CONJUGATION OF BILE ACIDS IN PATIENTS WITH HYPOTHYROIDISM (BILE ACIDS AND STEROIDS, 105)

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1 JOURNAL OF ATHEROSCLEROSIS RESEARCH *"205 CONJUGATION OF BILE ACIDS IN PATIENTS WITH HYPOTHYROIDISM (BILE ACIDS AND STEROIDS, 105) K. HELLSTROM AND J. SJOVALL Department of Medicine, Serafimerlasarettet, and Department of Chemistry, Karolinska lnstztutet, Stockholm (Sweden) (Received March 6th, 1961) INTRODUCTION It seems to be generally accepted that a connection exists between elevated serum lipids and atherosclerosis and one of the main aspects studied has been the significance of hypercholesterolemia in this disease. The cause of the elevated serum-lipid levels often found in atherosclerosis has not been established. Of many factors that influence the level of serum lipids the effect of thyroid hormones has been thoroughly investigated (see reviews by KRITCHEVSKY 1 and BOYD2). The clinical state of myxedema is accompanied by an increase of the serum-cholesterol level, while in hyperfunction of the thyroid the serum cholesterol is usually lower than normal. The mechanism by which thyroxine (and some of its analogues) lower serum cholesterol in man is not fully established. Since cholesterol synthesis is decreased in hypothyroidism it is conceivable that the excretion of cholesterol might be even more reduced. The main catabolic pathway of cholesterol is the formation of bile acids 3 which are excreted in the bile conjugated with glycine or taurine. In a previous investigation of the bile acids secreted in normal and diseased states 4, it was found that two patients with myxedema had ratios of glycine-conj ugated (G.B.A.) to taurine-conjugated (T.B.A.) bile acids of 8.0 and These values were much higher than the mean G.B.A./T.B.A. ratio of 3.1 found for normal subjects (healthy medical students). In order to investigate if a high G.B.A./T.B.A. ratio is a general finding in myxedema the biliary bile acids in hypothyroid patients have now been analyzed before and after treatment with desiccated thyroid, thyroxine, and l- and d-triiodothyronine. The effect of the administration of taurine on bile acid conjugation and serumcholesterol level has been studied in one patient. METHODS Bile samples were collected through a duodenal tube after intravenous injection of a cholecystokinin-pancreozymin preparations, 6. All samples were frozen immediately, and kept at --15 until analyzed. The bile acid separations and estimations were.[. Atheroscler. Res., 1 (1961)

2 206 K. HELLSTROM, J. SJ6VALL )(. ~ d d d d d "-: 0 0 d 0 0 ~ ~ ~ 0 0 ~ ~ ~ L3 "~-. -,~ u'; ',~ ~p~ ~ tt~ ~ 0,,1 ~ ~ ~ "~ ~ ~ ~1 ~1 ~ q ~ ~ 0 ~m f:uo ~j Z d '4,~ ~o ~ o~ o~ go o~ ~ I ~ ~ P-,,x= o ~ Z t~ ~1 ~ ~ I ~ I Z Z m Z I - o I ~ I +7 II b" N v v, ~ o F----, I I R ~' o ~ ~ ~ s ~ s ~ ~a~.~ '~ J. Atheroscler. Res., 1 (1961)

3 BILE ACID CONJUGATION AND HYPOTHYROIDISM 207 made by quantitative paper chromatography v. The ratio of glycine-conjugated to taurine-conjugated acids was determined, and the ratios glycocholic acid/glycochenodeoxycholic acid/glycodeoxycholic acid (G.C./G.C.D./G.D.) were also determined. Taurochenodeoxycholic acid and taurodeoxycholic acid were determined together. For eight patients, the bile acid pattern was determined before and after treatment with thyroid hormones. One patient was given 3 g taurine daily for 2 months before starting the treatment. For two additional patients the bile acid pattern was determined before treatment. The patient description is given in Table I. B.M.R. (basic metabolic rate) and serum-cholesterol values in most instances are mean values of several estimations made at the time of bile collection. P.B.I. (proteinbound iodine) values were taken before treatment, except in one instance noted in the table; the values given are for single determinations except for patient D.P. where three determinations were made (the mean value is given in the table) uptake was measured over the thyroid area 24 h after radio-iodine administration. The therapeutic treatment involved use of desiccated thyroid, L-thyroxine or L- triiodothyronine, and in one instance D-triiodothyronine* was used. RESULTS The analytical results are shown in Table I. In each instance a drop in the G.B.A./ T.B.A. ratio was found to occur after therapy. The mean value for ten patients before treatment was 8.8. The mean value for the eight treated patients was 3.4, which is quite close to the previously found mean value of 3.1 for normal subjects. At the same time the expected drop in serum-cholesterol levels was observed. The G.C./G.C.D./G.D. values generally showed some change after treatment. In several instances a relatively low proportion of glycochenodeoxycholic acid was found initially. Several cases require individual comment. Patient S.K. had the lowest G.B.A./ T.B.A. ratio (5.8) observed in the initial stage. 1 month before the second bile acid analysis an operation for thyroid cancer was carried out. 2 months after the last bile acid observations the patient died. Autopsy showed widespread cancer metastases and stones were found in the common bile duct. These circumstances might have influenced the bile acid-conjugation ratios (biliary stasis can cause a decreased G.B.A./T.B.A. ratio4). Patient R. J. had at the time of an earlier examination a normal G.B.A./T.B.A. ratio (3.6) and at that time she was not classified as a myxedema patient. At the time of the examination recorded in the table she was in a hypothyroid state, and the G.B.A./T.B.A. ratio was found to be 7.4. Patient O.J. received treatment for 2 weeks before the initial bile acid analysis was carried out. At that time the G.B.A./T.B.A. ratio was 7.9. * We are indebted to Smith, Kline and French Laboratories, Inc., Philadelphia, Pa., for supplies of this material. J. Atheroscler. Res., 1 (1961)

