One of 55 patients transplanted for sclerosing cholangitis during the cyclosporin-steroid era (March 1980-June 1986) developed intrahepatic biliary strictures in the absence of allograft rejection within the 1st year posttransplantation. Although many causes underlie biliary pathology in the postoperative period (i.e., arterial injury, ischemia, chronic rejection, cholangitis), recurrent disease remains a possibility. © 1988 Springer-Verlag

A. C. Stieber

A. J. Demetris

AJ Demetris

B Portmann

C. O. Esquivel

J Lerut

J Neuberger

J. Lerut

J. W. Marsh

JW Marsh

KA Porter

R. D. Gordon

RH Fennell

S Iwatsuki

S. Iwatsuki

T. E. Starzl

TE Starzl

PubMed

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Intrahepatic bile duct strictures after human orthotopic liver transplantation

Lerut, J

Demetris, AJ

Stieber, AC

Marsh, JW

Gordon, RD

Esquivel, CO

Iwatsuki, S

Starzl, TE

D-Scholarship@Pitt

Transplant Int (1988) 1: 127-130 ~qoAkpmiAkq f'i " ~ International _,0/ © Springer-Verlag 1988 Intrahepatic bile duct strictures after human orthotopic liver transplantation Recurrence of primary sclerosing cholangitis or unusual presentation of allograft rejection? J.Lerut1*, A.J.Demetris2, A.C.Stieber\ J.W.Marsh\ R.D.Gordon\ C.O.Esquivel\ S.Iwatsuki1, and T. E. Starzl1 1 Department of Surgery and 2 Department of Pathology, University Health Center of Pittsburgh, Pittsburgh, PA 15213, USA Abstract. One of 55 patients transplanted for scle-rosing cholangitis during the cyclosporin-steroid era (March 1980-June 1986) developed intrahepatic bil-iary strictures in the absence of allograft rejection within the 1st year posttransplantation. Although many causes underlie biliary pathology in the post-operative period (i. e., arterial injury, ischemia, chronic rejection, cholangitis), recurrent disease re-mains a possibility. Key words: Human orthotopic liver transplantation - Complications - Biliary tract - Primary sclerosing cholangitis - Recurrent disease - Rejection. Biliary tract complications after orthotopic liver transplantation (OLT) are frequent; they are mostly due to inappropriate reconstruction of the extrahe-patic bile duct [1]. Recurrent disease in the allograft is common after OLT in malignant biliary tract dis-ease but is very rare in benign biliary tract disease [2-6]. A patient presenting with a possible recurrent sclerosing cholangitis some months after liver trans-plantation is discussed. Case report On August 21, 1984, a 34 year-old male underwent OLT with a graft of identical blood group, type A, for end-stage primary scle-rosing cholangitis (PSC) (Fig. 1). He had been under medical management for severe ulcerative colitis since the age of 21. His past medical history revealed an uncomplicated cholecystectomy at age 27 and an appendectomy for perforative appendicitis * Present address: Universitatsklinik fUr Viszerale und Transplan-tationschirurgie, Inselspital, Freiburgstrasse, CH-3010 Bern, Switzerland Offprint requests to: T. E. Starzl, Department of Surgery, Falk Clinic 4 West, 3601 Fifth Avenue, Pittsburgh, PA 15213, USA 2 years later. During the latter postoperative recovery he presented with jaundice, attributed to sclerosing cholangitis. Because of persistence of the jaundice, percutaneous biliary drainage was attempted in 1982 and 1983. Finally, a choledocho-jejunostomy was carried out using a transhepatic, trans-anastomotic U-tube, which was removed 4 months later. Re-peated evaluations showed a progressive worsening of the liver disease, justifying a recommendation for treatment by OLT. The cholestasis worsened (total bilirubin, 23 mg%; alkaline phospha-tases, 2020 IU). Osteoporosis was responsible for compression fractures of thoracic vertebrae 8-10 and an aseptic necrosis of the left femoral head. Gastrointestinal bleeding due to portal hyper-tension also occurred. The liver grafting was uneventful: the allograft had a single arterial supply, the liver was reperfused after