Review Article Thyroid Disorders and Chronic Kidney...

Review ArticleThyroid Disorders and Chronic Kidney Disease

Mohamed Mohamedali Srikanth Reddy Maddika Anix VyasViswanathan Iyer and Pramil Cheriyath

Department of Medicine Pinnacle Health Affiliated to Penn State Hershey School of Medicine Harrisburg PA 17101 USA

Correspondence should be addressed to Mohamed Mohamedali mohdgafyahoocom

Received 26 November 2013 Revised 11 February 2014 Accepted 13 February 2014 Published 13 April 2014

Academic Editor Michael J Ross

Copyright copy 2014 Mohamed Mohamedali et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Thyroid hormones play a very important role regulating metabolism development protein synthesis and influencing otherhormone functions The two main hormones produced by the thyroid are triiodothyronine (T3) and thyroxine (T4) Thesehormones can also have significant impact on kidney disease so it is important to consider the physiological association of thyroiddysfunction in relation to chronic kidney disease (CKD) CKDhas been known to affect the pituitary-thyroid axis and the peripheralmetabolism of thyroid hormones LowT3 levels are themost common laboratory finding followed by subclinical hypothyroidism inCKD patients Hyperthyroidism is usually not associated with CKD but has been known to accelerate it One of the most importantlinks between thyroid disorders and CKD is uremia Patients who are appropriately treated for thyroid disease have a less chance ofdeveloping renal dysfunction Clinicians need to be very careful in treating patients with low T3 levels who also have an elevationin TSH as this can lead to a negative nitrogen balance Thus clinicians should be well educated on the role of thyroid hormones inrelation to CKD so that proper treatment can be delivered to the patient

1 Introduction

The function of the thyroid gland is one of themost importantin the human body as it regulatesmajority of the bodyrsquos physi-ological actionsThe thyroid produces hormones (T3 and T4)that have many actions including metabolism developmentprotein synthesis and the regulation ofmany other importanthormones Any dysfunction in the thyroid can affect theproduction of thyroid hormones (T3 and T4) which can belinked to various pathologies throughout the body One ofthe most important conditions that has been less studied isthyroid hormone levels and how they affect the progressionof CKD Disorders in renal function have been seen tocoexist with specific levels of thyroid hormone This studyis done to simplify the importance of interactions betweenthyroid function and kidney disease This information isessential as it shows a link between two separate conditionsInformation obtained from this paper will help to increaseclinical knowledge and enable clinicians to provide bettermanagement for their patients who have thyroid or kidneydysfunction

2 Methodology

A search for articles was done using PubMed Google ScholarCochran Review and review of journals within a medicallibrary Specific searches usedwere ldquothyroid function inCKDhypothyroidism hyperthyroidism chronic kidney diseasethyroid hormones in dialysis nephritic and nephrotic syn-drome thyroid cancer and glomerulonephritisrdquo The mostrelevant and current articles were selected and retrieved asavailable in their original form or abstracts All articles werereviewed relevant data was extracted from the most up todate information Prior studies and publications were alsoused

3 Thyroid Disease Epidemiology

Approximately 1 in 13 or 20 million people (735) havethyroid disease in the United States [1] Thyroid disorders areclassified into hypothyroid hyperthyroid and a subclinicalstate Based on the largest population study NHANES III46 of the US population is suffering from hypothyroidism

Hindawi Publishing CorporationInternational Journal of NephrologyVolume 2014 Article ID 520281 6 pageshttpdxdoiorg1011552014520281

2 International Journal of Nephrology

Hypothalamus

TRH released from hypothalamustravels to the anterior pituitary

TRH stimulates the release of TSH from the anterior pituitary

TSH travels to the thyroidwhere it stimulates the

production of T3 and T4

released from the

Elevated amounts of T3T4will cause negative feedbackon the hypothalamus andpituitary

(-)

(-)

Target cells of the body

T3 and T4

thyroid into circulationT4

T3

(-)

Figure 1

(03 clinical and 43 subclinical) and 13 from hyper-thyroidism (05 clinical and 07 subclinical) [2] Bothhypothyroidism and hyperthyroidism account for a high levelof morbidity in the United States

4 Chronic Kidney Disease

CKD is usually a progressive irreversible condition that isthe 8th leading cause of death in the United States [3]According to the population study 1 in 10 American adults(more than 30million people) suffer from some level of CKD[3] Risk factors for CKD include diabetes hypertensionhyperlipidemia and thyroid disorders

