ↑ arrhythmias, ↑ pulse, ↑ blood pressure, ↑ metabolic rate, ↑ appetite, ↑ weakness, ↑ mood swings, ↑ irritability, ↑ movement, ↑ perspiration, ↑ sensitivity to heat, ↑ weight loss, ↑ cardiac arrhythmias Excess metabolism is due to too much free thyroid hormone being made available to tissues such that permissive effects become too pronounced.

The fibrosis in Riedel Fibrosing Thyroiditis may involve?

Fibrosis may extend to involve local structures (ex: airway)

What is Subacute Granulomatous (De Quervain) Thyroiditis?

Granulomatous thyroiditis that *follows a viral infection*

What is the CP of Riedel Fibrosing Thyroiditis?

Hypothyroidism + a *"hard as wood", NON-tender"* thyroid gland

Thyroid effect on Cardiovascular

Increase HR and CO, vasodilation,

Effect on enzymes that are involved in Metabolism

Increased action, such as Malic Enzyme and Cytochrome Oxidase.

What is a possible complication of Hashimoto?

Increased risk for B-cell (marginal zone) lymphoma

Action of Thyroid hormone effect on Sex hormones

Increases transport capability for sex hormones such as testosterone, through increasing Sex Sterioid-binding golubluin.

Permissive action of thyroid hormone on the heart results in

Increasing beta adrenergic receptors

Thyroid Hormone: Effect on Respiratory System

Maintains Respiratory center

Thyroid effect on reproduction

Maintenance normal ovarian cycle and spermatogeniss depend on normal levels of TH

Euthyroid

Normal Thyroid

Thyroid effect on Skeletal system

Permissive effects on bone matrix

Primary Vs Secondary Hypothyroidism

Primary hypothyroidism: Thyroid Gland is underactive and does not Respond apporpriately to presence or absence of TSH. Example: reaction after radioactive iodine therapy or Thyroid Resection. Thyroid works shitty. Secondary Hypothyroidism - Thyroid gland is Normal, but there is LOW TSH so TH levels are also low. Example: Pituitary Resection can effect TSH production --> low stimulation of TH production.

Primary vs Secondary Hyperthyroidism

Primary: Thyroid gland is overactive, and does not respond to any feedback. T3/T4 levels would be very high. Does not respond to TSH presence or absence. Example: Graves Disease, An Antibody stimulates TSH receptor, which stimulates Thyroid Hormone Secretion. Secondary Hyperthyroidism: The Thyroid Gland responds appropriatly to TSH presence or absence, however there is too much TSH which leads to excessive TH. Example: Anterior Pituitary Tumor.

Thyroid effect on Metabolism

Stimulate Lipolysis, Stimulates Hpeatic Glycolysis and Gluconeogenisis.

Describe thyroid receptor and the mechanism of action of thyroid hormone

T4 is transparted into the cell T4 is converted to T3. T3 binds the Hormone receptor, forming a Hormone-Receptor Complex (in the nucleus) HRC binds to receptor sites on chromatin, activating mRNA transcription. mRNA leaves the Nucleus Ribosomes translate mRNA into new protein. *the effect of receptor binding to DNA is to modulate gene expresssion, either by stimulating or inhibiting specific genes.

Ix for graves

TFTs o TSH : Low <0.05mU/L or undetectable (0.4-5U/L): primary: TSH is low because of negative feedback from increased levels of circulating T3 and T4 secondary: increased TSH results in increased T3 and T4 o Total T3/T4 levels: increased o Free T3/T4- diagnosis confirmed with free T4 levels o If TSH is suppressed but free T4 levels are normal then, if not previously supplied, free T3 level is needed (T3 toxicosis occurs in 5% of patients) -Anti TPO&TGB Abs in 75% -TSH-R Abs 99% specificity -biopsy- exclude malignancy -RAIU- increased uptake

Effects of TH on Carbohydrate metabolism

TH stimulate all apsects of Carbohydrate metabolism. Enhance insulin dependent entry of glucose into cells increase gluconeogensis increase glycogenolysis.

Th effect on growth

TH stimulates Endochondrol ossification Linear bone growth Maturation of epiphyseal growth centers. Growth Hormone is depenedt on TH to "set the stage" deffeciency leads to dwarfism.

Which abs are more specfic to graves

TSH-R

Describe the Three states of the Hormone in the blood

There are Three states: Free, Bound and Bioavailable. Free: not bound to serum protein, and can cross the cell freely or directly bind to membrane bound receptors. Bound - Conjugated form with serum globlun/binding protein, and cannot freely cross cell membrane. Bioavailable- Hormone that is avaiable, same properties as free. key points: 1. Most molecules bind with weak affinity to albumin. 2. Bioavailable = Amount of free hormone + Amount bound to albumin. 3. The free and bioavailable fractions are what the body uses! 4. The higher the amount of Binding Protien, the less Hormone available.

Compare and Contrast Different forms of Thyroid Hormone

Thyroid hormones are derivatives of the the amino acid tyrosine bound covalently to iodine. Tyrosines are provided from a large glycoprotein called thyroglobulin, produced by follicular cell. Thyroxine (T4)- Most Mass, Most Abundant TRiiodothyronine - Most Potent, 10x more potent "Reverse T3" (inactive) - very low potency, is a partial agonist. All are produced under the control of TSH, side note: There are 134 tyrosines per thyroglobulin,so there is a large reservoir

What addition binding protien transports Thyroid Hormone

Transthyretin (Prealbumin) & Albumin, Trans carries 10% of T4 and 5% of T3, Albumin Carries about 15% of each. They both have LOW binding affinity, so it is essentially bioavailable.

