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    Prof. Ziv Ben-Ari

    Liver InstituteRabin Medical Center

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    Cholestatic Liver Diseases

    Primary Biliary Cirrhosis (PBC)

    Primary Sclerosing Cholangitis

    (PSC)

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    Case Presentation 1

    A 36 years old male

    Israeli origin

    Was diagnosed 6 years ago as inflammatory

    bowel disease (ulcerative colitis)

    Pancolitis, 4 years in remission

    Treatment rafassal 500mg x4/d

    A cousin ,was diagnose 1 year ago ascrohns disease

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    Case Presentation 1 cont

    On routine check up:

    Hepatomegaly 3cm below costal margin

    No other stigmata of chronic liver disease

    Increase serum cholestatic liver enzymes:

    Alk phos 420U/l, GGT 400U/l, AST 42U/l, ALT

    50U/l, total bilirubin 1.1 mg/dl, albumin

    4.1g/dl, other chemistry results normal, CBCnormal

    Increased serum cholestatic Vs. hepatocellular liver enzymes

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    Primary sclerosing cholangitis (PSC)

    Definition and epidemiology

    PSC is a rare but important cause of chronic liverdisease

    The disease is characterized by chronic

    inflammation and obliterative fibrosis of the intra-and/or extra-hepatic biliary tree which leads to bilestasis, hepatic fibrosis, and cirrhosis

    This can be complicated by portal hypertension,hepatic failure requiring transplantation

    First-degree relatives of patients with PSC have anearly 100-fold increased risk of developing PSC

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    Annual incidence rates between 0.9 and 1.3 cases per 100,000 population

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    Etiology

    PSC occurs primarily in patients with underlyingIBD; 70% to 80% UC

    2%-7.5% of patients with UC and 1.4% - 3.4% ofpatients with Crohns disease develop PSC

    An increased prevalence of HLA alleles A1, B8, andDR3 is observed in PSC

    An autoimmune disease

    Homing of memory lymphocytes to the biliary tract;

    Colonic inflammation produces memory T cells thathave the ability to bind biliary cells

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    Pathogenesis

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    ANA Ab and smooth muscle Ab occur in 20% - 50% of patients

    AMA are rarely found in patients with PSC

    The dominant autoantibodies in PSC is perinuclear antineutrophilic

    autoantibodies (pANCA), which are found in approximately 80% of

    patients but lack diagnostic specificity for PSC

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    Normal ERCP

    The gold standard for the diagnosis of PSC is ERCP

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    Typical radiologic findings include multifocal strictures and dilation

    involving the intrahepatic or extrahepatic biliary tract or both, thecharacteristic beads-on-a-string appearance

    The gold standard for the diagnosis of PSC is ERCP

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    Radiographic Features

    ERCP is successful in 95% of cases

    75% have involvement of both small

    and large ducts, 15% small ducts only,

    and 10% large ducts only.

    Serious complication pancreatitis,

    cholangitis, intestinal or bile duct

    perforation, and bleeding. Risks greater

    in patients with PSC

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    MRCP is the best initial approach to diagnosis of PSC

    Depicting ducts proximal to high grade strictures. Provides imaging of the rest of the abdomen.

    MRCP is purely diagnostic, not allowing intervention.

    The two methods yield similarsensitivity and specificity in demonstrating bile ductabnormalities leading to the diagnosis of PSC

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    Periductal fibrosis with inflammation,

    bile duct proliferation, and ductopenia.

    Fibro-obliterative cholangiopathy,

    periductal fibrosis (onion-skinning)

    the pathologic hallmark of PSC, is

    uncommonly observed (13.8%)

    The histologic findings of PSC are nonspecific

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    CLINICAL FEATURES

    Males are twice as commonly affected as females, between25-45 years of age

    Majority are asymptomatic 15%- 40% of cases,

    ALP is the most commonly elevated X 3-10 times

    AST and ALT levels are usually X 2-3 higher than normallevels

    Serum -globulin and IgA are increased in 40-50% Even asymptomatic the patient may have underlying

    advanced liver disease: cirrhosis and portal hypertension

    Fever, chills, right upper quadrant pain,

    itching and jaundice: ascending cholangitis

    One third episodes of bacterial cholangitis especiallyfollowing biliary interventions in patients with dominantstenosis