5 Thyroid Physiology (Figure 1)

T3 and T4 play a critical role in cell differentiation duringdevelopment and helpmaintainmetabolic homeostasis in theadults [4]

6 Thyrotropin Releasing Hormone (TRH)

TRH is a very small tripeptide amide L-pyroglutamyl-L-histidyl-L-prolineamide (L-PHP) [5] TRH release is influ-enced by thyroid hormones in circulation and control fromthe hypothalamus Once TRH is released from the hypotha-lamus it travels to the anterior pituitary where it interactswith TRH receptors (C-phosphoinositide pathway) to causethe release of thyroid stimulating hormone (TSH) (3)

7 Thyroid Stimulating Hormone (TSH)

TSH is a 28 to 30 kDa glycoprotein subset of the cystine-knot growth factor super family [6] It is produced from

the basophilic cells of the anterior pituitary gland Afterbeing released from the anterior pituitary TSH travels to thethyroid gland and binds with TSH receptors on thyroid cellsThis physiological action activates the second messengerpathway resulting in thyroid gene expression and the releaseof T3T4

8 Thyrotropin Molecular Structure (Figure 2)

Thestructure of the thyrotropin hormone consists of a human120572 subunit and 120573 subunit located on chromosomes 1 and 6respectively The alpha subunit gene contains 4 exons and3 introns which is twice larger than the 120573 subunit genecontaining 3 exons and 2 introns [6]The alpha subunit servesas the effector region for stimulation of the secondmessengerpathways The physiological action of the 120573 subunit plays animportant role in determining thyrotropinrsquos receptor speci-ficity

9 CKD in Relation to ThyroidDisorders (Figure 3)

As mentioned CKD affects the hypothalamus-pituitary-thyroid axis and the peripheral metabolism of thyroid hor-mone Low T3 is the most common laboratory finding andsubclinical hypothyroidism ismost common thyroid disorderfound in CKD patients [7] TSH levels are usually normalwith an altered circadian rhythm (comprised of TSH bioac-tivity) In uremia the pituitary receptor response to TRH isblunted causing a decrease in TSH release The response ofTSH to TRH is delayed because of the decreased clearanceand the increase of half-life of TSH [7] Abnormal serumconstituents found in uremic conditions can also displaceT3 and T4 from normal protein binding sites Normal orlow levels of T4 may be due to the monodeiodinase actionoccurring in the inner benzene ring instead of outer ringof T4 resulting in the formation of reverse T3 Reverse T3levels however are found to be normal in CKD patientsbecause it moves from the vascular space to extra vascularand intracellular spaces [7] Transient increases in T4 levelsare usually seen after hemodialysis This effect is mainly dueto the use of heparin as an anticoagulant which inhibits T4binding to proteins and leads to an increase in T4 levels [7]

Low T3 levels in CKD may be due to the iodothyroninedeiodinase (helps inT3 synthesis fromT4) affected by fastingchronic metabolic acidosis and chronic proteinmalnutritionseen in CKD Such factors influence the proteins binding toT3 [7] LowT3 levels inCKDmay also be due to the decreasedperipheral (extra thyroidal) conversion from T4 to T3 due todecreased clearance of the inflammatory cytokines such asTNF-alpha and IL-1 These cytokines inhibit expression of 151015840-deiodinase that helped convert T4 to T3 [8] Low free T3levels have shown to be an independent predictor ofmortalityin hemodialysis patients [9] Low T3 levels prior to renaltransplant are associated with posttransplant risks of graftloss [7] All clinicians are advised to check T3 levels beforerenal transplantation Low T3 levels in CKD may not beable to increase TSH levels Experimental evidence suggests

International Journal of Nephrology 3

12057211ndash20

12057288ndash92

12057233

ndash38 12057388ndash105

12057240ndash46

12057358ndash69

12057251-52

120572L1

120572L2

120572L3

120573L1

120573L2

120573L3

Figure 2 Structure of thyrotropin

that in uremia the sensitivity of thyrotrophs is increasedThis may account for the resetting of the central thyrostatindicating a lower level of the circulating thyroid hormonesand in turn affect the negative feedback inhibition [10]In CKD physiological compensation for low T3T4 (withnormal TSH levels) causes a reduction in protein catabolismwhich increases the nitrogen waste overload