4 208 K. HELLSTROM, J. SJOVALL Patient G. F. was the only patient receiving D-triiodothyronine (1.2 mg/day for 2 months). The serum cholesterol level and the G.B.A./T.B.A. ratio were lowered, and subjective and objective improvement were noted. TABLE II RESULTS OF BILE ACID AND CHOLESTEROL ANALYSES ON PATIENT D. P. IN THE HYPOTHYROID STATE, DURING TAURINE ADMINISTRATION AND DURING THYROID MEDICATION Pertod Date G.B.A./T.B.A. G.C./G.C.D./G.D. Serum cholesterol No treatment 24/ [ 1.0/ / /1.0/ / /1.0/ / /1.0/ Taurine 1 g 3 29/ /1.0/ daily 28/1-22/3 2/ [1.0/ / [1.0/ [ /1.0/ Desiccated thyroid 23/ /1.0/0.5 from 23/3-21/ /1.0/ * 24/ /t.0/0.6 * Mean value in the euthyroid state. In order to study the effect of orally administered taurine on bile acid conjugation and the serum-cholesterol level, patient D. P. was given 3 g of this amino acid daily for 2 months. The results of the analyses are shown in Table II. Serum cholesterol increased slowly until desiccated thyroid was given. Taurine did not appear to influence this rise whereas the G.B.A./T.B.A. ratio decreased markedly. DISCUSSION Human bile normally contains three major bile acids, cholic, deoxycholic and chenodeoxycholic, conjugated with glycine or taurine. The deoxycholic acid is a secondary product formed in the intestine from cholic acids, 9. Rat bile contains mostly cholic and chenodeoxyeholic acids, and from experiments with bile-fistula rats it is known that the proportion of chenodeoxycholic acid rises in the hyperthyroid state and falls slightly in the hypothyroid statel0,11. For the humans studied here, the proportion of chenodeoxycholic acid was somewhat smaller than usual in some instances, and some changes in the ratio were found after therapy. It must be noted, however, that large variations are found normally. The role of the type of bile acid conjugation (with glycine or taurine) in determining the amount of cholesterol degraded to bile acids is not known with certainty. It is known that for various animals the feeding of a diet low in sulfur-containing amino acids results in hypercholesterolemia (cf. ref. 12). The addition of methionine or cysteine to the diet under these circumstances results in a marked lowering of the serum-cholesterol level; taurine exhibits the same effect to a lesser degree. It is also J.,,4 theroscler. Res, 1 (1961)

BILE ACID CONJUGATION AND HYPOTHYROIDISM 209 known that the administration of taurine to healthy subjects decreases the G.B.A./ T.B.A. ratio in bilel~; this is also true for myxedema patients 18.

