Hepatology Research 9 (1997) 201–208

Short communication

Taurine attenuates the serum g-GTP-decreasingeffect of ursodeoxycholic acid in chronic hepatitis

patients

Hiroki Ishikawa *, Toshiaki Nakashima, Koji Inaba,Hironori Mitsuyoshi, Yoshiki Nakajima, Yoshikuni Sakamoto,

Masayuki Matsumoto, Takeshi Okanoue, Kei Kashima

Third Department of Internal Medicine, Kyoto Prefectural Uni6ersity of Medicine,Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602, Japan

Received 9 July 1997; received in revised form 2 October 1997; accepted 2 October 1997

Abstract

The effect of concomitant administration of taurine (Taurine Powder, 3 g day−1) andursodeoxycholic acid (UDCA) (Urso, 600 mg day−1) on the results of liver function testswas investigated in chronic hepatitis C patients. The mean ALT, ALP, g-GTP, and total bileacid (TBA) values during the 3 months before UDCA and/or taurine administration and the3 months after the start of the administration were compared in each patient. The resultsshowed that ALT and g-GTP improved 25 and 34%, respectively, and TBA increased 115%in the 32 patients treated with UDCA alone. This increase in TBA is thought to reflectUDCA-induced enlargement of the bile acid pool in the enterohepatic circulation. g-GTP didnot improve in the four patients simultaneously given taurine and UDCA. In addition, whentaurine was administrated to nine patients treated with UDCA for more than 6 months,g-GTP increased 16% and TBA decreased 22%, and the sequential changes in g-GTP andTBA levels were mirror images of each other. No marked changes in g-GTP or TBA werenoted in the seven patients treated with taurine alone. These findings indicate that taurineattenuates the effect of UDCA in decreasing serum g-GTP levels, probably because of thereduced bile acid pool size. © 1997 Elsevier Science Ireland Ltd.

* Corresponding author. Tel.: +81 75 2515519; fax: +81 75 2510710.

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H. Ishikawa et al. / Hepatology Research 9 (1997) 201–208202

Keywords: Taurine; Ursodeoxycholic acid; g -GTP; Total bile acid; Chronic hepatitis

1. Introduction

Ursodeoxycholic acid (UDCA) is effective in the treatment of chronic liverdiseases, including chronic hepatitis [1] and primary biliary cirrhosis [2]. It iswell-known to decrease patients’ serum g-GTP levels [3]. On the other hand,taurine, which has been used to treat acute hepatitis and cholestasis [4], is one of theamino acids that is conjugated to bile acids. g-GTP is associated with hepatocytemembranes, and the detergent action of bile acids causes leakage of g-GTP fromthe liver into the blood in hepatobiliary diseases. This means that the degree ofg-GTP solubilization depends on the hydrophobicity of the bile acids in theenterohepatic circulation [5]. Hydrophobic bile acids such as chenodeoxycholic acidand deoxycholic acid easily solubilize g-GTP, but UDCA, a hydrophilic bile acid,prevents g-GTP from solubilizing from membranes. It was noticed that serumg-GTP levels decreased strikingly in most chronic hepatitis patients treated withUDCA alone, but not in patients treated with UDCA and taurine, concomitantly.In this paper, to clarify the therapeutic efficacy of co-administration of UDCA andtaurine, the effects of taurine added to UDCA on the serum g-GTP levels andresults of other liver function tests were investigated in chronic hepatitis C patients.

2. Patients and methods

A total of 52 outpatients with chronic hepatitis C were selected. All were positivefor HCV serologic markers and had elevated ALT levels for more than 1 year.Chronic hepatitis was diagnosed clinically on the basis of the ultrasonographyfindings, laboratory data including ICG(Rl5) and platelet count, and histologicalfindings in the liver. Patients with fatty liver, or who were in the habit of drinkingalcohol, were excluded. A total of 32 patients (17 males and 15 females, aged 5798years, mean9S.D.) were given 600 mg day−1 UDCA (Urso, Tokyo-Tanabe,Tokyo, Japan) alone; four patients (one male and three females, aged 50916 years,mean9S.D.) were given both UDCA, 600 mg day−1, and taurine (TaurinePowder, Taisho, Tokyo, Japan), 3 g day−1, concomitantly; nine patients (fourmales and five females, aged 6198 years, mean9S. D.) were given taurine, 3 gday−1, in addition to UDCA after more than 6 months administration of UDCA,600 mg day−1; and seven patients (four males and three females, aged 55911years, mean9S. D.) were given taurine, 3 g day−1, alone. No significant differ-ences in mean age and sex ratio were observed among these four groups. Informedconsent was obtained from each patient, and the study protocol conformed to theethical guidelines of the 1975 Declaration of Helsinki as reflected in a prioriapproval by the institution’s human research committee.

