Primary Biliary Cirrhosis Primary Sclerosing Cholangitis

Primary biliarycirrhosis (PBC)

Primary sclerosingcholangitis (PSC)

The informed patient

Revised

edition 2009

© 2009 Falk Foundation e.V.All rights reserved.

Publisher

www.falkfoundation.org

8th revised edition 2009


Primary biliarycirrhosis (PBC)


Compiled byProf. Dr. U. Leuschner, Frankfurt am Main (Germany)

Author:Prof. Dr. U. LeuschnerKlinikum der UniversitätTheodor-Stern-Kai 760590 Frankfurt am MainGermany


Contents

Primary biliary cirrhosis (PBC) . . . . . . 5

What is primary biliary cirrhosis? . . . . . . . . . 5Frequency of the disease and its durationStaging

How does one recognize primarybiliary cirrhosis? . . . . . . . . . . . . . . . . . . . . . . . 10

How does your physician diagnose PBC? . . 11Physical examinationLaboratory tests, ultrasound tomographyTissue samples from the liver (liver biopsy)

What is the clinical course of PBC? . . . . . . . 14Associated “rheumatic” disordersLoss of bone mineral density (osteoporosis)Fatty stools (steatorrhea), vitamin deficiencysyndromesSkin changesComplications of complete cirrhosis

How does one treat PBC? . . . . . . . . . . . . . . . 18Drug treatmentResults and side effects of therapyTreatment of osteoporosis, steatorrhea andvitamin deficienciesLiver transplantation

Is primary biliary cirrhosis related toautoimmune hepatitis? . . . . . . . . . . . . . . . . . . 23

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

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Primary sclerosing cholangitis (PSC) 25

What is primary sclerosing cholangitis? . . . . 25StagingDifferences between PSC and primary biliarycirrhosis (PBC)Cancer risk

How does one recognize primarysclerosing cholangitis? . . . . . . . . . . . . . . . . . . 28

How does your physician diagnose PSC? . . 30Physical examination and diagnostic ultrasoundLaboratory testsEndoscopic retrograde cholangiography (ERC)Tissue samples from the liver (liver biopsy)

What is the clinical course of PSC? . . . . . . . 33

How does one treat PSC? . . . . . . . . . . . . . . . 35Drug treatmentEndoscopic treatmentLiver transplantationTreatment of associated inflammatorybowel disease

Is primary sclerosing cholangitis relatedto primary biliary cirrhosis or autoimmunehepatitis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

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Primary biliary cirrhosis (PBC)


What is primary biliary cirrhosis?Primary biliary cirrhosis (PBC) is a chronic, progressivedisease of the liver that is initially focal, i.e. it affectsonly certain regions of the liver, but over time pro-gresses to affect the entire organ. It starts in the smallbile ducts, which are destroyed by an inflammation.This results in retention of the bile produced in theliver and the deposition of toxic bile acids and othertoxic compounds.

Because the inflammation is not caused by whiteblood cells and no pus is produced, the disease isalso known as non-suppurative destructive bile ductinflammation. Its more common name, primary biliarycirrhosis, is due to the fact that the disease was for-merly identified only in its terminal stage, which ischaracterized by cirrhosis. Today, early diagnosis ispossible. The old name primary biliary cirrhosis, how-ever, has been retained because of its establishedplace in clinical practise. Because the blood or serumof patients with PBC contains so-called immunemarkers, which point to the presence of certain im-munological reactions, and corresponding cells arefound in the liver (see below), scientists speak of anautoimmune disease in which the cells of the immunesystem attack the body’s own tissues.

Frequency of the disease and its duration

In 80–90% of cases, primary biliary cirrhosis affectswomen, males only in 10–20%. The disease veryrarely strikes children but its frequency is higher thanthought even a few years ago.

Untreated, patients with PBC have an average sur-vival of 12 years, with a maximum of 20 years. The

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medications currently available have resulted in a sig-nificant prolongation of the clinical course and the op-tion of liver transplantation, which may ultimately berequired, can result in a large proportion of patientsbeing cured.

Staging

Current practice divides PBC into four stages (stagesI–IV), although the exact length of the individualstages is unclear.

Stage I: In this stage, the inflammatory changes arerestricted to the bile ducts (figure 1) and the immedi-ately surrounding connective tissue (non-suppurativedestruction of the bile ducts). The inflammatory cellsinvolved at this stage are so-called immunocompe-tent cells, which, as mentioned above, attack theperson’s own liver. Cells of this type are also foundin other immune diseases of the liver, for example inautoimmune hepatitis.

Stage II: This stage is characterized by increased for-mation of bile ducts (bile duct proliferation). Thesenew bile ducts try to replace the destroyed ones. Theinflammatory changes in the surrounding connectivetissue consolidate and may spread to neighboringliver tissue (figure 2).

Stage III: More and more bile ducts are now destroyed(bile duct rarefication). Adjacent hepatic tissue is in-creasingly affected by inflammatory change and anincrease in connective tissue heralds the onset ofcirrhosis (figure 3).

