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Vol. 17, No. 1Printed in U.S.A.0163-769xl96/$03.00/0Endocrine ReviewsCopyright 0 1996 by The Endocrine Society

Thyroid Hormone Metabolism and Thyroid Diseases inChronic Renal FailureELAINE MAY WTEINUniversity of Southern California School of Medicine, Los Angeles, California 90033

I. IntroductionII. Thyroid Hormone Metabolism in Chronic Renal FailureA. TSHB. T,C. T,D. rTsIII. Effects of Therapy in Chronic Renal FailureA. DialysisB. ErythropoietinC. ZincD. Thyroid hormone therapyE. Renal transplantationIV. Inorganic Iodide Metabolism in Chronic Renal FailureV. Thyroid Diseases in Chronic Renal Failure and RenalTransplantationA. GoiterB. Thyroid nodulesC. Thyroid carcinomaD. HypothyroidismE. HyperthyroidismVI. Summary and ConclusionsI. IntroductionE D-STAGE renal disease (ESRD ) is a relatively commonnonthyroidal illness, which induces significant mor-bidity and morta lity (1). In the United States, more than220,000 patients were being dia lyzed for ESR D in 1992, withan 8-9% annual increase in frequency over the last 10 years(1, 2). This rising incidence of ESRD reflects improved sur-vival rates of ESRD patients and increasing age of the generalpopulation, with the greatest increase in ESRD frequencybeing in people over 64 yr of age (2). ESRD is a moderate tosevere nonthyroidal illness and, as such, frequently altersthyroid hormone metabolism (3). In addition to metabolic

and endocrine derangements induced by ESRD, these pa-tients frequently have a multitude of nonrenal nonthyroidaldisorders that affect thyroid hormone metabolism, includ ingdiabetes mellitus (11, infections (l), and malnutrition (4-61,and they are treated by a varie ty of pharmacological agents.Knowledge of alterations of thyroid hormone metabolism ineuthyroid ESRD patients is required to accurately diagnoseand treat concurrent hypothyroid ism and hyperthyroidism.Furthermore, thyroid diseases including goiter, hypothy-roidism, thyroid nodules, and thyroid cancer may occurAddress reprint requests to: Elaine M. Kaptein, M.D ., Room 4250 GH,1200 North State Street, Los Angeles, California 90033.

more frequently in ESRD patients than in the general pop-ulation and may be underdiagnosed due to limited clin ica lawareness. Although principles of therapy for thyroid dis-eases are not altered in ESRD patients, radioactive iodidedosages for follicular thyroid cancer and hyperthyroidismmust be reduced to avoid radiation-related compl ications .This review wil l focus on: 1) thyroid hormone metabolismin euthyroid patients with ESRD, compared with nonrenalnonthyroidal disorders, hypothyroidism, and hyperthyroid-ism; 2) effects of reduced iodide excretion by residual renalfunction and different dia lys is regimens; and 3) frequency,diagnostic features, and specific treatment requirements ofthyroid disorders in ESRD patients, compared with nonrenalpatients.II. Thyroid Hormone Metabolism in ChronicRenal Failure

The hypothalamic-pituitary-thyroid hormone axis as wellas periphera l thyroid hormone metabolism are altered inESRD patients without concurrent thyroid disease. Simila r-ities and differences in thyroid hormone metabolism in ESRDand nonrenal nonthyroidal disorders are compared withthose of hypothyroidism and hyperthyroidism in Tables 1and 2.A. TSH

Basal serum TSH concentrations, diurnal variations, andglycosylation of TSH are altered in ESRD patients. In onestudy, basal serum TSH leve ls were above the normal rangeof 3.8 mu/liter in 12.5% of 40 euthyroid ESRD patients re-ceiving chronic hemodialysis therapy, with the highest valuebeing 5.4 mu/liter (7). In our study, 10.5% of 287 euthyroidESRD patients had serum TSH values above 5 mu/liter, and1% were above 10 mu/liter, in association with normal totalT4 and free T4 index values (3). All euthyroid ESRD patientswith TSH values between 10 and 20 mu/liter had repeat TSHvalues below 10 mu/liter (3). Transient TSH elevations, toabove 20 mu/liter in some instances, also occur during re-covery from acute nonrenal nonthyroidal illnesses @-lo),and then decrease in association with normal or rising totalT4 and free T4 index values (8-111, suggesting relief of pi-tuitary TSH suppression as illness severity decreases. In thegeneral hospital population, serum TSH levels above 20 mU/liter are as frequently due to nonthyroidal illness (3.3%) as toprimary hypothyroidism (3.3%), and TSH values between 6.8and 20 mu/liter are more frequently due to nonthyroidal

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46 KAFT EIN Vol. 17, No. 1illness (9.1%) than to primary hypothyroidism (1.5%) (10).Serum total T,, free T4 index, and free T4 by equilibriumdialys is values are usually normal in euthyroid sick patientswhen serum TSH concentrations rise transiently (8-11). Incontrast, sick patients with primary hypothyroidism havepersistently elevated serum TSH values in association withpersistently reduced total T,, free T4 index, and free T, leve lsby equilibrium dialy sis (3,8,10,11) (Table 1). Hypothalamicor pituitary lesions account for less than 5% of hypothyroid-ism and are usually associated with other endocrine defi-ciencies (including reduced cortisol, GH, and/or gonado-tropin levels, and persistently reduced total and free T,levels) and TSH values below 15 mu/liter (12) and, therefore,are distinqu ishable from the transient changes due to non-thyroidal illnesses.Reduced serum TSH levels have not been reported to datein euthyroid ESRD patients. Using an immunoradiometicTSH assay with a sensitivity limit of 0.06 mu/liter, none of40 euthyroid ESRD patients undergoing regular mainte-nance hemodialysis therapy had serum TSH values below 0.4.mu/liter (7). However, hospitalized patients have serumTSH values below 0.1 mu/liter more frequently due to non-thyroidal illnesses (10.3%) than to hyperthyroidism (3.3%) ina second generation TSH assay, which by definition has afunctional sensitivity limit of 0.1-0.2 mu/liter with a coef-ficient of variation of 20% in the clinical laboratory 00).Reduced serum TSH values could not be attributed to thedose or duration of glucocortico id therapy in these hospi-talized patients (10). However, high doses of exogenous glu-cocor ticoids and intravenous dopamine therapy may reduceserum TSH values in euthyroid and hypothyroid patients(13-15). Seventy-two percent of serum TSH values below0.10 mu/liter in euthyroid hospita lized patients with non-thyroidal illnesses were above 0.01 mu/liter using a thirdgeneration TSH assay (sensitivit y limit of 0.01-0.02 mU/liter), with normal TSH responses to TRH, while all sickhyperthyroid patients had TSH values persistently below0.01 mu/liter with absent TSH responses to TRH (16). Fur-ther, 73% of serum TSH values below 0.01 mu/liter in hos-pitalized patients, using a third generation assay, were due

to hyperthyroidism while the remaining 27% were second-ary to nonthyroidal illnesses (16). Interestingly, the highestfrequency of abnormal TSH values in 504 newly hospitalizedpatients occurred in the most severely ill patients, with ap-proximately 15% having reduced total T, and total T, leve lsas well as decreased serum TSH values using a second gen-eration assay (17). Further studies using second or thirdgeneration TSH assays must be conducted to define the fre-quency of reduced serum TSH values in euthyroid ESRDpatients.Serum TSH responses to exogenous TRH are typicallyblunted in euthyroid ESRD patients before as wel l as aftermaintenance dialys is therapy, as in nonrenal nonthyroidalillnesses and with caloric deprivation (18-22). Further, in-creases in serum total T, concentrations after exogenous TSHadministration may be diminished compared with normalsubjects, while increments in serum T, concentrations arenormal or blunted (18, 22). Despite these findings, steadystate thyroidal T, production rates are normal in ESRD pa-tients (19,23). Further, pharmacokinetics of exogenously ad-ministered TRH are altered in ESRD patients receiving main-tenance hemodialysis, with increased peak serum values (2.6times), prolonged half-l ife (2.5 times), and reduced clearancerates (71% of normal) (21). These findings may indicate im-paired exogenous TRH degradation and elimination in ESRDpatients (21) that may alter the TSH response to endogenousas well as to exogenous TRH.Normal serum TSH diurnal rhythm, characterized by peaklevels in the late evening or early morning and pulsatilerelease, is altered in ESRD patients. In 10 chronically hemo-dialyzed ESRD patients, TSH periodicity was shorter, pulseamplitude was smaller, and evening TSH rise was dimin-ished or absent (24). The nocturnal TSH surge was also absentin 90% of 20 euthyroid ESRD patients on maintenance he-mofiltration, while basal morning serum TSH concentrationswere normal (25) (Fig. 1). Interestingly, TSH clearance ratesare reduced to 57% of normal in renal failure patients (26),which may reflect reduced renal clearance (271, smooth outTSH variations, and contribute to reduced TSH pulse am-plitude in ESRD patients (24). However, the nocturnal TSH