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The mean serum ALT, ALP, g-GTP, and total bile acid (TBA) values during the3 months before UDCA and/or taurine administration and the 3 months after thestart of UDCA and/or taurine administration were compared. Mean values werecalculated from three to six points obtained during the 3 months. The percentagechange in laboratory values was calculated by using the following equation:percentage change (%)= (mean value after administration−mean value beforeadministration)/(mean value before administration)×100.

Inter-group differences in mean age, sex ratio and mean ALT, ALP, g-GTP, andTBA values before administration of UDCA and/or taurine were analyzed by theKruskal-Wallis test. Differences in mean ALT, ALP, g-GTP, and TBA valuesbetween before and after the administration in each group were statisticallyevaluated by the Wilcoxon rank sum test. Difference was considered statisticallysignificant at PB0.05.

3. Results

Improvement in ALT and g-GTP was found in most of the 32 patients treatedwith UDCA alone, and TBA markedly increased in all cases following administra-tion of UDCA (Fig. 1). The percentage change in ALT, ALP, g-GTP, and TBA(mean9S.D.) was −25.1916.2%, +1.198.0%, −34.3918.8%, and+115.39142.0%, respectively.

Fig. 1. Percentage change in serum ALT, ALP, g-GTP, and TBA levels following UDCA administrationto chronic hepatitis C patients. The bars indicate mean values9S.D. (n=32). Before, values (mean9S.D.) during the 3 months before UDCA administration; and after, values (mean9S.D.) during the 3months after UDCA administration. *PB0.05, compared to each value before UDCA administration.

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Fig. 2. Percentage change in serum ALT, ALP, g-GTP, and TBA levels following concomitantadministration of taurine and UDCA in patients with chronic hepatitis C. Data obtained from the samepatient are connected with a line (n=4). Before, values (mean9S.D.) during the 3 months beforeUDCA and taurine administration; and after, values (mean9S.D.) during the 3 months after UDCAand taurine administration.

A decrease in ALT and an increase in TBA were found in all four patientstreated with taurine and UDCA concomitantly (Fig. 2). The percentage change inALT, ALP, g-GTP, and TBA(mean9S.D.) was 16.494.8%, +1.094.4%, +15.0918.8%, and +30.7927.6%, respectively. g-GTP somewhat elevated (statisti-cally not significant) after concomitant administration of taurine and UDCA.

Fig. 3 shows the sequential changes in serum g-GTP and TBA levels in a typicalcase treated with taurine in addition to UDCA. The patient, a 68-year-old female,had an 8-year history of persistent ALT elevation. g-GTP markedly decreased andTBA increased following UDCA administration. Taurine was added to UDCAafter 7 months of UDCA administration, and this was followed by an increase ing-GTP and a decrease in TBA for about 6 months. Sequential changes in g-GTPand TBA levels which fluctuated later produced a so-called ‘mirror image’. In thiscase, ALT gradually elevated even after UDCA and taurine administration.

The effects of taurine on the results of the liver function tests of the patientstreated with UDCA are summarized in Fig. 4. Administration of taurine, inaddition to UDCA, increased g-GTP in eight of the nine patients, and decreasedTBA in all patients. No marked changes were noted in ALT or ALP. Thepercentage change in ALT, ALP, g-GTP, and TBA (mean9S.D.) was +5.3914.1, +5.696.7, +15.5912.7 and −21.9917.8%, respectively.

No marked changes in g-GTP or TBA were noted in the seven patients treatedwith taurine alone (not shown in the figure). ALT, ALP, g-GTP, and TBA values(mean9S.D.) were 58933 IU l−1, 165950 IU l−1, 32915 U l−1 and 11914mmol 1−1, respectively, during 3 months before taurine administration, and 50927

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IU l−1, 187970 IU 1−1, 29914 U 1−1 and 11916 mmol 1−1, respectively,during 3 months after taurine administration. The percentage change in ALT, ALP,g-GTP, and TBA (mean9S.D.) was −11.8912.3, +12.5913.7, −4.498.6,and +6.3918.9%, respectively.

