Dr/ Mohammed HussienAssistant Lecturer of Gastroentrology &

Hepatology Kafrelsheikh University

Is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to the formation of multifocal bile duct strictures. PSC is likely an immune mediated, in the majority of patients PSC are associated with inflammatory bowel disease (IBD),it may overlap other immune mediated liver diseases .

Maggs JR.,etal 2008).)

Small duct PSC is a disease variant which is characterizedby typical cholestatic and histological features of PSCbut normal bile ducts on cholangiography.

What is Primary sclerosing cholangitis (PSC)

Epidemiology

• The prevalence and incidence of PSC varies in different regions of the world. • The prevalence of PSC in ulcerative colitis has been

estimated to be ~5%. • The prevalence of IBD among European populations with

PSC is estimated to be 50%.• Gender : Approximately 60%–70% of patients with PSC and

UC are men, and age at diagnosis is usually 30–40 years

(Boonstra K , van Erpecum KJ , van Nieuwkerk KM et al.,2012)

:

Pathogenesis

Diagnosis of PSCA diagnosis of PSC is made in patients with

• Cholestatic biochemical profile• Cholangiography (e.g., magnetic resonance

cholangiography [MRC], endoscopic retrograde cholangiography [ERC], percutaneous transhepatic cholangiography)--- shows characteristic bile duct changes with multifocal strictures and segmental dilatations.• Secondary causes of sclerosing cholangitis have been

excluded.

Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC.

• History and assessment of signs and symptoms.• Serum biochemical tests & Autoantibodies.• Magnetic resonance cholangiography (MRC).• Endoscopic retrograde cholangiography (ERC).• Liver biopsy in selected patients.• Measuring serum immunoglobulin G4 (IgG4) levels.

Diagnosis/Evaluation

Signs and Symptoms

44% asymptomatic but most develop symptoms over time.

Pruritis, jaundice, pain and fatigue are common symptoms.

Later on develop symptoms of cirrhosis and portal hypertension.

Rectal bleeding should lead to consideration of IBD as well as bleeding from portal hypertension.

(Bjornsson E etal.,2008.)

Biochemical Tests• A cholestatic profile with elevation of ALP level,

Gamma-glutamyl transferase will be elevate and the aminotransferases are often elevated.

• Hypergammaglobulinemia IgM levels are found to be increased in ~50% of patients .

• Elevations of serum levels of IgG4 in ~10% of patients with PSC and may represent a distinct subset .

• Elevated IgG4 levels tend to have a more rapidly progressive disease. patients with IgG4-associated disease and PSC do appear to respond to corticosteroids.

(All patients with PSC should be tested at least once for elevated serum IgG4 level

AutoantibodiesA wide range of autoanti-bodies can be detected in the serum of patients with PSCindicating an altered state of immune responsiveness orimmune regulation.Serum Autoantibodies in Primary Sclerosing Cholangitis• Anti-neutrophil cytoplasmic antibody---- 50%–80%• Anti-nuclear antibody ----7%–77%• Anti-smooth muscle antibody ----13%–20%• Anti-endothelial cell antibody ----35%• Anti-cardiolipin antibody -----4%–66%• Thyroperoxidase -----7%–16%• Thyroglobulin------ 4%• Rheumatoid factor ------15%

( Portmann B etal., 2012 ).

Imaging

*Ultrasound, computed tomography or magnetic resonance imaging will be performed in the patient with persistent cholestatic liver tests to exclude biliary obstruction.

*MRCP is noninvasive, less expensive than ERCP, and

has no associated risk of pancreatitis .MRCP, however, does not allow sampling of strictures for brush cytology or biopsy, nor does it allow therapeutic interventions .

*ERCP had been the diagnostic procedure of choice..

Imaging of the biliary tract is the most important initial step.

Liver Biopsy

• is now seldom done to establish the diagnosis of PSC• Unexplained cholestastic liver tests; Small duct PSC liver biopsy is necessary to confirm this diagnosis .• The characteristic feature of liver biopsy,a periductal concentric “onion skin” fibrosis.

(Gossard AA etal., 2005).

Differential diagnosis of primary sclerosing cholangitis

• Secondary sclerosing cholangitis.• Cholangiocarcinoma.• IgG4-associated cholangitis.• Histiocytosis X.• Autoimmune hepatitis.• HIV syndrome.• Bile duct strictures.• Cholendocholithiasis.• Primary biliary cirrhosis.• Papillary tumors.

