Primary sclerosing cholangitis

THE NEW ENGLAND JOURNAL OF MEDICINE Nevertheless, in addition to medical therapy, a varietyof endoscopic, radiologic, and surgical procedures have been used to relieve the mechanical obstruction of thebile ducts that the disease produces. The availability ofliver transplantation has also greatly improved pa-tients' prospects for long-term survival.
PRIMARY SCLEROSING CHOLANGITIS
OUNG-MEE LEE, M.D., AND MARSHALL M. KAPLAN, M.D.
Thickening and induration of the common bile duct, seen at laparotomy, are characteristic of primary scle- PRIMARY sclerosing cholangitis, a chronic chole- rosing cholangitis.32 In early stages of the disease, the static liver disease of unknown cause, is character- liver may appear grossly normal. However, as the con- ized by ongoing inflammation, destruction, and fibro- dition progresses, the liver becomes coarsely nodular sis of intrahepatic and extrahepatic bile ducts.1-4 Over and stained with bile.
time, bile ducts become irregularly narrowed and oblit- Four histologic stages of primary sclerosing cholan- erated, and small intrahepatic ducts disappear. Focal gitis have been identified.32 Stage 1 represents the ini- bile-duct dilatation proximal to areas of stricture pro- tial lesion; the other stages presumably develop with duces a characteristic beaded appearance on cholan- time and the progression of the disease. Stage 1 is char- giography.5,6 Primary sclerosing cholangitis, although acterized by the degeneration of epithelial cells in the only about 1 percent as common as alcoholic liver bile duct and by infiltration of the bile duct by lympho- disease,7,8 is the fourth leading indication for liver cytes and, occasionally, neutrophils. There is inflamma- transplantation in adults in the United States.9 The dis- tion, scarring, and enlargement of the portal triads ease progresses silently, but relentlessly, in most pa- and, at times, portal edema. At stage 1, however, these tients and leads to cirrhosis, portal hypertension, and findings are not present outside the portal triads (Fig.
liver failure.10,11 1A and 1B). In some cases, there may be proliferation Seventy percent of patients with primary sclerosing of bile ducts in the portal triads, vacuolation of ductu- cholangitis are men, and the mean age at diagnosis is lar epithelial cells, and the formation of onionskin le- 39 years.12 The disease typically occurs in patients with sions, concentric layers of connective tissue surround- inflammatory bowel disease, but it may also occur alone ing bile ducts (Fig. 1C and 1D).33 Primary sclerosing or in association with retroperitoneal or mediastinal fi- cholangitis typically involves less inflammation in the brosis.13 Of the approximately 75 percent of patients portal triads than other chronic cholestatic liver diseas- with primary sclerosing cholangitis who have inflam- es, such as primary biliary cirrhosis. In stage 2, the le- matory bowel disease, about 87 percent have ulcerative sion is more widespread. The fibrosis and inflammation colitis and 13 percent Crohn's disease.14-21 Seen anoth- infiltrate the periportal parenchyma, where they even- er way, 2.5 to 7.5 percent of patients who present with tually destroy periportal hepatocytes in piecemeal ne- ulcerative colitis have, or will have, primary sclerosing crosis. Portal triads are often enlarged. Bile ductopenia cholangitis.22-24 The true frequency of primary scleros- is a prominent feature; concentric periductal fibrosis is ing cholangitis in patients with ulcerative colitis may less obvious. As the disease progresses to stage 3, por- actually be higher. Some patients who, in fact, have pri- tal-to-portal fibrous septa form. Bile ducts disappear mary sclerosing cholangitis may not undergo cholangi- or undergo severe degenerative changes. Cholestasis ography because they are asymptomatic and the results may be prominent, primarily in periportal and para- of their biochemical tests of liver function are only min- septal hepatocytes. Stage 4, the end stage, is charac- imally abnormal. The prevalence of ulcerative colitis in terized by frank cirrhosis; the histologic features dif- the United States is estimated to range from 40 to 225 fer little from those seen in other forms of that disease.
per 100,000.25,26 On the basis of this figure, the preva- In primary sclerosing cholangitis, however, there may lence of primary sclerosing cholangitis would be ap- also be changes associated with large-duct obstruction: proximately 1 to 6 cases per 100,000.