the completion of all four vascular anastomoses, and cold and warm ischemic times were within normal limits. The former Roux-en-Y-jejunal loop was reused for the end-to-side choledochojejunostomy. The anastomosis was carried out using a 12 French-feeding-tube stent and interrupted, absorbable 5-0 vicryl sutures. An intraoperative cholangiogram showed a normal intra- and extrahepatic biliary tree, an absence of leakage, and a patent anastomosis. The post-operative course was uneventful and the patient was discharged 20 days postsurgery with nearly normal liver function tests (LFT) [total/conjugated bilirubin (hi!. tl conj), 1.7/0.9 mg% ; alkaline phosphatase (alk.phos.) 228 IU; transaminases (SGPT/SGOT), 150125 lUll; Gamma-glutamyl-transpeptidase (G GTP), 64 IU; protime (PT), 11 s]. The rapid postoperative normalization of transaminases precluded major ischemic injury to the allograft during procurement and reimplantation. On January 11, 1985, the patient was readmitted due to ab-normal LFT (hi!. t., 1.4 mg%; alk. phos., 725 IU; SG PT ISGOT, 4001268 lUll; G GTP, 204 IU; PT, 12 s). The patient had no cholestatic symptoms. The biochemical abnormalities were at-tributed to an impaired cyclosporin absorption due to large amounts of diarrhea associated with a flu. Adjustment of the cy-closporin dose almost immediately normalized liver function (hi!. tl conj, 0.5/0.1 mg%; alk. phos., 341 IU; G GTP, 257 IU; SGPT/SGOT, 51128 lUll). A liver biopsy showed early changes of bile duct obstruction, such as duct dilatation, portal edema, marginal duct proliferation, and ductal ectasia. There were no re-markable signs of rejection, viral infection, or drug toxicity. On February 20, 1985, the patient was rehospitalized due to persistent liver function abnormalities in the absence of clinical symptoms (hil.tl conj., 1.8/0.2 mg%; alk. phos., 587 IU; SGPT ISGOT, 462/321 lUll; G GTP, 365 IU; PT, 11.4 s). A liver 128 Bilirubin [mg'I,1 T ransaminases [lUll) 12 10 8 6 4 0 300 250 200 150 100 50 1200 OLT # 431 o sGOT • sGPT Alk. phos.- r- GT 1000 o Alk. phos. • ¥-GT [IU) Creatinine [ mg 'I,) Cy A [mg/kg} Prednisone [ mg) 800 600 400 200 0 1 o 1.2 :t---v;;;;;;;;;;:~1IKf---;:-;:-:~1-1 0.8 0.4 160 120 80 40 l~~~~~~~~~~~ t LTR 10 15 20 1 Postop days 12 16 Postop. months Fig. 1. Biochemical evolution and immunosuppressive regimen of the case report biopsy confirmed changes consistent with biliary obstruction; portal fibrosis had worsened. There were almost no signs of graft rejection. Direct visualization of the biliary system by transhe-patic cholangiography revealed poor filling of the peripheral ducts and alternation of biliary tract strictures and dilatations. The extrahepatic biliary tract and choledochojejunostomy were normal. Brushcytology of the intra- and extrahepatic bile ducts was negative for tumor cells. Repeated Doppler ultrasonography showed normal arterial and venous allograft vascularization. Beginning April 1985 the patient underwent a new transhe-patic cholangiogram due to the development of cholangitis. The anastomosis was widely patent. On April 19, 1985, the stent was removed. A cholangiogram carried out at that time (Fig.2) con-Fig. 2. Percutaneous cholangiogram carried out in March 1985, confirming the peripheral intrahepatic biliary strictures in the presence of a patent biliodigestive anastomosis. The internal stent migrated into the jejunal limb Fig. 3. Needle liver biopsy specimen, showing portal tract with fibrosis, ductular proliferation, and absence of infiltrate as well as of vascular changes (H & E, x 96) firmed peripheral intrahepatic biliary strictures in the presence of a patent choledochojejunostomy. The liver function abnor-malities persisted on different occasions between May 1985 and June 1987 (bil.l., 0.5 mg%; alk. phos., 910 J U; SGPT/ SGOT, 145 / 82 lUl l; PT, 11.7 s). Histological examinations showed pro-gression of the biliary obstruction and advancing portal fibrosis without evidence of graft