Low serum total thyroxine and free triiodothyronine in patients with hepatic encephalopathy due to non-alcoholic cirrhosis

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1 Originl rticle Peer reviewed rticle SWISS MED WKLY 2003;133: Low serum totl thyroxine nd free triiodothyronine in ptients with heptic encephlopthy due to non-lcoholic cirrhosis Ertuǧrul Kycetin, Gurcn Kıskol, Ahmet Ky Selcuk University, Merm Medicl Fculty, Gstroenterology Division, Kony, Turkey Selcuk University, Merm Medicl Fculty, Endocrinology Division, Kony, Turkey Summry Principles: We evluted serum thyroid hormone levels in non-lcoholic cirrhotic ptients with nd without heptic encephlopthy. Methods: 15 consecutive ptients with heptic encephlopthy secondry to non-lcoholic cirrhosis (8 mles nd 7 femles, ge yers) nd 33 non-lcoholic cirrhotic ptients without encephlopthy (22 mles nd 11 femles, ge yers) were investigted. A control group consisted of 20 helthy sujects (10 men nd 10 women ged yers). The levels of serum triiodothyronine (T 3 ), thyroxine (T 4 ), thyrotropin (TSH), free T 3 (FT 3 ) nd free T 4 (FT 4 ) were studied in serum smples drwn in the morning. Thyroid function tests were set in reltion to the severity of heptic dysfunction nd to the presence or sence of heptic encephlopthy. Results: Serum levels of FT 3 nd totl T 4 (ut not totl T 3 nd FT 4 ) were significntly lower in ptients with heptic encephlopthy compred to decompensted cirrhotic ptients without encephlopthy (p = for T 4, P <0.05 for FT 3 ). Prothromin-time lso differed significntly etween decompensted cirrhotic ptients (Child C) with nd without encephlopthy groups (p = 0.002). Conclusions: These results suggest tht ptients with heptic encephlopthy secondry to decompensted non-lcoholic cirrhosis re typified y low FT 3 nd low totl T 4, s well s y prolonged prothromin time. Low FT 3 does not oviously put ptients t risk for heptic encephlopthy, nd thyroid prmeters re secondry nd lte events. Key words: cirrhosis; heptic encephlopthy; thyroid function tests Introduction The liver plys n importnt role in the metolism of thyroid hormones, eing involved in their conjugtion, excretion nd peripherl deiodintion, nd in synthesising thyroid inding gloulin (TBG) [1, 2]. Evidence of n ssocition etween chronic diseses of the liver nd thyroid ltertions hve often een reported, ut limited informtion is ville on thyroid function tests in non-lcoholic cirrhotic ptients with heptic encephlopthy. Most studies hve een crried out in ptients with cirrhosis of lcoholic origin. Studies hve reveled tht T 4 levels re usully within norml limits, ut, s cirrhosis progresses, FT 4 levels increse secondry to decresed serum levels of thyroxine-inding protein [3]. T 3 nd FT 3 concentrtions re usully decresed in correltion with the severity of the disese, ut this is still controverted [4]. To our knowledge, there hs een no previous study compring thyroid hormone levels in ptients with non-lcoholic decompensted cirrhosis nd those with cirrhosis complicted with heptic encephlopthy. In this study we investigted thyroid hormone levels in non-lcoholic decompensted cirrhotic ptients with nd without heptic encephlopthy. We lso ttempted to determine whether or not thyroid function tests my e useful prognostic indictor for the development of heptic encephlopthy in decompensted cirrhotic ptients. No finncil support declred.

