Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases

OBJECTIVE: We report five cases (four male; median age 20 yr, range 14-38 yr) of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. The patients presented with jaundice, elevated serum aminotransferase and alkaline phosphatase activities, hyperglobulinemia with high immunoglobulin G (IgG) levels, circulating antinuclear and/or smooth muscle autoantibodies (> or = 1:40), and moderate to severe interface hepatitis on liver biopsy (with biliary features in four). METHODS: All five fulfilled criteria for diagnosis of "definite" autoimmune hepatitis and showed marked responses to prednisolone and azathioprine therapy, with relapses occurring during reduction or withdrawal of treatment. Cholangiographic features of primary sclerosing cholangitis were found in three patients at presentation and after intervals of 7 and 14 yr in the other two. Only two had evidence of inflammatory bowel disease. Diagnostic criteria for identifying those patients who may benefit from immunosuppressive therapy were reviewed. RESULTS: Review of the literature revealed only 11 similar cases that were sufficiently well described for comparison. However, in contrast to these and the present cases, preliminary data from other studies have suggested a marked association with ulcerative colitis and a poor response to immunosuppressive therapy. CONCLUSIONS: It is recommended that the possibility of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome responsive to immunosuppressive therapy should be considered in any patient presenting with a hepatitic illness with hyperglobulinemia, antinuclear or smooth muscle autoantibodies, and biliary changes on liver biopsy. Cholangiography should be considered in such patients.     

Cytokine production from colonic T cells in patients with ulcerative colitis with and without primary sclerosing cholangitis

PURPOSE: Only five percent of all patients with ulcerative colitis develop primary sclerosing cholangitis. T cells accumulate at the sites of the colonic and bile duct inflammation in both ulcerative colitis and primary sclerosing cholangitis. T helper cell populations comprise functionally distinct subsets characterized by the cytokines they produce. Several alterations in cytokine production have been described in patients with ulcerative colitis. The aim of this study was to investigate possible differences in T helper subsets and cytokine production in peripheral blood and colonic mucosa among ulcerative colitis patients with and without primary sclerosing cholangitis. METHODS: Eleven patients with primary sclerosing cholangitis and extensive ulcerative colitis, 11 patients with extensive ulcerative colitis and no liver disease, and 5 patients without any history of liver disease who underwent routine colonoscopy because of previous polypectomy were included in the study. Colonoscopy with multiple biopsies was performed on all patients. Lamina propria mononuclear cells and peripheral blood mononuclear cells were isolated. A modified version of solid-phase enzyme-linked immunospot assay was used for the separate counting of cells producing interferon-gamma, interleukin-2 (T helper 1), and interleukin-4 (T helper 2). RESULTS: No differences in spontaneous production of cytokines from peripheral blood mononuclear cells was found among the three groups. Patients with primary sclerosing cholangitis compared with patients with ulcerative colitis without liver disease showed a significant increase in the number of cells secreting interferon-gamma after purified protein derivative stimulation (P < 0.02). More cells secreting interferon-gamma were found in the two ulcerative colitis groups than in the cell populations from healthy controls (P < 0.03). The number of cells secreting interferon-gamma in the primary sclerosing cholangitis group was significantly lower than in the ulcerative colitis group without liver disease (P < 0.04). The number of cells secreting interleukin-4 was lower in the primary sclerosing cholangitis group than among the patients with ulcerative colitis only (P = 0.05). CONCLUSION: Isolated lymphocytes from colonic mucosa differ in cytokine production in patients with ulcerative colitis with and without primary sclerosing cholangitis.     

What is the association of primary sclerosing cholangitis with sex and inflammatory bowel disease in Turkish patients?