rejection (Fig.3). On one occasion, a Iymphogranulomatoid nodule was seen near an interlobular bile duct (Fig.4). Portal inOammation was otherwise minimal. More than 3.5 years posttransplantation, the graft is still functioning well, which precludes a further histological examination of the organ as well as modification of the low-dose steroid -cyclosporin therapy. Fig. 4. Allograft liver biopsy ta ken 10 months postoperatively, showing portal fibrosis, mild du ct pro life ra tion and dilation . A sin gle Iymphogranul o mato id inna mmatory aggregate is seen near, but not in volvi ng, a septa l b ile duct (H & E, x 48) All posttra nsplant biopsies were obta ined according to a pro tocol defining the c rit e ria o f a llograft rejection [6J and pre-pa red with hematoxy lin-eosi n stai n (H & E), tri chrome orcei n and rhoda nine. All sp ec imens we re eva lu a ted for c irrhosis, mar-gina l ductula r prolifera tion , gra nul omas , porta l or septa l lymph-oid nodules, the presence a nd loca tion of choles tas is, po rta l and/ or central vein subendothe lia l in fi ltration, mo nonuclea r in-na mmato ry cell damage to bil e ducts, du ctul a r loss, and chronic a rteri a l and / or venous les ions as seen in a llogra ft rejection. Discussion C hanges in the peripheral intrahepatic bile ducts of a liver allograft m ay be the express ion of different phenomena : (a) inadequate liver procurement, (b) inappropriate biliary tract reconstruction or (C) arterialization of the allograft, (d) (chronic) allo-graft rejection, (e) recurrent primary biliary tract disease, and (f) primary or recurrent viral hepatitis (1, 2, 6, 7, 9]. Small intrahepatic ducts may be the primary ta r-get of damaging immune reactions (6, 8]. Rejection can cause rapid destruction of the interlobular bile ducts associated with severe centrilobular choles-tasis, margina l ductular proliferation, and nongran-ulomatous cell inOammation in the portal tracts . This rapidly progressive destruction, consistent with a major clinical and chemical cholestatic picture, has been described as the " va nishing bile duct syn-drome" (8]. These alterations occur in different form s related to different stages of development or to different immunosuppress ive regimens. They may even present as nonsuppurative destructive cholangitis, resembling the changes seen in primary bilia ry cirrhosis (PBq (6, 10]. Only 4 of 604 grafts (0.6%) carried out during the period between March 129 1980 and June 1986 had radiological abnormalities of the intra hepatic bile ducts s imilar to those de-scribed in this case report. These abnormalities oc-curred within the first 12 months after transplanta-tions carried out for a disease not primarily affect-ing the biliary tract. All four patients had histologi-cally proven graft rejection prior to the develop-ment of intrahepatic bilia ry strictures (2]. Recurrent biliary ma lignancy in the allogra ft is common after OLT; however, recurrent, primary, benign biliary tract disease in the allograft is excep-tional (6, 7]. Three cases of poss ible, late recurrence of PBe a fter OLT have been reported , although the changes in the bile duct fell short of those character-istic of PBe [5]. The liver biopsy changes in these pa tients were similar to those seen in chronic, rejec-tion, viral hepatitis, and graft-versus-host disease. Thus, the recurrence of PBe in liver allografts has not formally been proven (5]. This was also con-firmed in our recentl y reviewed series of 76 patients grafted during the period from March 1980 to Sep-tember 1985 for advanced PBe. No instance of re-current PBe was either clinically or histologica lly documented in the 52 surviving recipients with fol-low-ups of 1-6.5 years (3]. During the same period , 55 patients were grafted for primary sclerosing cholangitis (PSC) (4]. Only 1 of 37 surviving recipients with follow-ups of 1- 5 years developed chemica l and radiological ab-normalities of the primary disease 