CASE REPORT

Rapid Improvement of Icterus and Pruritus by the OralAdministration of Colestimide in TwoCases of

Drug-induced HepatitisMitsunori Tani, Yoshikazu Hayashi, Satoshi Okamoto, Shiro Yokohama, Mamoru Inaba,

Hiroshi Kubota and Kimihide Nakamura*

Abstract

Wereport two cases of drug-induced hepatitis refrac-tory to therapy of ursodeoxycholic acid and prednisolone,who were relieved of icterus and pruritus immediately bythe oral administration of colestimide. Their liver dysfunc-tion was not improved, by withdrawal of causative drugsor by treatment with prednisolone and ursodeoxycholicacid. Colestimide (3.0 g/day), a strong basic anion-exchangeresin, was orally taken before breakfast and evening meal,leading to rapid and complete relief of icterus and pruri-tus. These cases suggested that colestimide would be usefulfor patients with cholestasis in drug-induced hepatitis, be-cause this agent has few side effects and it is easy to take.(Internal Medicine 40: 1098-1103, 2001)

Key words: cholesthyramine, adverse effect, cholestasis

Introduction

Drug-induced hepatic disorder is a hepatic disorder mostfrequently seen in daily practice, second only to viral hepaticdisorder. Since a number of new drugs have been developed inrecent years, drug-induced hepatic disorder may show varioustypes of liver injury pictures or clinical pictures.Although most drug-induced hepatic disorder is improvedby early diagnosis and discontinuation of causative drugs, liverinjury and icterus may linger due to delayed hypersensitivityreaction in some cases. Drugs such as Stronger Neo- Minopha-gen C, ursodeoxycholic acid, and steroids are frequently effec-tive in these cases.Recently, however, we encountered 2 cases of refractoryhepatic disorder of cholestatic type in which icterus and pruri-tus were persistent after discontinuation of causative drugs but

effectively relieved by administration of colestimide. We herereport our experience with a review of the literature.

Case ReportsCase1A 32-year-old womanwas referred for gastroenterologyconsultation to evaluate pruritus and liver dysfunction. Her pastmedical history: was only significant for right ovariectomy dueto ectopic gestation. Oral treatment with ethinylestradiol,norgestrel (Duoluton®), an estrogen preparation, was started atthe Department of Obstetrics and Gynecology, Nayoro CityGeneral Hospital from July 6, 1999 for the treatment of ovar-ian insufficiency. Pruritus occurred and her urine became yel-lowish from July 16, and she visited the outpatient ward of thedepartment on July 26. Liver damage was observed, and shewas admitted in the department for further examinations andtreatment. After hospitalization, the oral therapy with the es-trogen preparation was discontinued, and Stronger Neo-Minophagen C (SNMC) at an intravenous dose of 40 ml and aliver hydrolysate preparation (Proheparum®) at an oral dose of600 mg/day were administered, but her hepatic dysfunctionwas aggravated gradually and she was referred to our Depart-ment of Gastroenterology. Physical examination revealed a ic-terus in the bulbar conjunctiva. Laboratory data on admissionrevealed a slight increase in WBCto 10,200/|il. Other param-eters of aspartate aminotransferase (AST), alanine aminotrans-ferase (ALT), lactate dehydrogenase (LDH), alkaline phos-phatase (ALP), total bilirubin (T.Bil), and direct bilirubin(D.Bil) were high, as shown by 220 IU/Z, 581 IU/Z, 323 IU/Z,15, 513 IU/Z, 3.8 mg/dl, and 2.2 mg/dl, respectively. HBs anti-gen and HA-IgM antibody were negative, HCVantibody wasnegative. Anti-nuclear antibody (ANA) and antimitochondrialantibody (AMA) were negative (Table 1). Abdominal ultra-sonography (US) and computed tomography (CT) showed nofinding indicative of obstructive j aundice. Ursodesoxycholic

From the Department of Gastroenterology, Nayoro City General Hospital and *the Second Department of Internal Medicine, Asahikawa Medical University,Hokkaido

Received for publication February 9, 2001 ; Accepted for publication June 26, 2001Reprint requests should be addressed to Dr. Mistunori Tani, the Department of Gastroenterology, Nayoro City General Hospital, West 7, South 9, Nayoro,