BACKGROUND/AIMS: In the Western world, primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is associated with inflammatory bowel disease (IBD), particularly chronic ulcerative colitis and, to a lesser degree, Crohn's disease. The goal of this study was to determine the prevalence of PSC in Turkish patients with IBD and chronic amebic colitis, a disease that is endemic in Turkey. METHODOLOGY: During a 10-year period, between 1986 and 1996, a total of 81 IBD (64 ulcerative colitis and 17 Crohn's disease) patients and 127 patients with chronic amebic colitis were seen and evaluated with radiologic, serologic, immunologic and pathologic tests. Whenever a clinical or biochemical finding suggested the presence of co-existent hepatic and/or biliary disease, the patient was further evaluated by liver biopsy, auto-antibodies and endoscopic retrograde cholangiopancreatography (ERCP) to determine whether they also had PSC or some other form of liver disease. As a disease control group, a total of 752 patients with clinical and/or laboratory evidence of pancreaticobiliary disease were also studied. In 86 of these 752 patients (10%), a primary disorder of the biliary tree was diagnosed by ultrasonography, computed tomography, peritoneoscopy, liver biopsy, ERCP and abdominal laparotomy. In addition, all 86 patients of the control group were evaluated endoscopically in order to determine whether they had any associated gastrointestinal condition of the upper or lower gastrointestinal tracts. After establishing final diagnoses of IBD, amebic colitis and PSC, these patients were evaluated with respect to their socio-economic status. A high protein diet (1.8 gram/kg/day) was administered to those patients with chronic amebic colitis and IBD during the active period of the disease. RESULTS: Of the 208 patients (81 with IBD and 127 with chronic amebic colitis), no cases of PSC were identified. Of the 86 patients in the control group with primary biliary tract disease, 45 had a biliary system malignancy, 14 had primary biliary cirrhosis (PBC), 16 had PSC, 3 had Caroli's disease, 6 had a common bile duct cyst, and 2 had gallbladder adenomatosis. All but 1 of the 16 patients with PSC were female. CONCLUSIONS: These data suggest that, in contrast to findings in Western Europe and the USA, in Turkey: 1) PSC is not regularly associated with idiopathic IBD; 2) most patients with PSC are female; 3) PSC accounts for only 18% of patients with a primary disorder of the biliary tree; 4) the incidence of small-duct primary sclerosing cholangitis is greater than that reported in the literature; and, 5) the incidence of IBD and PSC in Turkey is relatively lower than in other countries.     

Sclerosing cholangitis, race and sex

BACKGROUND: Primary sclerosing cholangitis develops in 3-10% of patients with ulcerative colitis, and may be associated with an increased cancer risk. Ulcerative colitis is probably less common in people of African origin than in populations of European descent. AIMS AND METHODS: To review the records of all patients under regular follow up for ulcerative colitis at St Bartholomew's Hospital (London, UK), a tertiary referral centre, prompted by discovering a cluster of cases with common features. RESULTS AND CONCLUSIONS: Among 166 patients with ulcerative colitis under regular follow up, only four (all women) are of African or Caribbean genetic origin, and three of these have developed sclerosing cholangitis within three years of presentation with colitis, compared with four of 162 patients of European or Asian descent (odds ratio 119, 95% confidence interval 8-3837; p = 0.0002). This cluster, which is not explained by common HLA DR or DQ type, suggests that Africans and Afro-Caribbeans, especially women, may be at increased risk of sclerosing cholangitis. This may reflect genetic influences on the development of enteric and hepatobiliary inflammatory disease.     

Small bile duct abnormalities and chronic intrahepatic cholestasis in Beh?et's syndrome

A 42-year-old man with Beh?et's disease of the intestinal type and a chronic cholestatic profile is presented. He had oral aphthea, genital ulcer, erythema nodosum, thrombophlebitis and central retinitis during the clinical course. Deep ileal ulcers recurred with massive bleeding and perforation. Cholestatic laboratory findings were also noted in the clinical course. A biopsied liver specimen, taken at the second operation for the ileal ulcer, showed chronic portal inflammation associated with ductopenia and epithelial degeneration of the small interlobular bile ducts, but periductal concentric fibrosis was not found. The patient died of sepsis 7 months after the last laparotomy. Although there was no significant abnormality in the large biliary tract at autopsy, pericholangitis in the small portal tracts and cholestasis were pronounced. Sclerosing cholangitis is one of well-known complications of ulcerative colitis or Crohn's disease. We report herein another rare association of small bile duct damage resembling sclerosing cholangitis with enteritis in Beh?et's disease.     

