Liver transplantation for primary sclerosing cholangitis

Although the development of interventional radiology and biliary surgical techniques has prolonged the survival time of patients with primary sclerosing cholangitis, liver transplantation remains the only effective treatment for patients with primary sclerosing cholangitis with liver cirrhosis. Several prognostic survival models have been establised for this disease, and the efficacy of actual liver transplantations has been reported in comparison with these survival models. One- and 5-year actuarial patient survivals after liver transplantation for primary sclerosing cholangitis were shown to be greater than and approximately equal to 90%, respectively. An association with cholangiocarcinoma is the most adverse factor affecting survival after liver transplantation for primary sclerosing cholangitis, while the association of inflammatory bowel disease or previous bili-ary surgery does not adversely affect the outcome of the liver transplantation. Recurrent sclerosing cholangitis is an important issue for posttransplant patients with primary sclerosing cholangitis, and occurs in 10%—20% of such patients. Although our understanding of recurrent sclerosing cholangitis is still in the early stages, its potential occurrence indicates the need for a longer follow-up period after liver transplantation.     

Surgical Management of Ulcerative Colitis in the Presence of Primary Sclerosing Cholangitis

INTRODUCTION: The surgical management of ulcerative colitis in the patient with primary sclerosing cholangitis is controversial. METHODS: This study was designed as a retrospective chart review of all patients with primary sclerosing cholangitis who were surgically treated for ulcerative colitis. RESULTS: Sixteen patients with primary sclerosing cholangitis and ulcerative colitis were identified. The indication for ulcerative colitis surgery was dysplasia in 7 patients (44 percent), cancer in 2 (13 percent), intractability in 4 (25 percent), and unknown in 1. Final colon pathology demonstrated cancer in three patients and dysplasia in four. Two patients had biliary cancer discovered at the time of orthotopic liver transplantation. Thirteen patients were known to have primary sclerosing cholangitis when they underwent surgery for ulcerative colitis; two patients with severe primary sclerosing cholangitis underwent simultaneous orthotopic liver transplantation/total abdominal colectomy and did well with subsequent ileal pouch reconstruction. Two patients had orthotopic liver transplantation first and then ileal pouch-anal anastomosis (1 patient) or total abdominal colectomy (1 patient) and did well. Seven patients had well-controlled primary sclerosing cholangitis on medication and underwent ileal pouch-anal anastomosis or total abdominal proctocolectomy without significant hepatic compromise. One patient with moderate primary sclerosing cholangitis underwent ileorectal anastomosis and had severe liver failure postoperatively but survived. Another patient with worsening primary sclerosing cholangitis after total abdominal colectomy has since developed persistent bleeding from peristomal varices. CONCLUSIONS: The overall cancer/premalignant lesion rate was high (50 percent in this study) in patients with primary sclerosing cholangitis and ulcerative colitis. Complications associated with the surgical management of ulcerative colitis are largely dictated by the degree of liver disease present at the time of surgery. Patients with significant primary sclerosing cholangitis that requires colectomy can undergo simultaneous orthotopic liver transplantation/total abdominal colectomy and then be candidates for subsequent ileal pouch-anal anastomosis reconstruction once liver function has improved. Patients with well-controlled primary sclerosing cholangitis can undergo ileal pouch-anal anastomosis surgery safely.     

Surgery for segmental primary sclerosing cholangitis

Primary sclerosing cholangitis is an uncommon chronic hepatobiliary disorder, and the definitive surgical treatment for symptomatic primary sclerosing cholangitis is liver transplantation. Although some cases with primary sclerosing cholangitis treated with hepaticojejunostomy or partial hepatectomy have been reported, the indications for these procedures and their long-term results have not been well defined or studied. We present three patients with segmental primary sclerosing cholangitis, and discuss the indication of surgical treatment for primary sclerosing cholangitis excluding liver transplantation. Three patients with segmental primary sclerosing cholangitis of the common bile duct and the hepatic ducts were treated by hepaticojejunostomy with partial resection of the common bile duct. We investigated clinical features such as angiography, cholangiography, and surgical treatment outcomes. It was difficult to differentiate primary sclerosing cholangitis from a cholangioma preoperatively, despite the use of cytology, angiography, and cholangiography. Two of the three patients were preoperatively suspected to have cholangioma. Segmental primary sclerosing cholangitis was diagnosed operatively. All patients were treated hepaticojejunostomy and achieved long-term survival. Although liver transplantation is the treatment of choice for primary sclerosing cholangitis, in cases of segmental primary sclerosing cholangitis, local resection of the involved structures may be curative. Resection of a discrete lesion may provide many years of survival with a good quality of life, in some cases obviating the need for liver transplantation.     

