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Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.

ed#% 1 &ecorded Overview: Dr. Bleich discussed the clinical and molecular aspects of hyperthyroidism. He also spoke about hypothyroidism, and the importance of T2 thyroid hormone. Objective 1: To be able to describe and identify clinical signs and symptoms of hyperthyroidism. A patient with Graves disease described her symptoms. The patient noticed her heart racin and felt palpitations. !he be an snorin and aspin for air when asleep. !he felt nervous, and be an visibly shakin . Her menstrual cycle became irre ular. !he suffered from mi ranes, loss of appetite, and nausea, leadin her to lose 2" lbs in two months. !he had hot flashes, and wore short sleeves even thou h it was cold outside. The fre#uency of her bowel movements increased to "$% times per day. Her vision was affected & she noticed blurred vision and spots. Her neck became swollen' it felt as if there were two lumps in it. After ( or " months, she saw a doctor, who found her to be tachycardic. Her heart rate was )(* beats per minute. !he was treated with a blood pressure medication, lopressor, which caused mi ranes and vomitin . !he went to the +,, where she was prescribed propanyl. !he found that this medication made her eyes sensitive to li ht, althou h the nausea and vomitin went away. !he went back to the +, a month later and a nuclear scan of her thyroid was done. The normal ran e for radioactive iodine uptake in 2" hours is )*$(%-, however this patient.s uptake was /0-. Additional physical e1amination revealed sli ht e1opthalamos, but no edema around the eyes. !he had an obvious oiter' her thyroid land was %$/ times lar er than normal. The oiter moves upon swallowin , and a bruit could be heard due to e1cess blood flow to the land. Althou h she was bein treated with B blockers, the patient still had a sli ht tremor. There was some heat eneration from her palms. !erration of the border of the nail bed 2plumer.s si n3 is another findin for Graves disease patients. The clinical manifestations of hyperthyroidism on skeletal muscle and fat include heat intolerance, muscle4body fati ue, and wei ht loss. All of these symptoms reflect increased thermogenesis. Signs and symptoms of hypothyroidism: 5atient had a total thyroidectomy in 2**( for thyroid cancer. !he be an to e1perience persistent wei ht ain, cold intolerance, and fati ue despite thyroid hormone replacement.

6mmediately after thyroidectomy in 2**(, patient.s T!H was hi h, and T" was low. 7ith replacement thyroid hormone, patient developed atrogenic hyperthyroidism. Dr. Bleich e1plained that patients are typically iven sli htly more thyroid hormone than needed.

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% 2 &ecorded Synthesis of Thyroid Hormones: ,ecall that thyro lobulin is the scaffold for thyroid hormone synthesis in the colloid.

,ecall from Dr. Thomas.s lecture & thyroid pero1idase 2T583 cataly9es the bindin of iodine to the tyrosine residues of thyro lobulin. T58 is also thou ht to cataly9e the couplin reactions.

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% ' &ecorded

:ote that this can occur in the thyroid and in peripheral tissues.

Dr. Bleich stressed the importance of T . Althou h there is not much in the literature about this thyroid hormone, it is an important contributor to thermo enesis, and it has its effect via a different mechanism than T( and T".

Objective

: !nderstand the effects of thyroid hormone on molec"lar reg"lation of thermogenesis.

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% 4 &ecorded T# and T$ hormone action: T( and T" are bound to thyroid bindin lobulin in the plasma. 6nside the cell, they bind to intracellular receptors that also act as transcription factors. The activated transcription factors bind to the thyroid hormone response element in the promoter re ion of the ene to "preg"late transcription of the gene for the "nco"pling protein %!&'(. The uncouplin protein enters the mitochondria and sits in the inner mitochondrial membrane, where it is important for thermo enesis of fatty acids. ,ecall that AT5 synthesis in the mitochondria is dependent upon the creation of a proton radient across the inner mitochondrial membrane The ener y to create the proton radient comes from the products of the ;rebs cycle. 5rotons diffuse throu h AT5 synthetase to produce AT5.

<atty acids provide carbons for the krebs cycle

=ncouplin protein acts as a proton sink to enerate heat. ,ecall that this protein is re ulated by T(.