the proliferation and dilatation of interlobular bile At the present time, there is no effective treatment ducts and increased numbers of periportal neutrophils for the disease.4 Preliminary data on drugs such as ursodiol27-29 and methotrexate30,31 show improved re- It is noteworthy that the pathognomonic sign of sults in biochemical tests of liver function, particularly primary sclerosing cholangitis — the onionskin le- decreases in serum alkaline phosphatase levels, as well sions — is rarely seen on percutaneous biopsy of the as occasional improvement in symptoms. However, liver. It is more common to find only a paucity of nor- there are no data to show that these drugs can favor- mal bile ducts and nonspecific fibrosis and inflamma- ably alter the course of primary sclerosing cholangitis.
tion in the portal triads. The diagnosis is thereforeusually made by cholangiography. Histologic exami-nation of the liver is used for confirmation and to de- From the Division of Gastroenterology, New England Medical Center, 750 termine the stage of disease. Since the progress and Washington St., Boston, MA 02111, where reprint requests should be addressedto Dr. Kaplan.
extent of the disease seen in biopsy tissue may vary, The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

Figure 1. Lesions in Primary Sclerosing Cholangitis.
Panel A shows acute bile-duct injury in a patient with early stage1 disease. The bile duct at the center is infiltrated with neutro-phils and lymphocytes. Epithelial cells are damaged. There areloosely arrayed concentric rings of connective tissue, separatedby clear zones of edema and inflammatory cells that surroundthe damaged bile duct. Panel B shows a stage 1 lesion. A bileduct contains vacuolated, degenerating epithelial cells and is in-filtrated by lymphocytes. The duct is surrounded by concentricrings of connective tissue with scant lymphocytic infiltrate. An ar-teriole is visible on the right. Panel C shows a stage 2 lesion. Anecrotic bile duct is at the center of an enlarged, scarred portaltriad. Note the onionskin appearance of the concentric rings ofconnective tissue. The inflammation and scar tissue extend intothe periportal parenchyma. Panel D shows another type of stage2 lesion, an enlarged portal triad with proliferating bile-duct tis-sue and neutrophils. These lesions are not specific to primary sclerosing cholangitis and may be seen in many types of chroniccholestasis. Panel E shows a normal portal tract, which containsa branch of the portal vein, an interlobular bile duct, and small arterioles. (Masson trichrome, 190.) accurate histologic staging requires the examinationof a sufficiently large specimen.
The cause of primary sclerosing cholangitis is un- known. However, a number of factors have been pro-posed that might cause recurring damage to the bileducts and lead to development of the disease. These in-clude chronic portal bacteremia, toxic bile acid metab-olites produced by enteric flora, toxins produced direct-ly by enteric bacteria, chronic viral infections, ischemic vascular damage, and genetic abnormalities of immu-noregulation.
The close association between primary sclerosing cholangitis and ulcerative colitis led researchers tothe hypothesis that chronic portal bacteremia mightcause chronic biliary tract infection, inflammation,portal fibrosis, and ultimately, primary sclerosing cho-langitis.34-36 One study reported portal bacteremia insome patients with ulcerative colitis who had had co-lonic surgery.35 However, further research did not con-firm the observation. In these later studies, patientswith primary sclerosing cholangitis did not have evi-dence of portal-vein phlebitis, a typical feature of por-tal bacteremia.37-39 Other researchers have suggested that primary scle- rosing cholangitis is the result of toxic bile acid me- The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved. THE NEW ENGLAND JOURNAL OF MEDICINE tabolites generated by the gut flora.40 Lithocholic eases such as Graves' disease, systemic lupus erythema- acid, formed from chenodeoxycholic acid by bacterial tosus, and myasthenia gravis.62 HLA-DRw52a is found 7-a-dehydroxylation in the colon, is hepatotoxic in ani- in a high proportion of patients with primary sclerosing mals.41 However, no major abnormalities in the compo- cholangitis, but not in all, as was initially reported.63,64 sition and concentration of bile acids have been found In patients with HLA-DR4, the course of primary scle- in the bile and portal blood of patients with either pri- rosing cholangitis tends to be accelerated.61 mary sclerosing cholangitis or chronic inflammatory Patients with primary sclerosing cholangitis have bowel disease.42 Moreover, lithocholic acid is rapidly signs of abnormal immunoregulation, including