Hokkaido096-8511

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Colestimide Improved Cholestasis

Table 1. Laboratory Data on Admission of Case 1H e m a to lo g y B l o o d c h e m i s t r y

W B C 1 0 ,20 0/u l A S T 2 2 0 I W l

N e u . 6 6 .2 % A L T 5 8 1 IU /Z

L y m . 2 5 . 0 % L D H 3 2 3 IU //

E o s. 0 . 9 % y- G T P 3 3 IU //

B a s. 1. 1 % A L P 5 1 3 IU //

R B C 5 1 5 x l O 4/u l T . B 3 . 8 m g / dl

H b 14 .1 g /d l D . B 2 . 2 m g / dl

H t 4 2 . 7 % B U N 9 . 2 m g /d l

P it 2 4 . 8 x l O 7 u l C re 0 .6 8 m g /d l

U rin a ly s is N a 1 4 2 m E q / /

B lo o d (+ ) K 3 . 5 m E q / Z

P ro te in (- ) c ¥ 1 0 5 m E q / Z

S u g a r (- ) T P 7 .5 g/ dl

B ilir u b in (+ ) A lb 4 .4 g/ dl

K e to n (+ ) T. ch 2 0 0 m g / d l

V i r u s m a rk e r T G 1 8 1 mg / d l

H A I g M A b (- ) F B S 9 9 m g/ d l

H B s A g (- ) C P K 3 4 3 IU /1

H B s A b (- ) Co a gu l at i on te s t

H C V A b (- ) P T 1 6 9 %

Im m u n o lo g y H P T 1 7 5 %

A N A (- )

A M A (- )

C R P 0 .3 m g/ d l

acid (UDCA) therapy, started at 600 mg/day, did not improveT.Bil while transaminase was improved, and so cholestyraminewas concomitantly administered at 9.0 g/day from July 29. Thelatter drug was discontinued due to retching on August 16. Pred-nisolone was administered at an oral dose of 30 mg/dayfor 2weeks from July 29 but discontinued on August 30 due to thelack of reduction of T.Bil. After echographic liver-biopsy, thelevel ofALTwas raised again, but the mechanismwas unclear.Colestimide was given at 3.0 g/day from August 23, leading toimprovement of pruritus as well as a reduction of T.Bil (Fig.1). The result of the lymphocyte stimulation test of Duoluton®was negative, but echographic liver-biopsy revealed bile pig-mentation Within centrilobular hepatic cells and bile embolusin the bile capillaries. Hepatocellular necrosis and inflamma-tory cell infiltration were relatively mild. Intralobular neutro-phils were minimal, and slight infiltration of lymphocyteswasfound in the portal region, showing pathological findings con-sistent with drug-induced cholestatic hepatitis (Fig. 2A, B).

Case2A 57-year-old manwas referred for our Department of Gas-troenterology consultation to evaluate fever and liver dysfunc-tion. Previously, he was well with no significant past medicalhistory. This patient visited a nearby clinic with complaints ofepigastric discomfort and swallowing difficulty on August 24,1999. Chai po tang, 9.0 g/day, clotiazepam, 15 mg/day,sucralfate, 1.2 g/day, azulene sulfonate sodium à"L-glutamine(Marzulene-S®), 1.5 g/day, and itopride hydrochloride, 1 50 mg/

day were prescribed. On August 29, fever and fatigability oc-curred. These symptomsbecame potentiated and he visited theDepartment of Respiratory Internal Medicine, Nayoro CityGeneral Hospital. Hematological examinations revealed liverdysfunction, and he was referred to our DepartmentofGastoenterology, and hospitalized for further examinations andtreatment. At physical examination, icterus was noted in hisbulbar conjunctiva, and no abdominal abnormality was observedexcept for mild epigastric tenderness. Laboratory data on ad-mission showed liver dysfunction, which was biliary system-predominant as shown by the following blood chemistry val-ues: AST, 78 IU/Z; ALT, 1 10 IU/Z; y-glutamyltranspeptidase (y-GTP), 395 IU/Z; ALP, 1,032 IU/Z; and T.Bil, 3.0 mg/dl. HBsantigen and HA-IgMantibody were negative, HCVantibodywas negative. ANAand AMAwere negative. As for tumormarkers, there was a slight increase in CA19-9 to 45.9 U/ml(Table 2). Based on the lack of evidence of dilation of the in-trahepatic or commonbile duct in abdominal US and CT, ob-structive jaundice was denied. SNMC(60) ml was intravenouslygiven every day, and UDCAwas administered at 600 mg/dayfrom September 4. UDCAtherapy was discontinued due toincreased T.Bil. Prednisolone was administered at 30 mg/dayfrom September 8, but did not improve the icterus or pruritusvery much. Cholestyramine therapy was started at 9.0 g/dayon September 2, but it was discontinued on September 3 be-cause of retching, and so colestimide was given at 3.0 g/dayfrom September 10. T.Bil decreased rapidly, and pruritus wasgradually relieved. The dose of prednisolone was reduced to