Primary sclerosing cholangitis

Opinion statement There is no proven medical therapy for primary sclerosing cholangitis. The goal of management should be treatment of symptoms and complications of cholestasis, as well as attempts at treating the underlying disease process. In addition, efforts should be made to recognize and treat or prevent the known complications of primary sclerosing cholangitis, such as fat-soluble vitamin deficiency, osteopenia, dominant biliary strictures, and cholangiocarcinoma. Although some medical therapy has been shown to improve serum liver test or histology results, there has been no effect on survival or time to liver transplantation. However, preliminary data on high-dosage ursodeoxycholic acid have been encouraging. Liver transplantation remains the only effective treatment and is recommended for patients with end-stage liver disease and symptomatic portal hypertension, liver failure, and recurrent or intractable bacterial cholangitis.     

Sclerosing Cholangitis: Pediatric Perspective

Sclerosing cholangitis is a rare progressive cholestatic liver disease affecting the biliary tract. It may be associated with other diseases including autoimmune hepatitis, immunodeficiencies, cystic fibrosis, and sickle cell disease. Sclerosing cholangitis not associated with other diseases is termed “primary sclerosing cholangitis,” which has a strong association with male gender, Caucasian race, and inflammatory bowel disease. Diagnosis is based on typical biochemical, radiologic, and histologic features. Medical management is directed mainly at managing complications (pruritus, cholangitis, strictures, and nutritional deficiencies). Administration of ursodeoxycholic acid results in biochemical improvement, but has not been proven to prolong transplant-free survival. Patients with autoimmune overlap respond to immunosuppression. The disease is typically progressive and evolves to biliary cirrhosis and possibly cholangiocarcinoma. Orthotopic liver transplantation remains the only life-extending alternative for patients with sclerosing cholangitis, with good long-term patient and graft survival, and recurrent graft primary sclerosing cholangitis in about 10% of children.     

Primary Sclerosing Cholangitis: The Emerging Role for Liver Transplantation

Primary sclerosing cholangitis is a progressive liver disease for which orthotopic liver transplantation is the only curative procedure. Questions exist regarding the role of temporizing procedures and the timing of transplantation. During the past 4 yr, we have performed liver transplants in 177 adult recipients. Twenty-six patients (14.6%) with primary sclerosing cholangitis received 30 transplants including 12 men and 14 women. The recipients were examined for a number of preoperative and postoperative variables. The 4-yr actuarial survival in patients with primary sclerosing cholangitis after transplantation was 88%. Patients were segregated according to preoperative risk variables. Twenty patients were low and medium risk, with one death (95% survival). Three patients were high risk, with two deaths (33% survival). In conclusion, orthotopic liver transplantation is safe and effective therapy for primary sclerosing cholangitis. Early referral for transplantation is recommended to reduce the mortality associated with this procedure in those with advanced hepatic failure.     

Recurrence of primary biliary cirrhosis, autoimmune cholangitis and primary sclerosing cholangitis after liver transplantation

Given the usually prolonged natural history of primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis, and the relatively recent introduction of orthotopic liver transplantation, our understanding of recurrence of these autoimmune diseases after orthotopic liver transplantation has been slow to evolve. Present data suggest that after orthotopic liver transplantation, patients with primary biliary cirrhosis will have persistence of serum antimitochondrial antibodies, develop histologic lesions suggestive of recurrent primary biliary cirrhosis with a frequency in the 8% to 16% range at 2 to 5 years after orthotopic liver transplantation, but will demonstrate little if any symptomatic disease as a consequence. Although data are extremely limited, autoimmune cholangitis patients will have a similar post-transplant course (without antimitochondrial antibodies). Recurrence of primary sclerosing cholangitis remains the most controversial, however, these patients probably develop nonanastomotic intrahepatic and extrahepatic strictures more frequently than patients without primary sclerosing cholangitis, with a frequency in the 20% to 25% range at 3 to 5 years. With longer patient follow-up and additional studies, it is hoped that our understanding of recurrent autoimmune biliary diseases will grow considerably in the future.     