infiltra- sulfated and rendered nontoxic in human tissue. This tion and destruction of bile ducts by lymphocytes,38 hy- metabolic process has not been found to occur in ani- pergammaglobulinemia with a disproportionate increase mals, in which lithocholic acid can induce liver dis- in serum IgM,65 perinuclear antineutrophil cytoplasmic antibodies,66 anticolon epithelial autoantibodies,67 cir- Research on animals suggests a third possible cause culating immune complexes,68 increased metabolism of of primary sclerosing cholangitis: bacterial products complement component C3,69 and activation of the com- acting as toxic proinflammatory agents. N-formyl plement system by the classic pathway.70 Primary scle- L-methionine L-leucine L-tyrosine is a peptide produced rosing cholangitis is associated with other disorders of by enteric flora. When this peptide, labeled with io- immunoregulation, including inflammatory bowel dis- dine-125, was introduced into the colons of rats with ease,21 thyroiditis, and type I diabetes.62 experimentally induced colitis, it was absorbed, under- The cellular immune system appears to play a part went enterohepatic circulation, and appeared unde- in primary sclerosing cholangitis. The total number of graded in bile.46 Histologic changes in the livers of the circulating T cells is decreased, whereas T cells are in- rats resembled those in primary sclerosing cholangitis, creased in the portal tracts.71-73 The ratio of CD4 to including periportal inflammation with neutrophils CD8 lymphocytes in the circulation is increased, as are and eosinophils clustered around bile ducts. The injec- the number and percentage of B cells.71 There is inhi- tion of killed, nonpathogenic Escherichia coli into the bition of leukocyte migration in the presence of biliary portal veins of rabbits produced portal-vein fibrosis.47 antigens74 and enhanced autoreactivity of portal T lym- Similar hepatic lesions developed in rats with experi- phocytes.75 Finally, the aberrant expression of class II mentally created blind loops in the jejunum after poly- antigens on bile-duct epithelial cells suggests that bile- mers prepared from the cell walls of intestinal bacteria duct epithelial cells act as autoantigens to host lym- were injected into the animals' portal veins.48 phocytes.76,77 It is unknown whether these immunologic The natural history of primary sclerosing cholangi- abnormalities are primary events or are due to the un- tis, however, argues against a major pathogenetic role derlying disease, although the ligation of bile ducts in for portal bacteremia or bacterial metabolites. Antibi- rats causes an aberrant expression of class II antigens otic treatment, for example, is not effective against the on bile-duct cells.78 disease.49 There is also no correlation between the se-verity of ulcerative colitis and that of primary scleros- ing cholangitis.21 Primary sclerosing cholangitis may The current criteria used to diagnose primary scle- develop years before the onset of colitis or years after rosing cholangitis are based on characteristic changes patients have had total colectomies.50 in the intrahepatic and extrahepatic biliary tree seen Chronic viral infections and ischemic damage to bile with endoscopic retrograde cholangiopancreatography ducts have also been implicated as causative factors in or transhepatic cholangiography. Before the diagnosis primary sclerosing cholangitis.51,52 Cholangitis caused of primary sclerosing cholangitis is established, disor- by cytomegalovirus in patients with acquired immu- ders that cause secondary sclerosing cholangitis must nodeficiency has a cholangiographic similarity to pri- be ruled out. These include chronic bacterial cholangi- mary sclerosing cholangitis.53 However, there are no tis in patients with bile-duct stricture or choledocholithi- data that suggest any relation in immunocompetent pa- asis, ischemic bile-duct damage due to treatment with tients.54,55 Likewise, no pathological data suggest that floxuridine,52 infectious cholangiopathy associated with ischemic damage to bile ducts is a cause of primary the acquired immunodeficiency syndrome,53 previous sclerosing cholangitis. Ischemia had been proposed biliary surgery, congenital biliary-tree abnormalities, because intraarterial injections of the chemotherapeu- and bile-duct neoplasms. The presence of these disor- tic agent floxuridine resulted in a clinical syndrome ders is typically ruled out by the use of patient histo- similar to that seen in primary sclerosing cholangitis.52 ries, blood-test results, characteristic cholangiographic Intraarterial floxuridine has been shown to cause nar- or ultrasound findings, or pathological findings from rowing and obliteration of the arteries supplying the bile-duct scraping and biopsies.