T hormone action:

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% ( &ecorded 7hile T( causes the production of =>5 as a means to enerate heat, T2 ensures that there is substrate provide the ener y needed to create a proton radient across the inner mitochondrial membrane. T2 hormone activates A?5 ;inase in the cytosol increased fatty acid o)idation ener y for thermo enesis Objective #: !nderstand how T thryoid hormone fills a gap in o"r present "nderstanding of thyroid hormone action. Dr. Bleich went throu h past and recent e1periments which help elucidate the function and importance of T2 thyroid hormone. 6n an e1periment published in )0/(, researchers made rats hypothyroid. 8nce the rats were hypothyroid, they could control the amount of thyroid hormone administered to them. ,ats were iven either T2 or T(. ,ats iven T2 had a much shorter time course than T( 2The increase in metabolic rate occurs and disappears faster3. This can be e1plained by the fact that the T2 mechanism of action involves protein phosphorylation, while T( relies upon the slower process of affectin protein production. 7hen researchers added actinomyocin D, an inhibitor of D:A synthesis, T( action was obliterated. This demonstrates that T( action is enomic.

6n a 2**2 study, rats were a ain made to be hypothyroid. T( was administered, however the en9yme needed to convert T2 to T( was inhibited. These rats showed a much smaller increase in thermo enesis than normal rats, indicatin the importance of T2 for thermo enesis. :ote@ dark rey curve for normal rats, white curve the rats without T2

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% ) &ecorded 6n another e1periment, normal rats were administered additional thyroid hormones. :ote that T2 administration has little effect in these rats, because they are makin their own.

6n the rats made to be hypothyroid and then administered different combinations of thyroid hormone, once a ain there is proof that T( affects ene e1pression and T2 acts via phosphorylation of e1istin protein. :ote that the effect of T2 2curve labeled with 58"3 occurs faster than that of T( 2labeled D:A3. 8nce a ain, the addition of actinomyocin D 2which inhibits D:A synthesis3 ablates the effect of T(. Aook at the chan e in the red curve.

How does T thyroid hormone increase thermogenesis*

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% * &ecorded T2 activates A?5 kinase phosphorylates acetyl >oA carbo1ylase 2A>>3 A>> is now inactive, results in a decrease in ?alonyl$>oA maloynyl$ >oA is an inhibitor of carnitine palmitol transferase 6 2>5T)3, therefore a decrease in malonyl$>oA will allow an increase in >5T) >5T) increases fatty acid transport into mitochondria increased o1idation of fatty acids

T2 effect & increased o1idation of fatty acid T( effect & increased uncouplin

This dia ram shows the competition between lucose and fatty acids to enter the mitochondria. 27ant to use the ener y source available. <or e1ample if you drink a soda, lucose uptake is favored over fatty acids3. Downre ulation of malonyl$>oA allows >5T) to let more fatty acids into the mitochondria.

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% + &ecorded +ormal reg"lation of metabolism re,"ires T and T#:

T levels in patients with thyroid disease: :ote that there is variation in the amount of T2 hormone in patients with hyperthyroid disease. Graves disease with wei ht ain is possible if there is poor conversion of T( to T2.

-eight gain and thyroid disease: ?etformin is a dru used to treat diabetes. 6t increases lucose uptake into cell, however patients typically do not ain wei ht. How is this possibleB ?etformin has a similar effect as hyperthyroidism upon adenosine deaminase. Hyperthyroidism was associated with a )%- decrease in adenosine deaminase activities in rat hearts. ?etform also inhibits A?5 deaminase.

Physiology: Endocrine Disease Clinical Correlation Dr. David Bleich April 4, 2011 11am Christine iordano ! iordacg"#mdn$.ed#% , &ecorded The inhibition of A?5 deaminase increase in A?5 kinase increased fatty acid o)idation

The increase A?5 kinase also increases "pta.e of gl"cose into the cell 2the oal of usin metformin to treat diabetes3. However, this gl"cose is stored as glycogen. 2A?5 kinase upre ulates lyco en synthase3

S"mmary of hormone levels in healthy controls and different disease states:

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