2 SWISS MED WKLY 2003;133: Mteril nd methods This study ws crried out in 15 ptients (men ge 51 ± 8.74 yers, rnge yers) with heptic encephlopthy due to non-lcoholic cirrhosis, consecutively dmitted to the Division of Gstroenterology, nd in 33 non-lcoholic cirrhotic ptients (men ge 55 ± 7.71, rnge yers) without encephlopthy. 20 helthy sujects (10 mle, 10 femle, ged 49.7 ± 8.45 yers, rnge yers) mtched for ge, height nd sex served s control group. None of the ptients or controls hd history of lcohol consumption. All the sujects were cliniclly euthyroid, none ws known to hve present or pst history of thyroid disese nd none ws tking ny drug known to ffect thyroid function. The min chrcteristics of the ptients re summrised in tle 1. The dignosis of cirrhosis ws sed on cse history, clinicl exmintion, iochemicl, endoscopic nd ultrsound findings, or liver iopsy. Liver iopsies were not performed if com, reduced cogulility or extensive scites ws present. The functionl severity of the liver injury ws determined on the sis of the Child-Pugh grding system [5]. The size of the groups were s follows: Child A: 9 ptients, men ge ± 8.81 yers (rnge yers), Child B: 11 ptients, men ge ± 7.80 yers (rnge yers), Child C: 13 ptients, men ge ± 9.40 yers (rnge yers). 27 ptients hd positive serologicl mrkers for virl heptitis (19 heptitis B surfce ntigen-ssocited nd 8 heptitis C virus ntiody-ssocited), the remining 6 hving cirrhosis of unknown origin. The degree of encephlopthy ws defined on the sis of previously reported criteri [6] rnked etween grde 1 nd grde 4. Encephlopthy ws relted to heptitis B virus in 10 ptients nd to heptitis C virus in 5. Heptitis B virus infection ws ssumed if heptitis B surfce ntigen ws detected in the ser, wheres heptitis C virus infection ws dignosed when nti-hcv ntiodies were found in n enzyme immunosorent ssy (Anti- HCV Enzyme Immunossy kit, Disorin S.A., Mdrid, Spin). Encephlopthic ptients were further divided into two groups, survivors nd non-survivors. On dmission, the following prmeters for evlution of the severity of liver dysfunction were recorded: lumin (n: g/dl); iliruin (n: mg/dl); serum sprtte trnsminse (AST) (n: U/L); serum lkline phosphtse (ALP) (n: U/l) nd prothromin time (n: [INR]). These iochemicl tests were performed y stndrd uto-nlyser methods. Plsm prothromin rtios were mesured with humn rin thromoplstin tissue (STA-Neoplstine CI Plus kits, Frnce). In ll cses, lood smples for hormone determintions were drwn in the morning fter overnight fsting. FT 3, FT 4, T 3, nd T 4 were mesured y competitive rdioimmunossy using DPC kit (Dignostic Products Corportion, United Kingdom). TSH ws mesured y n immunometric ssy method (DPC-UK). On the sis of the ptients nd control sujects thyroid function vlues we clculted 95% confidence intervl for this prmeter. Sttisticl nlysis Student s t test ws used to compre the continued vriles etween two groups. The nlysis of vrince (ANOVA) ws used to test the significnce of continued vriles within groups. All vlues re reported s men ± stndrd devition. The correltion etween serum lumin iliruin levels, prothromin time nd T 3, T 4, FT 3 levels in oth groups ws ssessed y Person s correltion coefficient. P vlue <0.05 ws considered sttisticlly significnt. Norml vlues in our lortory re s follows: FT 3: pg/ml; FT 4: ng/dl: T 3: mg/dl; T 4: µg/dl; TSH: µiu/ml. Tle 1 Min fetures of ptients nd control sujects. spectively; p <0.05), wheres there ws no difference in serum T 4, TSH nd FT 4 levels. Cirrhotic ptients with heptic encephlopthy hd significntly reduced serum levels of T 4, FT 3 nd T 3 compred to ll cirrhotic ptients (p = for T 4, p <0.001 for FT 3 nd p = for T 3 ), wheres there ws no difference in FT 4 nd TSH levels. No significnt differences in T 3, T 4, TSH, FT 3 nd FT 4 levels were oserved etween survivors nd non-survivors with heptic encirrhotic ptients