Etiology and natural history of primary sclerosing cholangitis

The etiology of primary sclerosing cholangitis remains unknown. Bacteria, toxins, viral infections, and immunological and genetic factors have all been proposed as etiological agents. Portal bacteremia, toxins absorbed from the diseased colon in inflammatory bowel disease, and cytomegalovirus and reovirus infections have been implicated by various investigators but there is little evidence to support these hypotheses. The close association between primary sclerosing cholangitis and various human leukocyte antigen haplotypes is now well established and lends support to the theory that immunologic and genetic mechanisms may be involved in its pathogenesis. Patients with primary sclerosing cholangitis may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ specific autoantibodies. The association between ulcerative colitis and primary sclerosing cholangitis remains unexplained and both groups of patients have a high prevalence of antibodies to the perinuclear cytoplasmic antigen. The long-term prognosis in primary sclerosing cholangitis is tempered by the development of cholangiocarcinoma in 6%—30% of patients when followed over long periods of time. Detecting cholangiocarcinoma early in a patient with primary sclerosing cholangitis is one of the most frustrating problems faced by a clinician while caring for these patients. The long-term outlook for patients with primary sclerosing cholangitis and cholangiocarcinoma remains dismal, whatever the treatment modality employed. However, the development of a multivariate statistical survival model from long-term survival data from the Mayo Clinic and other centers has been a major step in identifying individual primary sclerosing cholangitis patients at low, moderate, and high risk of dying. Such models have been useful for stratifying patients in therapeutic trials, for in patient counseling, and in patient selection and timing of liver transplantation.     

Outcome of Patients Undergoing Liver Transplantation for Primary Sclerosing Cholangitis

PURPOSE: The purpose of this study was to determine the outcome of patients with inflammatory bowel disease who underwent liver transplantation for primary sclerosing cholangitis. METHODS: All patients who underwent liver transplantation for primary sclerosing cholangitis at our institution were identified. A review of patients hospital and office charts was performed; all patients were then contacted, and a detailed survey was administered by telephone. RESULTS: Sixty-nine patients were identified. There were 53 males (76.8 percent) and 16 females, with a mean age of 45.3 (± 13.3) years. Fifty-two (75.4 percent) of the 69 patients had documented inflammatory bowel disease; of these, 40 had ulcerative colitis (76.9 percent), 11 had Crohns disease, and 1 had indeterminate colitis. Thirty-one patients (60 percent) were diagnosed with inflammatory bowel disease before primary sclerosing cholangitis, with a mean interval to diagnosis of primary sclerosing cholangitis of 10.8 (± 10.3) years. Seven patients had both diagnoses made at roughly the same time, and 14 patients initially were diagnosed with primary sclerosing cholangitis and subsequently were found to have inflammatory bowel disease, with a mean interval of 5.2 (± 4.4) years; 5 (35.7 percent) of those 14 patients were only diagnosed with inflammatory bowel disease after their liver transplant. The mean time from diagnosis of primary sclerosing cholangitis to liver transplantation was 6.1 (± 4.9) years. Since their transplant, 30.8 percent of patients rated their colitis as worse, 38.5 percent felt it was unchanged, and 30.8 percent felt that their colitis was better controlled. Eight (15.4 percent) of the 52 patients with inflammatory bowel disease denied having any knowledge of an increased risk of colorectal neoplasia. Four patients have required colectomy for colorectal neoplasia after liver transplantation, at a mean of 4.7 years after transplantation. Of the patients with inflammatory bowel disease, 42 (80.1 percent) had at least 1 posttransplant surveillance colonoscopy. Eight of the remaining ten patients had a colectomy, leaving only two patients (3.8 percent) who had not been surveyed. However, only 32 (61.5 percent) of the patients with inflammatory bowel disease have been on a surveillance regimen that would approximately conform to current screening recommendations. CONCLUSIONS: The activity of inflammatory bowel disease after transplantation is highly variable. Patients appeared to lack knowledge of their increased risk for colorectal neoplasia. Colorectal cancer is an uncommon but important complication in patients after liver transplantation for primary sclerosing cholangitis, and ongoing surveillance is required. Patients may require education to increase their awareness of the cancer risk and compliance with surveillance.     