10 Goiter in CKD

There is an increased prevalence of goiter (0ndash9) in patientswith CKD This may be due to the decreased clearanceof the inorganic iodides causing a hypertrophic effect onthe thyroid gland tissue leading to goiter [7] A decreasedclearance of goitrogenic substances like aryl acid due to CKDmay also be a factor [8] Research has shown that increasedserum iodine levels can result in prolongation of the Wolff-Chaikoff effect

11 Subclinical Hypothyroidism

Subclinical hypothyroidism is defined as an elevation inserum TSH concentration (normal range 5ndash10120583IUmL) inconjunction with a normal serum free T4 concentrationWith the decline in GFR the prevalence of subclinicalhypothyroidism increases consistently One study showedthat approximately 18 of the patients with CKD notrequiring dialysis have subclinical primary hypothyroidismThis finding is independently associated with a progressivelylower estimated GFR The prevalence of subclinical primaryhypothyroidism increased from 7 to 179 in individualswhose GFR has decreased from ge90mLmin to 60mLmin[11] Some researchers reported that hypothyroidism can

be corrected with restriction of dietary iodine in uremicpatients on dialysis which decreases the need for hormonereplacement therapy In one clinical trial the overall rate ofa decline in the estimated GFR was significantly greater inthose not treated with thyroid hormones compared to thosewho were treated with thyroid hormones

12 Hyperthyroidism (Figure 4)

The prevalence of hyperthyroidism in CKD patients is thesame as it is with the general population thus CKD isnot directly associated with hyperthyroidism However it isimportant to understand that aspects of hyperthyroidism canindeed accelerate CKDThese mechanisms are the following

(i) increased renal blood flow seen in hyperthyroidismresults in intraglomerular hypertension leading toincreased filtration pressure and consequent hyper-filtration Proteinuria seen in hyperthyroidism isknown to cause direct renal injury

(ii) increased mitochondrial energy metabolism alongwith downregulation of superoxide dismutase whichoccurs in hyperthyroidism contributes to an in-creased free radical generation that causes renalinjury

(iii) oxidative stress also contributes to hypertension inhyperthyroidism which contributes to CKD progres-sion [7]

13 Thyroid Disorders in Glomerular Diseases

Thyroid diseases including both hypo- and hyperthyroidismare associated with several types of glomerulonephritis


CKD

Hypothalamicpituitary axis

Normal TRH

Normal TSH with altered circadian rhythm and

glycosylation

Compromised bioavailability

Uremia causes a blunted and delayed

response of TSH receptors

The monodeiodinase reaction occurs on the

inner benzene ring of

will remain normal as it moves into intracellular and

extravascular spaces

Decreased GFR

Decreased GFR

Decreased clearanceof inflammatory

Decreasedclearance of

iodine and some

goitrogenic substances

Decreased peripheral

(the most commonfinding in CKD)

Hypothyroidism

Normalor low T4

conversion of T4

Low T3

cytokines like TNF-120572 and IL-1

Inhibited expression of

T4 leading to formationof rT3 rT3 serum levels

type 1 5998400-deiodinase

Figure 3

The types of glomerulonephritis seen in thyroid diseaseare membranous IgA mesangiocapillary membranoprolif-erative and minimal change glomerulonephritis Amongthese the most frequent is membranous glomerulonephri-tis [12] The two main histological changes seen are athickened glomerular basement membrane (GBM) due toimmune complex deposition and an increased mesangialand endocapillary cellularity [13] The pathophysiology linksbetween thyroid dysfunction and glomerulonephritis involveproteinuria and formation of immune complexes [12] Thisassociation is extremely common in autoimmune thyroiditisApproximately up to 50 of patients with autoimmunethyroiditis have the presence of immune complexes Thesecomplexes are mainly responsible for the alteration of therenal function by depositing on the basement membrane ofthe glomeruli Some studies have also reported a depositionof thyroglobulin in the basementmembrane of the glomeruliIn addition to thyroid diseases similar effects are alsoseen in other autoimmune disorders such as systemic lupuserythematosus (SLE) and diabetes [12]

14 Nephrotic Syndrome

Changes in the serum levels of thyroid hormone can affectnephrotic syndrome in many ways Due to proteinuria thereis a loss of many binding proteins including thyroxine-binding globulin (TBG) transthyretin or prealbumin andalbumin [12] Due to losses of these proteins there is areduction in serum T4 and total T3 levels In most circum-stances patients are euthyroid because the thyroid is able tocompensate for the proteinuria and free T3 and T4 levels arenormal [14] The role of using levothyroxine to replace ofthyroid hormones remains controversial

