Primary sclerosing cholangitis is a progressive inflammatory disease of the biliary ducts. The illness is normally associated with ulcerative colitis. Up to 90% of patients with primary sclerosing cholangitis have ulcerative colitis. Less frequently it can be associated with Crohn’s Disease. Conversely, the prevalence of sclerosing cholangitis in patients with ulcerative colitis is approximately 5%. It is a disease which predominantly affects men (only 30% of those affected are women).
Clinical signs and diagnosis
Clinical signs
Primary sclerosing cholangitis is frequently asymptomatic in the initial stages of the illness. It may be suspected if it has been discovered that there are changes to liver enzymes in patients with ulcerative colitis, in particular elevations of alkaline phosphatase. The patient may present in some cases with symptoms of pruritus and fatigue. Some 10 to 15% of patients present with fever, jaundice and pain in the right hypochondrium, which is explained by episodes of recurrent cholangitis.
Laboratory investigations
Laboratory investigations show a cholestastatic pattern of alteration of hepatic tests, predominantly with elevated alkaline phosphatase and gamma glutamyl transpeptidase (GGT).
Other changes in laboratory tests include the presence of anti-neutrophil cytoplasmic antibody, with a perinuclear pattern (p-ANCA), which occurs in approximately half of patients, elevated igm (50%), hypergammaglobulinemia (30%) and raised urinary copper level with low ceruloplasmin (common discovery in cholestasis diseases).
Imaging
The diagnosis of primary sclerosing cholangitis is reached by demonstrating typical alterations of the biliary tree, which include stenotic (narrowing) zones and multifocal dilatations. The diagnostic method of choice up to some years ago was carried out by means of retrograde endoscopic cholangiography. However, currently cholangiography by magnetic resonance (cholangio resonance) has practically replaced retrograde cholangiography. This latter is reserved for cases where the diagnosis is in doubt and when an intervention around the biliary duct is planned.
In the differential diagnosis of primary sclerosing cholangitis consideration must also be given to chronic bacterial cholangitis, ischemia of the biliary duct, infectious cholangitis (AIDS-associated cholangiopathy) and sclerosing pancreato-cholangitis (also called autoimmune pancreatitis).
Liver biopsy
Histology obtained through a liver biopsy can support the findings, but in the majority of cases it is not necessary for the purposes of establishing the diagnosis. It does, however, contribute to establishing the stage of the illness and the prognosis. The characteristic histological findings are the presence of fibrous tissue arranged in concentric form around the biliary ducts (‘onion skin’ lesion). The remainder of the lesions are similar to those of primary biliary cirrhosis. The fibrosis evolves typically in four stages.
- Stage 1: Monunuclear infiltrates in the portal triad. There can be peacemeal necrosis (borderline hepatitis).
- Stage II: Expansion of the fibrosis beyond the portal triad, with extension to the adjacent hepatic parenchyma.
- Stage III: Bridging fibrosis.
- Stage IV: Cirrosis.
Complications of primary sclerosing cholangitis
Cholestasis
In terms of the manifestation of cholestasis associated with primary sclerosing cholangitis the following should be mentioned:
- Pruritus (itching): See treatment of pruritus.
- Steatorrhea and liposoluble vitamin deficit: The decrease in the secretion of biliary acids towards the intestine interferes with the absorbtion of liposoluble vitamins. Although the diarrhea and frank steatorrhea are infrequent, the deficiency of Vitamins A, D E and K are relatively common. Within the differential diagnosis of the diarrhea are some conditions which are more frequent in patients with primary sclerosing cholangitis, such as chronic pancreatitis and celiac disease.
- Osteoporosis: Sclerosing cholangitis, like primary biliary cirrhosis, is frequently associated with osteoporosis. The cause of osteoporosis is not completely clear, given that the lack of Vitamin D produces osteomalacia as opposed to osteoporosis. Patients with sclerosing cholangitis have an increased risk of fractures, particularly patients who have had a liver transplant.
Dominant bile duct stenosis
Some patients develop stenosis in the hepatic ducts, presenting with obstructive jaundice. In these cases, differentiating the diagnosis from cholangiocarcinoma is very difficult. These stenoses can be managed successfully with endoscopic treatments (endoscopic retrograde cholangiopancreatography – ERCP). Ideally balloon dilatation is used, with a view to avoiding the use of prostheses (stents).
Cholangitis and lithiasis
Patients with sclerosing cholangitis have more incidence of biliary calculus, which can be of cholesterol or pigments. The cholangitis is a complication which in some cases is induced by manipulation of the bile duct, for example, following retrograde cholangiography or liver biopsy. Repeated episodes of bacterial cholangitis are one of the indications for liver transplant.
Cholangiocarcinoma
The risk to patients with primary sclerosing cholangitis of developing cholangiocarcinoma is 1.5% annually. Patients with ulcerative colitis have a greater risk. Cholangiocarcinoma is very difficult to diagnose in patients with sclerosing cholangitis and this should be suspected if there is an unexplained loss of weight or in light of any other prevailing stenosis of the biliary ducts. Within the tools which can help to establish the diagnosis are the serum tumour markers, like CA 19-9 (greater than 129 U/mL) and CEA, images such as magnetic resonance and possibly the PET scan, as well as direct methods such as brush cytology of the suspicious area. There are encouraging results using more sophisticated diagnostic techniques, such as digital analysis and the detection of antigens through fluorescence in situ hybridization (FISH) in the cytology samples.
Colon cancer
Patients with sclerosing cholangitis and ulcerative colitis have a greater risk of colon cancer. Therefore there must be periodic screening via colonoscopy to check for suspicious lesions and dysplasia findings.
Treatment
None of the current available treatments for primary sclerosing cholangitis have been shown to have a proven effect in modifying the natural evolution of the disease.
The most used medication is ursodeoxycholic acid, based fundamentally on the benefits of this biliary acid on other cholestatic diseases such as primary biliary cirrhosis. The use of this medication in a dose of up to 15 mg/kg has demonstrated biochemical benefits (decrease in alkaline phosphatase [FA] and gamma glutamyl transpeptidase [GGT]), but there have been no clear benefits either histologically or to the survival of patients. In fact, a recent study has shown no benefit of ursodeoxycholic acid, with higher mortality associated with its use. A new derivative of acid ursodeoxycholic called nor-ursodeoxycholic appears promising in pre-clinical studies.
Liver transplant is the treatment of choice in cases where the disease is advanced. The criteria for transplant are similar to those for any other chronic hepatic illness. An additional indication for liver transplant is the repeated presence of bacterial cholangitis. The presence of jaundice only is not considered an indication for transplant. The Mayo Clinic’s scores, which predict a mortality rate of 80% in the following 6 months is commonly accepted as the criteria for a patient being put on the transplant waiting list.
Prognosis
Primary sclerosing cholangitis is normally a progressive disease. The average survival rate without liver transplant is 12 years. Survival can be estimated most effectively using the Mayo Clinic’s Risk Score, which includes in the formula: age, variceal hemorrhage, albumin, bilirubin and SGOT. Sclerosing cholangitis may recur following liver transplant in 20% of patients.
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