Stage IV: Connective tissue has increased further andhas separated the remaining liver tissue into fields ofdifferent size. Because of the tendency of liver tissueto regenerate, regeneration nodes of varying size ap-pear (figure 4). This makes the surface of the liver

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Inflammatory cellswhich destroy thebile ducts

Connective tissue

Figure 1: PBC stage I

Figure 2: PBC stage II

Liver cells(Liver lobule)

Inflammation invadesthe liver tissue

The number of bile ductshas increased (bile ductproliferation) and bile ductsare destroyed

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The number of bile ducts isreduced (bile duct rarefication)

Connective tissueand the inflammationfurther invade the livertissue which is devidedin areas of different size

Figure 3: PBC stage III

Reduction of thenumber of inflam-matory cells

Intense augmentationof the connective tis-sue, which completelydivides the liver tissue(liver cirrhosis)

Figure 4: PBC stage IV

Regeneration nodules


bumpy. The bile ducts continue to disappear and in-flammatory cells in the surrounding connective tissuehave become fewer. We have now reached completecirrhosis (PBC). Since in complete liver cirrhosis notonly bile ducts have changed their course in the liverbut also blood and lymph vessels, blood and lymphcan be accumulated and esophageal varices and as-cites will develop.

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How does one recognize primarybiliary cirrhosis?The first symptom of PBC is often pruritus (itching),which can be mild but may be moderate or even se-vere, and which is most noticeable at night. Mostoften affected are the arms, back and legs. Prurituscan increase in the warmth (for example in the bed)or in dry air (heating period). Patients may also expe-rience significant fatigue or reduction in performanceas a first sign of the disease (table 1). More rarely,there may be yellowish gray subcutaneous depositsof fat, called xanthelasmata in the nasal region of theeyelids, though these more commonly do not appearuntil later in the course of the disease.

PBC may manifest itself for the first time followingpregnancy. In these cases, patients may have experi-enced gestational cholestasis (reduced outflow ofbile) during the last three months prior to delivery,which, however, resolves after the birth. Not longerafterwards, however, the same symptoms (especiallypruritus) recur. These cases of recurrent symptomsfollowing delivery are mostly due to PBC, as is easilydemonstrated using laboratory data (see below).

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Characteristics of PBC

• Females are most commonly affected, lessoften males

• First disease manifestation following pregnancy• Pruritus (itching of arms, legs, back)• Tiredness, fatigue, reduced performance• Sometimes xanthelasmata (subcutaneous fatdeposits in the eyelids)

Table 1


How does your physician diagnosePBC?In the past, PBC was difficult to diagnose. Because itwas typically first diagnosed in an advanced stage, itreceived the name “primary biliary cirrhosis”. Today,simple blood tests can confirm the diagnosis in earlierstages (stage I and II), when patients have not yet de-veloped cirrhosis.

Physical examination

In early disease stages, the physician typically findsno changes on physical examination. There is nojaundice (yellow discoloration of the skin and eyescaused by increase in serum bilirubin) and the liverand spleen are not enlarged. Ultrasound of the liverreturns normal findings or, if abnormal, are of the typeassociated with fatty degeneration (steatosis). In amore advanced stage, the liver may be enlarged, fol-lowed later by signs of cirrhosis (see table 4). At ultra-sound, the liver surface is wavy or bumpy, due toscar tissue the liver itself shrinks and decreases insize over time, and because a reverse blood flowexists spleen size increases. Since similar alterationscan be found in patients in whom liver cirrhosis devel-oped of different reasons all findings are not typicalfor PBC alone.

Laboratory tests, ultrasound tomography

Even at an early stage there are typical changes onlaboratory examinations of the blood. Almost 100%of patients show elevation of so-called antimitochon-drial antibodies (AMA) in the blood. AMAs are anti-bodies that circulate in the blood and are directed atthe mitochondria, cell organelles in which the energymetabolism of liver and bile duct epithelial cells islocated. AMAs, although they are not the cause of

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PBC, nor are they responsible for the severity ofthe disease, are strong evidence for the diagnosis(table 2). In addition, there are increased blood levelsof enzymes such as alkaline phosphatase (AP) andγ-glutamyltranspeptidase (GGT or γGT), which indi-cate inflammatory changes of the bile ducts andcholestasis. Also characteristic for the disease is anincrease in blood levels of a protein called im-munoglobulin M (IgM). If these parameters in theblood are increased and if repeated examinationsdocument the presence of AMAs, the diagnosis ofPBC can be considered confirmed, even when thepatient has no symptoms. Levels of other liverenzymes, such as alanine aminotransferase (ALT),aspartate aminotransferase (AST) and glutamate-de-hydrogenase (GLDH), which indicate inflammatorychanges in the liver, may be slightly elevated. This isdue to the fact that the inflammation primarily affectsthe bile ducts, not the liver tissue itself.