15 Thyroid Cancer and Kidney Disease

The incidence of thyroid cancer has increased worldwideWomen are 3 times more likely to be diagnosed with thyroidcancer [12] Patients with thyroid cancer are also predisposedto other types of cancer including renal cell carcinomaMany studies are looking at the relationship between thyroidhormones and reproductive cancers Other types includeparenchymal epithelial tumors oncocytoma collecting ducttumors and renal sarcoma Kidney metastasis from thyroidcarcinomas is seen in papillary [15ndash21] follicular [22ndash26]and anaplastic thyroid cancers [27] Kidney tumors can alsometastasize to the thyroid gland

16 Effects of Dialysis on ThyroidHormones Hemodialysis

Most patients on hemodialysis (HD) are euthyroid [12]Systemic acidosis time on dialysis markers of endothelialdamage and inflammation from HD are associated with lowT3 levels [12] Low total T4 levels with increased free T4 levelsare seen as heparin inhibits T4 binding to proteins therebyincreasing a free T4 fraction in these patients TSH is elevatedin 20 of patients on HD usually in the range of 5ndash20mUL[7] HD affects the cellular transport of TSH which might actas a compensatory mechanism for maintaining an euthyroidstatus [12]

17 Peritoneal Dialysis

Peritoneal dialysis (PD) is usually associated with low T3 lev-els and subclinical hypothyroidism [8] Low T3 levels mightbe due to inflammation and malnutrition in PD as there is


Hyperthyroidism

Proteinuria

Increased renalblood flow

results in increasedfiltrationpressure

leading tohyperfiltration

Free radicalgeneration due

to downregulation ofsuperoxide dismutase

Accelerationof

CKD

Figure 4

an association between free T3 CRP and serum albumin[28] Subclinical hypothyroidismmay be due to a decrease iniodide clearance Iodide clearance is donemainly by glomeru-lar filtration thus in advanced CKD iodide excretion isdiminished with subsequent elevation in plasma inorganiciodide concentration Such increases in total body inorganiciodide may block thyroid hormone production which mayexplain the high incidence of subclinical hypothyroidism inCKD patients The T4 and T3 losses are minor (10 and 1resp) and easily compensated in PD [7] Thyroid hormonesupplementation is not necessary in patients on PD

Thyroxine-binding globulin (TBG) is lost along with T4and T3 in the PD however TBG levels are normal Recentstudies have demonstrated that subclinical hypothyroidism isassociated with an increased risk for cardiovascular diseaseand can cause mortality in CKD patients

18 Renal Transplant

Renal transplantation is known to normalize thyroid hor-mone levels Gradually within 3 to 4 months low T3 andT4 return to normal in renal transplant patients Duringthe first few months of transplant T4 is reduced less thanthe pretransplant stage and gradually returns to normal [8]Normally free T3 and thyroid volume will correlate withgraft function in posttransplantation patients The low T3levels before transplant are associated with future risk ofgraft loss and thyroid hormone supplementation will not beuseful treating these patients with thyroid hormones is notnecessary [8]

19 Conclusion

Thyroid disorders and CKD are independently some of themost prominent medical conditions found in patients in

the United States Due to the high prevalence of both it isimportant to consider the physiological association of thyroiddysfunction in relation to kidney disease The most commonchanges in CKD relating to the thyroid gland are of lowT3 levels and subclinical hypothyroidism The prevalence ofsubclinical hypothyroidism increases consistently in patientswho have a decline in GFR Low T3 normal to reducedT4 levels and normal TSH often result in increased thyroidgland volume In turn a decrease in renal function alsoaccounts for an ineffective clearance of abnormal serumconstituents inflammatory cytokines iodide excretion andan increase of nitrogen conservation All of these factorshave been clinically proven to affect the normal physiologyand metabolism of thyroid hormones Hyperthyroidism isusually not associated with CKD but is known to accelerateit It is very important to consider all clinical features andthyroidmanifestations in those patients with CKDAs seen inmany evidence-based studies and current clinical cases thereare distinct relationships in thyroid dysfunction and kidneydisease and vice versa

Clinicians including nephrologists must consider thedangers of thyroid disease and its appropriate treatmentin conjunction to treating CKD Patients who receiveappropriate treatment for their thyroid disease have a de-creased chance of developing or exacerbating renal dysfunc-tion However treating patients with a mild elevation of TSH(less than 20 IUmL) results in a negative nitrogen balance byincreased muscle catabolism Clinicians should look for lowT3 levels in patients prior to renal transplant as low levels areassociated with renal graft loss

