Altered cyclosporine absorption in a patient with ulcerative colitis , sclerosing cholangitis and pancreatic insufficiency

MG SWAIN, H WITT-SULLIVAN, R OGILVIE, l WANLESS,) HEATHCOTE. Altered cyclosporine absorption in a patient with ulcerative colitis, sclerosing cholangitis and pancreatic insufficiency. Can J Gastroenterol 1991;5(4): 133-136. Pancreatic insufficiency leading to a ltered cyclosporine absorption is reported in a 37-year-old man with ulcerative colitis and sclerosing cholangitis. Asymptomatic chronic pancreatitis occurs frequently in patients with ulceraLive colitis, and even more commonly when there is coexistent sclerosing cholangiris. However, pancreatic insufficiency has been documented in only one patient previoLrsly with ulcerative colitis and sclerosing cholangitis. Pancreatic function testing can help co identify the complex etiology of malabsorption in these patients and is recommended in patients when liver transplantation is contemplated, as pancreatic insufficiency may alter the absorption of cyclosporine.

Troubles d'absorption de la ciclosporine chez un patient porteur de colite ulcereuse, de cholangite sclerosante et d'insuffisance pancreatique RESUME: On rapporte des troubles d'absorption de la ciclosporine attribuables a une insuffisance pancreatique chez un patient age de 37 ans et porteur cl'une colite ulcereuse et d'une cholangite sclerosante.Une pancreatite chronique asymptomatique accompagne sou vent une co lite ulcereuse, sunout doublee d'une cholangitc sclerosance.Pourtant, l'insuffisance pancreatique n'a ece rapportee quc chez un seu l patient souffrant des deux affections citees.Les examens de la fonction pancreatique peuvent aider a reconnaicre les causes complexes de malabsorption chez ces malades.On les recommande clans le cas des candid::ics a la transplantation du foie, ecan t donne qu'une insuffisance pancrcatique peuc perturber !'absorption de la ciclosporine.cerative col itis and sclerosing c ho langitis is well established ( 1-3).However, a relationshi p between these two cond itions and pancreatic disease has also been noted ( 4-9).Pancreatic due cal abnorma li ties and interstitia l change~ consistent with chronic pancreatiLis have hcen described in patients with ulcerative colitis (4-9), and pancrccititis occurs more commonly in patienb with primary scler,)sing c ho langitis than wou ld be expected hy c ha nce a lone (8,9).Elevation of panc reatic isnamylase levels, indicative of pancreatic damage, have heen noted in paLi ents with primary sc lerosing cholangitis, but none of these patients had pancreatic insufficiency (9).However, pancreatic insufficiency has been documented in one patient previously wi th sclerosi ng chola ngicis and ulcerative colitis ( 1 O); the present case record describes a si milar pcitient.Pancreatic disecise in patients with ulce ra tive colitis coupled with sclerosing cholangitis could lead to a ltered absorption of fatsoluble compounds such as cyclosporine.T his possibility has implicaLions fo r paLients who receive liver transplants fo r primary sclerosing c ho langitis and who th us requ ire adequate absorption of cyclosporinc to prevent graft reject ion.

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Figure 1) Liver hwpsy demonstratinit the loss of bile ducts from portal tracts consistent with sclerosing cholangius TABLE 1 Cyclosporine blood concentrations after oral (5 mg/ kg) or intravenous cyclosporine (2.5 mg/ kg) with or without oral pancreatic supplementation (lipancreatin: three tablets with each meal) The patient received o standard llquid breakfast ot 08:00 with the cyclosporine ond then standard meals were given ot 12:30 ond 17:00.Values were determined by rodioimmunoossoy, ond ore expressed os ng/mL.Cyclo Cyclosporine: IV Intravenous CASE PRESENTATION An asymrtomatic 3 7-year-old man r resented because of infertility and wm, found to have abnormal liver enzymes.Three years after rresenratinn the patient noticed the gradual onset of fatigue, and subsequently comrlaineJ of frequent, semi-liquid, foul-smelling, blood-tinged stools.He experienced an l 1.4 kg (25 lb) weight loss over four months desrire a good appetite.He did not complain of Jry eyes.There wa~ no rast history of bowel, liver or p,mcreatic disease, ethanol ahuse, or drug in-gestion.Physical examination was within normal limits except for scleral ictcrus anJ a palpable spleen tip.Laboratory data revealed hemoglobin 9 I 23 g/L, leukoc~te count 4.9xl0 /L, rlatelets 264x IO /L, aspartate aminotransferase 157 U/L (normal less than 40), alanine aminotransferase 257 U/L (normal less than 40), gammaglutamyl trnnsfcrase 969 U/L (normal nine to 43), 5' nucleotidase 178 U/L (normal five to 19), alkaline phosphatase I 080 U/L (normal 20 to JOO), albumin 41 g/L (normal 39 to 51 ), amylase 606 U/L (normal Oro 1800), and total bil iruhin 51 µmol/L (normal two to 20).The prothrombin time and values fo r scrum electrolytes, glucose, triglycerides and calcium were all normal, and an anti• mitochondrial antibody test wa~ negative.