TABL E 1. Serum thyroid hormone levels in thyroidal and nonthyroidal disordersFree T,index Free T, T, Bindingcapacity Free T,index TrT, Free ITS TSH TSH Responseto TRH

High PI, state of NT1 I&I

I N, D N, D N, D I I N, 1 N, DHigh TBG states I N IHyperthyroidism I I I N, D :

N I N N NI I I D Absent

Normal PI, stateof nonrenal NT1 NI

: N:I N, I N, D N, DI I

2:: N I N, I N, Dof ESRD N, 1 N, D N, D N, I N, DLow TT, stateof nonrenal NT1 D D N D D D I I D, N, I N, Dof ESRD D D N D D D N I N, I N, DLow TBG states D N,D N D D N D N N N

Primary hypothyroidism D D D I N, D N, D D D I ICentral hypothyroidism D D D - D D D D N, I N, DI, increased; D, decreased; N, normal; -, no data, TT,, total T,; TT,, total T,; TrT,, total reverse T,, NTI, nonthyroidal illness. [Adapted from

E. M. Kaptein : Thyroid hormone metabolis m in illness. In: Hennem ann G. (ed) Thyroid Hormone Metabolism , Basic and Clinica l EndocrinologySeries, Volum e 8, Marcel-Dekker Inc., New York, NY, vol 8:297-333, 1986; (23) and E. M. Kapte in et al: Thyroid hormone metabolis m: acomparative evaluation. In: Ferguson DC (ed) The Veterinary Clinics of North America: Sma ll Anim al Practice: Thyroid Disorders, WBSaunders, Phila delph ia, vol 24:431-466, 1994 (128).]

a Free T, by direct equilib rium dialysis.

on May 28, 2005edrv.endojournals.orgDownloaded from


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February, 1996 THYROID ABNORMALITIES AND CHRONIC RENAL FAILURE 4712 1 ESRD m10 -

O-

NORMALS 0I

Night TSH Morning TSH Peak after TRHFIG. 1. Serum TSH levels at night and in the morning, and peak TSHvalues after TR H administrat ion in ESRD pat ients and normal con-trols. [Reproduced with permission from L. Bartalena et al. : ClinNephrol 34:30-34, 1990 (25). ]

rise is also diminished in patients with nonrenal nonthyrdi-da1 illnesses and during fasting (171, suggesting a predom-inance of nonrenal factors. However, this central TSH dys-regulation does not reduce thyroida l T, production rates (23).TSH glycosylation is altered in euthyroid patients withsevere nonthyroidal illnesses, including ESRD (28, 29), andaltered glycosylation may change the plasma half-life of TSH(12). In addition, a-subunit leve ls are 14 times higher ineuthyroid ESRD patients than in healthy euthyroid subjects,while TSH and a-subunit response to exogenous TRH arenormal or impaired (30). In vitro bioactivity of extracted TSHdetermined by CAMP release from cultured rat thyroid(FRTL-5) cells (detection limit of 1.0 mu/liter) was highlycorrelated with immunoreactive TSH in both hemodialyzedESRD patients and normal subjects (31) (Fig. 2). However, inpatients with central hypothyroidism, in vitro bioactivity ofTSH is normal while in viva bioactivity, as determined by theratio of increments in serum T, to those in serum TSH afterTRH, are reduced (12) (Fig. 3). In viva bioactivity of TSH inESRD patients may also be reduced since the ratio of in-creases in serum T, to those in serum TSH after TRH are only46% of the normal ratio (18).

Bioactivity of TSH[d/P TSH equivale nt)

FIG. 2. Relat ionship between bioact iv-i ty and immuno react ivity of TSH in nor-mal subjects and in ESRD pa t ients. [Re-produced with permission from M.Horimoto et al.: Actu Endocrinol(Copenh) 121:191-196, 1989 (3U.l

B. T4Serum total T, concentrations, T4 binding to serum ca rrierproteins, and serum free T, estimates by some methods maybe reduced in euthyroid patients with ESRD , as they are inother nonthyroidal illnesses, despite normal T, production

rates (Table 1). Total T, and free T, index values were de-creased in 21% and 13%, respectively, of 287 euthyroid ESRDpatients, unrelated to presence or duration of dia lys is ther-apy (3). Serum albumin levels were significantly lower indialys is patients with subnormal than in those with normaltotal T4 concentrations (3). Serum albumin levels correlatewith morbidity and mortality in ESRD patients receivinghemodialysis or chronic ambulatory peritoneal dialysis(CAPD) therapy (1,4,5), suggesting reduced total T4 valuesmay relate lo severity of malnutrition and nonthyroidal ill-ness in ESRD patients, as in nonrenal nonthyroidal illnesses(17, 23).Low total T, values in ESRD patients are primarily relatedto impaired T, binding to serum carrier proteins (Table 1).Free fractions of T4 by tracer equilibrium dialys is are normal(32,33) or increased in ESRD patients (34), T,-binding glob-ulin (TBG ) concentrations are normal (33-38) or increased(32, 391, and transthyretin concentrations are normal (34),while serum albumin leve ls may be reduced (32, 34, 35).Inhibitors of T4 binding to serum carr ier proteins in euthy-roid uremic patients may include elevated serum levels of3-carboxy+methyl-5-propyl-2-furanpropanoic acid (CMPD,indoxyl sulfate, and hippuric acid in uremic serum (17,40),as well as increased serum levels of interleukin-lfi (IL-l@,tumor necrosis factor (TNF-a), and their respective spec ificinhibitors (41). In nonuremic patients, elevated levels of oleicacid (42), interleukind (IL-6) (43), and TNF-(U (44) may re-duce T, binding to serum carr ier proteins, as may elevatedbilirubin and nonesterified fatty acids in association withhypoalbuminemia in hepatic failure (45). In addition, exog-enous inhibitors of T4 binding lo serum carrier proteins, suchas furosemide, nonstero idal antiinflammatory drugs, andheparin, may play a role (46). Sera from sick patients alsoinhibit in vitro T, binding to solid matrices in assays (47), withT, binding to charcoal matrix being impaired to a greater

Bioactivity of TSH( mu /P TSH e q u iva le n t )

10

. / .

8Jl Y =1 .0 4 x +0 .1( r =0.93)1

0 5 I O 0 5 1 0

NORMAL lmmvnoreactavity of TSH ESRD Immr..ctlYilyof TSH( d /P) ( mUlO



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48

FIG. 3. Left , In vivo bioact iv ity of TSHdetermined as rat ios of serum T, in-c reases to mean serum TSH increases30,60, and 90 min after exogenous TRHadministrat ion in normal subjects andin pat ients with central hypothyroid-ism. Right, Rat ios of in vit ro TS H bio-act iv ity to TSH immu noact ivity in nor-mal subjects and in pat ients withcentral hypothyroidism. N.S., Nonsig-nif icant. [Reproduced with permissionfrom M . Horimoto et al. : J Clin Endo-crinol Metab 80:1124-1128, 1995 (12).0 The Endocrine Society. ]

KAPTEIN

mea:&H (ng/uU)p


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February , 1996 THYRO ID ABNORMA LITIES AND CHRO NIC RENAL FAILURE 49T4 values in serum; however, in patients with nonthyroidalillnesses their performance varies (51). Direct equilibriumdialysis, tracer equilibrium dialysis, and ultrafiltration meth-ods use minimally diluted serum and separate free frombound T4 across a semipermeable membrane; the direct equi-librium dialys is method is commercially available. Free T,index methods correct total T, values directly or indirectlyfor altered serum concentrations of TBG. Immunoextractionor RIA methods estimate free T, by either a T, analog ortwo-step-back-titration with a solid phase T, antibody, with-out use of semipermeable membranes to separate free frombound hormone. By design, a ll free T, methods providenormal values for healthy euthyroid subjects with modestlyincreased or decreased TBG concentrations (low levels inhypothyroidism and high values in hyperthyroidism) in oth-erwise well patients (51). However, in patients with signif-icant reductions of serum T, binding to serum carrier pro-teins, such as in nonthyroidal illnesses, all but the directequilibrium dialys is method may provide spurious results(51).