Conflict of Interests

The authors declare that there is no conflict of interests


References

[1] Prevalence and Incidence of Kidney disease and thyroid disor-der Right diagnosis from Health Grade

[2] J G Hollowell NW StaehlingW Dana Flanders et al ldquoSerumTSH T4 and thyroid antibodies in theUnited States population(1988 to 1994) National Health and Nutrition ExaminationSurvey (NHANES III)rdquo Journal of Clinical Endocrinology andMetabolism vol 87 no 2 pp 489ndash499 2002

[3] ldquoCenters for Disease Control and Preventionrdquo Leading Causesof Death 2009 httpwwwcdcgovnchsfastatslcodhtm

[4] J L Jameson andA PWeetmanHarrisonrsquos Principles of InternalMedicine 18th Edition Disorders of the Thyroid Gland

[5] L Luo J Z Luo and I Jackson ldquoTripeptide amide L-pyroglu-tamyl-histidyl-L prolineamide (L-PHP Thyrotropin- ReleasingHormone TRH) promotes insulin-producing cell prolifera-tionrdquo Current Aging Science vol 6 no 1 pp 8ndash13 2013

[6] M W Szkudlinski V Fremont C Ronin and B D WeintraubldquoThyroid-stimulating hormone and thyroid-stimulating hor-mone receptor structure-function relationshipsrdquo PhysiologicalReviews vol 82 no 2 pp 473ndash502 2002

[7] G Basu and A Mohapatra ldquoInteractions between thyroiddisorders and kidney diseaserdquo Indian Journal of Endocrinologyand Metabolism vol 16 no 2 pp 204ndash213 2012

[8] V S Lim V S Fang A I Katz and S Refetoff ldquoThyroid dys-function in chronic renal failure A study of the pituitarythyroid axis and peripheral turnover kinetics of thyroxine andtriiodothyroninerdquo Journal of Clinical Investigation vol 60 no3 pp 522ndash534 1977

[9] C Zoccali F Mallamaci G Tripepi S Cutrupi and P PizzinildquoLow triiodothyronine and survival in end-stage renal diseaserdquoKidney International vol 70 no 3 pp 523ndash528 2006

[10] E D Avner and W Harmon 2004 Pediatric NephrologyLippincott Williams ampWilkins Philadelphia Pa USA 2004

[11] M Chonchol G Lippi G Salvagno G Zoppini M Muggeoand G Targher ldquoPrevalence of subclinical hypothyroidism inpatients with chronic kidney diseaserdquo Clinical Journal of theAmerican Society of Nephrology vol 3 no 5 pp 1296ndash13002008

[12] P Iglesias and J J Dıez ldquoThyroid dysfunction and kidneydiseaserdquo European Journal of Endocrinology vol 160 no 4 pp503ndash515 2009

[13] B Akikusa Y Kondo and Y Iemoto ldquoHashimotorsquos thyroiditisand Membranous nephropathy developed in progressive sys-temic sclerosis (PSS)rdquo American Journal of Clinical Pathologyvol 81 no 2 pp 260ndash263 1984

[14] E I Feinstein E M Kaptein J T Nicoloff and S G MassryldquoThyroid function in patients with nephrotic syndrome andnormal renal functionrdquo American Journal of Nephrology vol 2no 2 pp 70ndash76 1982

[15] D P Sarma and G T Simmons ldquoIntraglomerular metastasesfrom papillary carcinoma of the thyroidrdquo The Journal of theLouisiana State Medical Society vol 141 no 6 pp 26ndash28 1989

[16] M J Liou J D Lin M H Chung C T Liau and C HsuehldquoRenal metastasis from papillary thyroid microcarcinomardquoActa Oto-Laryngologica vol 125 no 4 pp 438ndash442 2005

[17] F P Ruggiero E E Frauenhoffer and B C Stack Jr ldquoPapillarythyroid cancer with an initial presentation of abdominal andflank painrdquoAmerican Journal of Otolaryngology-Head and NeckMedicine and Surgery vol 26 no 2 pp 142ndash145 2005

[18] A Gamboa-Dominguez and A Tenorio-Villalvazo ldquoMetastaticfollicular variant of papillary thyroid carcinoma manifested asa primary renal neoplasmrdquo Endocrine Pathology vol 10 no 3pp 265ndash268 1999