6 months post-transplantation. The first posttransplant biopsy showed minimal or no rejection and early changes in biliary obstruction. In the subsequent percutaneous biopsies, the changes in biliary obstruction and portal fibrosis progressed despite the absen ce of rejection. The paraductal lymphogranulomatoid nodule seen in this case was never observed in our previous trans-pla nt biopsies (6]. Evidence of rejection or hepatitis could not be demonstrated in a ny of the allograft biopsies. The normalization of liver function fol -lowing cyclosporin dose adjustment could be ex-pla ined by a mitigated rejection episode. However, the serial biopsy changes in the absence of allograft rejection are indicati ve of biliary tract pathology that would be consistent with but by no means diag-nostic of recurrent sclerosing cholangitis. It is possible that the etiology of the intrahepatic bile duct strictures in this patient was due to recurrent pse, as no other cause or process capable of caus-ing strictures could be identified. However, since there are so many other causes of biliary strictures and because the diagnosis depends on a clinico-pathological correlation, we ca nnot be certain . This observation suggests that the recurrence of pse in 130 allografts, if possible, is rare. However, chronic allo-graft rejection must be ruled out by serial liver bi-opsies, as peripheral intrahepatic biliary strictures can be an unusual consequence (or some modified form) of graft rejection. In the present case report, the long-term stabilization of the patient's condition as well as of his liver function, despite identically low immunosuppression, argues against this hy-pothesis. References 1. Demetris AJ, Jaffe R, Starzl TE (1987) A review of adult and pediatric post transplant liver pathology. In: Rosen PP, Fech-ner RE (eds) Pathology annual, vol 22. Appleton-Lange, Nor-walk, pp 347-386 2. Esquivel CO, Van Thiel DH, Bernardos A, Demetris AJ, lwatsuki S, Markus B, Gordon RD, Marsh JW, Makowka L, Tzakis A, Todo S, Gavaler J, Starzl TE (1988) Liver trans-plantation for primary biliary cirrhosis. Hepatology 3. Fennell RH, Shires RH, Vierling JH (1983) Relationship of pretransplant hepatobiliary disease to bile duct damage oc-curing in the liver allograft. Hepatology 3: 84-89 4. Iwatsuki S, Starzl TE, Gordon RD, Esquivel CO, Todo S, Tzakis A, Makowka L, Marsh JW, Miller CM (1987) Late mortality and morbidity after liver transplantation. Trans-plant Proc 19: 2373-2378 5. Lerut J, Gordon RD, Iwatsuki S, Shaw BW Jr, Esquivel CO, Tzakis A, Starzl TE (1987) Biliary tract complications in 393 human liver transplantations. Transplantation 43: 47-51 6. MarshJW, Twatsuki S, Makowka L, Esquivel CO, Gor-don RD, Todo S, Tzakis A, Van Thiel D, Starzl TE (1988) Or-thotopic liver transplantation for primary sclerosing cholan-gitis. Ann Surg 207: 21-25 7. Neuberger J, Portmann B, MacDougall B, Caine RY, Wil-liams R (1982) Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 306: 1-4 8. Porter KA (1969) Pathology of the orthotopic homograft and heterograft. In: Starzl TE, Putnam CW (eds) Experience in liver transplantation. Saunders, Philadelphia, pp 422-471 9. Portmann B, Neuberger JM, Williams R (1983) Intrahepatic bile duct lesions. In: Caine RY (ed) Liver transplantation. Grune & Stratton, New York London, pp 279-287 10. Starzl TE, Iwatsuki S, Shaw BW Jr, Gordon RD, Esqui-vel CO, Todo S, Kam T, Lynch S (1985) Factors in the devel-opment of liver transplantation. Transplant Proc 17: 107-119 

Intrahepatic bile duct strictures after human orthotopic liver transplantation - Recurrence of primary sclerosing cholangitis or unusual presentation of allograft rejection?

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Intrahepatic bile duct strictures after human orthotopic liver transplantation - Recurrence of primary sclerosing cholangitis or unusual presentation of allograft rejection?

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