Free T, immunoassays depend upon serum protein-boundT4 dissociation to stabilize free T4 concentrations during as-say perturbations (52). Consequently, reduced protein-bound T4, induced by severe nonthyroidal illnesses, mayresult in inappropriately low serum free T, estimates (52).Underestimation of free T, due to protein-bound T, depen-dence has been demonstrated with a one-step labeled T4analog kit (Coat-a-Count, Diagnostic Produc ts Corp., LosAngeles, CA), a one-step labeled T, antibody FT, kit(Amerlex-MAB, Eastman Kodak, Rochester, NY) and a two-step immunoextraction FT, assay kit (Clinical Assays Gam-maCoat Free T, Two-step, Incstar Corp., Stillwater, MN) (52).Free T4 values paralleled concentrations of protein-bound T,in these nondialysis methods (52). As expected, free T, levelsdetermined by direct equilibrium dialysis are minimally de-pendent upon protein-bound T, concentrations (52) and arenormal or elevated in 96% of patients with severe nonthy-roidal illnesses who have reduced serum total T, concentra-tions (53).When compared with direct equilibrium dialysis, tracerequilibrium dialysis overestimates the free fraction of T, andfree T, values in sera from normal and pregnant patients butnot from patien ts with TBG deficiency or with the low totalT4 state of nonthyroidal illnesses, due to TBG and protein-bound T, dependency of the tracer equilib rium dia lysismethod (54). As a result, free T4 values are lower than normalin severely ill patients with nonthyroidal illnesses when de-termined by tracer equilibrium dialys is but normal by directequilibrium dialysis (54).In vitro sequestration of free T,, independent of serum-protein T, binding, occurs to a major extent in nond ialysisfree T, immunoassay methods (Clinical Assays Gamma-Coat Free T, Two-Step, Incstar; Stratus II Free T,, BaxterDiagnostics, Deerfield, IL; AxSym Free T,, Abbott Labo-ratories, Abbott Park, IL; IMx System Free T,, Abbott Lab-oratories; Clinica l Assays GammaCoat Free T, Direct One-Step, Incstar; ACS Free T,, Ciba Corning DiagnosticsCorp., Medfield MA; and Coat-a-Count Free T,, Diagnos-tic Products Corp.) (55). In these free T, methods, T, isbound by high capacity, low affinity adsorption sites on

solid surfaces, on proteins including T, antibodies, and onother materia ls in the assay that compete for the label (55).T, sequestration accounts for 26-99% of actual free T,required to obtain expected free T, measurements in stan-dard solutions in nondialysis assays, contributing to theunderestimation of free T, concentrations in low total T,states of nonthyroidal illnesses (55). T, sequestration alsooccurs in the direct equilibrium dialysis free T, assay dur-ing the dia lysis procedure, due to T, adsorption onto solidsurfaces, but to a much lesse r extent than for the immu-noassays (55). This in vitro sequestration in the direct equi-librium dialysis free T, method may account for the re-duced free T, values by the direct equilibrium method in4% of patients with the low total T, state of severe non-thyroidal illness (53).In ESRD patients, serum free T, estimate values aremethod dependent, as in nonrenal nonthyroidal illnesses (51,53). Circulating free T, levels were normal in 87-97% ofeuthyroid patients with ESRD by tracer equilibrium dialys is(32, 34, 56, 57), in all 21 patients by SPAC -ET ET, RIA kitmethod (BYK-Sang tec, Dietzenbach, Germany) (40), and in79-97% of ESRD patients by Liso-phase free T, method(Lepetit-Sclavo, Milan, Italy) which utilizes column adsorp-tion chromatography of free T, followed by T, RIA in theeluate (25,58). Total T, concentrations were reduced in 24-83% of these ESRD patients (34, 56-58), or mean total T,values were normal (32) or reduced to 55-70% of normalmean values (25, 40). In contrast, free T, estimates werefrequently decreased in sera from ESRD patients using freeT, index (21-59% low) (3, 57), immunophase (75%) (57), orliquisol(31%) (57) methods, in association with reduced totalT, levels in 31%-41% of these patients (3,57). Normal in vimproduction rates of T4 (23,34,51) and of rT, from T, (23,34,51) in euthyroid ESRD patients (Table 2) indicate that cir-culating free T, leve ls are normal and low free T, estimatesby some free T, methods are spurious.In nonrenal nonthyroidal illnesses, free T, values by directequilibrium dialysis, SPA C-ET free T, RIA kit (BYK-Sangtec,Dietzenbach, Germany), and Amerlite MAB free T, lumino-metric assay (Kodak Clinical Diagnostics Ltd., Cardiff,Wales, UK), were normal in 96-100% of euthyroid patientswith low total T, levels, while free T, values determined bytracer equilibrium dialys is methods were only normal in70-81% (53). Other free T, methods provided low free T,values in lo-100% of euthyroid sick patients with reducedtotal T, concentrations (53); for example, free T, index valueswere reduced in 50-80% (53). In the general population, freeT, index values are reduced as frequently due to nonthyroi-da1 illnesses (0.2-1.1%) as to primary hypothyroidism (0.6%-1.1%) (lo), while in ESRD patients free T, index values arereduced more often due to nonthyroidal illness (20-33%)than to hypothyroidism (3%-S%) (3). Thus, interpretation offree T, values in sick patients requires knowledge of per-formance of a given free T, method in nonthyroidal illnessto avoid misdiagnosis and inappropriate treatment.In the general population, transiently elevated free T, in-dex values without thyroid disease occur as frequently (0.2-0.9%) as hyperthyroidism (0.3%-0.5%) (10) and are associatedwith mild nonthyroidal illnesses and acute psychiatric dis-orders (23). Euthyroid ESRD patients rarely have elevated



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50 KAPIEIN Vol. 17, No. 1total T4, free T, index, free T, by tracer equilib rium (3,32,34,59), or SPAC -ET methods (40), due to the severity of theirnonthyroidal illnesses and malnutrition (23). In euthyroidpatients with nonrenal nonthyroidal illnesses and normaltotal T, concentrations, free T, values by direct or tracerequilibrium dialys is methods, ultrafiltration methods,WAC-ET free T4 RIA kit (BYK-Sangtec, D ietzenbach, Ger-many), Amerlite MAB free T, luminometric assay (KodakClinica l Diagnostics Ltd), Abbott TDX (Abbott Laboratories),and Clinica l Assays 2-step methods (Incstar) were elevatedin 24-56% (53). These elevated free T, values may rela te todecreased T, clearance rates since T4 production rates arenormal or reduced (23) (Table 2). In contrast, serum total andfree T, values are elevated in hyperthyroidism secondary toincreased T, production rates by the thyroid gland or toexcess thyroid hormone administration (Table 2).C. T3