In more advanced disease stages (stages III and IV),there is hardly any further change in laboratory para-meters. Thus, laboratory values by themselves say littleabout the stage of the disease. In late stages, liverfunction gradually declines, resulting in a drop in theprotein (albumin) concentration of the blood and in

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Characteristic laboratory findings in PBC

• Elevated alkaline phosphatase (AP) andγ-glutamyltranspeptidase (GGT, γGT)

• Slight increase of the transaminases(AST and ALT)

• Often significant increase in immunoglobulin M(IgM)

• Evidence of antimitochondrial antibodies (AMA)

Table 2


clotting factors. Bilirubin, the main pigment of the bile,however, increases and patients develop jaundice. Atthe beginning only in the eyes, lateron all over theskin. Because bilirubin is not excreted by bile but byurine the urine is dark while the stool is getting light.

Ultrasound examination now reveals a liver surfacethat is irregular. There is also evidence of disturbedblood supply to the liver (collateral circulation), accu-mulation of fluid in the abdominal cavity (ascites) andsometimes of an enlarged spleen.

Laboratory tests should, depending on the severityof the disease, be obtained every 4–12 weeks, withfollow-up ultrasound examinations every 4–8 months.

Tissue samples from the liver (liver biopsy)

Sampling of tissue obtained by ultrasound-guidedpuncture of the liver is done only at the time of first di-agnosis for histological confirmation. Although it iscurrently a matter of discussion whether, given thehighly reliable nature of the available laboratory tests,liver biopsy is necessary at all, the fact that PBC is adisease requiring life-long treatment and possibly livertransplantation underscores the importance of con-firming the diagnosis by histological examination ofthe tissue. Once the diagnosis has been confirmed,further biopsies are not required unless there is suspi-cion of hepatocellular carcinoma. For liver biopsy, thepatient is usually admitted to the hospital for one anda half days to monitor for complications, such asbleeding or bile leakage, which, however, are ex-tremely rare. Liver puncture can also be done on anoutpatient basis in cases in which timely access tomedical care in the case of complications is assured.

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What is the clinical course of PBC?

Common symptoms

In its earlier stages, PBC usually causes no typicalcomplaints. Pruritus (see above), which in some pa-tients may occur early and long before a final diagno-sis of PBC is made, may in some cases not occuruntil later, even sometimes for the first time in a termi-nal disease stage. Typical for PBC is tiredness, fatigue,and a drop in productivity.

Associated “rheumatic” disorders

Some patients report symptoms affecting the jointsand muscles. These are called associated rheumaticsymptoms. Also considered a rheumatic disease isthe so-called Hashimoto thyroiditis. In this disease,the body produces antibodies against thyroid tissue,which is gradually destroyed. Another disorder in whichautoimmunological cases have been discussed is theso-called Sicca syndrome. It is characterized by re-duction in the secretions of the large glands, such asthe tearr, vaginal and salivary glands and the pan-creas (table 3).

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Important associated disorders in patientswith PBC

• Associated rheumatic disordersJoint complaintsHashimoto thyroiditisSicca syndrome

• Osteoporosis• Vitamin deficiency• Skin changes typical for cirrhosis (see table 4)• Hepatocellular carcinoma

Table 3


Loss of bone mineral density (osteoporosis)

Osteoporosis, which is a loss of bone mass, occursearly in patients with PBC. Why this occurs in thesepatients is unknown. Because PBC most commonlyaffects women and because women not infrequentlysuffer from osteoporosis following menopause, it issometimes not possible to distinguish between thesetwo forms. The extent of osteoporosis can be mea-sured radiologically (DEXA scan). In some cases, pa-tients require treatment with medication.

Fatty stools (steatorrhea), vitamin deficiencysyndromes

Sicca syndrome results in dry mucous membranes(e.g in the eyes) and is also associated with reducedproduction of enzymes by the pancreas which are re-quired for digestion of fats. Fat cannot be cleaved byenzymes in the gut and is excreted via the stool(steatorrhea). In this case, the fat content of the stoolis increased (steatorrhea). Because bile acids arenecessary for the absorption of fats and fat-solublevitamins (vitamins A, D, E and K in the gut), cholesta-sis in the liver resulting in a deficiency of bile acids inthe bowel together with Sicca syndrome contributesto fatty stools and vitamin deficiencies. A deficiencyof vitamin A results in night blindness; vitamin D defi-ciency promotes development of osteoporosis, whilereduced levels of vitamin K is associated with disor-ders of blood coagulation. In most patients, however,vitamin deficiency syndromes are not significant andmay be mild, so that the above-mentioned symp-toms do not develop and no treatment as a rule is re-quired.

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Skin changes

We have already mentioned the xanthelasmata, orsubcutaneous deposits of fat in the eyelids. Smallfatty tumors, called xanthomata, may also develop onthe hands, feet or buttocks. As PBC progresses fromits early to late stages, the classical signs of liver cir-rhosis develop (table 4). On the skin, there may bestar-shaped lesions called spider naevi. The color ofthe lips and tongue may become darker (lipstick-lips)and the skin appears thinner, especially on the faceand brow.