Liver biopsy showed fibrosis and the almost meal absence of bi le ducts in the portal tracts compatible with sclerosing cholangitis (Figure 1).Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated an apparently normal extrahcpatic biliary system, but the intrahcpatic branches were irregular, as was the pancreatic duct (Figure 2).Colonoscopy showed a pancolirn and biopsies were consistent with ulcerative colitis.Fecal fat excretion was elevated (3 7 and 61 mmol/day; normal less than 18).A secrctin test showed decreased maximal bicarbonate secretion (77 mEq/L; normal greater than 90).A small bowel biopsy was normal.Comruted tomography scan and ultrasound of the abdomen were normal.
A:; liver tramplantation is the only known effective cure at present for sclcrosing cholangitis, the patient was assessed .is a potential candidate.Since cyclosporine would he used for 1mmunosuppression after transplantation there was concern that with the p;itient's rancrct1ti c insufficiency, cyclosporine, which is highly fatsoluhle, would be bound in the gut and poorly absorbed.Therefore, oral cyclosporine absorption studi es were performed an<l hlooJ concentrations determined with no pancreatic supplement and with pancreatic surplementation (lipancrcatin: three tablets with each meal) (Table I).Intravenous cyclosporinc was give n (2. 5 mg/kg over 3 h) on Jays 2 and 3 (on and off I ipancreatin, respectively) to reflect I 00% bioavailability of the cyclobpO• rine.Oral cyclosporine (5 mg/kg) wa, then administered with and without lirancreatin supplementation (days 4 and I, rcsrectivcly ), and blood cnn-centration~ of cyclo5porine were determined hy radioimmunmssay specific for the parent compou nd.From the blood concentrations, rharmacokinetic analysis using n two compartmcn1 model with Gauss-Newton and New-ton-Raphson proce<lures revealed no difference in lhc climinalio n kinetics of intravenous cyclosporine in the presence or absence of lipancrearin (area under the 'concentration over time' curve 14.2 mg•h/L versus 13.3; total c learance 12.3 L/h versus 13.2; beta half-life 8.6 h vmus 8.8).The apparent in itial volume of J istrihution for intravenous cyclosporine was smal !er in the presence of lipancrealin ( 17 L versus 44 ), resu lting in higher hlood concentrations.The authors have no explanation for this.The oral a<lmmtstration of cyclosporine with lipancreatin supplementation resu lteJ in a marked <lecrease in the time to peak bloo<l cyclospori ne concentrations (less than I h versus 5; normal 2 to 4).However, the overall hioava ilability of cyclosporine was not improved by lipancreatin supplementation (16.4% with lipancreatin versus 24.0% without ; normal 20 to 40%), and was in fact lower than that seen wilhoul lipancrearin supplementation.

DISCUSSION
The presem pmienr ha<l concomitant ulcerative colitis, sclerosing cholangitis and pancreatic exocrine insufficiency.The association between ulcerative colitis anJ sclerosmg cholangitis is well established (1-3).However, the relatio nsh ip between these two con<litions and clinically significant pancreatic abnorma li ty i~ incompletely documented (4-10).An increased frequency of pancreatic changes in ulcerative colitis consistent with chronic pancreatitis has been describe<l in post mo rtem and ERCP examinations.Ball ct al ( 5) described interstitial par.creatitis in 46 of 86 consecut ive post mortem exam inations performed in patients with ulcerative colitis.ERCP c hanges compatible with chronic pancrealitis were described by Axon et al ( 4) in 59 patiems, five of whom had inflammatory bowel disease; however, nnne ha<l symptomatic pancreatic insuffic iency.Seven patents with ulcerative colitis and sclerosing cholangitis were Jescribed by Borkj e et al (6) an<l fou r of these also had ahnormal pancrearograms at ERCP.None had clinically significant pancreatic insufficiency.In a series of 20 patients wiLh primary sclerosing cholangitis, I 3 ha<l associated ulceralive colitis and two haJ ERCP~ con~istent with panc reatitis.Pancreatic secretin sti mulation tests were performcJ o n these patients and all were normal (9).