Total and free T, concentrations are frequently reduced inpatients with ESRD, as in other nonthyroidal illnesses (3,20,23) (Table 1). Of 287 euthyroid patients with ESRD, 76% hadtotal T, levels below 100 ng/dl, and 66% had free T, indexvalues under 100 (3). Reduced T3 leve ls are due to decreasedperipheral tissue conversion of T, to T,, while thyroid glandproduction of T, is normal and T, clearance ra tes are normalor decreased, as in other nonthyroidal illnesses (19, 20,231.Impaired conversion of T4 to T, may relate to concurrentnonthyroidal illnesses, malnutrition, and humoral factorsincluding cytokines. Direct correlations between total T, andboth serum albumin (r = 0.57) and transferrin (r = 0.54)levels in ESRD patients (3) support a role for malnutrition.CMPF, hippuric acid, and indoxyl sulfate in uremic humansera and bilirubin and nonesterified fatty acids in nonuremichuman sera inhib it T4 uptake and subsequent deiodinationof T4 by rat hepatocytes in vitro and may reduce T, produc-tion from T, in viva (17, 40, 45, 49). Plasma levels of IL-l&TNF-a, and their specific inhibitors are elevated in both un-dialyzed and dialyzed ESRD patients (41). In hospitalizedpatients, serum total T, levels correlate inve rsely with serumIL-6, free fatty acid-albumin ratios, and bilirubin-albuminratios (43) and with TNF levels in nursing home residents(60). Further, TNF given to healthy subjects decreases serumT, and TSH levels and increases rT, levels (61).Although T, is the most metabolically active thyroid hor-mone, ESRD patients with reduced serum free T, concen-trations are clini cally euthyroid (56). Tissue effects of T3 aremediated by T, nuclear receptor proteins, which are encodedby c-e rb-A (Y- and p-genes (62). In 12 euthyroid ESRD pa-tients, six on hemodialysis and six on CAPD therapy, c-erb-A(Yand p mRNA levels in peripheral mononuclear cells wereincreased 9.5- and 12.5-fold, respective ly, compared withnormal subjects (62) (Fig. 4). In euthyroid chronic liver dis-ease patients, c-erb-A cr and /3 mRNA concentrations wereincreased 3- and 5-fold, respectively, in peripheral mononu-clear cells, and 20- and 5.5-fold, respectively, in liver tissue(62) (Fig. 4). After liver transplantation, c-erb-A (Y mRNAlevels were normal in peripheral mononuclear cells but el-evated in posttransplant liver tissue compared with donorliver samples (62) (Fig. 4). In euthyroid critically ill patients,

CONTRO L LIVER RENAL ICU

t1 I\EN iC" IV REN ICU 2?2E-1IF .o --00 :. C LIV REN IC"r LWER USSUECO NTRO L L IVER TX CONTR OL LIVER TX

,tFIG. 4. Top, Thyroid hormone receptor mRNA levels in polymorpho-nuclear cells (PMNC), and serum free T4, free Ts, and TSH values incontrol subjects and patients with chronic liver disease, chronic renaldisease, or from intensive care unit (ICU). Bot tom, Thyroid hormonereceptor mRNA levels in PMNC and liver tissue, and serum free T4, freeT,, and TSH values in control subjects and patients with chronic liverdisease and post-liver transplantation (TX). [Adapted with permissionfrom G. R. Williams et al.: Luncet 2:1477-148 1,1989 (62). 0 The LancetLtd.]



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February, 1996 THYROID ABNORM ALITIES AND CHRONIC RENAL FAILURE 51only c-erb-A p mRNA was increased 2.3-fold (62). In patientswith nonthyroidal illnesses, an increased synthesis of T3 re-ceptor in the face of reduced serum free T3 leve ls was pos-tulated to maintain a euthyroid status in target tissues, whichmay be tissue specific (62). In uremic rats, nuclear T, contentwas reduced in liver but unaltered in the pituitary gland,indicating tissue heterogeneity (631 and perhaps species dif-ferences.D. rT3

Patients with ESRD have normal total serum rT, levelsrather than the elevated values observed in most nonrenalnonthyroidal disorders (20, 23, 32, 34) (Table 1). In ESRD,normal serum total rT3 levels are associated with elevatedfree rT, concentrations, due to reduced free rTa clearancerates (23,32). In addition, ESRD patients have normal totalrT, clearance rates and rT, production rates from T,, in-creased rT, fractional transfer rates from serum to tissue sites,and enhanced tissue rT, binding, suggesting a shift of rT3from vascula r to extravascular sites (23,32,34) (Table 2). Incontrast, patients with nonrenal nonthyro idal disorders andelevated tota l and free serum rT, levels have reduced serumtotal and free clearance rates (20, 23) (Table 2). Althoughserum total rT, levels are also normal with decreased serumT, concentrations in patients with acute renal failure, ne-phrotic syndrome with normal glomerular filtration rates,and primary hyperparathyroidism, alterations in rT3 pro-duction, clearance, transfer, and tissue hormone binding dif-fer among these disorders (11). In contrast, in hypothyroid-ism, rT, production from T, is reduced in association withlow serum clearance rates (64) (Table 2). The clinical signif-icance of these differences remains to be defined.

I I I . Effects of Therapy in Chronic Renal FailureMedical therapy in ESRD patients may alter thyroid hor-mone metabolism. Treatment for uremia in ESRD includeshemodialysis in 56%, functioning renal transplants in 28%,and home peritoneal dia lys is in 9% (2). In addition, effects oferythropoie tin for treatment of anemia and of zinc and thy-roid hormone replacement therapy w ill be discussed.

A. DialysisDialysis therapy, as currently prescribed in the UnitedStates, does not significantly normalize thyroid hormonemetabolism in ESRD patients. In 306 ESRD patients, serumtotal T4 and T,, free T4 and free T, index, and TSH values weresimila r in nondialyzed patients and those receiving an av-erage of 9 h of hemodialys is week ly (3) and were not alteredby chronicity of hemodialysis therapy (3,391. In contrast, inan Australian study (65), serum total T, and total T3 con-centrations were higher in patients receiving 27 h of hemo-dialys is per week than in those receiving 18 or 15 h per week,and total T4 and T, levels correlated inversely with serumcreatinine values in blood taken immediately before a dial-ysis treatment. Further, serum total T ,, free T4 index, total T,,TBG, and TSH levels, and TSH responses to TRH were sim-ilar in patients undergoing CAPD and hemodialysis therapy

(58, 66-681, while serum TBG and albumin concentrationswere lower in the CAPD patients (581, due to ongoing peri-toneal losses.B. Erythropoietin

ESRD patients frequently have anemia, primarily due toerythropoietin deficiency, and correction of anemia with re-combinant erythropoie tin reverses some of the endocrinealterations (22). In ESRD patients on maintenance hemodi-alysis therapy, blunted serum TSH responses to exogenousTRH normalized after correction of anemia with erythropoi-etin, wh ile serum total T4 and free T4 and free T, (Amersham,Arlington Heights, IL) responses remained blunted (221 (Fig.5). Anemia may induce relative tissue hypoxia, which de-creases pituitary responsiveness to TRH, and is reversed byerythropoietin, or erythropoietin could have a direct trophiceffect (22).C. Zinc

Patients with renal failure commonly have zinc deficiency,which in turn has been associated w ith decreased serum T,* *M-

lo-

0. , . , . , 1 , . ( . , 1BtSELl?E 30 60 90 120 160

11 510 5

95a575655545 I * I - , . I . , , , d

EiASEl!N E 30 60 90 120 180TIME IN MN

FIG. 5. Effects of correction of anem ia with erythropoietin (EPO) onTSH and total T, responses to TRH in hemodialysis patients com-pared with normal volunteers. *, P < 0.05, post-TRH vs. baseline; +,P < 0.05, pre- and post-TRH patients compared with controls. [Re-produced with permission from G. Ramirez et al.: J Clin EndocrinolMetab 74:517-524, 1992 (22). 0 The Endocrine Society.]



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52 KAPTEIN Vol. 1 7, No. 1and Ta concentrations as well as blunted TSH response toTRH (38). Zinc supplementation to eight ESRD patients re-ceiving intermittent peritoneal dialys is therapy increasedlow basal serum zinc levels toward normal, in associationwith normalization of serum total T, and T, concentrations(38) (Fig. 6). Changes in TSH, T,, and T, values correlateddirectly with changes in serum zinc levels (38) (Fig. 6).D. Thyroid hormone therapy

Decreased T, production from T , in ESRD may providemetabolic adaptation for energy conservation, as in nonrenalnonthyroidal illnesses and caloric deprivation (17,20,68,69).Catabolism of protein stores, as indicated by increased ni-trogen excretion and negative nitrogen balance, were in-duced by administration of near-physiological quantities ofT, (50 pg/day for 9 days) to ESRD patients without concur-rent thyroid disease (68) (Fig. 7). Conversely, when serum T,concentrations were reduced in these patients by Ipodate (1g/day for 9 days), nitrogen excretion decreased (68) (Fig. 7).Nitrogen balance correlated inversely with serum total T,

20

IS

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300I50 250

OL - - 05oL - -BASAL TREATMENT BASAL TREATMENT

2ooo 25

1500 20

1000 I5

500OL - -

BASAL TREATMENT 0 BAZ TRGMENT

concentrations in these ESRD patients but not in controlsubjects (68) (Fig. 7). These findings indicate that thyroidhormone therapy should be reserved for ESRD patients withdocumented hypothyroidism (17, 69).E. Renal transplantation