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Signs of liver cirrhosis (due to PBC, PSCand other causes)

• Skin changesSpider naevi (dilated small blood vessels)Lipstick or lacquer lips (degeneration of lip skin,darkening of the red color of the lips)Red tongue (degeneration of the epithelium ofthe tongue)Thinning of the skin (disturbance of the nutritionof the skin with degeneration)

• Ascites (fluid in the abdominal cavity)• Edema (swelling of the legs)• Black and blue marks after very minor injuries(tendency to bleed)

• Loss of body hair (chest and abdomen) in males• Signs that are not observable by the patient:Esophageal varices (varicose veins in theesophagus)Reduced brain function (hepaticencephalopathy)

Table 4


Complications of complete cirrhosis

The complete or near-complete transformation of theliver into scar tissue results in a significant reduction inblood flow through the organ. Instead, the blood flowsthrough so-called collateral pathways that bypass theliver. These include varices of the esophagus, whichmay bleed profusely. There may also be accumulationof fluid in the abdominal cavity (ascites) and brainfunction may also be affected (hepatic encephalopa-thy), which can further complicate the clinical picture.In the terminal stage about 3% of patients develophepatocellular carcinoma.

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How does one treat PBC?As late as 1985, PBC was considered an untreatabledisease. Today, this disease is amenable to bothtreatment with drugs and with liver transplantation.

Drug treatment

Treatment with medication begins as soon as the di-agnosis is confirmed, regardless of disease stage.Treatment consists in the administration of ursodeoxy-cholic acid (UDCA), a bile acid that normally occurs inonly small amounts in humans. The daily UDCA doseis 13–15 mg per kilogram of body weight. UDCAshould be taken in two to three doses per day, treat-ment should not be interrupted. Interruption of thera-py results in a renewed worsening (rebound effect)in laboratory values (table 5). Recent studies haveshown that in some patients a combination of UDCAwith a cortisone preparation (prednisone, budesonide)or, at least initially, with the immunosuppressant med-ication, azathioprine, is superior to the effects of UDCAalone. Further data are needed before this combina-tion can be recommended as standard therapy. In

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Drug therapy of PBC

• Ursodeoxycholic acid (UDCA): 13–15 mg perkilogram of body weight daily

• Therapy starts immediately after the diagnosisis confirmed

• Duration of therapy: life long or until livertransplantation

• If response to UDCA is inadequate, combinationwith cortisone, budesonide or azathioprine (stillbeing tested in studies)

Table 5


patients who do not respond sufficiently to UDCAalone a combination therapy should be initiated al-ready now. Combination therapy should only be startedin patients with the early stages I or II of PBC.

Results and side effects of therapy

In infrequent cases, UDCA is associated with diar-rhea. As a rule, however, the drug is taken withoutany side effects. Many patients have been treatedwith UDCA over a period of 12–22 years without anyneed to interrupt or discontinue the drug due to sideeffects.

As an effect of treatment during the first six monthsthe liver enzymes γGT and GLDH drop by up to 80%,followed by improvements in AP and IgM by 30–60%and finally of the inflammation parameters, AST andALT. Only the concentrations of AMAs remain un-changed. In 30% of patients with relatively low initialconcentrations, value return to normal after three tofive years of therapy, while in the remaining 70% theyimprove significantly but never completely return tonormal.

It has been shown that therapy with UDCA improvesnot only the laboratory values but also histologicalfindings. The development of esophageal varices isslowed, the need for liver transplantation is delayedand patients’ life expectancy is improved.

Less clear is the effect of UDCA on symptoms suchas fatigue and pruritus, which may sometimes be-come intolerable (table 6). The treatment of these twosymptoms has been shown to be especially difficult,requiring much patience and endurance from bothphysician and patient. It appears to be the case thatpatients with mild cholestasis (slight elevation of APand GGT, but normal bilirubin) are more often free ofcomplaints than are patients with high values.

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Treatment of osteoporosis, steatorrhea and vitamindeficiencies

Osteoporosis, which develops at an early diseasestage, can today be treated very effectively with bis-phosphonates. In women with postmenopausal os-teoporosis, bisphosphonates resulted in preventionof bone loss and even in restoration of bone mass.This effect has not yet been proven in patients withPBC but is considered very likely. For this reason,these drugs are also used in patients with PBC.Treatment with vitamin D and calcium is also effec-tive. In all cases patients should maintain a regular,balanced Western diet and get plenty of outdoorexercise, which also helps prevent osteoporosis(table 7). Female sex hormones (estrogens) also pre-vent osteoporosis. Because estrogens, however, alsopromote cholestasis, their use in PBC is controversial.