Primary sclerosing cholangitis--an ulcerative colitis-associated illness with surgical consequences

Primary sclerosing cholangitis (PSC) is generally associated with ulcerative colitis (UC). The disease typically progresses slowly, but ultimately, and leads to cirrhosis, liver failure or bile duct cancer. PSC patients with simultaneous ulcerative colitis are also at higher risk for colorectal cancer. At the present time, there is no effective treatment for PSC, although preliminary data show encouraging results after treatment with ursodeoxycholic acid. However, there are no data concerning the delay or prevention of progress of the disease with this drug, because follow-up time is not yet long enough. Isolated bile duct strictures should be treated endoscopically. The possible effect of proctocolectomy on the course of PSC is controversial. Liver transplantation is the therapy of choice for PSC in its final stage. The 5-year survival rate (89%) is significantly better than after transplantation for other indications. Patients with ulcerative colitis have to be followed up by lifelong colonoscopy. Although the course of UC after transplantation is mostly asymptomatic, these patients are at higher risk for colorectal cancer.     

Possible cholestatic injury from ranitidine with a review of the literature

BACKGROUND: Controversy persists regarding primary sclerosing cholangitis (PSC) as a risk factor for colorectal carcinoma in patients with chronic ulcerative colitis. Small sample size and differing endpoints have contributed to variation among reported studies. This large case-control study was conducted to examine the possible association between PSC and colon carcinoma in patients with ulcerative colitis. METHODS: From Mayo Clinic records spanning 1976-1994, 171 cases with both ulcerative colitis and colorectal carcinoma and 171 contemporaneous controls with ulcerative colitis but no colorectal neoplasia matched with regard to age, gender, extent, and duration of colitis were identified. The diagnosis of PSC required cholangiographic confirmation. Analysis employed a multivariate logistic regression model. RESULTS: The prevalence of PSC was similar in cases (18%) and controls (15%) (P = 0.54). The adjusted odds ratio for colorectal carcinoma with PSC was 1.23 (95% confidence interval, 0.62-2.42). CONCLUSIONS: Based on this large case-control study, there was no association between PSC and colorectal carcinoma in patients with ulcerative colitis.     

Bile duct carcinoma associated with chronic ulcerative colitis

Patients with chronic ulcerative colitis are prone to a variety of liver disorders. This case report illustrates development of bile duct carcinoma in a patient with long-standing inactive colitis. The report emphasizes the association of chronic ulcerative colitis with bile duct carcinoma and discusses the radiologic preoperative evaluation of the ulcerative colitis patient who develops jaundice.     

p53 and Bax activation in 6-hydroxydopamine-induced apoptosis in PC12 cells

We report a patient with Sj?gren's syndrome and multiple gastrointestinal manifestations who successfully responded to therapy with ursodeoxycholic acid. Our patient had sialoadenitis with dry mouth, dry eyes, arthralgia, chronic pancreatitis, sclerosing cholangitis, and pulmonary infiltrations. The first signs of disease were the symptoms of chronic pancreatitis followed by icterus, caused by extrahepatic bile duct obstruction. Sclerosing cholangitis was diagnosed by liver biopsy and endoscopic retrograde cholangiography. Sialoadenitis, causing dry mouth, was verified by buccal biopsy. Pulmonary infiltrations were seen on standard chest x-ray, and also shown by high-resolution computed tomography examination. Obstructive icterus and even pulmonary infiltration responded successfully to treatment with ursodeoxycholic acid.     

Liver transplantation in a 29-year-old patient with gallbladder carcinoma complicating primary sclerosing cholangitis

Patients with primary sclerosing cholangitis (PSC) are at increased risk for cholangiocarcinoma. This tumor usually is a fatal complication, median survival after diagnosis is less than six months. In an asymptomatic 29-year-old patient with long-standing PSC and ulcerative colitis, routine abdominal ultrasound demonstrated an irregular mass, 11 x 13 mm, in the gallbladder. Cholecystectomy was performed, and histological examination demonstrated a moderately differentiated adenocarcinoma with infiltration of all layers of the gallbladder and invasion of local lymphatic vessels. Extensive diagnostic work-up failed to consistently demonstrate metastatic disease, and the patient was offered a liver transplantation. 24 months after the operation, the patient feels well and there is no indication of tumor recurrence. In carefully selected patients with gallbladder carcinoma complicating PSC, liver transplantation may be a therapeutic option.     

Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy for symptomatic choledocholithiasis after recent myocardial infarction

In the general population, endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy is preferable to surgery as therapy for gallstone pancreatitis and acute cholangitis. It is particularly attractive to perform therapeutic. ERCP for symptomatic choledocholithiasis after recent myocardial infarction because of the increased risk of the alternative therapy of cholecystectomy and choledochal exploration. However, after myocardial infarction, patients might theoretically be particularly susceptible to the cardiopulmonary risks of ERCP. The safety of therapeutic ERCP after myocardial infarction is unknown, with only one previously reported case. In a review of 11,367 patients with acute myocardial infarction at four hospitals, four patients (0.04%) underwent therapeutic ERCP after recent myocardial infarction, for indications of recent biliary pancreatitis in three of the patients and recent cholangitis in all four. Cholangitis occurred before, simultaneous with, or after myocardial infarction in the four cases. Initially, the cholangitis was managed medically in three patients. The fourth patient underwent cholecystostomy with local anesthesia. ERCP was performed at 15, 25, 30, or 56 days after myocardial infarction. Endoscopic cholangiography revealed multiple choledocholithiasis in all cases. The calculi were successfully extracted by endoscopic papillotomy and by sweeping the choledochus with a balloon-tipped catheter or basket in all cases. During ERCP, the vital signs remained stable; no cardiac arrhythmias or cardiovascular complications occurred. However, one patient developed mild pancreatitis after ERCP, which rapidly resolved with medical therapy. The four patients rapidly improved after ERCP, with normalization of serum levels of routine biochemical parameters of liver function. These four cases and the one prior case report demonstrate that therapeutic ERCP is not absolutely contraindicated after myocardial infarction and suggest that therapeutic ERCP is preferable to surgery for symptomatic choledocholithiasis after myocardial infarction because of the increased mortality of surgery after myocardial infarction.     

Sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease whose aetiopathogenesis is unknown. PSC is frequently associated with inflammatory bowel disease, in particular chronic ulcerative colitis, is most commonly observed in young males and is clinically characterized by fatigue, pruritus and jaundice. The diagnosis is supported by a cholestatic biochemical profile and histological abnormalities, and confirmed by visualization of an abnormal biliary tree. The natural history of the disease is currently being evaluated but is generally recognized to be slowly progressive, leading to complications of chronic cholestasis, portal hypertension and biliary cirrhosis. There is no specific medical treatment, and orthotopic liver transplantation remains the only definitive treatment for patients with end-stage PSC. A more rational approach to medical therapy will ensue upon a better understanding of the aetiopathogenesis of this disease.     

Complete heteronuclear NMR resonance assignments and secondary structure of core binding factor beta (1-141)

We report a patient who developed significant liver dysfunction following therapy with terbinafine. At the end of a 3 1/2-wk course of terbinafine, he developed progressive jaundice and pruritus. His serum bilirubin peaked at 30.9 mg/dl 3 wk after discontinuing terbinafine. A liver biopsy revealed mild to moderate mixed cellular infiltrate in the portal tracts, and hepatocellular and canicular cholestasis. His liver tests normalized 100 days after stopping terbinafine.     

Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis

Treatment of patients with cholestatic liver diseases with ursodeoxycholic acid has been shown to have beneficial effects that may be related to a shift in the balance between hydrophilic and hydrophobic bile acids in favor of hydrophilic bile acids. During treatment of patients with primary sclerosing cholangitis with ursodeoxycholic acid, plasma concentrations of some endogenous bile acids decrease. To test whether the changes in plasma bile acids are due to decreases of their pool sizes or synthesis rates, we determined bile acid kinetics of cholic and chenodeoxycholic acid in six patients with primary sclerosing cholangitis, of whom four also had ulcerative colitis. All patients were studied before and 3 mo after the start of ursodeoxycholic acid treatment. Six healthy subjects served as controls. In patients with primary sclerosing cholangitis, pool sizes of cholic and chenodeoxycholic acid were considerably smaller than those in healthy controls; after ursodeoxycholic acid treatment they were unchanged. Fractional turnover and synthesis of cholic acid increased significantly after ursodeoxycholic acid administration. Fractional turnover of chenodeoxycholic acid also increased significantly, whereas synthesis of this bile acid was unchanged. Our data indicate that in patients with primary sclerosing cholangitis, pool sizes of bile acids are reduced. The decrease of levels of endogenous bile acids in plasma under ursodeoxycholic acid treatment despite unchanged bile acid pool sizes indicates redistribution of the bile acids into the enterohepatic circulation, probably because of improved hepatic clearance after ursodeoxycholic acid treatment.     

Pericholangitis and sclerosing cholangitis are risk factors for dysplasia and cancer in ulcerative colitis

Known risk factors for the development of dysplasia and cancer in ulcerative colitis (UC) patients are: 1) increased extent and duration of disease and 2) increased age at symptom onset. This case-control study was performed to determine whether cholestatic liver disease is associated with neoplastic transformation. Twenty-nine UC patients with extensive disease of long duration and dysplasia or cancer detected in a cancer surveillance program were pair-matched to UC patients without neoplasia from a large inflammatory bowel disease registry matched on extent of disease, sex, and calendar year of disease onset. Of the 29 cases, 10 were found to have cholestatic liver disease; nine with pericholangitis and one with primary sclerosing cholangitis (PSC). Two controls had PSC. Cholestatic liver disease was a significant risk factor for the development of dysplasia or cancer (odds ratio 9.00, 95% confidence interval 1.14-71.0). Increased age at symptom onset also was found to be a significant risk factor for neoplasia (odds ratio 1.04 for each additional year, 95% confidence interval 1.00-1.08) that did not exhibit confounding or interacting effects with cholestatic liver disease. The degree of neoplasia (low-grade dysplasia, high-grade dysplasia, or cancer) did not appeared to affect the results. Therefore, cholestatic liver disease, either pericholangitis or PSC, was significantly associated with the development of dysplasia or cancer in UC patients and should be considered an important risk factor for neoplastic transformation.     

Bone disease in patients with primary sclerosing cholangitis: prevalence, severity and prediction of progression

BACKGROUND/AIMS: Osteopenia is a common complication in some chronic cholestatic liver diseases. Our aims were to determine the prevalence and severity of bone disease in patients with primary sclerosing cholangitis; and identify risk factors to predict the presence and progression of osteopenia. METHODS: Eighty-one patients involved in a randomized trial of ursodeoxycholic acid were analyzed. Bone mineral density of the lumbar spine was determined at entry and at annual intervals. RESULTS: Bone mineral density of the lumber spine in primary sclerosing cholangitis patients was significantly lower than expected when compared to normal values adjusted for age, sex and ethnic group at entry (p<0.005), and after 1 year (p<0.05), 2 years (p<0.05), 4 years (p<0.005) and 5 years of follow-up (p<0.005). Seven patients (8.6%) had bone mineral density of the lumber spine below the fracture threshold at entry. These patients were significantly older, had a longer duration of inflammatory bowel disease and more advanced primary sclerosing cholangitis. The rate of bone loss in primary sclerosing cholangitis patients and expected in normal controls was 0.01+/-0.02 g x cm(-2) x year(-1) and 0.003+/-0.003 g x cm(-2) x year(-1), respectively (p = NS), and was similar in patients receiving placebo and ursodeoxycholic acid. Age was the only variable inversely related with baseline bone mineral density of the lumber spine (p<0.0001). None of the variables predicted progression of the bone disease. CONCLUSIONS: Severe osteoporosis occurs in few patients with primary sclerosing cholangitis, but it should be suspected in patients with longer duration of inflammatory bowel disease and more advanced liver disease. Its presence, severity and progression cannot be accurately evaluated by routine clinical, biochemical, or histological variables. Ursodeoxycholic acid does not affect the rate of bone loss in primary sclerosing cholangitis.     

