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Ulcerative Colitis After Liver Transplant and Immunosuppression

1999; Lippincott Williams & Wilkins; Volume: 28; Issue: 2 Linguagem: Inglês

10.1097/00005176-199902000-00023

1536-4801

Seema Khan, Steven N. Lichtman, Jorgé Reyes, Carlo Di Lorenzo,

Microscopic Colitis

It has been postulated that inflammatory bowel disease (IBD) occurs because of environmental and host factors that alter immune responses in a genetically susceptible host. Therapy is intended to suppress active inflammation and maintain remission with anti-inflammatory and immunomodulatory agents. The reported incidence of hepatobiliary disorders associated with IBD is 5% to 95% (1). This is a brief report of the development of ulcerative colitis (UC) in three patients who were maintained with immunosuppressive therapy after liver transplant. In this context, the usually implicated immune mechanisms in IBD and possible immune dysregulation after transplantation and administration of immunosuppressive agents is discussed. CASE 1 A 16-year-old girl, 5 years after orthotopic liver transplant for autoimmune hepatitis (AIH), was evaluated for abdominal pain and bloody diarrhea of 2 weeks' duration. Autoimmune hepatitis was diagnosed based on histologic analysis of the hepatectomy specimen, which showed portal-to-portal bridging fibrosis, bile ductular proliferation, and chronic inflammatory cells. Abdominal pain was nondescript, diffuse, and aggravated by meals. Bowel movements occurred four to five times a day, were loose, and contained bright to dark red blood. There was no history of infectious contacts, recent travel, or antibiotic use, but she admitted to stress due to academic examinations. The posttransplant course had been complicated by episodes of graft rejection at 10 days, 7 months, and 10 months, treated by increased immunosuppression. Cytomegalovirus (CMV) status was known to be positive in the donor and negative in the recipient. Within the first year after transplantation, the patient was treated for CMV hepatitis and Clostridium difficile colitis with ganciclovir and metronidazole, respectively. One year after transplantation, posttransplantation lymphoproliferative disorder (PTLD) developed, complicated by bowel perforation. It was treated with acyclovir, ganciclovir, lowering of immunosuppression, and resection of a portion of the mid ileum. She recuperated from these complications and was well until the current manifestations. Her medications were 3 mg tacrolimus twice daily and trimethoprim sulfamethoxazole. On examination she appeared well nourished, with weight of 64.9 kg and height of 165 cm. She had well-healed abdominal surgical scars, generalized deep palpation tenderness, a perianal tag, and guaiac-positive stools. Initial investigations showed mild leukopenia (leukocyte count, 3500/mm3 × 1000); thrombocytopenia (92000 103/mm3); and Epstein-Barr virus (EBV), determined by polymerase chain reaction, of 40 genomes/100,000 lymphocytes (N = none detected). Findings were normal in a liver profile; stool cultures for ova, parasites, and C. difficile toxin were negative; and a computed tomographic scan of the chest and abdomen was normal. On colonoileoscopy, pancolitis and normal terminal ileum were seen. Histologic analysis showed a dense infiltration of plasma cells and lymphocytes mixed with neutrophils and eosinophils, cryptitis, crypt abscesses, reduced number of goblet cells, no granulomas, and scattered EBER (EBV early RNA)-positive cells (Fig. 1). No CMV inclusions were seen. She was treated with ganciclovir and temporary cessation of immunosuppression for suspected PTLD. Findings in a second colonoscopy with biopsies for persistent symptoms 3 weeks later were unchanged. Change in medication to sulfasalazine brought on a gradual resolution of diarrhea and abdominal pain within 3 weeks. Follow-up has lasted almost most 11 months, during which time maintenance immunosuppression therapy has consisted of 1 g sulfasalazine three times daily, 4 mg tacrolimus twice daily, and prednisone tapered to 5 mg every day. Her liver functions have been stable, and there has been no recurrence of UC.FIG. 1: A section of colonic mucosa with in situ hybridization for Epstein-Barr virus showing positive cells (arrows) in the background of diffuse mixed inflammation.CASE 2 A 14-year-old girl exhibited ascites, rapid weight gain, splenomegaly, and pitting edema of lower extremities from ankles to knees. Anti-smooth muscle antibody was 1:1280 (normal, <1:40); immunoglobulin (Ig) G, 4.8 g/dl (normal, 0.3-1.5 g/dl); total protein, 8.6 