After successful renal transplantation, serum thyroid hor-mone levels may be affected by glucocorticoids, other phar-macological agents, and concurrent nonthyroidal disorderssuch as infections (20). In 11 patients treated with azathio-prine and prednisone (unspec ified dose) 6 months after suc-cessful renal transplantation, reduced serum total T, con-centrations, T, production rates, and T, to T, conversion ratesreturned to normal (19). In 18 renal transplant patients, 24months or more after renal function was stable on azathio-prine, low dose prednisone (10 mg/day), and cyclosporineA, serum thyroid hormone leve ls were not different fromnormal; however, serum T, values correlated inversely (r =-0.61) with the prednisone dose (70). In 36 ESRD patientsreceiving prednisolone (15 mg/day) and azathioprine 2 to 98

51

.r = 0.82I- Y=

rlp 3- P-=

wf+ 2-3& -

i o-------

-110 I 2 3 4 5 6 7 8 9 IOChange in 221 uHol / l

FIG. 6. Left, Serum thyroid hormone levels before and after 4 weeks of zinc therapy. ESRD patients received 28 peritonea l dialysis exchangesper week. Rig/z& Correlation between changes in plasma levels of TSH, T,, and zinc after 4 weeks of zinc therapy. [Reproduced with permissionfrom F. Arreola et al. : Horm Metab Res 25:539-542, 1993 (38J.l



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February, 1996 THYROID ABNORM ALITIES AND CHRONIC RENAL FAILURE 53ESRD o

~ j:: :,;;r

$ -2.0 --b -8 -3.0 I 1 m , Iit i 2.0 0 50 100 150 200 250$ NO-S1.5 0 ms0" 1.0 0L

.=t

0.5!!

.O m0.0 0 m

-0.5 lt-1.0-1.5 I 0 l-2.0 I,

50 100 150 200 250Serum lT,, mg/d/

FIG. 7. Nitrogen balance in ESR D pat ients and normal subjects be-fore (open squares) and after administration of L-T, (closed squares)or ipodate (closed circles). [Reproduced with permission from Black-well Science, Inc., V. S. Lim et al. : Kidney Znt 28:541-549, 1985 (68).1months after renal transplantation, basal TSH values werenormal, while TSH responses to TRH remained blunted in 12patients (71). Patients with normal TSH response to TRH hadnormal serum total T4 values, while total Ts levels werereduced to 85% of normal, and those with blunted TSHresponse to TRH had total T4 and T, concentrations reducedto 90% and 77% of normal, respective ly (71). In these patients,TSH response to TRH and serum total Ts values correlatedinversely with prednisolone dose (71). In 10 ESRD patientsstudied before, and 1,3, and 6 months after renal transplan-tation, serum total T, and T, concentrations were in thenormal range before transplantation, followed by decreasedtotal T4 values to 59% of baseline at 1 month, 72% at 3 months,and 83% at 6 months and reduced total Ts values to 64%, 88%,

and 100% of baseline values, respective ly, after transplanta-tion (72). Al l patients received immunosuppressive therapywith cyclosporine A and azathioprine, while prednisone wastapered from 60 mg/day to 10 mg/day (72). In normal sub-jects, short-term administration of large doses of glucocor-ticoids (dexamethasone 2-8 mg/day or prednisolone 60 mg/day) suppresses the hypothalamic-pituitary-thyroid axis andreduces serum T, levels, by impairing T4 to T, conversion(73-77), with changes being dose-dependent (78). Thus, lowdose prednisone (10 mg/day) therapy in stable renal trans-plant recipients minimally affects T4 to T, conversion orserum T3 concentrations, while higher doses significantlychange thyroid hormone metabolism.

IV. Inorganic Iodide Metabolism in Chronic RenalFailureIodide removal from the body occurs primarily by renalexcretion (79). Urinary Na i311clearance rates are 25-35% ofcreatinine clearance rates in subjects with normal renal func-tion (79-82) (Table 3). In patients with severe renal insuffi-ciency (mean creatinine clearance rates of 4-11 ml/min), Nai3iI clearance rates average 50-57% of creatinine clearancerates (79,801. However, with creatinine clearance rates below6.3 ml/min, Nai311 clearance rates may exceed creatinineclearance rates (80). In subjec ts with normal renal function,56% of a IO-mg iodide load i s excreted in 24 h, compared with11% excretion in patients with renal insufficiency (creatinineclearances ~44 ml/min) (83).Serum inorganic iodide levels are increased 4 to 9 timesnormal in ESRD patients, despite decreased dietary iodideintake, due to reduced renal excretion of iodide (~5 ml/min)(18,79,80). After dietary iodide restriction for 2-15 weeks in

patients wi th creatinine clearance rates from 5-44 ml/min,serum iodide levels were still 3.5 times normal (83). Althoughinorganic iodide is removed by all forms of dialysis , serumiodide levels were elevated in 84% of patients receivingmaintenance hemodialysis and in 92% of patients receivingCAPD therapy (84). Elevated serum iodide levels in somedialyzed ESRD patients may relate to ongoing use of povi-done-iodine for disinfecting shunt and catheter sites. How-ever, discontinuation of povidone-iodine for 3 months de-creased serum iodide levels only modestly in CAPD patientsand did not change serum iodide levels in hemodialysispatients (84). Thus, iodide from dietary and percutaneousTABLE 3. Iodide clearance rates by dialysis in ESR D pat ients

Normal

Duration oftherapy(h/week)NA

Time perweek (%)NA

Creatinineclearance(liters/week)1008

Iodide clearanceDialysis Kidneys

(% of normal GFR)NA 25-35

HoursbetweenIs11 anddialysis

NA

Effectiveiodidehalf-life(h)8-10HD 9-12 5-7 129 154 50CCPD 56-70 33-42% 56 - c5CAPD 168 100 72 -


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54 KAPIEIN Vol. 17, No. 1sources frequently exceeds iodide removal by dialys is andresidual renal function in ESRD patients. Increased totalbody inorganic iodide may induce goiter formation and/orreversible hypothyroidism in ESRD patients who cannot es-cape from the inhibi tion of iodide organ ification induced byiodide excess (the Wolff-Chaikoff effect) (83, 85-87).Na i311clearance rates in ESRD patients depend upon thetype, duration, and frequency of dia lys is therapy, and, withintermittent dialysis, the interval between Na i I adminis-tration and the next dialysis procedure (Table 3). Clearancerates of Na i3iI during hemodialys is therapy average 154ml/min (81,88) compared with normal renal clearance ratesof 25-35 ml/min (79-82) (Table 3). However, most ESRDpatients only receive 3-4 h of hemodialysis therapy threetimes a week, resulting in rapid Na 13iI clearance by dialysisfor only 5-7% of each week (Table 31. Na i3 iI half-life betweenhemodialys is treatments depends upon residual renal func-tion, resulting in Na i3i I clearance rates of less than 5 ml/min(82, 88) (Fig . 8). Due to rapid Na 1311clearance during he-modialysis, effective Na l3 I half-life depends upon the in-terval between Na 1311administration and the first hemodi-alysis procedure, being 20 h when hemodialysis was initiatedimmediately after the dosage (Fig. 8) and 47 h when hemo-dia lys is was delayed 48 h (88), compared with an 8-10 h Na1311half-life in subjects with normal renal function (89, 90)(Table 3). Indeed, effective half-li fe of Na 1311 n a thyroidcancer patient was predicted to be 2% times normal if the first10 h hemodialysis was given 24 h after the dosage, and 4Y2times normal if dialysis was delayed for 48 h (91). Datadefining Na 1311 learance rates by current hemodialysis tech-niques are limited to three case reports and require furtherdefinition to more accurately establish dosage guidelines.Na 1311clearance rates during 40 consecutive peritonealdialys is exchanges were similar to normal renal iodide clear-ance rates (92). However, with chronic intermittent dialys is