Laboratory tests in patients with primary sclerosing Genetic and immunologic factors appear to play a cholangitis usually show a cholestatic pattern, but bio- part in primary sclerosing cholangitis, although the dis- chemical abnormalities alone are never diagnostic.
order is not inherited in any distinct pattern. There are The serum alkaline phosphatase level is usually ele- familial occurrences of this uncommon disease,56,57 vated, although there are reports of patients in whom as well as an association between primary sclerosing the disease has been diagnosed by cholangiography cholangitis and HLA-B8, DR3, DR2, and DR4.58-61 who have normal levels.79 Most patients have slight HLA-B8 and DR3 are associated with autoimmune dis- increases in serum aminotransferase levels, but the The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

level of serum albumin is normal early in the disease.
Patients with active inflammatory bowel disease, how-ever, have decreased serum levels of albumin, reflect-ing the severity of that illness. In early stages of pri-mary sclerosing cholangitis, serum bilirubin valuesare usually normal, but they gradually increase as thedisease progresses. Occasionally, striking fluctuationsin bilirubin levels may occur even at early stages. Thecause is unknown, but the changes may reflect tran-sient blockage of strictured bile ducts by inflamma-tion, infection, sludge, or small gallstones. Hypergam-maglobulinemia is found in about 30 percent ofpatients, and increased IgM levels in 40 to 50 per-cent.26 Autoantibodies are less frequent than in auto-immune chronic active hepatitis and primary biliarycirrhosis. About 65 percent of patients with primarysclerosing cholangitis have perinuclear antineutrophilcytoplasmic antibodies80 and HLA-DRw52a.64 Anti–smooth-muscle antibodies are present in 11 percent ofpatients and antinuclear antibodies in 6 to 35 percent,but antimitochondrial antibodies are almost never ob-served.26 As in other chronic cholestatic liver diseases,levels of hepatic and urinary copper are increased, asis the serum ceruloplasmin level. Because copper isexcreted primarily in bile, the amount of copper in thebody increases as cholestasis worsens.
Visualization of the biliary tract is essential for mak- ing the diagnosis of primary sclerosing cholangitis. En-doscopic retrograde cholangiopancreatography is themethod of choice. Percutaneous cholangiography istechnically more difficult in patients with the diseasebecause intrahepatic bile ducts are often attenuated orreduced in number. Transhepatic cholangiography is Figure 2. Endoscopic Retrograde Cholangiogram of a 62-Year- performed only if endoscopic retrograde cholangiopan- Old Woman with Primary Sclerosing Cholangitis.
creatography is unsuccessful. The characteristic radio- There are multiple narrowings and dilatations of intra- and extra- logic findings of primary sclerosing cholangitis include hepatic bile ducts.
multifocal strictures and dilatations, usually involvingboth the intrahepatic and extrahepatic biliary tree(Fig. 2). Diffuse strictures with short intervening seg- atograms are normal.83 This disease is probably the ments of normal or dilated bile duct produce the classic same as the condition called pericholangitis in ulcer- beaded appearance. In early stages, the only cholangi- ative colitis.84,85 ographic abnormality may be fine ulcerations of the Although percutaneous liver biopsy may support the common bile duct similar to those seen in the colon in diagnosis of primary sclerosing cholangitis, it is rarely early ulcerative colitis (Fig. 3). In other patients, there definitive. Rather, it is useful in staging and in deter- may be deep ulcerations in the common duct (Fig. 4).
mining the prognosis. Neither histologic examination In our experience with more than 100 patients with pri- nor cholangiography alone will reliably reflect the se- mary sclerosing cholangitis, 87 percent had involve- verity of the disease. Both must be used with blood ment of both intrahepatic and extrahepatic bile ducts, tests and with imaging or endoscopic tests that show 11 percent had involvement of the intrahepatic bile the presence and severity of portal hypertension.
ducts alone, and 2 percent had involvement of only theextrahepatic bile ducts (unpublished data). The gall- bladder and cystic duct are involved in as many as 15 The majority of patients are initially asymptomatic, percent of patients.81,82 but can typically be identified on the basis of abnormal There is one putative variant, called small-duct pri- results on biochemical tests of liver function, particu- mary sclerosing cholangitis, in which the affected bile larly elevated levels of serum alkaline phosphatase or ducts are too small to be seen by cholangiography.