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Treatment of osteoporosis in PBC

• Adequate physical exercise outdoors• Well-balanced diet• Bisphosphonates and/or calcium and vitamin D• Estrogens (in females)

Table 7

Treatment of pruritus

• Ursodeoxycholic acid (UDCA)• Colestyramine or• Colestipol or• Opiate antagonists or• Combination of the above treatments

Table 6


Fatty stools, which occur less frequently, can becombated by reducing the fat content of the dietto 40–50 grams daily. If this is not sufficient, patientscan be given enzyme-containing medications. Ifthese, in turn, do not produce the desired effect, pa-tients are advised to prepare their food with modified,easily absorbable fat such as Ceres margarine. Thesemodified fats do not require to pancreatic enzymes tobe broken down before they are absorbed in thesmall bowel.

If patients experience vitamin deficiencies, regular in-jections of the fat-soluble vitamins A, D, E and K arerecommended, but unfortunately these drugs are nolonger available. Because they are injected into mus-cle, they cannot be lost with fatty stools.

Liver transplantation

As the disease progresses and liver function cannotbe maintained, or if there are complications or itchingbecomes unbearable, liver transplantation representsthe most effective option. Although transplantation ofthe liver is one of the most major operations in mod-ern medicine, the technique has become very refinedand is very effective. Following liver transplantation,patients undergo follow-up treatment with the long-term goal of preventing rejection of the transplantedorgan. This treatment consists of administration ofso-called immunosuppressants (table 8), which manyphysicians give in combination with UDCA.

Following transplantation, PBC may recur in a smallnumber of patients in the transplanted liver or theymay develop a different type of liver damage (e. g. re-jection, changes in blood vessels). In these cases,patients are treated with medications as long as pos-sible but in some cases a second liver transplantationmay be necessary.

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Immunosuppressive therapy optionsfollowing liver transplantation

• Cortisone preparations (e. g. prednisolone orprednisone)

• Cyclosporin A• Tacrolimus• Azathioprine• Mycophenolate Mofetil• Combination of the above medications

Table 8


Is primary biliary cirrhosis related toautoimmune hepatitis?Indeed, there is a small proportion of patients withPBC whose laboratory parameters and findings frommicroscopic analysis of liver tissue point equally toPBC and to autoimmune hepatitis. Other patients,who suffered initially from PBC, later showed signs ofincreasing inflammation, and finally they showedsigns of both PBC and chronic autoimmune hepatitis.Such cases of mixed disease are called “overlap syn-dromes”.

The small number of patients with overlap syndromemay respond to a combination of UDCA (13–15 mgper kilogram of body weight per day) and a low-dosecortisone preparation, possibly in combination withthe immunosuppressant azathioprine.

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Summary– Primary biliary cirrhosis (PBC) is a chronic inflam-

matory autoimmune disease of the liver.

– Beginning at the small bile ducts and graduallyextending to the liver tissue, PBC leads ultimatelyto liver cirrhosis.

– The average survival of untreated patients is 12–20years from first diagnosis.

– Because of improvements in laboratory diagnos-tics, PBC can today be identified in an early dis-ease stage.

– Drug therapy consists in life-long administration ofursodeoxycholic acid (UDCA) beginning immedi-ately after confirmation of diagnosis.

– UDCA improves liver enzyme values and histolog-ical findings, postpones the need for liver trans-plantation and extends life expectancy.

– Liver transplantation remains as an option whentherapy with medications is no longer effective.

– Results of liver transplantation are very good andare steadily improving.

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Primary sclerosing cholangitis (PSC)


What is primary sclerosingcholangitis?Primary sclerosing cholangitis (PSC) is a chronic liverdisease that is characterized by inflammation duringwhich onion skin-like layers of connective tissue de-velop around the small bile ducts. As the amount ofconnective tissue increases, the bile ducts are oc-cluded (closed off) and cholestasis develops, which, ifextensive, leads to jaundice. These areas of inflam-mation subsequently involve neighboring liver tissue,leading to cirrhosis as the terminal stage of the dis-ease. Although PSC is an autoimmune disease, thereare no specific immune markers in serum. There are,however, cells known as immunocompetent cells thatare capable of attacking the body’s own tissue, suchas bile ducts or liver tissue. The frequency of PSC isnot exactly known but it is being much more fre-quently diagnosed.

Staging

PSC is divided into four stages (stages I–IV; table 9).

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Stages of PSC

Stage I Inflammation and connective tissueproliferation around the small bileducts

Stage II Inflammation passes into the liver withfurther scar tissue formation

Stage III More severe scar tissue formationStage IV Biliary liver cirrhosis

Table 9

Differences between PSC and primary biliarycirrhosis (PBC)

Despite superficial similarities, PSC differs from PBCnot only in terms of the above mentioned histologicalor microscopic changes but also in other aspects. InPSC, the bile duct changes develop not only in theintrahepatic bile ducts but may also affect the largecommon bile duct outside the organ leading from theundersurface of the liver to its entrance into the boweland may occur simultaneously both intra- and extra-hepatically. The gallbladder, however, is rarely affect-ed.