[19] M Inahara K Mikami T Tobe H Suzuki and H Itou ldquoA caseof thyroid cancer metastasizing to the bilateral kidneysrdquo ActaUrologica Japonica vol 48 no 5 pp 315ndash317 2002

[20] K Abe T Hasegawa S Onodera Y Oishi and M SuzukildquoRenal metastasis of thyroid carcinomardquo International Journalof Urology vol 9 no 11 pp 656ndash658 2002

[21] R C Smallridge M R Castro J C Morris et al ldquoRenalmetastases from thyroid papillary carcinoma study of sodiumiodide symporter expressionrdquo Thyroid vol 11 no 8 pp 795ndash804 2001

[22] C Von Falck G Beer K F Gratz and M Galanski ldquoRenalmetastases from follicular thyroid cancer on SPECTCTrdquo Clin-ical Nuclear Medicine vol 32 no 9 pp 751ndash752 2007

[23] A Kumar M Nadig V Patra D N Srivastava K Kerma andC S Bal ldquoAdrenal and renal metastases from follicular thyroidcancerrdquo British Journal of Radiology vol 78 no 935 pp 1038ndash1041 2005

[24] H Iwai Y Ohno H Ito T Kiyokawa and N Aoki ldquoRenalrupture associated with a poorly differentiated follicular thyroidcarcinoma metastasizing to the thigh muscle lung and kidneyrdquoInternal Medicine vol 44 no 8 pp 848ndash852 2005

[25] J M Regojo Balboa D Sanchez Zalabardo J Rioja Zuazuet al ldquoFollicula carcinoma of the thyroid manifested initiallyasympton primary renal neoplasmrdquoActas Urologicas Espanolasvol 28 no 4 pp 308ndash310 2004

[26] D V Matei F Verweij E Scardino et al ldquoLate solitary thyroidcarcinoma metastasis to the kidney a case reportrdquo AnticancerResearch B vol 23 no 1 pp 561ndash564 2003

[27] S Moudouni I En-Nia N Rioux-Leclerc J Patard F Guilleand B Lobel ldquoRenal metastasis of a carcinoma of the thyroidrdquoProgres en Urologie vol 11 no 4 pp 670ndash672 2001

[28] G Enia V Panuccio S Cutrupi et al ldquoSubclinical hypothy-roidism is linked to micro-inflammation and predicts death incontinuous ambulatory peritoneal dialysisrdquoNephrology DialysisTransplantation vol 22 no 2 pp 538ndash544 2007

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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BioMed Research International

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Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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OphthalmologyJournal of


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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Hypothalamus

TRH released from hypothalamustravels to the anterior pituitary

TRH stimulates the release of TSH from the anterior pituitary

TSH travels to the thyroidwhere it stimulates the

production of T3 and T4

released from the

Elevated amounts of T3T4will cause negative feedbackon the hypothalamus andpituitary

(-)

(-)

Target cells of the body

T3 and T4

thyroid into circulationT4

T3

(-)

Figure 1

(03 clinical and 43 subclinical) and 13 from hyper-thyroidism (05 clinical and 07 subclinical) [2] Bothhypothyroidism and hyperthyroidism account for a high levelof morbidity in the United States

4 Chronic Kidney Disease

CKD is usually a progressive irreversible condition that isthe 8th leading cause of death in the United States [3]According to the population study 1 in 10 American adults(more than 30million people) suffer from some level of CKD[3] Risk factors for CKD include diabetes hypertensionhyperlipidemia and thyroid disorders

5 Thyroid Physiology (Figure 1)

T3 and T4 play a critical role in cell differentiation duringdevelopment and helpmaintainmetabolic homeostasis in theadults [4]

6 Thyrotropin Releasing Hormone (TRH)

TRH is a very small tripeptide amide L-pyroglutamyl-L-histidyl-L-prolineamide (L-PHP) [5] TRH release is influ-enced by thyroid hormones in circulation and control fromthe hypothalamus Once TRH is released from the hypotha-lamus it travels to the anterior pituitary where it interactswith TRH receptors (C-phosphoinositide pathway) to causethe release of thyroid stimulating hormone (TSH) (3)