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    Clinical Manifestations

    Fatigue and pruritus are common

    Jaundice and weight loss, or portal hypertension

    in advanced stages. A rare presentation variceal

    hemorrhage, end-stage liver disease, or

    cholangiocarcinoma

    Serum bilirubin usually is normal or slightly

    elevated, in advanced disease, superimposedmalignancy, or choledocholithiasis, serum

    bilirubin values can reach very high levels

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    Clinical Presentation of PSC

    Symptom

    Jaundice

    Pruritus

    Abdominal pain

    Weight loss

    Fatigue

    Fever/cholangitis

    Asymptomatic

    % of pts

    30-72

    28-69

    24-72

    29-79

    65-66

    13-45

    7-44

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    Natural history of PSC

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    Survival in PSC

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    PSC and IBD

    70% patients with PSC have IBD as well, typically UCand less commonly Crohns disease with colonicinvolvement

    IBD is diagnosed before PSC in 75% of cases andafterward in the remainder

    There is no correlation between the severity of PSCand that of the associated IBD

    IBD in PSC is characterized by a high prevalence ofpancolitis

    PSC-IBD patients require thorough colonoscopicsurveillance with extensive biopsy sampling

    Therapy of IBD has little effect on the course of PSC,and vice versa

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    Colonic neoplasia

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    Colorectal neoplasia in PSC-IBD

    The cumulative incidences of colorectal carcinoma at 10, 20, and 25 years

    in PSC-IBD patients are 5%, 31%, and 50%, respectively

    Ch l i i

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    Cholangiocarcinoma

    Cholangiocarcinoma (CCA) occurring in 4%- 20% of PSC patients;30% to 50% diagnosed within 2 years of identifying PSC

    Serum CA19-9 remains the most used marker for a cutoff of 129U/mL provided sensitivity of 78.6%, specificity of 98.5%

    US, CT, and MRI have inadequate sensitivity to distinguishcholangiocarcinoma from PSC

    Endoscopic biopsy and biliary brushing for cytology, digital imageanalysis, and FISH have good specificity but poor sensitivity

    Complete resection is the only treatment offering long-term survival Treatment : Neoadjuvant chemoradiotherapy with subsequent liver

    transplantation

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    Ursodeoxycholic Acid (UDCA)

    A non-hepato-toxic,hydrophilic bile acid

    It protects cell membranes against the

    detergent effect of hydrophobic bile acid

    It stimulates the excretion of toxic bile acids

    Reduce HLA class 2 experssion on bile-ducts

    Decrease cytotoxic attack of T-cells on bile-

    ducts

    Immunosuppressive and other agents

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    Immunosuppressive and other agents

    Ursodeoxycholic acid (cont)

    A choleretic effect, direct and indirect cytoprotective effects,immunomodulatory effects, and downregulation of apoptosis

    Treatment with standard-dose (10-15 mg/kg) UDCA did notshow significant improvements in histology or survival

    High-dose UDCA (2030 mg/kg) might cause an improvement in

    liver biochemistry, histology, and cholangiographicappearance???.

    Ineffective: D-penicillamine, Colchicine, methotrexate,cyclosporine, and transdermal nicotine, pentoxifylline,silymarin, oral nicotine, pirfenidone, budesonide, cladribine,etanercept, mycophenolate mofetil, glucocorticoids andtacrolimus

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    Liver Transplantation

    Liver transplantation remains the only

    proven long term treatment for PSC

    Major indications include: recurrent bacterialcholangitis despite intensive medical and

    endoscopic therapy, jaundice that cannot betreated endoscopically or medically,decompensated cirrhosis

    The 1-, 2-, and 5-year survival rates for

    patients who received a first liver allograft forPSC were 90%, 86%, and 85%, respectively

    PSC recurred in 37% of patients at a medianof 36 months

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    PSC patients survival after liver transplantation

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    In our patient

    Previous diagnosis of IBD

    Increased cholestatic liver enzymes

    Hepatomegaly

    Proceed to ERCP/MRCP (preferable)

    No need for a liver biopsy for diagnosing

    PSC

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    In our patient

    URSO (25mg/kg) (select the higher dose)

    Periodical follow-up visits to

    hepatology/GI clinic

    In case liver cirrhosis develop considerliver transplantation

    Check periodically serum markers for

    cholangiocarcinoma (CA19-9)