A further important difference between PSC and PBCis that, in PSC, 80–90% of patients also suffer frominflammatory bowel disease (IBD) characterized by in-flammation and ulceration of the mucosal membraneof the bowel. In 10–15% of cases, this inflammatorybowel disease is of the type known as Crohn’s dis-ease, while the remaining 80–85% of patients showsigns of ulcerative colitis.

A further important difference is that PSC may alsoattack children and adolescents, while PBC occursalmost exclusively in adults. Up to 80% of PSC pa-tients are men, unlike PBC which, in 90% of cases,affects women (table 10). And finally, in PSC differenttypes of malignancies can develop, while in PBC onlyliver cell carcinoma has been described.

Cancer risk

Patients with PSC are at an increased risk of devel-oping cancer, which means that regular follow-up isadvisable. About 10% of patients develop carcinomaof the bile ducts, which in 30% of patients developsearly and later is seen less often. The risk of develop-ing colon carcinoma in patients with associated ul-

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cerative colitis is higher than in patients with ulcera-tive colitis but without PSC. For this reason, patientsshould undergo colonoscopy at regular intervals. Ac-cording to the most recent studies, the risk of devel-oping carcinoma of the pancreas is 14 times higherthan in the general population, underscoring the im-portance of regular ultrasound examinations. And fi-nally also the development of gallbladder carcinomahas been described more often, especially in patientswith gallbladder polyps.

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Differences between PBC and PSC

• PSC: Bile duct changes both intra- andextrahepatic

• PSC: Antimitochondrial antibodies (AMA)absent

• PSC: 80–90% of patients also haveinflammatory bowel disease

• PSC: Predominantly affects men• PSC: May also affect children and adolescents• In PSC different types of malignancies candevelop

Table 10

How does one recognize primarysclerosing cholangitis?The disease course of PSC is usually more severeand varied than that of PBC. Patients frequently reportfeeling generally unwell, with reduced performanceand tiredness as the first symptoms. Pruritus (itching)is common. Fever indicates a concomitant bacterialinflammation of the bile ducts. Transient or more per-sisting yellow discoloration of the eyes (scleral icterus),sometimes with mild skin jaundice, can occur as aresult of occlusion of the bile ducts (table 11). Suchocclusions may occur because of inflammation, nar-rowing of the ducts caused by scar tissue formationor because of the presence of sludge (thickened bile)or small stones, which may occur in high-gradechanges of the bile ducts.

If patients at the same time suffer from one of theabove mentioned inflammatory bowel diseases (ul-cerative colitis or Crohn’s disease), they may experi-ence abdominal pains of varying severity, diarrhea

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Symptoms and findings in PSC

• Tiredness, fatigue, reduced performance• Significant feeling of general illness• Subfebrile or febrile temperatures• Itching (pruritus)• Recurring jaundice• Joint complaints• Weight loss• Upper abdominal complaints*)• Soft stools, bleeding, diarrhea*)

*) Symptoms of concomitant ulcerative colitis orCrohn’s disease

Table 11


and weight loss. The severity of IBD associated withPSC, however, may be mild and may come to lightonly upon questioning by the physician.

In addition, there may be rheumatic changes in thejoints and other associated symptoms (see table 3).In a later disease phase, patients develop the symp-toms of liver cirrhosis (see table 4).

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How does your physician diagnosePSC?

Physical examination and diagnostic ultrasound

In early stages of PSC, physical examination mayoften reveal no evidence of the underlying disease.The liver may be slightly enlarged but may also benormal in size. In the late stages characteristics ofliver cirrhosis can be detected (see PBC, table 4). Ifpatients at the same time suffer from one of the in-flammatory bowel diseases, they may experiencepain with pressure to the abdomen. The physicianmay feel a lump representing several bowel loops orhear gurgling and other noises throughout the wholeabdomen. If the disease has progressed as far ascirrhosis, the changes given in table 4 will often befound.

Ultrasound examination of the liver initially finds onlyuncharacteristic changes, but as the disease pro-gresses, ultrasound demonstrates widening and out-pouching of the bile ducts. In the final stage we havethe picture of complete cirrhosis with an irregular liversurface, shrinkage and enlargement of the spleen.

Laboratory tests

In PSC, laboratory tests show significant increases inserum especially of the enzymes that point to cholesta-sis, such as alkaline phosphatase (AP) and γ-glutamyl-transpeptidase (GGT or γGT), and to a lesser extentof the hepatic transaminases (alanine aminotrans-ferase: ALT; aspartate aminotransferase: AST). Theserum concentration of the bile pigment bilirubin de-pends on the disease stage and on the associatedcomplications, such as gallstones. Unlike primary bil-iary cirrhosis (PBC), the other important liver diseaseassociated with cholestasis, PSC, is not characterized

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by increased titers of antimitochondrial antibodies(AMA), which is typical for PBC (in PSC there are notypical antibodies at all). In addition, the erythrocytesedimentation rate (ESR) and the number of whiteblood cells may be elevated. In a more advancedstage of the disease, there may be a reduction in thenumber of blood platelets, which are trapped in theenlarged spleen and destroyed and which can be ob-served in all types of liver cirrhosis. Bilirubin increasesand the protein synthesis of the liver and the forma-tion of coagulation factors is reduced (see PBC).