Primary biliary cirrhosis and primary sclerosing cholangitis

Primary biliary cirrhosis and primary sclerosing cholangitis are the most common chronic cholestatic liver diseases in adults that lead to biliary cirrhosis and its inherent complications such as portal hypertension and liver failure. Although important advances in the understanding of the pathogenesis of these conditions have been accomplished in the last two decades, much work is needed to uncover the interaction of genetic and immunologic mechanisms involved in their pathogenesis. Ursodeoxycholic acid at dosage of 13 to 15 mg/kg/d is the only agent that can currently be recommended in the treatment of PBC. No medical therapy aimed at disrupting disease progression is available for patients with primary sclerosing cholangitis, although several agents with different properties are currently under evaluation. Liver transplantation is the treatment of choice for patients with primary biliary cirrhosis and primary sclerosing cholangitis with end-stage liver disease.     

Advances in primary sclerosing cholangitis

Primary sclerosing cholangitis is an increasingly recognized chronic cholestatic liver disease. It frequently occurs in association with chronic ulcerative colitis and is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The cause is unknown, although many mechanisms have been considered, including infectious, toxic, and immunologic. The prognosis varies. No adequate treatment exists, although a number of potential treatments have been evaluated in uncontrolled trials, and the results of controlled trials have only recently been reported. Liver transplantation has recently been shown to be an effective treatment for end-stage disease. These various advances in our understanding of primary sclerosing cholangitis are reviewed.     

Medical Problems Occurring After Orthotopic Liver Transplantation

Liver transplantation is complicated by specificmedical problems. Diabetes mellitus occurs in 4-20% ofpatients undergoing liver transplantation. Patients withprimary sclerosing cholangitis and ulcerative colitis experience up to a 13% incidence ofcolon cancer after transplantation. Lymphomas occur in1-3% of patients after transplantation and account for57% of malignancies occurring in adult patients. Atraumatic bone fractures occur in 22-38% ofpatients and neurological complications, includingseizures, headache, and neuropathy occur in 19-47% ofpatients following liver transplantation. Patients undergoing liver transplantation may experiencerecurrence of their primary liver disease: hepatitis B,hepatitis C, primary biliary cirrhosis, autoimmunehepatitis, or primary sclerosing cholangitis. In patients not receiving immunoprophylaxis aftertransplantation for chronic hepatitis B, recurrenthepatitis B is seen in up to 90% of patients. This canbe markedly reduced with hyperimmune globulinimmunoprophylaxis. Recurrent hepatitis C is seen in the majorityof patients; current treatment modalities areinadequate. Recurrence of primary biliary cirrhosis orprimary sclerosing cholangitis in the allograft isinfrequent. Autoimmune hepatitis may recur in up to 26% ofpatients following liver transplantation. Primarydisease recurrence in the allograft and preventivestrategies are discussed.     

Medical and endoscopic treatment in primary sclerosing cholangitis

Primary sclerosing cholangitis is an important cause of chronic cholestatic liver disease. The aetiology is still unknown and an immunological basis is discussed. The disease results in diffuse narrowing and irregularities of intra- and extra-hepatic bile ducts that may lead to biliary cirrhosis. Progression of the disease is highly variable and fluctuating. An important issue is the risk for developing cholangiocarcinoma. For end-stage disease liver transplantation is the only therapeutic option. If strictures of the extra-hepatic bile ducts are demonstrable, endoscopic interventions are effective palliative treatment options. The use of immunosuppressive or anti-inflammatory drugs has been shown to have no influence on the course of primary sclerosing cholangitis.     

Sarcoidosis mimicking primary sclerosing cholangitis requiring liver transplantation

Sarcoidosis is a systemic granulomatous disease of unknown etiology. The association of the cholestatic pattern usually seen in sarcoidosis, with biliary duct changes resembling primary sclerosing cholangitis (PSC) is rare. Liver transplantation permits the histological evaluation of the complete explanted liver, making the diagnosis more reliable. In conclusion we present our experience with two patients with sarcoidosis requiring liver transplantation, who presented with clinical and radiological findings characteristics of primary sclerosing cholangitis.     

