A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.
His physical examination is normal. Routine laboratory testing shows the following:
- Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
- White blood cell count 6.7 × 109/L (3.5–10.5)
- Platelet count 279 × 109/L (150–450)
- Alkaline phosphatase 387 U/L (45–115)
- Total bilirubin 0.9 mg/dL (0.1–1.0)
- Aspartate aminotransferase (AST) 35 U/L (35–48)
- Alanine aminotransferase (ALT) 30 U/L (7–55).
WHAT IS THE DIAGNOSIS?
1. Based on this information, which of the following is the most likely diagnosis?
- Autoimmune hepatitis
- Primary sclerosing cholangitis
- Primary biliary cirrhosis
- Idiopathic adulthood ductopenia
Primary sclerosing cholangitis
The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:
- Characteristic cholangiographic abnormalities of the biliary tree
- Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
- Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.1
At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.2 In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.3 At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.4
Two large epidemiologic studies (one from Olmsted County, MN,5 the other from Swansea, Wales, UK6) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.
It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.5 In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.
Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,7 and it may cost less per diagnosis.8
Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.9
Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.10 Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels10—unlike the pattern in our patient.
Primary biliary cirrhosis
Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:
- Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
- Antimitochondrial antibody
- Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.11
In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.
Idiopathic adulthood ductopenia
Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).12 Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.12,13