Answers

Short answers

1 Primary sclerosing cholangitis with an extrahepatic (common hepatic duct) dominant stricture.

2 Cross sectional imaging, biliary cytology, and tumour markers.

3 Balloon dilation and stenting have shown mixed results, and medical treatment has been disappointing. Orthotopic liver transplantation is the only intervention that has been shown to improve outcome in this condition.

Long answers
1 Diagnosis
Endoscopic retrograde cholangiopancreatography showed beading and ectasia (fig 2; small arrows) as a result of multifocal stricturing and dilatation of the intrahepatic and extrahepatic biliary tree. This is diagnostic for primary sclerosing cholangitis.

View larger version (62K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2 Results of endoscopic retrograde cholangiopancreatography. The large arrow shows a dominant stricture. Smaller arrows show characteristic beading and ectasia. Surgical clips left over from a previous cholecystectomy are also evident (arrowheads)

 
Primary sclerosing cholangitis is a chronic progressive cholestatic disease of the liver and bile ducts, with an unknown aetiology. In this condition, progressive inflammation, stricturing, and fibrosis of the intrahepatic and extrahepatic biliary system often leads to chronic cholestasis and eventually liver failure. It is strongly associated with ulcerative colitis, with a reported prevalence of up to 44%.¹ However, the diagnosis of primary sclerosing cholangitis may predate, coincide, or follow that of ulcerative colitis.

Primary sclerosing cholangitis affects up to 21 men per 100 000 and six women per 100 000, which gives a 70% male predominance.² This is despite ulcerative colitis having an even sex distribution in the population. The mean age at diagnosis is 40 years, and the main presenting symptoms are fatigue and pruritus. Liver blood tests show a cholestatic pattern, and the diagnosis is confirmed by the classic findings of beading and ectasia at cholangiography. Serological findings of raised IgM (50% of patients) and a positive P-ANCA (perinuclear staining antineutrophil cytoplasmic antibodies) test (80%) are helpful but not diagnostic.³

In addition to the classic appearance of primary sclerosing cholangitis, this patient also has a common hepatic duct dominant stricture (fig 2, large arrow). Dominant strictures occasionally occur in patients with primary sclerosing cholangitis and need to be treated.⁴ These strictures can develop anywhere in the intrahepatic or extrahepatic biliary system and can be difficult to distinguish from a cholangiocarcinoma because both conditions can have similar clinical and radiological features.

People with primary sclerosing cholangitis are at increased risk of developing cholangiocarcinoma—they have a 15% lifetime risk⁵ and an annual incidence of 0.5-1%.⁶ However, routine screening of patients with cholangitis for cholangiocarcinoma has shown no benefit.^{5 6}

2 Further investigations
This patient has a dominant stricture in the common hepatic duct. With the information provided it is impossible to say whether this is a cholangiocarcinoma or just a benign stricture secondary to cholangitis. To make this distinction, the patient needs a computed tomography scan and biliary cytology to be performed and tumour markers to be measured. Even if these tests are negative, cholangiocarcinoma cannot be completely excluded, because one study found an unsuspected cholangiocarcinoma in 10% of patients having a liver transplant for primary sclerosing cholangitis.⁷

3 Treatment options
Benign biliary strictures in primary sclerosing cholangitis are often treated with endoscopic or radiological balloon dilation or stenting. These techniques can result in clinical, biochemical, and radiographical improvements.⁸ However, one report found no significant differences over time in bilirubin and alkaline phosphatase concentrations between patients with an untreated dominant stricture and those without a stricture, which implies that these strictures do not greatly contribute to cholestasis.⁹ Conversely, a few studies have since shown significantly improved survival over that predicted when dominant strictures are treated with repeated balloon dilation, stent placement, or both techniques (85% v 65%).¹⁰

Medical treatment of primary sclerosing cholangitis has been disappointing. Various drugs have been used, mostly immunosuppressives, but none has improved the natural course of the disease or improved survival. Ursodeoxycholic acid improves biochemical parameters but most studies show no survival benefit.¹¹ Immunosuppressants such as corticosteroids, ciclosporin, methotrexate, tacrolimus, and penicillamine have all been studied. Although some have shown biochemical improvement, none has improved survival or reduced the need for liver transplantation.^{12 13 14}

Symptoms of chronic cholestasis are fatigue and pruritus, both of which can be disabling. Pruritus is a common symptom in primary sclerosing cholangitis, but its pathological basis is undetermined. Several hypotheses have been proposed, including the accumulation of bile acid and endogenous opioid activity.^{15 16} If obstruction cannot be relieved endoscopically or radiologically, pruritis can be difficult to treat. Bile acid resins such as cholestyramine have been used with some success, as has rifampicin, although this should be used with caution because it has been associated with hepatitis and severe idiosyncratic reactions. Phenobarbital and opiate antagonists have also been used, although both can have serious side effects.^{17 18}

Median survival without liver transplantation is around 12 years from diagnosis. This figure is significantly worse for patients who are symptomatic at diagnosis.¹⁹ Liver transplantation is the treatment of choice for all patients with advanced disease. Five year survival can be as high as 88%.²⁰ Indications for transplantation are similar to those for other forms of end stage liver disease. Some reports have described the recurrence of primary sclerosing cholangitis in up to 20% of transplant recipients at 10 years.²¹ Several factors have been associated with recurrence, but all are poorly understood.

The presence of cholangiocarcinoma on a background of primary sclerosing cholangitis has a poor prognosis, with only 10% of patients surviving for two years. Liver transplantation is contraindicated in this situation because the recurrence of cancer means that survival is significantly lower (23%) than expected,²² although preoperative radiotherapy can significantly improve prognosis in highly selected patients. Thus, when confronted with a patient with a dominant stricture (like the patient in question), it is vital to do a full set of investigations to try to exclude cholangiocarcinoma before proceeding to orthotopic liver transplantation.

Cite this as: BMJ 2009;338:a3175