g-glutamyltransferase. These abnormalities persist, and Hence, cholangiograms appear normal. The preva- eventually cholangiography, liver biopsy, or both, are lence of small-duct primary sclerosing cholangitis is performed. Liver-biopsy findings are usually either non- unknown. It is diagnosed in patients with inflammatory specific or suggestive of primary sclerosing cholangitis; bowel disease who have biochemical tests of liver func- the cholangiogram shows the characteristic changes.
tion that show cholestasis and characteristic liver biop- Although asymptomatic, some patients may have sur- sies, but whose endoscopic retrograde cholangiopancre- prisingly advanced disease, as measured both histolog- The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

THE NEW ENGLAND JOURNAL OF MEDICINE those who were asymptomatic, and the survival ofasymptomatic patients was significantly shorter thanthat of a matched control population. Other studieshave reported similar findings, with median survival of9 to 12 years from diagnosis.87-90 There is no relationbetween the course of primary sclerosing cholangitisand that of accompanying inflammatory bowel disease.
Primary sclerosing cholangitis often occurs and wor-sens in patients whose inflammatory bowel disease hasbecome quiescent after colectomy.
Multivariate analysis has been used to identify prog- nostic variables and to develop models that predict theprogression of primary sclerosing cholangitis. In a re-cent study of patients at five referral centers, the vari-ables that adversely affected survival were age, serumbilirubin and hemoglobin levels, hepatic histologicstage, and the presence of splenomegaly.91 According tothe study's model, the probability of surviving fiveyears from the time of diagnosis was 78 percent. In an-other study, prognostic variables included hepatomeg-aly, splenomegaly, serum alkaline phosphatase level, Figure 3. Endoscopic Retrograde Cholangiogram of a 28-Year- histologic stage, and age.90 Although these models are Old Man with Ulcerative Colitis and Early Primary Sclerosing useful in classifying participants in therapeutic trials, they may have limited application to the timing of liver The patient presented with intense pruritus and a fivefold in- transplantation in individual patients because of the crease in the serum alkaline phosphatase level. There are fineulcerations (straight arrow) of the common bile duct and subtle great variability of the disease.
narrowings (curved arrow) and dilatations of the intrahepatic It is important to recognize a major difference be- ically and radiologically. Some patients may remain tween cholestatic liver diseases, such as primary scle- asymptomatic for many years. Eventually, the serum rosing cholangitis, in which bile ducts are the targets of bilirubin level begins to increase or the serum albumin the inflammatory and destructive processes, and chron- level decreases (or both). When symptoms of itching,fatigue, jaundice, and weight loss develop, the patientsusually have advanced disease.
In 10 to 15 percent of patients, fever, night sweats, chills, pain in the right upper quadrant, itching, orjaundice is present at the time of diagnosis.86 Despitethese symptoms, blood-test results, histologic featuresof the liver, and cholangiographic findings are similarto those in asymptomatic patients. The episodes of fe-ver and chills are often accompanied by transient wor-sening of the results of biochemical tests of liver func-tion; these episodes are indistinguishable from thoseproduced by acute bacterial cholangitis. They may lastfrom hours to days, but usually end without specifictreatment. Antibiotics are rarely helpful, and blood cul-tures rarely positive. It is not known whether these ep-isodes are caused by bacterial infections in areas nearstrictured and transiently occluded bile ducts or wheth-er they are simply part of the underlying inflammatoryprocess.
Although the majority of patients with primary scle- rosing cholangitis are asymptomatic at the time of di- Figure 4. Endoscopic Retrograde Cholangiogram of a 44-Year- agnosis, most eventually have symptoms of fatigue, Old Man with Primary Sclerosing Cholangitis and Crohn's itching, and jaundice. Cirrhosis, portal hypertension, and liver failure follow. In one study, the mean age of There are deep ulcerations (solid arrow) in the common hepatic patients at diagnosis was 39.9 years; the median length duct and left intrahepatic bile duct, similar to those seen in thecolon in patients with colitis. There are filling defects (open ar- of survival was 11.9 years from diagnosis.12 Patients row) consistent with intraductal stones. The partially filled gall- who were symptomatic at diagnosis lived less long than bladder is visible on the left, and the endoscope is in place.