Pancreatic insufficiency associated with ulcerative colitis and intrahepalic sclerosing c holangilis has been described in a 19-year-old female (10).This patient developed steawrrhea and jaundice simultaneously one year prio r to the d iagnosis of ulcerative coli tis.The present patient became jaundiced hefore developing symptoms of ulcerative colitis or pancreatic insufficiency.There was no evidence of alcohol abuse, gallstones, hypercalccmia or hyperlipidemia, and the patient had never received systemic steroids or sulphasa lazine.5-Aminosalicylic acid therapy was begun after the diagnosis of pancreatic insufficiency was made.
The pathogenesis of the pancreatic ahnormal tly tn assoc iauon wnh ulc erative cnlilb and sclerosing cholan.giLisb unknown.Borkjc cl al (6) postulated that the triad of ulcerative colit is, sclerosing cholangitb anJ p,mcremitis might he manifestations of an autoimmune disease with generic predisprn.1tion.This hypothesis has been supporte<l by lhe finding of an association hetwecn chronic pancreatil is, sclcrosing cholangitis and the sicca complex (11,12).Recently, Lhe specific h uman lymphocyLe antigen (HLA) haplotypc, HLA -DRw52a, has been described in patients with sclerosing cholangitis, again suggesting a generic prc<lisposition (13).Epstein ct al (9) have proposed Lhe same hypothesis in their primary hil iary c irrhosis patienls with pancreatic ahnormalilies.Sicca ~yn<lrome was also noted to he an add itional feature of primary biliary c irrhosis but not sclerosing cholangiLis (9).It h as also been suggeste<l that sclcrosing cholangiLis might predispose co hile SWAIN ec al reflux into the pancreatic duct and so give rise to c hronic pancreatitis ( 6, l 4 ).
P,mcrcatic ductal al:mormalities have been demonstrated in patients with ulcerative colitis without sclerosing cho lang icis (4 ).H owever, pancreatic insufficiency has on ly been demonstrated in ulcerative colitis patients with sclerosing ch o langitis (10).This suggests that the re is a correlation between sy mptomatic disease of the bile duct and that of the pancreatic duct.Pancreatic insuffi c iency in the present patient resu lted in a de-c reased rate of absorpt ion of cyclosporine which was corrected by pancreatic enzyme supplementation.However, the ove rall bioavailability o f oral c yclosporine was not improved by the additio n of pancreatic supplements.Blood cyclosporine concentrations were higher after intravenous cyclosporine in che presen ce of lipanc reatin supplementation Jue to a smaller apparent initial volume of dis tribution without alterat io n of elimina tion kinetics.
There is no ready explanation for this, but a n alteration in circulating lipid bo wel Jiseasc.C lin RaJinl 1979;30: l 79-82.The pancreatic ducts in primary biliary c irrhosi:, anJ scleros ing chnlangitis.Scand J Gastrocntcrol I 985;20(Suprl I 07): 32-5.8. Smith MP, Ll)e RH.Sclcmsing cho lang1tis.A review of recent case rl'ports and associated dis.:;1ses and fou r ncw ca,cs.Am J Surg 1965; 11 0:239-46. 9. Ersrcin 0, C hapman RW, Lake-Bakaar G, ct al.The pancrea, in primary biliary c irrhosis and r rimary profiles in spite of a fixed Jie t may he respons ihlc.Since th e radioimrnunnassay was spec ifi c for the parent compound, entcrohepatic rec1rculrition of cyclosporinc metabo lit es cannot account for the higher blood concen trations of cyc losporin e.In summary, pancreatic func tion testi ng in patients wi1h ulcerauve coli tis and sclerosing c holangit is should be considered if li ver transplantation is contemplated, s ince pancreatic insuffi c iency may a lter the ab~,Hption ki netics of cyc losporinc.