Ulcerative colitis and an abnormal cholangiogram

ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE

2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?

• Crohn disease of the small bowel is the most common form
• Liver disease often precedes the bowel disease
• Treating the underlying bowel disease improves the long-term prognosis for the liver condition
• Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone

From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.^14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.¹

Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.^15,16

No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.¹⁷

In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.¹⁸ Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.^19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.¹⁵

TREATMENT AND PROGNOSIS

After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.

3. Which is the only life-prolonging therapy for primary sclerosing cholangitis?

• Methotrexate (Trexall)
• Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
• UDCA at a high dosage (20–30 mg/kg/day)
• Liver transplantation

Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.

In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.^21–23

In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,^24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.^26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.²⁷ One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.²⁸ However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.

Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.²⁹ Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.³⁰ Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.³¹

4. In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?

• Colon cancer
• Cholangiocarcinoma
• Osteoporosis
• Fat-soluble vitamin deficiency
• All of the above

All are potential long-term complications.

Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.¹⁸ According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, ^19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.

Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.^1,20 In a retrospective study of 30 patients,³² the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.

At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.

Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.³³ A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.³⁴

Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.³⁵ Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis³⁶ and can be considered in patients with advanced osteoporosis.

Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.³⁷ Patients can undergo simple oral replacement therapy.