The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved. ic hepatocellular diseases, such as hepatitis, in which tients. Cholestyramine is effective for patients who have hepatocytes are the targets. When bile ducts are de- adequate bile flow.93 The dose is 4 to 8 g taken two stroyed, they do not regenerate or they do so ineffec- or three times daily. It usually takes two to four days tively.86 An example of this is the vanishing-bile-duct for cholestyramine to relieve itching. The drug is not syndrome associated with rejection in orthotopic liver helpful if bile flow has already been greatly decreased.
transplantation.92 In contrast, hepatocytes have an Colestipol hydrochloride, another ammonium resin, enormous capacity to regenerate. If patients with fulmi- may be an alternative for those who cannot tolerate cho- nant hepatitis survive, they recover fully and regain lestyramine. Other therapies that have been used in normal liver function. Likewise, patients with autoim- patients unresponsive to cholestyramine include nal- mune hepatitis who are deeply jaundiced and have oxone,95 methyltestosterone,96 phenobarbital,97 rifam- striking hypoalbuminemia may respond dramatically to pin,98 plasmapheresis,99 ondansetron,100 antihistamines, glucocorticoids and regain normal liver function. How- ursodiol,101 S-adenosylmethionine,102 and ultraviolet ever, there appears to be only a finite number of bile ducts, which do not regenerate adequately when de- Steatorrhea and malabsorption of fat-soluble vita- stroyed. Primary sclerosing cholangitis should therefore mins may occur late in the course of primary scleros- be treated early in its course, before the serum level of ing cholangitis. Fat malabsorption in patients with bilirubin becomes permanently elevated. A serum bili- jaundice is usually related to decreased secretion of rubin level persistently greater than 1.5 mg per deciliter conjugated bile acids into the small intestine. Other (26 mmol per liter) is a sign of a poor prognosis and causes are pancreatic insufficiency104,105 and celiac dis- may indicate irreversible, medically untreatable dis- ease,106 both of which may be associated with primary sclerosing cholangitis. Asymptomatic vitamin A defi- The treatment of primary sclerosing cholangitis has ciency was found in almost 50 percent of patients with been limited by uncertainty about its cause. As yet, no primary sclerosing cholangitis in one study.107 A clin- medical therapy has been proved effective. The medi- ically important vitamin K deficiency rarely occurs cal response to the illness may be divided into the unless the patient has chronic jaundice and takes cho- management of symptoms and complications, and the lestyramine regularly. Similarly, deficiencies of vita- treatment of the underlying disease process. But for pa- mins D and E are uncommon and infrequently asso- tients with end-stage disease who have symptomatic ciated with clinical symptoms.108 However, there have portal hypertension, liver failure, and recurrent or in- been reports of metabolic bone disease and compres- tractable bacterial cholangitis, liver transplantation is sion fractures of the spine.109 As in primary biliary cir- the only effective treatment.
rhosis, the bone disease is due to osteoporosis ratherthan osteomalacia. Fat-soluble vitamin levels should Management of Chronic Cholestasis and Its Complications
be monitored and deficiencies treated with supple- Many of the symptoms of primary sclerosing cholan- gitis are similar to those of other cholestatic diseases, Antibiotics have no role in slowing the progression of such as primary biliary cirrhosis. However, unique primary sclerosing cholangitis but have been used to problems result from the mechanical bile-duct obstruc- treat recurrent episodes of cholangitis. Bacterial cho- tion characteristic of the disease, including bacterial langitis is typically associated with biliary surgery, bile- cholangitis, sepsis, and the formation of pigment stones duct stones, or obstructing strictures. Tetracycline was within the obstructed bile ducts. In addition, patients determined to be ineffective in one small study of pa- with primary sclerosing cholangitis are at risk for bile- tients with primary sclerosing cholangitis,49 but prophy- duct cancers. These cancers may be very difficult to dis- lactic antibiotics, usually amoxicillin, ciprofloxacin, or tinguish from the tight bile-duct strictures typically trimethoprim–sulfamethoxazole, are often used for re- seen in primary sclerosing cholangitis.
current episodes of cholangitis. Anecdotal reports sug- Symptoms of primary sclerosing cholangitis include gest that such drugs reduce the frequency and severity fatigue, pruritus, and steatorrhea. One of the more of bacterial cholangitis. Additional controlled trials are bothersome symptoms is pruritus. Itching is worse at needed to test this hypothesis.