What is a possible complication of De Quervain Thyroiditis?

Usually is self-limited, but rarely may progress to hypothyroidism

Resp changes in graves

dyspnoea

what effect does graves have in children

excessive growth

features of myxedema coma

hallmark symptoms of decreased mental status and hypothermia hyponatremia, hypotension, hypoglycemia, bradycardia, hypoventilation, and generalized edema often presen

Rx for hashimoto

levoThyroxine b-blocker or CCB (thyrotoxic phase) -surgery -Radioactive thyroid ablation

CV effects in thyroidism

o AF § Especially in elderly § Thyroid functions should be tested in AF o Tachycardia

· Skin and hair changes in graves

o Pretibialmyxedema o Skinthinning o Warmand moist skin o Palmarerythema o Hairloss or fine/thinning hair o Clubbing(10-20%) o Onycholysis(rare) o Hyperpigmentationand vitiligo o Thyroid acropachy: extreme manifestation, with clubbing,painful finger and toe swelling, and periosteal reaction in limb bones.

neuro changes in graves

o Psychosis o mania o Impairedconsciousness levels

MSK changes in thyroidism

o Tremor o Briskreflexes o muscleweakness and wasting

feature pf thyroid storm

o severe hypermetabolism including hyperthermia and mental disturbance, tachycardia, arrythmias accompanied by pulmonary pede,a or congestive heart failure. N&V and diarrhoea

Myxedema coma

severe hypothyroidism complicated by trauma, sepsis, cold exposure, MI, inadvertent administration of hypnotics or narcotics, and other stressful events - medical emergency!

Thyroid effect on endocrine

stimulate secretion of insulin, PTH and ACTH TH is a modulator

Thyroid Effect on GI

stimulates motility, Food up take, glucose absorption

TH effect on CNS

too much leads to anxiety too little leads to feeling sluggish

cardio symp in hypothyroidism

§ Bradycardia § Hypertension

MSK symptoms in hypothyroidism

§ Delayed reflexes § Carpal tunnel § Serous cavity effusions § Cramps

Neuro symptoms in hpothyroidism

§ Depression § Mental slowing § Difficulty concentrating § Poor memory § Paraesthesia

Resp signs in hypothyroidism

§ Hypoventilation

URogenital symptoms in hypothyroidism

§ Menhorrhagia § Loss libido § Reduced fertility

o Skin and hair in hypothyroidism

§ Puffy ace, hands, and eet (myxedema) § Dry, coarse skin § Hair loss § Decreased sweating § Thinning of skin § Retarded nail growth

GI symptoms in hypothyroidism

§ Weight gain § Poor appetite § Constipation

what genes are associated w/ graves dz?

· HLA-DR, CTLA-4 , CD25 , PTPN22 (a T cell regulatory gene) and TSH-R polymorphisms.

Symptoms in graves

· Hyperactivity,irritability, altered mood · Heatintolerance, sweating · Palpitations · Fatigue,weakness · Weightloss with increased appetite · Diarrhoea,steatorrhea · Polyuria · Lossof libido · Oligomenorrhoea(infrequent periods) · Menorrhagia(very heavy periods) · rarelythere may be psychosis · periodicparalysis (common in Asian males) · impairedconsciousness

Toxic nodular goitre /adenoma /plummer's disease

· Hyperthyroidism arises from a multinodular goitre -autonomously fnodunctioning thyroid nodule which secretes T3&4 -can be multiple thyroxine secreting nodule (multipe) -Accounts for 35% hyperthyrpoidism -common in women and elderly +40 -can be cancerous or benign -can present with dysphagia

Aetiology of Hypothyroidism

· femalegender · geneticsusceptibility: increased frequency in patients with Down's syndrome, Turner'ssyndrome, certain HLA alleles, cytotoxic T-lymphocyte-associated protein 4(CTLA-4) · familyHx or personal Hx of other autoimmune diseases • cigarette smoking · highiodine intake · stressand infection otherautoimmune diseases: pernicious anaemia, systemic lupus erythematosus, Addisondisease, celiac disease, and vitiligo

Hypothyroidism

• Metabolism too low • Clinical Features of Hypothyroidism ↑Weakness, ↓Mental activity, ↓Physical activity, ↓Tolerance to cold, Facial edema, Dry coarse skin, Lethargy, Slowness of gait, Dullness of mind, Thick tongue, Heart flabbiness With too little TH available, permissive effects are minimal and other hormones are less effective than they need to be for proper homeostasis.

Three types of Deiodinase tissue

• Type 1 Deiodinase, found in liver and kidney This type is responsible for most of the T3 in the systemic circulation • Type 2 Deiodinase, found in the brain, pituitary, and brown adipose tissue This type is responsible for the conversion of T4 to T3 within the cell, to be used within that tissue • Type 3 Deiodinase, found in the brain, skin, and placenta This type is for inactivation, conversion of excess T4 into the metabolite, "Reverse T3"

sick euthyroid syndrome

• changes in circulating thyroid hormones amongst patients with serious illness, trauma, or stress • not due to intrinsic thyroid or pituitary disease -initially low T3, then low TSH -when they recover TSH shoots up

Ix for thyroditis

• initial elevated free T4, T3, low TSH, RAIU markedly reduced • marked elevation of ESR in painful variety only • as disease progresses values consistent with hypothyroidism may appear

features of thyroditis

• two forms painful ("De Quervain's") thyroid, ears, jaw, and occiput painless ("Silent") • fever and malaise may be present, especially in De Quervain's • postpartum: thyrotoxicosis 2-3 mo postpartum with a subsequent hypothyroid phase at 4-8 mo postpartum • may be mistakenly diagnosed as postpartum depression