Pouchitis Disease Course after Orthotopic Liver Transplantation in Patients with Primary Sclerosing Cholangitis and an Heal Pouch-Anal Anastomosis

Objective: Primary sclerosing cholangitis is associated with the development of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. This study determined the effect of liver transplantation for primary sclerosing cholangitis on the disease course of pouchitis.
Methods: Seven patients with an ileal pouch-anal anastomosis for ulcerative colitis underwent liver transplantation for primary sclerosing cholangitis. The medical record was reviewed to determine the pouchitis activity and pattern (no pouchitis, single acute, recurrent acute, chronic) before and after transplantation.
Results: Five of seven patients had pouchitis before transplant [recurrent acute (n = 3), chronic (n = 2)], and four of those five continued to have pouchitis after transplant (all chronic). Pretransplant sera were positive for antineutrophil cytoplasmic antibody in 6/6 patients, compared to 5/6 patients posttransplant. One patient with pouchitis pre-transplant became negative for antineutrophil cytoplasmic antibody posttransplant but continued to have pouchitis.
Conclusion: Pouchitis occurs frequently in patients with primary sclerosing cholangitis and an ileal pouch-anal anstomosis for ulcerative colitis. Liver transplantation does not alter the disease course of pouchitis for most of these patients.     

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease

We identified and analyzed 45 patients with asymptomatic primary sclerosing cholangitis to better understand the natural history of this disease. Disease progression was monitored at regular intervals for the development of symptoms and physical signs as well as changes in liver biochemistry, cholangiography, and liver histology. During a median follow-up of 75.2 mo, 34 patients (76%) had evidence of disease progression. Fourteen patients (31%) developed liver failure which resulted in death or referral for liver transplantation. For patients with primary sclerosing cholangitis, survival curves computed using the Kaplan-Meier method were significantly worse than expected when compared to age-, sex-, and race-specific survival rates for the United States north central population (p less than 0.001). These findings indicate that primary sclerosing cholangitis is generally a progressive disease with considerable morbidity and mortality even when detected before the onset of symptoms.     

Treatment of primary biliary cirrhosis and primary sclerosing cholangitis: Use of ursodeoxycholic acid

Considerable progress has been made in the management of cholestatic liver diseases during the past decade. Various therapeutic agents have been proposed and evaluated for treatment of patients with primary biliary cirrhosis and primary sclerosing cholangitis. These treatments include ursodeoxycholic acid plus immunosuppressive and antiinflammatory drugs such as glucocorticoids, azathioprine, colchicine and methotrexate. Although these two diseases are grouped together as chronic cholestatic liver diseases, there are important differences between them, particularly with respect to response to treatment. Primary biliary cirrhosis responds much better to medical treatment. Ursodeoxycholic acid has emerged as the most commonly used medication in the treatment of these diseases. Ursodeoxycholic acid therapy is safe and has been associated with improvement of biochemical test results for liver function in patients with primary biliary cirrhosis and primary sclerosing cholangitis. However, questions remain about the long-term efficacy of the drug in halting histologic progression, although ursodeoxycholic acid does improve survival without the need for liver transplantation after 4 years of treatment in patients with primary biliary cirrhosis. Ursodeoxycholic acid is unproven in the treatment of primary sclerosing cholangitis.     

A case of sclerosing cholangitis showing response to prednisolone]

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibrosis and destruction of intra- and extrahepatic bile ducts resulting in hepatic failure and death. Only the liver transplantation is the possible treatment for patients to survive. There has been a few reports that steroid is an effective treatment in autoimmune variant sclerosing cholangitis, which is thought to be a familial diseases with different etiology, and steroid responsive biliary strictures be named as immunoglobulin G4 (IgG4)-associated cholangitis (IAC). There is no reliable data regarding effective steroid treatment in autoimmune variant sclerosing cholangitis in Korea. We report a case of 32-year-old male with sclerosing cholangitis, who was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) and liver biopsy, showing favorable response to prednisolone therapy.     

Infliximab for ulcerative colitis following liver transplantation

Primary sclerosing cholangitis is a chronic cholestatic disease with a progressive course, often culminating in hepatic transplantation. When associated with primary sclerosing cholangitis, ulcerative colitis commonly follows a mild course before, but a more progressive course following liver transplantation, with a significant proportion of patients becoming steroid dependent and/or requiring colectomy. We report the first case demonstrating the efficacy and safety of infliximab therapy for ulcerative colitis following hepatic transplantation.