Internal Medicine Vol. 40, No. 1 1 (November 2001)1099

Tani et al

^0^s****^ Prurit i s -"""--

^_____^ Colestimi.de 3.0 g/day

140mi somi loomi 60mi100QQ0I 6°mi Ifl00fiQ0QPrednisolone 1 | ^ m30mg/day 20mg 10mg ' t

-- -i 300mgUDCA600 mg/day »

Cholestyramine 9.0 g/day Ii I ALP

9- 600~ 600- J\ /

500- 500- N, TBil >V\^

6- 400- 400- /&^^ /^Ss\_k ' D

3- 200- 200- \ / ^\

0 0 0^ ^ ^ ^

Admission Liver biopsy DischargeJul 26, 1999 Aug ll Aug 31 Sep 27

Figure 1. Clinical course of case 1. ALT ( O ): alanine aminotransferase, ALP ( å¡ ): alkaline phosphatase, T. Bil ( # ): totalbilirubin.

Figure 2. Histological examination of the specimen by echographic liver biopsy demonstrates that hepatocellular necrosis andinflammatory cell infiltration are mild. A: Portal area (HE stain, x200), B: Central vein area (HE stain, x200).

1100 Internal Medicine Vol. 40, No. 1 1 (November 2001)

Colestimide Improved Cholestasis

Table 2. Laboratory Data on Admission of Case 2H e m a to lo g y B l o o d c h e mi s t r y

W B C 4 , 40 0 / ul A S T 7 8 IU //

N e u t. 4 8 . 1 % A L T 1 10 I U /Z

L y m . 2 8 . 9 % L D H 2 3 5 IU //

E o s. 8 . 7 % Y -G T P 3 9 5 IU //

B a so . 1. 4 % A L P 1 ,0 32 IU //

R B C 4 99x 1 0 4/u l T. B 3 . 0 m g /d l

H b 14. 4 g/d l D . B 2 . 1 m g /d l

H t 4 4 . 2 % B U N 8 . 8 m g / dl

P it 1 9 .8 x l O 4/u l C re 0. 8 5 m g /d l

U rin a ly sis N a 1 3 9 in E q //

B lo o d (- ) K 3 . 5 m E q / Z

P ro te in (- ) c ¥ 1 0 2 m E q / Z

S u g a r (- ) T P 6 .9 g/ dl

B iliru b in (+ ) A lb 3.6 g/d l

F e c e s F B S 1 4 8 m g /d l

O c c ul t b l oo d (- ) T .c h 2 0 0 m g / d l

T u m o r m a r k e r T G 1 5 4 m g / d l

C E A 2 .7 n g/ m l Co a gu l at i on te s t 1 0 8 . 6 %

C A 1 9 -9 4 5 . 9 U / m l P T 1 10 %

Vi r u s m a r k er H P T

H A I g M A b (- ) Im m u n o lo g y 1. 7 m g /d l

H B s A g (- ) C R P (- )

H B s A b (- ) A N A (- )

H C V A b (- ) A M A

10 mg/day, and oral prednisolone therapy was discontinued onSeptember 30. Liver damage did not recur thereafter, and hewas followed at the outpatient ward (Fig. 3). Echographic liver-biopsy on September 13 during hospitalization showedpericentral intrahepatic cholestasis with mild inflammation inthe portal region. These findings were not specific to drug-induced hepatitis, but along with his clinical findings, it wasconsidered that this patient presented with findings observedduring recovery from drug-induced hepatitis of the cholestatictype (Fig. 4A, B).