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    Case Presentation 2

    46 years old female

    Born in Ucreinia, 32 years in Israel

    Medical history: rec UTIs

    On routine check-up tests incrased serumcholestatic liver enzymes : ALP 480U/L,

    GGT 380U/L, normal transaminases, total

    bilirubin 1mg/dl, albumin 4.1g/dl, protein

    8.1g/dl

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    Case Presentation 1cont

    Medical history: no pruritus, rec UTI due to

    E. coli, no drugs, mother had hypothyroidism

    Laboratory tests: autoAbs

    (ANA,AMA,ANCA), Igs (IgG&IgM), r/o otheretiologies, serology for hepatitis C and B

    Imaging abdominal U/S

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    Primary Biliary Cirrhosis

    A slowly progressive autoimmune disease, primarily affectswomen

    Peak incidence in the fifth decade of life, uncommon < 25 years

    Histopathologically characterized by portal inflammation andimmune-mediated destruction of the intrahepatic bile ducts

    Loss of bile ducts leads to decreased bile secretion and theretention of toxic substances within the liver, resulting infibrosis, cirrhosis, and eventually, liver failure

    Serologically characterized by AMA, present in 90 95% ofpatients, detectable years before clinical signs appear

    The immune attack is predominantly organ-specific, althoughthe AMA are found in all nucleated cells

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    The prevalence differs considerably in different geographic areas, ranging from 40 to

    400 per million

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    Pathogenesis

    The paradox of PBC is thatmitochondrial proteins are present

    in all nucleated cells, yet the

    autoimmune attack is directed with

    high specificity to the biliary epithelium.

    The specificity of pathological changes

    in the bile ducts, the presence of

    lymphoid infiltration in the portal tracts,

    and the presence of major-histocompatibility

    -complex class II antigen on the biliary

    epithelium suggest that an intense

    autoimmune response is directed

    against the biliary epithelial cells.

    The destruction of biliary cells is

    mediated by liver-infiltrating

    autoreactive T cells

    E id i l i d ti f t

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    Epidemiologic and genetic factors

    PBC is considerably more common in first-degree relatives ofpatients than in unrelated persons

    There is little association between PBC and the presence of anyparticular major-histocompatibility-complex alleles

    There are no clear genetic influences on the occurrence

    of PBC

    The ratio of women to men with the disease can be as high as

    10 to 1

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    Environmental factors

    Molecular mimicry is the most widely proposed

    mechanism for the initiation of autoimmunity in PBC

    Bacteria; E coli, elevated incidence of urinary tractinfections in patients with PBC and the highly conserved

    nature of the mitochondrial autoantigens autoantigens.Antibodies against the human pyruvate dehydrogenasecomplex react well against the E. colipyruvatedehydrogenase complex

    Xenobiotic-metabolizing, gram-negative bacterium called

    Novosphingobium aromaticivorans. it has four lipoyldomains with striking homology with human lipoylatedautoantigens

    Pathological findings

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    The liver is not affected uniformly, and a single biopsy

    may demonstrate the presence of all four stages at the

    same time. Asymmetric destruction of the bile ducts

    within the portal triads

    Pathological findings

    Stage 1 localization of inflammation to theportal triads. In stage 2, the number of normalbile ducts is reduced, and inflammation extendsbeyond the portal triads into the surrounding

    parenchyma. In stage 3, fibrous septa linkadjacent portal triads. Stage 4 represent end-stage liver disease, characterized by cirrhosiswith regenerative nodules

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    Diagnosis

    The diagnosis of PBC is based on threecriteria: the presence of detectable AMA inserum, elevation of liver enzymes (mostcommonly ALP) for more than six months,

    and compatible histologic findings 5-10 % of patients have no detectable AMA,

    but their disease appears to be identical tothat in patients with AMA

    ANA are found in approximately 50 % ofpatients with PBC

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    Mitochondrial Antibodies

    Circulating IgG Ab against

    mitochondria are found in 95% of

    patients

    They are non-organ and non-species

    specific. The significance of the AMA

    and its relationship to the etiology is

    uncertain

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    The targets of the AMA are members of

    the family of the pyruvate dehydrogenase

    complex (PDC)