with ll cirrhotic ptients control sujects heptic encephlopthy survivors non-survivors Child A Child B Child C Numer Mles/femles 5/4 3/3 6/3 8/3 10/3 10/10 Age (yr) * 53.4 ± ± ± ± ± ± 8.45 Durtion of disese (yr) * 3.8 ± ± ± ± ± 0.52 *Dt given s men ± SEM Results The thyroid function tests in non-lcoholic cirrhotic ptients with encephlopthy, in non-lcoholic cirrhotic ptients without encephlopthy nd in control ptients re shown in tle 2. Compred to controls, ptients with heptic encephlopthy nd decompensted cirrhotic ptients (Child C group) showed significnt decrese in T 3 nd FT 3 levels (98.7 ± 17.4 ng/dl vs ± 9.6, ± 8.21 for T 3 nd 2.76 ± 0.45 pg/ml vs 1.61 ± 0.38 nd 1.15 ± 0.25 for FT 3 re-

3 Thyroid function tests in non-lcoholic cirrhosis 212 Tle 2 Thyroid hormone levels in ptients nd control sujects. Hormone non-lcoholic cirrhotic ptients with cirrhotic ptients control encephlopthy sujects ll ptients survivors non-survivors ll ptients Child A Child B Child C (n = 20) (n = 15) (n = 9) (n = 6) (n = 33) (n = 9) (n = 11) (n = 13) T3 (ng/dl) ± 9.6 d 43.4 ± ± ± ± ± ± 8.21* 98.7 ± 17.4 T4 (µg/dl) 4.28 ± 1.53 e 4.36 ± ± ± ± ± ± ± 2.68 TSH (µu/ml) 1.22 ± ± ± ± ± ± ± 0.63 FT3 (pg/ml) 1.15 ± 0.25 c f * 1.14 ± ± ± ± ± ± 0.38 g * 2.76 ± 0.45 FT4 (g/dl) 0.85 ± ± ± ± ± ± ± ± 0.42 p <0.05 (Child C nd heptic encephlopthy vs controls) p = (Heptic encephlopthy vs ll cirrhotic ptients) c p <0.001 (Heptic encephlopthy vs ll cirrhotic ptients) d p = (Heptic encephlopthy vs ll cirrhotic ptients) e p = (Heptic encephlopthy vs Child C) f p <0.05 (Heptic encephlopthy vs Child C) g p <0.05 (Child C vs Child A nd Child B) Tle 3 Lortory dt in control sujects nd in ptients with cirrhosis. non-lcoholic cirrhotic ptients with cirrhotic ptients control encephlopthy sujects ll ptients survivors non-survivors ll ptients Child A Child B Child C (n = 20) (n = 15) (n = 9) (n = 6) (n = 33) (n = 9) (n = 11) (n = 13) HBV relted HCV relted Cryptogenic Alumin (g/dl) 2.61 ± ± ± ± ± ± ± ± 0.29 Biliruin (mg/dl) 3.68 ± ± ± ± ± ± ± ± 0.18 ALP (U/L) 220 ± ± ± ± ± ± ± ± 12 AST (U/L) 47 ± 8 43 ± 6 54 ± 8 54 ± 9 49 ± 12 6 ± ± 8 17 ± 6 Prothromin time 2.21 ± ± ± ± ± 0.22 c 1.58 ± 0.25 c 1.86 ± 0.42 c 1.12 ± 0.19 (INR) P <0.03 (Child A nd Child B vs encephlopthy) P <0.05 (Child A vs encephlopthy) c P <0.001 (Child A, Child B nd Child C vs encephlopthy) cephlopthy (p <0.375). Serum T 4 nd FT 3 levels were significntly decresed in ptients with encephlopthy compred with decompensted (Child C) cirrhotic ptients (p = for T 4, p <0.05 for FT 3 respectively). Decompensted cirrhotic ptients hd significntly lower serum T 3 nd FT 3 levels thn Child A nd Child B groups (p <0.05). No significnt differences were oserved when serum T 4, TSH nd FT 4 levels were compred mong Child A, Child B nd Child C groups. Cirrhotic ptients nd controls iochemicl dt which reflect the severity of the liver disese re presented in tle 3. Of cirrhotic ptients with encephlopthy, 11 elonged to Child C group nd 4 to Child B group. Routine lortory tests did not significntly differ etween survivors nd non-survivors. Sttisticl nlysis reveled significnt inverse correltion etween serum FT 3 concentrtions nd the severity of liver dysfunction. An inverse correltion ws oserved etween serum iliruin nd T 3, T 4 levels (r = 0.65, p = for T 3, r = 0.298, p = for T 4 ) s well s etween prothromin time nd T 3, T 4 nd FT 3 levels in oth groups (r = 0.594, p <0.01 for T 3, r = 0.476, p = for T 4, r = 0.515, p = for FT 3 ). On the other hnd, positive correltion ws found etween serum lumin levels nd T 3, T 4 nd FT 3 levels (r = 0.634, p <0.001 for T 3, r = 0.397, p = for T 4, r = 0.394, p = for FT 3. Prothromin time ws significntly longer in ptients with heptic encephlopthy thn in Child C ptients without encephlopthy (p = 0.002). However, no difference ws oserved etween lumin nd iliruin levels.