Multidisciplinary team in Management of Primary sclerosing Cholangitis

MEDICAL TREATMENT• Ursodeoxycholic acid (UDCA) • Immunosuppressive and other Agents ENDOSCOPIC MANAGEMENT• ERCP with balloon dilatationSurgical Management• Biliary reconstruction • LIVER TRANSPLANTATIONSPECIAL SITUATIONS• PSC AND IBD• Risk of Colonic Malignancy• HEPATOBILIARY MALIGNANCIES AND GALLBLADDER DISEASE• PSC-AIH Overlap Syndrome• PSC in Children• Immunoglobulin G4-Associated Cholangitis• Fertility and Pregnancy in PSCGENERAL MANAGEMENT• The management of pruritus • The Mangament of Portal Hypertension• Metabolic Bone Disease• FAT-Soluble Vitamin Deficiencies

Multidisciplinary

Management

Ursodeoxycholic acid (UDCA) • In doses -------->28mg/kg/day.• Many practitioners are using a dose of ~20

mg/kg/day.• Although data from well-controlled clinical

trials are lacking.

At this time, there is no established medical treatment for patients with PSC.

( Angulo P etal., 2000)

MEDICAL TREATMENT

Immunosuppressive and other AgentsOther treatments that have been tested without any obvious proven clinical benefit or improvement of liver biochemistriesinclude:• Azathioprine.• Budesonide.• Methotrexate.• Metronidazole. • Mycophenolate mofetil .• Nicotine. • Pentoxifylline .• Prednisolone. • Tacrolimus. • Vancomycin.

( Angulo P etal., 2000).

1 . ERCP with balloon dilatation is recommended for PSC patients with dominant stricture and pruritus, and/or cholangitis, to relieve symptoms.

2 . PSC with a dominant stricture seen on imaging should have an ERCP with cytology, biopsies, and fluorescence in-situ hybridization (FISH), to exclude diagnosis of cholangiocarcinoma.

3 . Antibiotic prophylaxis to prevent post-ERCP cholangitis. (Preoperative antibiotics followed by a 3- to 5-day course post ERCP have been

advised, using quinolones or cephalosporins.)

4 . Routine stenting after dilation of a dominant stricture is not required, whereas short-term stenting may be required in patients with severe stricture.

ENDOSCOPIC MANAGEMENT

(Merion RM etal., 2005).

• Biliary reconstruction by biliary-enteric drainage allows prolonged clinical improvement, with resolution of jaundice and cholangitis, but has significant risk of cholangitis and increased rates of mortality .• Post-operative scarring also increases the

difficulty of liver transplantation. • Surgical drainage procedures have largely

been discontinued in favor of transplantation due to the superior outcomes of liver transplantation .

Surgical Management

• Liver transplantation, when possible, is recommended over medical therapy or surgical drainage in PSC patients with decompensated cirrhosis, to prolong survival. • Patients should be referred for liver

transplantation when their Model for End-Stage Liver Disease (MELD) score exceeds 14.

LIVER TRANSPLANTATION

• In specific clinical circumstances, patients with PSC may be offered additional MELD points, to improve their priority for receiving a donor organ for liver transplantation.

• MELD exception points can be approved by the United Network for Organ Sharing Regional Review Board for the following.

indications:

1 . Recurrent episodes of cholangitis, with >2 episodes of bacteremia or >1 episode of sepsis .2 . Cholangiocarcinoma <3 cm in diameter, without evidence of metastasis, undergoing treatment through an institutional review board-approved clinical trial.3 . Intractable pruritus.

• Recurrence of PSC after liver transplantation Affecting as many as 20% of patients at 5 years after transplant .• The majority of patients tolerate recurrent

diseasewithout significant morbidity or mortality, but progressive disease can occur in as many as one- third of patients with recurrent PSC.

( Angulo P etal., 2000)

The prevalence of IBD in PSC is much higher than previously thought and recent reviews have stated that up to 80% of patients with PSC have IBD

SPECIAL SITUATIONS

● Extensive colitis (with right-sided predominance of inflammatory activity)● Rectal sparing● Backwash ileitis● Mild or quiescent course● Increased risk of colorectal neoplasia● Increased risk of pouchitis in patients undergoing proctocolectomy with IPAA● Increased risk of peristomal varices in patients undergoing proctocolectomy with ileostomy

Characteristics of Inflammatory Bowel DiseaseAssociated with Primary Sclerosing Cholangitis

PSC AND IBD

Recommendations1 . Annual colon surveillance preferably with chromoendoscopyis recommended in PSC patients with colitis beginning atthe time of PSC diagnosis. 2 . A full colonoscopy with biopsies is recommended in patientswith PSC regardless of the presence of symptoms to assessfor associated colitis at time of PSC diagnosis.

3 . Some advocate repeating the exam every 3–5 years in thosewithout prior evidence of colitis.

• The risk of colorectal dysplasia and cancer is significantly higher (approximately four- to five fold) among patients with PSC and

• IBD compared with those with IBD without PSC.

• 5-Acetylsalicylic acid may also reduce the risk of colonic malignancy

• .