Differential effects of insulin-like growth factor-I and follicle-stimulating hormone on proliferation and differentiation of bovine cumulus cells and granulosa cells

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) has been suggested as a risk factor for the development of colorectal cancer in ulcerative colitis (UC); however, previous studies of this association have been limited by small numbers of patients with PSC or have been performed retrospectively. This study prospectively evaluates the risk and natural history of colonic tumorigenesis in patients with PSC and UC and compares it with patients with UC without PSC. METHODS: Twenty patients with PSC and UC and 25 control patients with UC were followed prospectively by colonoscopic surveillance using extensive mucosal biopsy sampling. All control patients with UC had disease extending beyond the sigmoid colon of > or = 8 years' duration; patients with PSC and UC were studied regardless of disease duration. RESULTS: Forty-five percent (9 of 20) of the patients with PSC and UC had dysplasia compared with 16% (4 of 25) of the control patients with UC (P < or = 0.002). Prior liver transplantation did not affect the risk of colonic dysplasia. The time course for progression to dysplasia was similar between the patients with PSC and UC and the patients with UC; however, the patients with PSC and UC were five times more likely to develop dysplasia. CONCLUSIONS: Patients with PSC and UC represent a subset of patients with UC who are at markedly increased risk for colonic neoplasia and who need close colonoscopic surveillance with extensive biopsy sampling.     

Reconstruction of saddle nose deformities using porous polyethylene implant

Background: Troglitazone is a new drug for the treatment of type 2 diabetes. Although mild liver injury occurred in 1.9% of participants in controlled trials, the U.S. Food and Drug Administration has received reports of five postmarketing cases of severe liver disease that resulted in death or liver transplantation. OBJECTIVE: To report the clinical and histopathologic characteristics of a patient with troglitazone-associated severe liver injury leading to transplantation. DESIGN: Case report. SETTING: Two university hospitals. PATIENT: A 55-year-old woman taking troglitazone, 400 mg/d, and insulin, 120 U/d. INTERVENTION: Discontinuation of troglitazone therapy, pretransplantation liver biopsy, and liver transplantation. RESULTS: Early nonspecific symptoms were attributed to other causes and were not evaluated. After the patient had used troglitazone for 3.5 months, massive loss of liver parenchyma and symptoms of liver failure developed, necessitating liver transplantation. CONCLUSION: Troglitazone may cause subfulminant liver failure.     

Serious, prolonged hypoglycaemia with glibenclamide in a patient with Mendenhall''s syndrome

Mendenhall's syndrome, characterized by familial insulin resistant diabetes, pineal hyperplasia and multiple somatic abnormalities, is associated with defects involving the alpha-subunit of the insulin receptor. The associated insulin-resistant diabetes is extremely difficult to treat; insulin is required in very large doses to control hyperglycaemia and oral hypoglycaemic agents are ineffective. We report a case of severe, prolonged hypoglycaemia that occurred in a 24-year-old patient with Mendenhall's syndrome following therapy with glibenclamide. He had glibenclamide 10 mg daily for 1 week following which he was admitted to hospital in hypoglycaemic coma with blood glucose levels < 1.0 mmol/l. This subject had undergone hypophysectomy at the age of 11 years. Prior to pituitary ablation, oral hypoglycaemic agents did not improve glycaemic control. Thus, previous hypophysectomy in this patient appears to have made it possible for glibenclamide to exert its hypoglycaemic effect. The occurrence of hypoglycaemia in this patient suggests alternative mechanisms for insulin action in conditions characterized by severe insulin resistance due to insulin receptor defects.     

Pulmonary vasculitis as an extraintestinal manifestation in ulcerative coliltis

Pulmonary complications are rarely reported in association with ulcerative colitis. Our patient had ulcerative colitis, diagnosed three decades earlier. Following a relapse of his ulcerative colitis, the patient developed bloodstained sputum. Chest CT-scan showed signs of pulmonary tissue infiltration indicating pulmonary vasculitis. No causative agent for this clinical condition was found. Testing for ANCA showed the vasculitis to most likely be secondary to his ulcerative colitis. The lung lesions responded to corticosteroid therapy within a week, and the following chest CT-scan was normal.