Discussion

The reported number of drug-induced hepatitis cases hastended to increase with the recent development of many noveldrugs and the increased elderly population. In particular, dur-ing the last 10 years, the ratio of drug-induced hepatitis hasshown an increseasing tendency among the causes of fulmi-nant hepatitis (1, 2). No specific marker is available at present,however, for the early diagnosis of drug-induced hepatitis, anddiagnosis solely depending on the judgement of several condi-tions is unavoidable in many cases. It is important to collectadequate information by interview and to exclude other pos-sible causes of hepatitis, such as hepatitis viruses, alcohol andautoimmune hepatitis. In order to improve the ability to diag-nose drug-inducedhepatitis, a recent article reports an attemptto score items including the use of drugs which have been re-ported to induce hepatitis and then to make the diagnosis ac-

cording to the total score (3). These 2 cases were both prob-able diagnosis according to their criteria. Further, according tothe generally accepted criteria of diagnosis in Japan, these 2cases were suspected diagnosis. However, this time these 2 caseswere diagnosed as drug-induced hepatitis by excluding all othercauses and clinical findings.It is also reported that patients with hepatitis induced bycertain drugs present with specific pathological findings (4). Itis accepted that, in manycases, a definite diagnosis of drug-induced hepatitis is made after liver biopsy-based histopatho-logical examination.

UDCAand prednisolone are accepted to be effective andare widely used for the treatment of drug-induced cholestatichepatitis. Neither of these agents was very effective for thepresent two cases.For the treatment of pruritus associated with cholestasis,cholestyramine, an anion exchange resin which adsorbs bileacid and prevents its resorption in the intestinal tract, has beenconsidered to be effective (5, 6). Cholestyramine has also beenaccepted to be effective for pruritus associated with renal fail-ure and hematological disorders (7, 8)'and has been used widely.Wecannot rule out the possibility that substances which di-rectly or indirectly induce pruritus may appear in bile, or nor-mal bile maycontain pruritus-inducing substances. It is esti-mated that these substances stimulate fecal excretion of bileacids, and are adsorbed by drugs inducing enterohepatic circu-lation and meals (cholestyramine, polyunsaturated fatty acid,dietary fiber) (9) and are excreted from the body.

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^S*1^ Pruri t i s ^"s^^Cholestyramine PI I 7"9.0 g/day U I Colestimide 3.0 g/day

å  SNMC -. - -- -. --, _» -- -. -_ --

P^- - iflOODOOOflOO

Prednisolone 30mg ^J"^ i1Qm^

I UDCA600mg I

10- 1,500- 500- j*

|[6-5900-5300- / à"/Vi ALP ^\

" 4-< 600- < 200- 1 Qr-O^^f^ V T.Bil^^^\\^

0 0 o_ _j^ ^ ^ ^ L_Admission ERCPLiver biopsy Discharge

Sep 1, 1999 Sep 9 Sep 13 Sep 28 Oct 6

Figure 3. Clinical course of case 2.

Figure 4. Histological examination of the specimen by echographic liver biopsy shows pericentral intrahepatic cholestasis withmild inflammation in the portal region. A: Portal area (HE stain, x200), B: Central vein area (HE stain, xlOO).