***The mechanism for increased risk of colon cancer in PSC–IBD is unknown, but exposure of the colonic mucosa to toxic bile acids, namely secondary bile acids that may promote carcinogenesis such as deoxycholic acid, So (low-dose UDCA ) may be effective

Risk of Colonic Malignancy

Recommendations• Consider screening for cholangiocarcinoma with regularcross-sectional imaging with ultrasound or MR and serial CA 19-9 every 6–12 months .• Cholecystectomy should be performed for patients with PSC

and gallbladder polyps >8 mm, to prevent the development of gallbladder adenocarcinoma.

HEPATOBILIARY MALIGNANCIES AND GALLBLADDER DISEASE

( Merion RM etal., 2005).

.

*The prevalence of autoimmune hepatitis in patients with PSC is ~10%.

*Patients with autoimmune hepatitis and PSC overlap syndrome tend to be younger than 25 years of age.Recommendations

1 . Further testing for autoimmune hepatitis is recommended for patients with PSC <25 years of age or those with higher than-expected levels of aminotransferases usually 5× upper limit of normal.

2 . MRCP is recommended for patients <25 years of age withautoimmune hepatitis, who have elevated serum ALP usuallygreater than 2× the upper limit of normal.

(Kashyap R etal.,2010)

PSC-AIH Overlap Syndrome

• PSC appears to be much less common among children than adults (prevalence 20% lower than in adults ).• PSC in children is more often associated with higher

serum aminotransferase levels and concomitant autoimmune hepatitis, leading to the use of the term “Autoimmune sclerosing cholangitis”.• Cholangiocarcinoma appears to be rare & Current

guidelines do routine surveillance for cholangiocarcinoma.

(Gregorio GV ,etal.,2001)

PSC in Children

• IgG4-associated pancreatitis and cholangitis in patients who present with sclerosing cholangitis & less likely to have IBD .• IgG4-associated autoimmune pancreatitis is

characterized by strictures in the pancreatic duct, elevated IgG4 levels and response to immunosuppressive therapy.

This condition may be associated with biliary strictures and elevated plasma IgG4 levels,

and liver biopsy may reveal a lymphoplasmacytic infiltrate.

Immunoglobulin G4-Associated Cholangitis

• The pruritus may be so intense that early delivery may occur by induction.• No deterioration of liver function during or after

pregnancy has been reported, and outcome has been satisfactory for both patients and children.• Treatment of PSC during pregnancy with UDCA(10-15 mg/kg) has been promising, and no adverse effects in patients or newborns have been noted.• Regarding the effect of pregnancy on the disease

course of IBD in general, pregnancy did not influence disease phenotype or resection rates, but was associated with a reduction in number of flares in the years afterwards.

Fertility and Pregnancy in PSC

(Lindor KD etal.,2009)

The management of pruritus

GENERAL MANAGEMENT

• Local skin treatment should be performed with emollients and/or antihistamines in patients with PSC and mild pruritus to reduce symptoms

• Bile acid sequestrants such as cholestyramine should be taken (prescribed) in patients with PSC and moderate pruritus to reduce symptoms. Second-line treatment such as rifampin and naltrexone can be considered if cholestyramine is ineffective or poorly tolerated

The Mangament of Portal Hypertension• Recommend screening for varices in patients

with signs of advanced disease with platelet counts <150×10 3 /dl. 4 .

• Tips (transjugular portosystemic shunt).• Management of Ascites & Encephalopathy.• Surgical Portosystemic Collateral ( should

avoided in patient child B & C ).• IBD associated with PSC may require

proctocolectomy and peristomal varices develop in 25% of patients (can be avoided by ileal pouch–anal anastomosis in place of an ileal stoma).

(Herlong HF etal.,2001)

Metabolic Bone Disease

FAT-Soluble Vitamin Deficiencies

• Patients with PSC should undergo bone mineral density (BMD) screening at diagnosis with dual energy X-ray absorption at diagnosis and repeated at 2- to 4-year intervals.

• Fat-soluble vitamin defi ciencies can occur in late stages of PSC

• when patient becomes jaundiced. Levels of vitamins A, E, and D

• should be assessed in patients with advanced disease

(Angulo etal.,2001)

Measure IgG4 levels in all patients at diagnosisAssess for varices in patients with platelet count below 150 x 103 /dl or cirrhosis.

Assess bone density every 2–4 years with dual energy x-ray absorptiometry. Assess for fat soluble vitamin deficiency in patients with advancedز

disease/jaundice.

Monitor liver biochemistries every 3–4 months for signs of strictures, tumors, orsymptoms of autoimmune hepatitis.

Consider screening every 6–12 months for cholangiocarcinoma with cross-sectionalimaging (ultrasound or MRI) and CA 19–9.

Provide colonscopic screening annually in patients with co-existent inflammatorybowel disease

In patients with deterioration and a dominant stricture perform ERCP withperi-procedure antibiotics and consider balloon dilation, with stent if needed.

Refer for liver transplantation if MELD score exceeds 14 and consider for casessuspicious for complicating cholangiocarcinoma.

PrognosisThe estimated 10-year

survival for patients with PSC is approximately 65% in

a population based study