There were no significant inter-group differences in mean ALT, ALP, and g-GTPvalues before administration of UDCA and/or taurine. In the patients treated withtaurine in addition to UDCA (Fig. 4), TBA level before taurine administration wasstatistically higher than in three other groups because of UDCA administration inadvance. No severe complications were noted in the patients treated with UDCAand/or taurine.

4. Discussion

UDCA administration significantly decreased serum levels of both ALT andg-GTP, and simultaneously increased the serum TBA level of patients with chronichepatitis C. Since serum TBA levels reflect the size of the enterohepatic bile acidpool [6], it was suggested that UDCA administration enlarged the enterohepaticbile acid pool size. It has been postulated that the efficacy of UDCA resides in its

Fig. 3. Typical course of serum ALT, g-GTP, and TBA levels following administration of taurine to ahepatitis patient being treated with UDCA (68 years old, female, chronic hepatitis C).

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Fig. 4. Percentage change in serum ALT, ALP, g-GTP, and TBA levels following administration oftaurine to patients being treated with UDCA for more than 6 months. Data obtained from the samepatient are connected with a line (n=9). Before, values (mean9S.D.) during 3 months before taurineadministration; and after, values (mean9S.D.) during 3 months after taurine administration. *PB0.05,compared to each value before taurine administration.

ability to increase the hydrophilicity of bile acid composition [7]. This protectshepatocytes against the detergent action of hydrophobic bile acids, and thus serumALT and g-GTP levels decreased after UDCA administration. Although serumg-GTP and ALP levels are usually considered markers of cholestasis [8], serum ALPlevels were unchanged by UDCA in these cases, suggesting that the g-GTP-decreas-ing effect of UDCA is not involved with the improvement of secretary function ofhepatocytes.

On the other hand, serum g-GTP levels did not decrease in the patients treatedwith taurine and UDCA, concomitantly, and the increment in TBA tended to besmall in comparison with patients treated with UDCA alone. These findings led tothe hypothesis that taurine may attenuate both the decrease in g-GTP and theincrease in TBA induced by UDCA. In order to clarify whether this hypothesis iscorrect, serum g-GTP and TBA levels were examined following administration oftaurine to patients being treated with UDCA. The results showed that taurineadministration simultaneously increased the g-GTP levels and decreased the TBAlevels of these patients.

Since the conjugation of bile acids depends on the taurine concentration in theliver, the ratio of taurine-conjugated bile acids markedly increases after administra-tion of taurine [9]. It has been reported that taurine conjugation of bile acidsincreases to about 50% following taurine administration, as opposed to 25–30%normally [10]. In contrast, UDCA administration causes no changes in the conjuga-tion pattern of bile acids [11]. Absorption of bile acids is maintained by both apassive diffusion system operating throughout the intestine and an active (energy-dependent) transport system located in the distal portion of the ileum [12,13].

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Unconjugated dihydroxy bile acids such as UDCA undergo only passive transport,while taurine-conjugated bile acids undergo only active transport [13,14]. Thus, lesstaurine-conjugated UDCA is thought to be absorbed in the intestine than unconju-gated UDCA. Based on the above, the present findings seemed to suggest that thetotal amount of UDCA in the enterohepatic circulation decreased following taurineadministration, because most of the UDCA should have been conjugated withtaurine.

On the other hand, no marked changes in g-GTP or TBA levels were observedin the patients treated with taurine alone. This suggests that the bile acid pool sizemight change little following taurine administration, because the pool size shouldbe relatively small in the patients who were not treated with UDCA.

In conclusion, the present study revealed that taurine attenuated the serumg-GTP-decreasing effect of UDCA in hepatitis patients. However, the presentfindings by no means rule out the possibility of co-administration of taurine andUDCA in the treatment of liver diseases, because the pharmacological effects ofthese two agents on the liver are different [15].

Acknowledgements

Part of this work was presented at the 31st General Meeting of the JapaneseSociety of Hepatology (West), held in Yokkaichi, Japan on 29 November, 1996.

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