    These target antigens are located

    in the inner mitochondrial membrane

    The dominant epitope recognized by AMA is located within the lipoyl domain

    he antigenic component specific for PBC is M2

    Four M2 antigen polypeptides were identified, all components of the PDC

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    Clinical findings

    PBC is diagnosed earlier in its clinical

    course; 50 -60% of patients are

    asymptomatic at diagnosis, one third of

    patients may remain symptom-free for manyyears

    Overt symptoms develop within 2-4 years in

    the majority of asymptomatic patients

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    Asymptomatic patient

    Routine biochemical screening: ALP&GGT

    Survival at least 10 years

    Course is variable and unpredictable

    Some will stay asymptomatic and some

    will run a progressive downhill course

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    Fatigue has been noted in up to 78 % of patients and can be a

    significant cause of disabilityPruritus occurs in 20-70 % of patients, can be the mostdistressing symptom. Onset usually precedes the onset of

    jaundice by months to years. Endogenous opioids may have arole

    Discomfort in the right upper quadrant occurs in approximately

    10% of patients

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    Clinical findings

    Hyperlipidemia, osteopenia/osteophorosis, andcoexisting autoimmune diseases, including Sjogrenssyndrome, scleroderma and hypothyroidism

    Malabsorption, deficiencies of fat-soluble vitamins, andsteatorrhea are uncommon except in advanced disease

    Portal hypertension does not usually occur until later inthe course of the disease

    Rarely, patients present with ascites, hepaticencephalopathy, or hemorrhage from esophagealvarices

    The incidnece of hepatocellular carcinoma is elevatedamong patients with long-standing histologicallyadvanced disease

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    Other diseases associated with PBCinclude interstitial pneumonitis,

    celiac disease, sarcoidosis, renaltubular acidosis, hemolytic anemia, andautoimmune thrombocytopenia

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    Physical Examination

    Normal in early disease stage

    Might be later: jaundice, hyperpigmentation,

    xanthelasmas, tendinous & planar

    xanthomas, hepatomegaly, splenomegaly,clubbing, bone tenderness, ecchymoses

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    Biochemical tests

    ALP and GGT and bilirubin Cholesterol IgM

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    Diagnosis

    Middle-aged woman

    Increase cholestatic liver enzymes

    (ALP&GGT)

    AMA (M2) positive (>1:80)

    Liver biopsy could be performed to

    confirm the diagnosis and for

    staging

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    In Our Patient

    A middle-aged asymptomatic women

    Family history of thyroid disease

    Past history of recurrent UTI

    Elevated ALP & GGT

    Positive M2, hypercholesterolemia, eyelid

    xanthelasma

    Normal liver & spleen (abdominal U/S)

    Liver biopsy

    N t l hi t d i

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    Natural history and prognosis

    The prognosis is much better now than itformerly was as a result of treatment inearlier stages of disease

    In at least 25-30 % of patients with PBC whoare treated with URSO, a complete responseoccurs, characterized by normal biochemicaltest results and stabilized or improvedhistologic findings in the liver

    In untreated patients, the median time untildeath or referral for liver transplantation isonly 9.3 years

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    Survival of PBC patients asymptomatic and

    symptomatic

    Treatment of symptoms and complications

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    y p ppruritus

    Ammonium resin cholestyramine, at a dose of 8 to 24 g daily, willrelieve pruritus in most patients.

    Rifampin, at a dose of 150 mg twice daily, is effective in patients

    who do not respond to cholestyramine.

    The opioid antagonists naloxone and naltrexone may be effective in

    patients who do not respond to cholestyramine or rifampin

    U d h li id (URSO)

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    Ursodeoxycholic acid (URSO)

    URSO 12-15 mg/kg per day, is the only approved drug

    Improve biochemistry

    URSO significantly reduced the likelihood of livertransplantation or death after four years

    Ursodiol appears to be safe and has few side effects It delays the progression of hepatic fibrosis in early-stage

    PBC and delays the development of esophageal varices,but it is not effective in advanced disease

    Two meta-analyses questioned the efficacy of ursodiol Colchicine and methotrexate Cyclosporine,Azathioprine,

    mycophenolate, Penicillamine , ChlorambucilThalidomide, Silymarin

    Eff t UDCA i l

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    UDCA-treated

    Placebo group

    Effect on UDCA on survival

    Predicted group

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    Steroids

    Prednisone has little efficacy and

    increases the incidence of osteoporosis

    Budesonide improves liver histology and

    the results of biochemical tests of liverfunction when used with URSO, but it may

    worsen osteopenia

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    Liver Transplantation

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    Liver Transplantation

    Liver transplantation has greatly improved

    survival in patients with PBC, and it is the

    only effective treatment for those with liver

    failure

    The survival rates are 92% 85% at one

    and five years, respectively

    AMA status does not change. PBC recurs

    in 15 % of patients at 3 years and in 30 %at 10 years

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    In Our Patient

    URSO in a dosage up to 15 mg/kg

    until normalization of ALP & GGT achieved

    Bone densitometry

    Serum cholesterol control

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