mg/dl (normal, 5.5-7.5 mg/dl); albumin, 1.6 g/dl (normal, 3.5-5.0 g/dl); prothrombin time, 19 seconds (normal, < 12.8 seconds); aspartate aminotransferase, 150 IU/L (normal, < 50 IU/L); alanine aminotransferase, 188 IU/L (normal, < 50 IU/L), and platelet, 71,000/mm3 (150-300 × 103/mm3). α1-Antitrypsin level; ceruloplasmin; 24-hour urine copper concentration; serum ferritin concentration; hepatitis A, B, and C serologies; antinuclear antibody, antimitochondrial antibody, antiliver kidney-microsomal antibody, and thyroid functions were all normal. Analysis of a liver biopsy specimen showed extensive interlobular fibrosis with hepatocellular degeneration. An endoscopic retrograde cholangiopancreatographic study produced normal findings. Because of an incomplete response to prednisone and azathioprine, evident by persistently elevated liver transaminases and advanced cirrhosis on a second liver biopsy, she eventually received a liver transplant 17 months after the diagnosis was made. One year after transplant, while receiving 7.5 mg prednisone and 75 mg azathioprine daily and 225 mg cyclosporine twice daily, bloody diarrhea developed. Cyclosporine levels ranged between 180 and 275 ng/ml. Stool studies were negative for bacterial enteropathogens, C. difficile, ova, and parasites. The CMV serology was negative for IgM and positive for IgG. A colonoscopy with biopsies that did not include intubation of the terminal ileum showed marked chronic active colitis, crypt abscesses, and crypt branching. No CMV inclusions were seen. With the exception of a mild relapse of colitis treated by increasing the dose of prednisone to 40 mg per day, her symptoms have abated, and she has maintained normal liver enzyme levels. Length of follow-up has been 34 months, and she is presently taking 1 g sulfasalazine and 175 mg cyclosporine twice daily and 100 mg azathioprine daily. CASE 3 A female infant at 20 months of age exhibited jaundice and marked hepatosplenomegaly. A diagnosis of AIH was considered on the basis of a liver specimen that showed fibrosis and piecemeal necrosis. Abnormal laboratory values were total bilirubin, 4.7 (normal, <1.5, mg/dl); direct bilirubin, 3.2 mg/dl (normal, <1 mg/dl); alanine aminotransferase, 190 IU/l (normal, <50 IU/l); aspartate aminotransferase, 174 IU/L (normal, <50 IU/l); γ-glutamyl transpeptidase, 387 IU/L (normal, <39 IU/l); alkaline phosphatase, 480 IU/L (normal, 125-500 IU/l); and prothrombin time, 14.6 seconds (normal, < 12.8 seconds). Results of tests for metabolic defects of amino and organic acids, α1-antitrypsin deficiency, Wilson's disease, bile acid metabolism disorders, and hepatitis B were negative. Elimination of fructose from the diet did not affect her status. Because of a poor response to daily doses of 2 mg/kg prednisone and 1.5 mg/kg azathioprine during the ensuing 2 years, the medications were discontinued. She had recurrent episodes of jaundice characterized by transaminase levels elevated 10-fold, cholestatic enzyme levels elevated 10- to 20-fold, and poor liver synthetic function. A re-evaluation was significant for positive perinuclear antineutrophil cytoplasmic antibodies and small ductal sclerosing cholangitis determined by endoscopic retrograde cholangiopancreatography. At age 13 years she underwent liver transplant. Pathologic analysis of the explant showed micronodular cirrhosis, multifocal loss of ductules, piecemeal necrosis, and parenchymal cholestasis consistent with primary sclerosing cholangitis (PSC). Two months after transplantation, she was treated for CMV antigenemia with ganciclovir and intravenous immunoglobulin. Six months after transplant, bloody diarrhea developed with nocturnal symptoms. At the time, immunosuppression therapy consisted of 5 mg prednisone every other day and 2 mg tacrolimus and 750 mg mycophenolate mofetil twice daily. Serum tacrolimus concentrations varied between 8.4 and 12.9 ng/ml. Infectious causes were excluded by stool studies. A diagnosis of UC was made on the basis of a colonoscopy limited to the colon, showing pancolitis and biopsy findings of chronic active colitis and crypt abscesses. No CMV inclusions were present on biopsy specimens. She has been observed for 6 months and has had no recurrence of UC. Medications include 10 mg prednisone and 50 mg azathioprine daily and 500 mg sulfasalazine and 2 mg tacrolimus twice daily. DISCUSSION The incidence of IBD in the general population is 3 to 20 per 100,000 cases annually (2,3). An alarmingly high incidence (206 in 100,000) of new-onset IBD has been reported in solid-organ transplant recipients (4). Riley et al. (4) described 