Endoscopic retrograde cholangiography (ERC)

The decisive diagnostic method consists of the radio-logical imaging of the intra- and extrahepatic bile ductsystem (endoscopic retrograde cholangiography).With this method, similar to gastroscopy, an endo-scope is passed through the mouth and advancedinto the duodenum. Radiological contrast medium isinjected directly into the bile duct through the endo-scope. ERC visualizes the typical outpouchings andinterruptions in both the intra- and extrahepatic bileducts that occur even at early stages of the disease.These changes are so typical that a single look at theradiological images permits the correct diagnosis.The only entities which must still be excluded areAIDS-related inflammation of the bile ducts, changesfollowing liver transplantation and changes due to thelocal use of anti-cancer medications (table 12). Be-cause these other diagnoses are easily excluded by acareful case history, ERC represents the most reliablemethod for diagnosing PSC.

The bile ducts and changes due to PSC can also bevisualized using magnetic resonance cholangiogra-phy (MRC). Although this spares the patient from“swallowing the tube” the images that are possible

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with the method at the present time are less satisfac-tory than those provided by ERC. In addition, MRC isa purely radiological technique which, unlike ERC,does not include the capability for any instrumentalintervention (e.g. dilatation) of the bile ducts. In 10–15%MRC is unable to diagnose PSC.

Tissue samples from the liver (liver biopsy)

A histologic-microscopic confirmation of the diseaseis not actually obligatory. However, because of theneed for life-long medication therapy and the possi-bility of the future need for liver transplantation, thehistologic confirmation of the diagnosis is desirable.Tissue is obtained by fine needle puncture of the liverin local anesthesia under ultrasound guidance.

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Diseases with endoscopic (ERC) findingsof the bile ducts similar to those seen inprimary sclerosing cholangitis (PSC), whichmust be differentiated from PSC and furtherdifferential diagnoses of PSC

• AIDS cholangitis• Bile duct inflammation due to local applicationof cytostatic (anticancer) agents

• Blood circulation problems in the area of the bileducts after liver transplantation

To be differentiated on the basis of ERC, clinicalpicture and laboratory values (differentialdiagnosis):• Primary biliary cirrhosis (PBC: ERC normal)• Bacterial bile duct inflammation (ERC, bloodtests similar)

• Bile duct inflammation caused by parasites(ERC, blood tests similar)

Table 12


What is the clinical course of PSC?PSC is more seldom when compared to PBC, but ifone looks for PSC in patients with inflammatorybowel disease its number rises. PSC follows a chron-ic clinical course with numerous disease flares andwithin 15–20 years it progresses to liver cirrhosis. Inits early stages, however, even over several years, itmay go unnoticed. If, however, the laboratory para-meters of cholestasis (AP, GGT) are elevated in thepresence of unexplained upper abdominal com-plaints, stool irregularities, and especially soft stools,PSC with associated chronic bowel disease mustalways be suspected (table 13).

In rare cases (8–10%), patients with PSC may devel-op carcinoma of the bile ducts. The diagnosis of car-cinoma of the biliary system is not easy. If this diseaseis suspected, every effort must be made to exclude itusing all methods available, including blood tests,ERC (mentioned above), biopsy (tissue sample fromthe suspected region) and a brush biopsy of the sus-picious area. The risk of cancer has already been dis-cussed above.

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Symptoms of PSC associated with ulcerativecolitis or Crohn’s disease

• Abdominal pain• Porridgy, watery, sometimes bloody diarrhea:3–10 or more times daily

• Weight loss• Conjunctivitis• Joint complaints• Open tracks at the end of the bowel (fistulas)• Dough-like, red swellings of the legs (erythemanodosum)

• For further details see table 11

Table 13


How does one treat PSC?

Drug treatment

Previous pilot studies with a low dose of ursodeoxy-cholic acid (UDCA, 10–15 mg/kg of body weightdaily) have shown that UDCA positively influencedsome laboratory data, but had no effect on liver his-tology or life expectancy. Since in a recent study ahigher dose of UDCA was associated with unwantednegative results when compared to placebo, the“European Association for the Study of the Liver”(EASL) does not recommend the general use ofUDCA in PSC. Unlike in PBC, combination regimens,e. g. of UDCA with prednisone or with azathioprine,have not been shown to be effective or have not yetbeen adequately tested. Details regarding the treat-ment of symptoms and associated health problemscan be found in tables 6 and 7, where UDCA shouldbe omitted. The treatment of PSC has neither a posi-tive nor a negative effect on the associated boweldisease and vice-versa.