bedtime and in warm weather and may be exacerbated Dominant strictures of the extrahepatic bile ducts, by eating rich, fatty meals. It can be severely debilitat- which cause or exacerbate symptoms, occur in 15 to 20 ing, interfere with sleep, and provoke extensive excori- percent of patients with primary sclerosing cholangi- ations. The cause of the pruritus is unknown. The re- tis.110 Endoscopic balloon dilation of strictures, with or tention of bile acids and their sequestration in skin are without the placement of stents, has relieved symp- not the cause. Nevertheless, bile acid–binding resins toms of jaundice, pruritus, and fever, and has reduced are an effective treatment, presumably because they serum levels of alkaline phosphatase and aminotrans- bind to the true pruritogenic agent excreted in bile.93 ferases in selected patients.110 In several retrospective More recently, the accumulation of endogenous opiates studies, patients appeared to have fewer episodes of has been proposed as a cause of the pruritus. Opiate cholangitis if they were treated endoscopically with antagonists may decrease pruritus, and there are in- papillotomy of Oddi's sphincter, nasobiliary catheter creased serum concentrations of endorphin-like sub- irrigation of the common bile duct with glucocorti- stances in patients with other chronic cholestastic liver coids, or dilation of strictures with either balloons or diseases, such as primary biliary cirrhosis.94 stents.111-113 Results of biochemical tests and cholangi- The pruritus can be effectively treated in most pa- ographic findings improved in some patients so treat- The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved. THE NEW ENGLAND JOURNAL OF MEDICINE ed. There are no controlled trials evaluating endoscop- progression of disease.124 Finally, corticosteroids may ic therapy, but there appears to be little risk and some hasten the onset and progression of osteoporosis and in- potential benefit from this approach.
crease spontaneous bone fractures. There is, however, Another method of managing dominant strictures, one favorable report. In an uncontrolled trial of cortico- surgical dilation, or choledochojejunostomy, is now rare- steroid use, 10 patients with prefibrotic primary scleros- ly used. Surgery carries the risk of postoperative infec- ing cholangitis had improvements in the results of both tion and increases scarring in the porta hepatis, poten- blood tests and histologic examination of the liver. Four tially complicating future liver transplantation.114 The of these patients remain well after 11 years and are still development of stomal varices is a complication unique receiving low-dose prednisone (LaBrecque DR: person- to patients with advanced primary sclerosing cholangi- al communication).
tis who have undergone colectomy and ileostomy.115Treatment of bleeding from the stomal varices is diffi- cult and usually requires either a central portosystemic Penicillamine has been evaluated in a double-blind shunt or liver transplantation.
prospective trial of patients followed for 36 months.125 There is an increased incidence of cholangiocarci- The drug produced the expected urinary excretion of noma in patients with primary sclerosing cholangitis, copper, but had no beneficial effect on symptoms, bio- about 9 to 15 percent.116,117 Patients with long-standing chemical test results, liver histology, disease progres- ulcerative colitis and cirrhosis are at highest risk.118,119 sion, or survival. In addition, 21 percent of the patients The early diagnosis of bile-duct carcinoma is ham- had major side effects from penicillamine. The toxicity pered by the lack of sensitive, specific serologic markers and the lack of efficacy have discouraged further use of as well as the insensitivity of biliary cytology. Often an unsuspected cholangiocarcinoma is found after livertransplantation, when the resected liver is examined in the pathology laboratory.120 Unfortunately, there is no Ursodiol has been associated with a clear improve- reliable way to distinguish a dominant stricture from a ment in the results of biochemical tests of liver function cholangiocarcinoma, even after repeated imaging, en- in primary sclerosing cholangitis. Therapy with the doscopic biopsies, and cytologic examination. Most ex- drug leads to a two-to-threefold increase in the serum perts suggest that patients with a high likelihood of bile acid concentration. There is an increase in the bil- cholangiocarcinoma should be referred for liver trans- iary and urinary excretion of bile acids and an increase plantation and should undergo pretransplantation lap- in bile flow. In vitro, ursodiol stabilizes liver-cell mem- arotomy in order to rule out the extrahepatic spread of branes exposed to toxic concentrations of the naturally cancer.116,120,121 Unfortunately, treatment of cholangio- occurring bile acid chenodeoxycholic acid.126 Several carcinoma by resection, chemotherapy, and radiation open-label trials of ursodiol have reported improve- has had discouraging results, as has liver transplanta- ments in symptoms and in the results of liver-function tion for clinically apparent tumors.120 tests.27,28,127,128 There is no information on the cholangi-ographic appearance of the biliary tree. In a prospec- Medical Therapy for Primary Sclerosing Cholangitis
tive, randomized, double-blind, placebo-controlled tri- A variety of immunosuppressive, antiinflammatory, al, there was improvement in the results of biochemical and antifibrotic agents have been used to treat primary tests of liver function and liver histology in those pa- sclerosing cholangitis. However, no drug has been tients receiving ursodiol.29 However, there was no dif- shown to improve the natural history of the disease.