14 adult transplant recipients with new-onset IBD at a mean of 4 years after transplant while undergoing different immunosuppression regimens. The presentation, immunosuppressive agents, and response to conventional anti-inflammatory therapy in our patients are similar to those in their patients. None of the children we report had a family history of chronic diarrhea, bloody stools, or IBD. Patients 2 and 3 represent the earliest diagnosed cases of IBD after transplant (1 year in patient 2 and 6 months in patient 3). Epstein-Barr virus-associated PTLD was an important consideration in the first case in view of the patient's previous history and EBER-positive cells seen in colonic specimens. The patient's subsequent clinical course marked by clinical improvement in response to azulfidine was more typical of IBD. Although not fully understood, an immune-mediated mechanism is thought to be basic to the cause of IBD. This notion is supported by its association with other disorders with an autoimmune basis. Specifically, the incidences of PSC and AIH in IBD patients are 70% and 13%, respectively (1,5). There is considerable overlap in the clinical, biochemical, immunologic, and histologic features of PSC and AIH. A high prevalence of perinuclear antineutrophil cytoplasm antibodies has been identified in the serum of patients with UC (50-80%); PSC (70%), and AIH (92%) (6). Perdigoto et al. (7) in a review of 12 patients with UC and AIH found cholangiographic abnormalities typical of PSC on re-evaluation in 5 of them. The results of a cholangiogram changed the diagnosis in our patient 3 from AIH to PSC. It appears from reports in the literature that in the context of IBD and associated liver disorders, either disease can remain active or even progress, regardless of the status of the other (8-10). In recent years, new therapeutic methods targeting immune mediators have emerged in the field of autoimmune diseases. In the pathogenesis of IBD, the most important cytokines are interleukin (IL)-1, -2, -6, and -8; interferon-γ and tumor necrosis factor-α produced by activated T-helper lymphocytes. Cyclosporine and tacrolimus are potent immunosuppressive agents that control cytokine production and have been shown to improve disease activity in UC and Crohn's disease (11). Tacrolimus inhibits IL-2 transcription, thereby inhibiting the CD4 T-helper-1 lymphocyte response to foreign antigens (12). It is also selectively inhibits secretion of IL-3, IL-4, and interferon-γ (11). Cyclosporine has comparable actions and inhibits the function of T-helper lymphocytes (13). Based on experience with renal transplants, impaired T-cell IL-10 secretion together with impaired T- and CD4-helper cells may be important in maintaining stable graft function in patients with liver grafts treated with tacrolimus and cyclosporine (14). Interleukin-10 is important in the regulation of proinflammatory cytokines and T-cell responses. Human and murine CD4+ T cells in the presence of IL-10 produce a clone of the CD4+ T-cell subset with low proliferative action, low levels of IL-2, and no IL-4, thus preventing colitis (15). To our knowledge, cytokine profiles in transplant recipients with IBD have not been studied. An imbalance of T-cell types and impaired interleukin responses in susceptible patients with liver grafts may allow IBD to develop. Specifically, CD8 suppressor cells may decrease to a greater extent, thereby increasing the T-helper-T-suppressor ratio. This is based on cases describing an association of IBD disease activity with low CD4 counts and exogenous IL-2 in immunosuppressed patients with HIV and renal cell carcinoma (16,17). In 55 liver transplant recipients with PSC, graft rejection was more frequent and severe in younger patients with associated IBD. In this study there was also a higher incidence of severe acute rejection in patients receiving transplants for immunologic liver diseases (8). Such rejection is characterized by progressive lymphocytic infiltration of the graft and is thought to be T-cell mediated (18). Younger patients had a greater risk of severe rejection, recurrent PSC, and poor control of IBD after transplantation (8). The patients we reported, however, have maintained stable graft function and have not experienced chronic or severe rejection. In summary, these cases describe the unusual development of ulcerative colitis after liver transplantation and immunosuppression therapy. Future research in the immunology of IBD and better characterization of transplant recipients with IBD may answer questions related to its cause in this unique group of patients.