5 BILE ACID CONJUGATION AND HYPOTHYROIDISM 209 known that the administration of taurine to healthy subjects decreases the G.B.A./ T.B.A. ratio in bilel~; this is also true for myxedema patients 18. In the present study the previous observation that the G.B.A./T.B.A. ratio is high in the hypothyroid state was confirmed and extended. After therapeutic treatment the G.B.A./T.B.A. ratio returned towards the normal level, suggesting that the metabolic pathway to taurine-conjugated bile acids is in some way influenced by thyroid hormones. Since the administration of taurine results in a marked lowering of the G.B.A./T.B.A. ratio there might possibly be a relative deficiency of taurine for bile acid conjugation in hypothyroid subjects. The high serum-cholesterol levels observed for patients in this study is also in accordance with past experience; the marked lowering of serum-cholesterol levels after treatment occurs at the same time that the G.B.A./T.B.A. ratio approaches the normal range. It is not known if this correspondence has significance in terms of the metabolic pathway from cholesterol to the bile acids, or whether other mechanisms regulating serum-cholesterol synthesis or metabolism are involved. The results obtained with patient D. P. where taurine administration greatly increased the proportion of taurine-conjugated bile acids whereas the serum cholesterol continued to increase seem to indicate that the changes observed are independent of each other. The observation that D-triiodothyronine is effective in lowering the serum-cholesterol level, and in changing the G.B.A./T.B.A. ratio, points to a series of events other than those involved in a generalized rate increase in metabolic functions. The calorigenic activity of this compound is approx. 10 /o of that of the L-isomer, but the hypocholesteremic effect is about the same for both D-and L- thyroxine and D- and L-triiodothyroninel4,15. These effects are under further investigation with a view to determining whether the rate of conversion of cholesterol to bile acids is reduced in the hypothyroid state, and whether the rate is affected at the same time as the changes in the G.B.A./T.B.A. ratio. ACKNOWLEDGEMENT This work has been supported by grants from the Swedish Insurance Companies and from Svenska NationalfSreningen mot Tuberkulos och andra Folksj ukdomar. SUMMARY The G.B.A./T.B.A. ratio for biliary bile acids was determined for ten hypothyroid patients by quantitative paperchromatographic techniques. The ratio was high in every instance, but after therapeutic treatment with desiccated thyroid, L-thyroxine or L-triiodothyronine the ratio returned toward the normal range. Treatment with D-triiodothyronine also resulted in a sharp drop in the G.B.A./T.B.A. ratio. A pronounced decrease of the G.B.A./T.B.A. ratio could be obtained by oral administration of taurine which did not, however, lower the serum cholesterol. ]. Atheroscler. Res., 1 (1961)

6 210 K. HELLSTROM, J. SJOVALL RI~SUM1~ Le rapport G.B.A./T.B.A. des acides biliaires est mesurd chez 10 patients hypothyroidiens par des techniques quantitatives de chromatographie sur papier. Ce rapport est constamment dlev6 chez ces malades. I1 revient dans les limites normales sous l'influence d'un traitement par l'extrait thyroidien, la L-thyroxine ou la L-triiodothyronine. I1 baisse aussi tr+s nettement sous l'influence de la D-triiodothyronine. Enfin, il s'abaisse beaucoup apr+s l'administration per os de taurine, laquelle, cependant, ne diminue pas la cholest6roldmie. ZUSAMMENFASSUNG Bei 10 hypothyreoten Patienten wurde der G. B. A./T. B.A. Quotient der bili/iren Gallens~iuren mit der quantitativen Papierchromatographie bestimmt. Der Quotient war in jedem Falle hoch, aber nach Behandlung mit getrockneter Schilddrtise, L-Thyroxin oder L-Trijodthyronin kehrte er in den normalen Bereich zurfick. Behandlung mit D-Trij odthyronin ftihrte auch zu einem steilen Absinken des G.B.A./T.B.A. Quotienten. Eine ausgepr~tgte Erniedrigung konnte durch orale Gabe yon Taurin erzielt werden, das jedoch den Serumcholesteringehalt nicht verminderte. REFERENCES 1 D. KRITCHEVSKY, Metabolism, 9 (1960) G. S. BOYD, J. Atheroscler. Res., 1 (1961) S. BERGSTR6M AND 13. BORGSTR6M, Ann. Rev. Bzochem., 25 (1956) j. SJ6VALL, Clin. Ch~m. Acta, 5 (1960) j. HIRSCrI, E. H. AHRENS, Jr, AND D. N. BLANKENHORN, Gastroenterology, 31 (1956) 274. s B. BORGSTROM, A. DAI~LQVlST, G. LONDH AND J. SJ6VALL, J. Clin. Invest., 36 (1957) j. SJ6VALL, Clan. Chim. Acta, 4 (1959) 652. s S. LINDSTEDT, Arkiv Kemi, 11 (1957) P.-H. EKDAHL AND J. SJ6VALL, Acta Chir. Scan&, 114 (1957) j. C. THOMPSON AND H. M. VARS, Proc. Soc. Exptl. Biol. 3led., 83 (1953) 246. al S. ERIKSSO~, Proc. Soc. Exptl. Biol. 3Ied., 94 (1957) O. PORTMAN AND E. Y. STARE, Physzol. Rev., 39 (1959) 407. aa j. SJ6VALL, Proc. Soc. Exptl. Bzol. 3Ied., 100 (1959) p. STARR, J. Clin. Endocrzn. and Metab., 20 (1960) G. S. BOYD AND M. F. OLIVER, Brit. 3Ied. Bull., 16 (1960) K. HELLSTROM, to be published. J. Alheroscler. Res., 1 (1961)

Bile acid metabolism. doc. Ing. Zenóbia Chavková, CSc.

Bile acid metabolism. doc. Ing. Zenóbia Chavková, CSc. Bile acid metabolism doc. Ing. Zenóbia Chavková, CSc. Bile acid metabolism Importance: Availability for fat & cholesterol absorption Regulates total body pool of cholesterol Factors that synthesis promote