4 SWISS MED WKLY 2003;133: Discussion Thyroid dysfunction hs een reported previously in vriety of non-thyroid illnesses including liver, pulmonry nd renl neoplstic disese, severe systemic illness, fsting, mlnutrition, postopertive stte, physicl trum nd cute infections. Low totl nd free T 3 with norml totl T 4 nd thyrotropin concentrtions in the sence of clinicl hypothyroidism hve een frequently reported in ptients with non-thyroidl illnesses [7, 8, 9]. Severl investigtions hve een performed to ssess the reltionship etween liver disese nd thyroid hormones [1, 2, 7, 10]. Hepner nd Wlfish reported significnt inverse correltion etween serum T 3 concentrtions nd the severity of liver dysfunction. A progressive decrese in T 3 levels in chronic liver diseses hs een descried s indictive of poor prognosis [10 12]. Authors scried this finding to diminished conversion of T 4 to T 3 nd impired metolism of thyroxine-inding proteins. In the present study we demonstrted fll in FT 3 nd T 3 prllel to severity of the disese, nd good correltion etween T 3 concentrtions, serum lumin nd prothromin time. These results suggest tht serum T 3 nd FT 3 concentrtions my e considered sensitive index of heptic function in liver disese. We chose non-lcoholic ptients ecuse lcohol is considered to hve direct toxic effect on thyroid prenchym, s previously descried in chronic lcoholics [13]. Borzio et l. compred cirrhotics with norml sujects nd chronic heptitis ptients. They suggested tht T 3 serum levels inversely prlleled severity of liver dysfunction [2]. Thyroid function tests hve lso een performed in cute heptitis [14]. T 4 hs een found to e elevted in ptients with cute virl heptitis due to elevtion of TBG (possily secondry to relese from injured heptocytes). Our study differs from previous investigtions in tht we determined the ltertions of thyroid hormone level in non-lcoholic decompensted cirrhotic ptients with nd without heptic encephlopthy. We found significnt reduction in serum FT 3 in non-lcoholic cirrhotic ptients compred with control group, the lowest vlues eing found in ptients with heptic encephlopthy. Low FT 3 levels my e due to reduced extr-thyroidl T 4 -to-t 3 conversion, the mechnism eing inversely relted to the degree of heptic dysfunction. We found no significnt difference in functionl thyroid prmeters etween ptients surviving nd not surviving heptic encephlopthy (p <0.375), ut Guven et l. hve reported lower T 3 levels in ptients who died thn in ptients who survived [7, 10, 15]. The reson for this difference is not cler. In conclusion, ptients with decompensted liver disese complicted y heptic encephlopthy susequent to non-lcoholic cirrhosis were found to hve exceedingly low serum FT 3 nd T 4 levels. Depressed serum FT 3 nd T 4 levels, together with prolonged prothromin-time, therefore pper to e chrcteristic of sugroup of decompensted cirrhotic ptients prone to develop heptic encephlopthy. Correspondence: Dr. Ertuǧrul Kycetin Selcuk Universitesi Merm Tip Fkultesi Ic Hstliklri AD, Gstroenteroloji BD Merm/Kony Turkey E-Mil: ekycetin@mynet. com References 1 B RR. Associtions etween diseses of the thyroid nd the liver. Am J Gstroenterol 1984 ; 79: Borzio M, Cldr R, Ferrri C, Borzio F, Piepoli V, Romussi M. Thyroid function tests in chronic liver disese: evidence for multiple normlities despite clinicl euthyroidism. Gut 1983; 24: Binchi GP, Zoli M, Mrchesini G, Volt U, Vecchi F, Iervese T, et l. Thyroid glnd size nd function in ptients with cirrhosis of the liver. Liver 1991; 11: Sheridn P: Thyroid hormones nd the liver. J Clin Gstroenterol 1983; 12: Pugh RN, Murry-Lyon IM, Dwson JL, Pietroni MC, Willims R. Trnsection of the oesophgus for leeding oesophgel vrices. Br J Surg 1973; 60: Ferenci P, Lockwood A, Mullen K, Trter R, Weissenom K, Blei AT. Heptic encephlopthy definition, nomenclture, dignosis, nd quntifiction: finl report of the working prty t the 11 th World Congress of Gstroenterology, Vienn, Heptology 2002; 35: Chopr IJ, Solomn DH, Hepner GW, Morgenstein AA. Misledingly low free thyroxine index nd usefulness of reverse triiodothyronine mesurement in non thyroidl illnesses. Ann Intern Med 1979; 90: Kptein EM, Weiner JM, Roinson WJ, Wheeler WS, Nicoloff JT. Reltionship of ltered thyroid hormone indices to survivl in nonthyroidl illnesses. Clin Endocrinol 1982; 16: Bermudez F, Surks MI, Oppenheimer JH. High incidence of decresed seruµm triidothyronine concentrtion in ptients with nonthyroidl disese. J Clin Endocrinol Met 1975; 41: Hepner GW, Chopr IJ. Serum thyroid hormone levels in ptients with liver disese. Arch Intern Med 1979 ; 139: Wlfish PG, Orrego H, Isrel Y, Blke J, Klnt H. Serum triiodothyronine nd other clinicl nd lortory indices of lcoholic liver disese. Ann Intern Med 1979; 91: Klchko DM, Johnson ER. The liver nd circulting thyroid hormones. J Clin Gstroenterol 1983; 5: Hegedus L. Decresed thyroid glnd volume in lcoholic cirrhosis of the liver. J Clin Endocrinol Met 1984; 106: Grdner DF, Crithers RL, Utiger RD. Thyroid function tests in ptients with cute nd resolved heptitis B virus infection. Ann Intern Med 1982; 96: Guven K, Kelestimur F, Yucesoy M. Thyroid function tests in non-lcoholic cirrhotic ptients with heptic encephlopthy. Eur J Med 1993;2: 83 5.

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