100.0 T o--oEIlood (cpm)*-*Survey meter (mR/h)e a---aNormal half-life

% 10.0&I0 5.0.* 0rix 1.0

0.1-l I0 40 00 12 0 16 0Time after I311 administration (hl

FIG. 8. Whole-body exposure rates (closed circles) and radioactivityin blood (open circles) after Na i3iI administration to an ESRD patientpost thyroidectomy for papillary carcinoma. Hemodialysis therapywas given immed iately after the dosage and repeated every 48 h asindicated by the arrows. The hatched area depicts normal serum andtotal body half-life of Na i3iI in subjects with normal renal function(89,901. [Adapte d with permission from D. W. Morrish et al.: Cancer66:2509-2513 , 1990 @).I

therapy, peritoneal dialys is removal of iodide only occu rs for36-48 h every 7 days, accounting for 21-29% of the totalweek (Table 3). Thus, Na 1311 emoval rates would only benormal if ESRD patients received the radioiodide dosa F eimmediately before peritoneal dialys is therapy. If the Na Idosage were administered immediately after chronic inter-mittent peritoneal dialys is therapy, to minimize radiationexposure to personnel and limit cost, effective radioiodidehalf-li fe would be proportional to residual renal function,which is minimal in these patients (82,88) (Table 3). In CAPDpatients who received three to four peritoneal dialys is ex-changes per day, average serum iodide half-li fe was 45 hcorn ared to 9.7 h in patients with normal renal function (89).Na P311 clearance data are not available for ESRD patientsreceiving chronic automatic nightly peritoneal dialys is(CCPD) for 8-10 h per day (33-42% of the week); however,their peritoneal creatinine clearance rates are similar to thoseof CAPD patients (93) and iodide clearance rates may also besimilar (Table 3). Thus, peritoneal clearance rates of Na 13*1depend upon frequency and duration of peritoneal fluidexchanges and, in some instances , on the interval between Na1311dosage and the next dia lysis therapy. Peritoneal mem-brane function and, therefore, iodide clearance rates may alsovary among patients and over time.

V. Thyroid Diseases in Chronic Renal Failure andRenal Transplantat ion

ESRD patients may have a higher frequency of goiter,hypothyroidism, thyroid nodules, and thyroid carcinomathan the general population. The frequency of thyroid dis-eases in ESRD may be increased by older age, diabetes mel-litus , and iodide retention. In 1991, 45% of ESRD patientswere over the age of 65 yr, and 33% of ESRD was due todiabetes mellitus (1).A. Goiter

Goiter prevalence in ESRD patients varies from 0% inGreat Britain and Austria to 58% in Utah, suggesting geo-graphic differences (3) (Table 4). Techniques for thyroid ex-amination also play a role, since goiter frequency was 0% bypalpation but 60% by ultrasonography in Denmark (3). In LosAngeles, 43% of ESRD patients had palpable goiters com-pared with 6.5% of hospita lized patients of sim ilar age, gen-der, and racial background without renal disease (3) (Table4). Goiter was more frequent (50%) in those receiving he-modialysis for more than 1 yr than in those dialyzed for lessthan 1 yr or not at all (39%) (3). The female-male ratio was1.4:1 in ESRD patients with goiters compared with 2.8:l in thecontrol group, suggesting uremia-related factors may pre-dominate (3). Goiter frequency in ESRD patients did notrelate to age, race, diabetes mellitus, TSH or PTH levels, orto antimicrosomal antibody titers (3).Goiter formation in some ESRD patients may reflectincreased serum inorganic iodide levels since iodide ex-cess may block thyroid hormone production in patientswith preexisting thyroid gland abnormalities such asHashimotos thyroiditis, previously treated Graves dis-ease, or after hemithyroidectomy, as wel l as in patientson May 28, 2005edrv.endojournals.orgDownloaded from


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February, 1996 THYROID ABNORMALITIES AND CHRONIC RENAL FAILURE 55TABL E 4. Prevalence of goiter and antithyroid antibody titers in ESRD

End-stage renal disease Control popula tionLocation No. Goiter ATA titers No. Goiter ATA titers(%I (%I (o/o) (%)

Denmark 40 60 7 40 0 -Utah 53 58 0 - 8 -California 306 43 7 139 6.5 1.4Il l inois 24 37 0 - - 10South Africa 85 32 - - -Japan 60 30 - 224 6.7 -Israel 46 24 - - -Switzerland 50 20 - - - -Belg ium 17 12 0 - - -Maryland 38 8 0 - - -Alberta 54 2 13 - - -Great Britain 25 0 - - -Austria 107 0 - - -

Abbreviations: ATA, Positive antithyroid antibody titers: No., number of patients studies. [Ada pted from E. M. Kaptei n et al. : Medicine67:187-197, 1988 (31.1

a No thyroid enlargeme nt clinically but increased thyroid gland volume using ultrasonography.-, No data.

with apparently normal thyroid glands (86, 87). Thyro id subjects without renal disease, 4 weeks of iodide admin-gland size decreased significan tly after 2-15 weeks of di- istration (27 mg daily) increased thyroid gland volume byetary iodine restriction of Japanese patients with revers- 16% from 16.5 to 19.1 g, as determined by high resolutionible primary hypothyroidism due to an iodide organifi- ultrasound scanner (Fig. 10) (86). These subjects also hadcation defect and elevated nonhormonal iodide levels due transient decreases in serum free T, values (enzyme-linkedto renal insufficiency (creatinine clearances from 4.7-43.5 immunosorbent assay, Amersham, Aylesbury, Bucking-ml/min) (83) (Fig. 9). In contrast, patients in the same hamshire, UK) with increases in mean serum TSH (0.95-study with irreversib le hypothyroidism had no change in 2.43 mu/liter ) (Fig. 10) and serum thyroglobulin (12.1 tothyroid gland size after iodine restriction (83). In normal 37.1 pg/liter) (86). These changes most likel y reflectednmol/l

FIG. 9. Changes in renal function, non-hormonal iodide, thyroid weight, andserum thyroid hormone levels during2-15 weeks of dietary iodide restrictionin patients with reversible hypothyroid-ism and renal dysfunction. [Reproducedwith permission from K. Sato et al. : ActaEndocrinol (Copenh) 126:253-259,1992 (831.1

Serum T3

6 AThyroid weight

nmol/l

s ASerum T4

B Anon-hormonal

mu/I

11 6 ASerum TSH

mmol/l h

01 s Aiodine Serum urea nit!

w

500.

O-

600 i

6 ASerum Tg

s ASerum Cr



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56 KAPTEIN Vol. 17, No. 1

.115 -

8i!28 10 5

: A

95 l P


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February, 1996 THYROID ABNORMALITIES AND CHRONIC RENAL FAILURE 57Thyroid carcinoma was also found in 36% of 11 ESRDpatients from Japan with secondary hyperparathyroidism atsurgery, compared with 11% in an autopsy control group,and serum C-terminal PTH levels were higher in those withthyroid carcinoma (94). In contrast, only 2.4% of of 123 ESRDpatients undergoing surgery for severe secondary hyperparathyroid ism in the United Kingdom had thyroid carcinoma,all of which were papillary in type (101). Interestingly, 4.5%of 351 patients in the United States with primary hyperpar-athyroidism had thyroid carcinomas at neck exploration, ofwhich 88% were papillary-follicu lar (96). Elevated PTHleve ls may have contributed in the 44% of thyroid cancerpatients, without prior radiation exposure, who had primaryhyperparathyroidism (96), as well as in ESRD patients withsecondary hyperparathyroidism.Risk of malignancy increases linearly with time after renaltransplantation and may relate to immunosuppression ther-apy (102). Of 6353 renal transplant patients in Australia andNew Zealand, 33% developed malignancies by 10 yr, 50% by15 yr, and 60% by 19 yr with most being skin cancers (103).