1102 Internal Medicine Vol. 40, No. ll (November 2001)

Colestimide Improved Cholestasis

A recent report describes that, in bile, anion-exchange resinpreparations reduce dihydroxy bile acids (CDCAand DCA) inbile acid fraction (10). It is also reported in recent years thatlipophilic CDCAand DCAinduce dose-dependent histaminerelease from mast cells but hydrophilic bile acids do not havesuch action (1 1). It is considered, therefore, that lipophilic bileacids deposited in the skin exert no direct action on nerve end-ings but may be associated with the onset of pruritus via de-granulation of mast cells.To our regret, the exact mechanismof the reaction ofcolestimide in cholestasis is unclear, because serum bile acidswas not measured in the present cases. Further considerationof many cases of drug-induced hepatitis with cholestasis isnecessary via evaluation of serum bile acids.Anion exchange resins, which are not absorbed in vivo, ad-sorb bile acids in the intestinal tract and excrete substances sothat enterohepatic circulation of bile acid is inhibited, leadingto promotion of cholesterol catabolism. Currently, anion ex-change resin preparations are used for the treatment of hyper-cholesterolemia, with relatively high safety because of theirnonabsorbable nature ( 1 2). The drawbacks of the existing agentcholestyramine are that larger doses are needed per adminis-tration and the necessity to suspend before dosing as well asfrequent gastrointestinal adverse reactions including abdomi-nal distention and constipation, resulting in greater stress onthe patient (12, 13).The present 2 patients could not ingest the drug due to retch-ing, and it was replaced with colestimide, which could be takensatisfactorily without the occurrence of the symptom, and ic-terus and pruritus were improved early after colestimide dos-ing.

Colestimide, at approximately 1/4 of the dose of cholestyra-mine, reduced cholesterol to the same extent as cholestyraminein a phase III comparative study. Colestimide adsorbs bile acidat smaller doses, leading to improved compliance (12). It isalso reported that colestimide affects adsorption of other drugsto a lesser extent compared to cholestyramine (14).In conclusion, patient compliance is more satisfactory with

colestimide compared to cholestyramine, which has been usedconventionally. Colestimide is effective for the treatment oficterus and pruritus in cholestatic hepatitis, and colestimide isthus considered to be one of the agents which should be usedearly in patients with this condition.

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Nippon Naika Gakkai Zasshi 84: 177-182, 1995.2) Sato S, Suzuki K, Takikawa Y. Fulminant hepatitis: epidemiology and

diagnosis. Nippon Naika Gakkai Zasshi 88: 626-631, 1999.3) Maria VA, Victorino RM.Development and validation of a clinical scalefor the diagnosis of drug-induced hepatitis. Hepatology 26: 664-669, 1997.

4) Kaplowitz N, Aw TY, Simon FR, Stolz A. Drug-induced hepatotoxicity.Ann Intern Med 104: 826-839, 1986 (clinical conference).

5) Yokomori H, Oda M, Kamegaya Y, et al. Rapid improvement of intrac-table pruritus in a case with primary biliary cirrhosis by a combined therapyof ursodeoxycholate (UDCA) and cholestyramine (CS) -Serum bile acidanalysis-. Acta Hepatology Jpn 37: 102-108, 1996 (in Japanese, Abstractis English).

6) Datta DV, Sherlock S. Cholestyramine for long term relief of the prurituscomplicating intrahepatic cholestasis. Gastroenterology 50: 323-332,

1966.

7) Silverberg DS, Iaina A, Reisin E, Rotzak R, Elihou HE. Cholestyraminein uremic pruritus. Br Med J 1: 752-753, 1977.

8) Chanarin I, Szur L. Relief of intractable pruritus in polycythaemia rubravera with cholestyramine. Br J Haematol 29: 669-670, 1975.

9) Nakamura T, Kasai T, Tusima H, et al. Effect of cholestyramine and applefiber on hepatic pruritic patients evaluated from fecal bile acid and fattyacid excretion. J Biliary Tract Pancreas 10: 209-213, 1989 (in Japanese).

10) Kajiyama G, Tazuma S, Yamashita G, et al. Effect ofMCI-196 on biliarylipids metabolism in patients with hypercholesterolemia. J Clin Ther Med12: 1349-1359, 1996 (in Japanese, Abstract is English).

1 1) Quist RG, Ton-Nu HT, Lillienau J, Hofmann AF, Barrett KE. Activationof mast cells by bile acids. Gastroenterology 101: 446-456, 1991.

12) MCI-196 study group. Study on the usefulness ofMCI-196 in patientswith hypercholesterolemia. J Clin Ther Med 12: 1641-1692, 1996 (inJapanese, Abstract is English).

13) Borgeat A, Wilder-Smith O, Mentha G, Huber O. Propofol and cholestaticpruritus. Am J Gastroenterol 87: 672-674, 1992.

14) Kawai M, Takada M, Mitsuka M. The interaction between MCI-196 anddrugs. Jpn Pharmacol Ther 24 ( suppl ) : 607-610, 1996 (in Japanese,Abstract is English).

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