7 Thyroid Stimulating Hormone (TSH)

TSH is a 28 to 30 kDa glycoprotein subset of the cystine-knot growth factor super family [6] It is produced from

the basophilic cells of the anterior pituitary gland Afterbeing released from the anterior pituitary TSH travels to thethyroid gland and binds with TSH receptors on thyroid cellsThis physiological action activates the second messengerpathway resulting in thyroid gene expression and the releaseof T3T4

8 Thyrotropin Molecular Structure (Figure 2)

Thestructure of the thyrotropin hormone consists of a human120572 subunit and 120573 subunit located on chromosomes 1 and 6respectively The alpha subunit gene contains 4 exons and3 introns which is twice larger than the 120573 subunit genecontaining 3 exons and 2 introns [6]The alpha subunit servesas the effector region for stimulation of the secondmessengerpathways The physiological action of the 120573 subunit plays animportant role in determining thyrotropinrsquos receptor speci-ficity

9 CKD in Relation to ThyroidDisorders (Figure 3)

As mentioned CKD affects the hypothalamus-pituitary-thyroid axis and the peripheral metabolism of thyroid hor-mone Low T3 is the most common laboratory finding andsubclinical hypothyroidism ismost common thyroid disorderfound in CKD patients [7] TSH levels are usually normalwith an altered circadian rhythm (comprised of TSH bioac-tivity) In uremia the pituitary receptor response to TRH isblunted causing a decrease in TSH release The response ofTSH to TRH is delayed because of the decreased clearanceand the increase of half-life of TSH [7] Abnormal serumconstituents found in uremic conditions can also displaceT3 and T4 from normal protein binding sites Normal orlow levels of T4 may be due to the monodeiodinase actionoccurring in the inner benzene ring instead of outer ringof T4 resulting in the formation of reverse T3 Reverse T3levels however are found to be normal in CKD patientsbecause it moves from the vascular space to extra vascularand intracellular spaces [7] Transient increases in T4 levelsare usually seen after hemodialysis This effect is mainly dueto the use of heparin as an anticoagulant which inhibits T4binding to proteins and leads to an increase in T4 levels [7]

Low T3 levels in CKD may be due to the iodothyroninedeiodinase (helps inT3 synthesis fromT4) affected by fastingchronic metabolic acidosis and chronic proteinmalnutritionseen in CKD Such factors influence the proteins binding toT3 [7] LowT3 levels inCKDmay also be due to the decreasedperipheral (extra thyroidal) conversion from T4 to T3 due todecreased clearance of the inflammatory cytokines such asTNF-alpha and IL-1 These cytokines inhibit expression of 151015840-deiodinase that helped convert T4 to T3 [8] Low free T3levels have shown to be an independent predictor ofmortalityin hemodialysis patients [9] Low T3 levels prior to renaltransplant are associated with posttransplant risks of graftloss [7] All clinicians are advised to check T3 levels beforerenal transplantation Low T3 levels in CKD may not beable to increase TSH levels Experimental evidence suggests


12057211ndash20

12057288ndash92

12057233


12057240ndash46

12057358ndash69

12057251-52

120572L1

120572L2

120572L3

120573L1

120573L2

120573L3



10 Goiter in CKD













CKD


Normal TRH


glycosylation








Decreased GFR

Decreased GFR



iodine and some




Hypothyroidism

Normalor low T4

conversion of T4

Low T3





Figure 3











Hyperthyroidism

Proteinuria






Accelerationof

CKD

Figure 4



18 Renal Transplant


19 Conclusion







References


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















12057211ndash20

12057288ndash92

12057233


12057240ndash46

12057358ndash69

12057251-52

120572L1

120572L2

120572L3

120573L1

120573L2

120573L3



10 Goiter in CKD













CKD


Normal TRH


glycosylation








Decreased GFR

Decreased GFR



iodine and some




Hypothyroidism

Normalor low T4

conversion of T4

Low T3





Figure 3











Hyperthyroidism

Proteinuria






Accelerationof

CKD

Figure 4



18 Renal Transplant


19 Conclusion







References


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















CKD


Normal TRH


glycosylation








Decreased GFR

Decreased GFR



iodine and some




Hypothyroidism

Normalor low T4

conversion of T4

Low T3





Figure 3











Hyperthyroidism

Proteinuria






Accelerationof

CKD

Figure 4



18 Renal Transplant


19 Conclusion







References


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Hyperthyroidism

Proteinuria






Accelerationof

CKD

Figure 4



18 Renal Transplant


19 Conclusion







References


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Thyroid Disorders and Chronic Kidney...

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