In another Australian study of 5879 patients, probab ility ofdeveloping cancer 20 yr after renal transplantation was 54%for skin cancers, 21% for nonskin cancers, and 63% overall(102).Renal transplant recipients appear to have an increasedfrequency of thyroid malignancies. Risk of thyroid carci-noma in patients in Australia and New Zealand with a func-tioning renal transplant for 10 yr or more was estimated tobe increased 322 times (103). In 876 patients in Cincinnatiwith renal transplants for a median of 49 months, 8.3% ofnonskin cancers were papillary-follicu lar thyroid carcinomas(104), compared with 1.2% in the general population (99). Inthe Cincinnati Transplant Tumor Registry of 4899 de no~tononskin cancers in organ transplant recipients, including85% with renal transplants, 2.0% were carcinomas of thethyroid (102). In 3468 Japanese renal transplant patients, 13%of malignancies were thyroid carcinoma (105). In the UnitedKingdom and parts of Europe (EDTA-ERA registry), thyroidcancer frequency was increased about 6.5 times in youngfemale renal transplant recipients (ages 15-34 yr) comparedwith the general population (100).When follicular thyroid malignancies are diagnosed, Na13*1ablation of the thyroid remnant and metastases, and TSHsuppression with L-T~ may be required (106). Radiation doseto the thyroid remnant and functioning metastases, and tocri tica l organs like bone marrow, depends upon Na 13rI up-take by target tissues and total body half- lives of iodinatedcompounds (90). Na r3iI uptake by the thyroid remnant andmetastases may be reduced in ESRD patients due to in-creased total body iodide (19, 84). Iodide restriction beforeNa r3rI therapy should be attempted. However, stoppingpovidone-iod ine use for 3 months was only modestly effec-tive in CAPD and ineffective in hemodialysis patients (84).After Na 1311 dministration, the majority of radioactivity inthyroid cancer patients is sodium iodide, even with func-tioning metastases (107). Effective Na i3rI half-life in ESRDpatients depends upon residual renal function, type of di-alysis, and, with intermittent dialysis, the interval betweenNa r3*I administra tion and the next dia lysis therapy (Table3) (Fig. 8). In ESRD patients, Na 13*1 emoval by native kid-

neys plus dialysis therapy is reduced compared with normal,effective total body half-life of Na 13rI is increased (Table 3),and, consequently, Na 13*1 dosa es must be decreased inproportion to prolongation of Na !?311half-life to avoid excessradiation exposure to critica l organs (106). CAPD patientsreceiving three to four eritoneal exchanges per day requireda decrease in the Na l3PI dosage from 150 mCi to less than 30mCi (891. In patients receiving hemodialysis, contaminationof equipment with Na 1311was minimal even after largedosages (88). However, Na 13iI should be given 48-72 hbefore the next hemodia lysis (88, 91) to minim ize radiationexposure to personnel and allow administra tion of less than30 mCi of Na 13rI, a dose that can be given as an outpatient(106).D. Hypothyroidism

Primary hypothyroidism may occur in up to 9.5% of ESRDpatients compared with 0.6-1.1% of the general population(3) (Table 51. In Los Ange les, 2.6% of 306 ESRD patients hadprimary hypothyroidism, characterized by persistently ele-vated TSH values to above 20 mu/liter and reduced serumtotal T, and free T, index va lues (3). Eighty-e ight percent ofhypothyroid ESRD patients were female, 75% were over age50 yr, 50% had elevated antimicrosomal antibody titers, 50%had goiter, and 50% had diabetes mellitus (3). No relation-ship between hypothyroidism and goiter or elevated anti-microsomal antibody titers was noted. However, nonuremicinsulin-dependent diabet ics have an increased frequency ofelevated antimicrosomal antibody titers (17%), as well as ofhypothyroidism (3%), as do the elderly (3, 108) and patientswith system ic lupus erythematosus, suggesting an autoim-mune component may be present.

Iodide excess may contribute to the increased frequency ofhypothyroidism in ESRD patients, particularly those with aniodide organification defect (83, 1091, concurrent Hashimo-tos thyroiditis, previously treated G raves disease, or afterhemithyroidectomy. Povidone-iodine may induce hypothy-roidism in some CAPD patients (llO), and Amiodarone, aniodide-rich antiarrhythmic drug, induced reversible hypo-thyroidism in a hemodialysis patient (111). Further, hypo-thyroidism was reversed after 2-15 weeks of dietary iodinerestriction in 83% of 245 Japanese patients with mild to severerenal dysfunction (creatinine clearances 4.7-43.5 ml/min)and elevated nonhormonal iodine levels, who had a thyro i-da1 iodide organifica tion defect (83) (Fig. 9). In these patients,serum iodide levels fell below 50 pg/liter in 93%, and meanTSH values dropped from 51 mu/liter to 5 mu/liter as totalT, values rose from 56 nmol/liter to 88 nmol/liter (83) (Fig.9). Antithyroid antibodies were present in 64% with revers-ible and 76% with irreversible hypothyroidism, suggestingautoimmune thyro iditis was not a factor (83). Likewise, threeJapanese ESRD patients ingesting a high iodide diet hadhypothyroidism, thyromegaly, and iodide organification de-fects, which reversed with iodide restriction (109). Further,the frequency of high urinary iodide levels in Japan corre-lated with that of thyroid autoantibody-negative hypothy-roidism, but not with hyperthyroidism, supporting a role foriodide excess in inducing hypothyroidism (87) (Fig. 11).In patients with ESRD, clinical and biochemical manifes-on May 28, 2005edrv.endojournals.orgDownloaded from


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58 KAPTEIN Vol. 17, No. 1TABLE 5. Prevalence of altered free T, index values due to thyroidal and nonthyroidal i l lnesses in ESR D

Free T, indexLocat ion No. Reduced

Hypothyroid (o/o) Sick (%)Elevated

Hyperthyroid (o/o) Sick (%)End-stage renal failureMichiganCaliforniaIsraelJapanCaliforniaMarylandAustriaInsulin-dependent diabetes mell i tusScot landGreat BritainGeneral populationCaliforniaCalifornia

16 824=46

3::b

38107605 3.0 0.7 0255 2.7 23.0 0

2122 1.1 1.1 0.32704 0.6 0.2 0.5

9. 56.36.53.22.60

0

-33.319.6-22.5--

000. 90.2

FT,I , f ree T, index. [Adapted from E. M. Kantein et al. : Medicine 67:187-197, 1988 (3j. lD Children. -* [Data from S.-I . Takeda et al. : Nephron 65:51-55, 1993 (1091.1-, No data available.

r=o.xoll=0HakodateCF) wo.05a

b 3-$ 2-J l-&Ii 7 l -PPwow.Rmol(M)

5 10 15 20 25 30 (%)

Rum;i(M)Hakodate(F)l r=0.038t7=0"S

Nemuro(M) 0 Sawom(M) Hclaka(M) Hakcdate(M)Ii . .5 IOO 155 200 255 300 (%)%)

Wakkanm(M)&l l8 . . SapwoW

Frequency of high urinary iodi de concentrationFIG. 11. Relat ionship between the frequency of high urinary iodidelevels and thyroid autoant ibody (TAA) negat ive hypothyroidism (top)and hyperthyroidiem (bottom). [Reproduced with permission from N.KOMO et al. : J Clin Endocrinol Metab 78:393-397, 1994 (87). 0 TheEndocrine Society. ]

tations of hypothyroidism are frequently mimicked ormasked by concurrent ESRD (112), malnutrition, diabetesmellitus, and aging (108). Thus, a high index of suspicion forhypothyroidism must be present for patients at risk , andbiochemical confirmation must be obtained before L-T* ther-

apy (112). Biochemical features include persistently elevatedTSH values to above 20 mu/liter and reduced serum total T,and free T4 index values (3, 110-112).A screening serum TSH concentration is most cost-effec-tive for primary hypothyroidism since reduced total T4 andfree T4 index values were present in 24% and 13%, respec-tively, of euthyroid ESRD patients while only 1% had TSHvalues above 10 mu/liter, and all TSH values between 10 and20 mu/liter were transient (3). None of the ESRD patientswith normal free T4 index values were diagnosed to haveovert hypothyroidism. A free T4 estimate, preferably free T4by direct equilibrium dialysis , may play a confirmatory role(51). When a biochemical diagnosis of hypothyroid is estab-lished, a reversible cause such as iodide excess due to con-trast agents, povidone or Amiodarone administra tion,should be sought. If hypothyroidism is irreversible, L-T~therapy should be initiated (113-115).The absorption rate of L-T* , which is normally 50-80%, isunaltered in ESRD and after renal transplantation (19). Theinitial dosage regimen for L-T, should be based on the car-diovascular status of the patient and adjusted to achieveeuthyroidism as determined by clinical symptoms and signsand serum TSH levels. Since 10% of ESRD patients are eu-thyroid with serum TSH values between 5 and 10 mu/liter(3,7), a conservative approach would be to adjust the dosageto attain TSH values in this range, unless otherwise indicated.Increasing the L-T~ dosage until serum TSH values are withinthe normal range may induce mild hyperthyroid ism andprecipitate cardiac events in some ESRD patients, particu-larly those with diabetes mellitus, the elder ly, and those withsubclinica l or overt ischemic heart disease. Total T4 and mostfree T, estimates should not be relied upon to adjust the L-T,dosage since these values are frequently reduced in euthy-roid ESRD patients (3).