ference in patient survival or in referral for liver trans- The evaluation of treatment has been limited by the in- plantation. There are no data on the long-term efficacy dolent course of primary sclerosing cholangitis in most of ursodiol.
patients and the spontaneous exacerbations and remis-sions in others. Hence, it takes years before any treat- ment can be shown to alter the natural history. Of the On the basis of clinical and histologic improvements various drugs used to treat primary sclerosing cholan- in 2 patients with primary sclerosing cholangitis, we gitis, only a few have been evaluated in randomized, conducted an open-label trial of oral methotrexate in controlled trials.
21 patients with the disease, 7 of whom had cirrhosis aswell30,129,130 (and unpublished data). No patients with cirrhosis had improvement in their condition. In patients Despite anecdotal reports of improvement in patients without advanced disease, there was improvement in with primary sclerosing cholangitis who took cortico- symptoms and in the results of biochemical tests of liv- steroids,122,123 there is little enthusiasm for their use for er function. Follow-up liver biopsies revealed histologic several reasons. Approximately 75 percent of patients improvement, primarily decreased inflammation. Most with primary sclerosing cholangitis have chronic inflam- patients in this group had less stricturing on cholangi- matory bowel disease and are already being treated ography after one to eight years of methotrexate. How- with corticosteroids while primary sclerosing cholangi- ever, in a recently concluded prospective, double-blind tis develops and progresses. Furthermore, combined study, methotrexate produced no therapeutic benefit.31 treatment with both corticosteroids and colchicine nei- Although methotrexate, as compared with placebo, sig- ther improved biochemical test results nor slowed the nificantly reduced the serum levels of alkaline phos- The New England Journal of Medicine Downloaded from nejm.org on April 22, 2013. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved. phatase, it had no effect on serum levels of bilirubin, after transplantation, it is important to continue mon- aminotransferases, or albumin, or on the rate of refer- itoring for colon cancer in patients with primary scle- ral for liver transplantation. Half the patients in this rosing cholangitis who also have chronic ulcerative study already had cirrhosis and may have had medical- ly irreversible disease. A larger randomized, controlledtrial including only patients without cirrhosis is needed to evaluate methotrexate further.
Primary sclerosing cholangitis remains an enigmatic, difficult-to-treat disease. Progress in treating or pre- Other Medical Agents venting this disease will be slow until its cause is better There have been anecdotal reports of the treatment understood. The indolent beginnings of the illness for of primary sclerosing cholangitis with azathioprine, col- most patients and its slow rate of progression belie its chicine, cholestyramine, antibiotics, and cyclosporine, true severity. Often, physicians delay treatment, or the but no convincing evidence that any of these agents is referral of patients to centers conducting controlled tri- effective.131-135 als, until the disease has become symptomatic andhence untreatable. Most symptomatic patients have ad- vanced and medically irreversible disease. In the fu- The close association between primary sclerosing ture, asymptomatic patients with only early cholangio- cholangitis and ulcerative colitis, along with the hypo- graphic and histologic changes should be included in thetical role of enteric bacteria in the disease's patho- prospective trials of new therapies. New strategies that genesis, has led some to consider proctocolectomy as a employ combinations of drugs such as ursodiol, metho- treatment. But in one retrospective study of patients trexate, antibiotics, and other immunomodulatory com- with both primary sclerosing cholangitis and chronic pounds appear to be the most promising approach to ulcerative colitis, patients who underwent proctocolec- treatment at this time.
tomy had no improvement in biochemical test results,cholangiography, hepatic histology, or survival.50 Proc- tocolectomy should be performed only because of the 1. Chapman RWG, Arborgh BA, Rhodes JM, et al. Primary sclerosing cho- severity of proctocolitis.
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