Endoscopic treatment

Since at present there is no medicamentous treat-ment which is able to re-open bile duct stenoses andstrictures, for these patients endoscopic balloon di-latation is to be recommended. In endoscopic bal-loon dilatation, as in gastroscopy, an endoscope ispassed through the mouth and advanced into thebowel to the site of the opening of the common bileduct. From here, a thin catheter is inserted into thebile duct. At the end of the catheter is a balloon,which can be expanded by injection of fluid (figure 5).This process widens the bile duct and areas of nar-rowing are expanded and made passable for bile

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fluid. When endoscopic treatment was combinedwith UDCA in some patients, general condition, labo-ratory findings and life expectancy improved; but alsothese data have to be confirmed in future studies untilcombination treatment can be recommended forgeneral use.

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Figure 5: Typical situation in PSC with significantchanges in both the intra- and extrahepatic bile ductsystem. The catheter has been advanced through theendoscope, but the balloon has not yet been inflated.

extrahepaticbileducts

intrahepaticbileducts


Liver transplantation

If, after sometimes many years, patients with PSCcan no longer be effectively treated with drug and en-doscopic therapy, liver transplantation is the last treat-ment option. Following transplantation, patients re-ceive so-called immunosuppressants, as shown intable 14.

Treatment of associated inflammatory bowel disease

Patients with PSC who simultaneously suffer fromCrohn’s disease of the small intestine are treated witha cortisone preparation, such as prednisolone, in theacute phase. Once the bowel disease has gone intoremission, the cortisone is gradually withdrawn. IfCrohn’s disease is restricted to the colon, patientscan undergo long-term treatment with mesalazine(table 15). That mesalazine is able to prevent diseaserecurrence remains unclear.

If, as is much more common, PSC is associated withulcerative colitis, treatment of an acute flare is like thatin Crohn’s disease, but with the addition of mesalazine.Maintenance treatment for prophylaxis against a newdisease flare also consists of mesalazine.

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Immunosuppressive agents after livertransplantation

• Cortisone preparations (e. g. prednisolone orprednisone)

• Cyclosporin A• Tacrolimus• Azathioprine• Mycophenolate Mofetil• Combination of the above medications

Table 14

In Crohn’s disease, surgery is indicated only in thecase of severe complications. Because Crohn’s dis-ease may recur after surgery in another, previouslyunaffected segment of the bowel, it is advisable topostpone surgery as long as possible in order thatpatients do not develop a short-bowel syndrome.

If serious complications require surgery in patientswith ulcerative colitis, however, the total removal ofthe colon (total colectomy) cures the disease. Natu-rally, one attempts to avoid this large operation,which is possible in most patients. Neither the med-ical nor the surgical treatment of the bowel diseaseappears to have any effect on the biliary disease.

Treatment must be flexible and tailored to the pa-tient’s exact situation.

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Treatment of inflammatory bowel diseases inpatients with PSC

• Cortisone preparations in acute flares and insmall bowel involvement

• Cortisone preparations are “tapered” overone year

• Mesalazine with colon involvement• Reduced-dose mesalazine as maintenancetherapy

• Combination of both drugs• Local treatment with enemas and suppositories• Surgery

Treatment must be carried out very carefully.

Table 15


Is primary sclerosing cholangitisrelated to primary biliary cirrhosisor autoimmune hepatitis?This question cannot yet be answered with certainty,although there are cases described in which chronicautoimmune hepatitis has transitioned to PSC or ofpatients with PSC or PBC who simultaneously hadchronic autoimmune hepatitis. These data mightcause one to postulate that PSC, PBC and chronicautoimmune hepatitis may somehow be related. Be-cause our understanding of the possible relationshipsbetween these diseases is limited, we will not discussthem at this point.

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Summary– Primary sclerosing cholangitis (PSC) is a chronic

inflammatory autoimmune disease of the liver.

– PSC leads to connective tissue encasement ofthe small and large bile ducts both within and out-side the liver and gradually results in liver cirrhosis.

– PSC most commonly affects males.

– About 80–90% of patients also suffer from an in-flammatory bowel disease (IBD: ulcerative colitisor Crohn’s disease)

– Bile duct carcinoma develops in about 10% of pa-tients; patients also have a higher risk of cancer ofthe colon, pancreas and gallbladder.

– At present there is no medicamentous therapy forPSC. Although with a low dose of UDCA somepositive results have been described, the limiteddata base does not yet allow a specific recom-mendation for the general use in PSC. A higherdose of UDCA was associated with unwanted re-actions. Therefore, the only treatment option wehave is endoscopic dilatation of bile duct stric-tures.

– When endoscopic treatment is not successful orthe risk of complications exists, liver transplanta-tion will become necessary.

– The success rate of liver transplantation is verygood.

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Further information for patients withliver and biliary diseases:

– A Guide for Patients with Liver Diseasesincluding Guidelines for Nutrition (F80e)70 pages

– What you should know about gallstonetreatment (Li82e)30 pages

These brochures can be ordered free of chargefrom Falk Foundation e.V. or the local Falk partner.

www.falkfoundation.org

U82

e8-10/2009/5.000Konk

Primary Biliary Cirrhosis Primary Sclerosing Cholangitis

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