Failure of serum TSH values to normalize in a patientreceiving 1.6 pg/kg body weight L-T,/day may indicatenoncompliance with the dosage regimen, interference withintestinal absorption, or increased losses or degradation rateson May 28, 2005edrv.endojournals.orgDownloaded from


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February, 1996 THYROID ABNORMALITIES AND CHRONIC RENAL FAILURE 59of T, (113). T, and T, may be bound in the gastrointestinaltract by aluminum hydroxide, ferrous sulfate, cholestyra-mine, sucralfate, colestipol, activated charcoal, soya flour,food (113), and kayexylate (116). These agents may interruptenterohepatic circu lation of T, and T, and increase excretionrates from the body, even when agents are not given con-currently with L-T~ (117). In addition, in ESRD patients re-ceiving CAPD, T, losses in peritoneal fluid range from 8-29pg/day (66,110). Commonly administered pharmacologicalagents, including phenobarbital, phenytoin, carbamazepine,and rifampin, induce hepatic microsomal drug-metabolizingenzymes and increase rates of T4 degradation by the body(113). These causes should be sought and corrected if pos-sible when an ESRD patient requires more than predicteddosages of L-T~ to attain euthyroidism.E. Hyperthyroidism

In ESRD, hyperthyroidism may occur with a frequencysimilar to that of the general population (3). However, only10 cases are reported in the medical literature (3, 118-124).Of these, all were female, five were over the age of 60 yr, andfive were under the age of 40 yr. Eight of ten had goiter andthree had diabetes melli tus. Hyperthy roidism was due toGraves disease in eight and to multinodular toxic goiter intwo patients. C linical features in seven patients includedpalpitations (71%), weight loss (71%), weakness (43%), atria1fibrillation or flutter (43%), irritabil ity (43%), tremor (29%),heat intolerance (29%), confusion (29%), and nervousness(14%). Five of seven patients had atypical presentations,three of whom were over the age of 60 yr, consistent withatypical clinical manifestations of hyperthyroidism in theelderly who may present primarily with anorexia, card io-vascular dysfunction, and weight loss (125). One elderlypatient had recurrent atria1 fibril lation , hypotension on he-modialysis, and sinus tachycardia (119), while another pre-sented with cachexia and psychiatric symptoms (122), andone young woman had only weakness and severe weight loss(121). Thus, hyperthyroidism should be suspected in ESRDpatients with unexplained symptoms and signs includingweight loss, atria1 fibrillation, angina pectoris, or congestiveheart failure.Biochemical manifestations of hyperthyroidism may bemasked by changes due to nonthyroidal illnesses, includingreduced T, binding to serum carrier proteins and impairedT, conversion from T,. Nine of 10 hyperthyroid ESRD pa-tients had elevated total and/or free T, leve ls and normal orincreased T, values (118-124). Thus, normal or reduced T,values may not exclude hyperthyroidism since extrathyroi-da1 T, production is reduced (20). Serum TSH values usingsecond or third generation assays have not been reported inhyperthyroid ESRD patients, but TSH values were reducedto less than 0.01 mu/liter in associa tion with an absent TSHresponse to TRH in all hospitalized hyperthyroid patients(16). Currently, a serum TSH concentration measured in asecond- or third-generation assay is the most cost-effectivescreening test for hyperthyroidism in ESRD patients, withfree T, and free T, estimates and TSH response to TRH asconfirmatory tests (24).When hyperthyroidism is diagnosed, the specific etiology

should be determined and appropriate therapy initiated(126,127). The dosages and efficacy of propy lthiouracil andmethimazole do not appear to be altered in hyperthyro idESRD patients (121). However, methimazole is not protein-bound and should be administered after hemodialys is (121).If Na 13iI therapy is used, the dosage should be decreased inproportion to reduced radioiodide clearance rates by dialys isand residual renal function (Table 3). In contrast to athyreoticthyroid cancer patients, hyperthyro id patients have a func-tioning thyroid gland that incorpora tes 13*1 nto iodothyroni-nes, primarily T, and T,. Consequently, the 1311half-life inblood of a hemodialyzed ESRD patient increased progres-sively with time, with a final physical half-life of 8.05 daysfrom 9-15 days after adminis tration (124) (Fig . 12), mostlike ly reflecting the serum half-life of radiolabeled T,.Hyperthyroid hemodialysis patients reported in the liter-ature received 7-24 mCi radioiodide (118-122,124), a dosagesimila r to that of patients with normal renal function. In twocases, Na i3 iI was administered 72 h before the next hemo-dialysis , at which time no radioactivity was detected inequipment or effluent (120,124). Rad iation doses to thyroid

~~~Oyy;o0 IO 30Time. h

t?g IOE6aR2:BsX

-0

6 9 1.2 15Time. days

FIG. 12. Total serum 1311 activity, after correction for nhvsical decayof i3iI, in a chronic hemodialysis patients with Graves disease afteran oral dose ofNa-i3iI. The hatched area Cto~j and the line labele d Nai3iI Normal t1/2 (bottom) are data from subjects with no rmal renalfunction (89, 90). [Reproduced with permission from J. R. Nibhanu-pudy et al.: Am J Nephrol 13:214-217, 1993 (124).]



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60 KAPTEIN Vol. 17, No. 1and critical organs such as bone marrow in ESRD patientsdialyzed 72 h after the Na 13iI dosage were probably 4- to6-fold that of patients with normal renal function (91). Toavoid risks of excess radiation exposure in hyperthyroidESRD patients (1061, Na i3iI dosages shou ld be reduced inproportion to decreases in Na i3iI removal rates from thebody, as determined by residual renal function and type,frequency, and duration of dia lysis therapy, and should begiven 48-72 h before the next hemodialys is (Table 3).

VI. Summ ary and ConclusionsPatients with ESRD have multiple alterations of thyroidhormone metabolism in the absence of concurrent thyroiddisease. These may include elevated basal TSH values, whichmay transiently increase to greater than 10 mu/liter, bluntedTSH response to TRH, diminished or absent TSH diurnalrhythm, altered TSH glycosylation, and impaired TSH andTRH clearance rates. In addition, serum total and free T, and

T, values may be reduced, free rT, levels are elevated whiletotal values are normal, serum binding protein concentra-tions may be altered, and disease-specific inhibitors reduceserum T, binding. Changes in T, and T, transfer, distribution,and metabolism resemble those of other nonthyroidal il l-nesses, while changes in rT, metabolism are disease specific.Dialysis therapy minima lly affects thyroid hormone metab-olism, while zinc and erythropoietin administration maypartially reverse thyroid hormone abnormalities. Thyroidhormone metabolism normalizes with renal transplantation;however, glucocorticoid therapy may induce additionalchanges.ESRD patients may have an increased frequency of goiter,thyroid nodules, thyroid carcinoma, and hypothyroidism.Goiter and hypothyroidism may be induced by iodide ex-cess, due to reduced renal iod ide excretion, and may bereversed with iodide restriction in some patients. The in-creased frequency of thyroid nodules and malignancies inESRD may relate to secondary hyperparathyroidism. Afterrenal transplantation, the higher frequency of thyroid ma-lignancies may relate to the immunosuppressed state.Clinica l symptoms and signs and biochemical features ofhypothyroidism and hyperthyroidism may be altered byconcurrent ESRD. ESRD patients with hyperthyroidism orfollicular neoplasms require reduced dosages of Na i3i-Idepending upon type, frequency, and duration of dia lys istherapy.

References1. US Renal Data System USRDS 1994 Annual Data Report, The

Nationa l Institutes of Health, Na tional Institute of Diabetes andDigestive and Kidney Diseases, Bethesda, MD. Am J Kidney Dis24[Suppl2]:S12-S94

2. Excerpts from the United States Renal Data System 1993 Annu alData Reuort, The Nationa l Institutes of Health, Nationa l Instituteof Diabhtes and Digestive and Kidney Diseases, Bethesda, MD. AmJ Kidney Dis 22[Sup pl 2]:17-68

3. Kapte in EM, Quion-Verde H, Choo ljian CJ, Tang WW, FriedmanPE, Rodriquez HJ, Massry SG 1988 The thyroid in end-stage renaldisease. Medicine (Baltimore) 67187-197

4. Blake PG, Flowerdew G, Blake RM, Oreopoulos DG 1993

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6.7.

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!! Thyroid Hormone Metabolism and Thyroid Diseases in Chronic Renal Failure

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