Prof. Ziv Ben-Ari

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Cholestatic Liver Diseases

• Prof. Ziv Ben-Ari
• Liver Institute
• Rabin 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 as crohns
  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, CBC normal

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
  liver disease
• The disease is characterized by chronic
  inflammation and obliterative fibrosis of the
  intra- and/or extra-hepatic biliary tree which
  leads to bile stasis, hepatic fibrosis, and
  cirrhosis
• This can be complicated by portal hypertension,
  hepatic failure requiring transplantation
• First-degree relatives of patients with PSC have
  a nearly 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 underlying
  IBD 70 to 80 UC
• 2-7.5 of patients with UC and 1.4 - 3.4 of
  patients with Crohns disease develop PSC
• An increased prevalence of HLA alleles A1, B8,
  and DR3 is observed in PSC
• An autoimmune disease
• Homing of memory lymphocytes to the biliary
  tract Colonic inflammation produces memory T
  cells that have 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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The gold standard for the diagnosis of PSC is ERCP
Normal ERCP
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The gold standard for the diagnosis of PSC is ERCP
Typical radiologic findings include multifocal
strictures and dilation involving the
intrahepatic or extrahepatic biliary tract or
both, the characteristic beads-on-a-string
appearance
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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 similar sensitivity and
  specificity in demonstrating bile duct
• abnormalities 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,
  between 25-45 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
  normal levels
• 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
  especially following biliary interventions in
  patients with dominant stenosis

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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, superimposed
  malignancy, 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
  UC and less commonly Crohns disease with colonic
  involvement
• IBD is diagnosed before PSC in 75 of cases and
  afterward in the remainder
• There is no correlation between the severity of
  PSC and that of the associated IBD
• IBD in PSC is characterized by a high prevalence
  of pancolitis
• PSC-IBD patients require thorough colonoscopic
  surveillance 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

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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 129 U/mL provided sensitivity of 78.6,
  specificity of 98.5
• US, CT, and MRI have inadequate sensitivity to
  distinguish cholangiocarcinoma from PSC
• Endoscopic biopsy and biliary brushing for
  cytology, digital image analysis, 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

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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 not show significant improvements in
  histology or survival
• High-dose UDCA (2030 mg/kg) might cause an
  improvement in liver biochemistry, histology, and
  cholangiographic appearance???.
• Ineffective D-penicillamine, Colchicine,
  methotrexate, cyclosporine, and transdermal
  nicotine, pentoxifylline, silymarin, oral
  nicotine, pirfenidone, budesonide, cladribine,
  etanercept, mycophenolate mofetil,
  glucocorticoids and tacrolimus

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Liver Transplantation

• Liver transplantation remains the only proven
  long term treatment for PSC
• Major indications include recurrent bacterial
  cholangitis despite intensive medical and
  endoscopic therapy, jaundice that cannot be
  treated endoscopically or medically,
  decompensated cirrhosis
• The 1-, 2-, and 5-year survival rates for
  patients who received a first liver allograft for
  PSC were 90, 86, and 85, respectively
• PSC recurred in 37 of patients at a median of 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 consider liver
  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 serum
  cholestatic 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 1 cont

• Medical history no pruritus, rec UTI due to
• E. coli, no drugs, mother had hypothyroidism
• Laboratory tests autoAbs (ANA,AMA,ANCA), Igs
  (IgGIgM), r/o other etiologies, serology for
  hepatitis C and B
• Imaging abdominal U/S

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Primary Biliary Cirrhosis

• A slowly progressive autoimmune disease,
  primarily affects women
• Peak incidence in the fifth decade of life,
  uncommon lt 25 years
• Histopathologically characterized by portal
  inflammation and immune-mediated destruction of
  the intrahepatic bile ducts
• Loss of bile ducts leads to decreased bile
  secretion and the retention of toxic substances
  within the liver, resulting in fibrosis,
  cirrhosis, and eventually, liver failure
• Serologically characterized by AMA, present in 90
  95 of patients, detectable years before
  clinical signs appear
• The immune attack is predominantly
  organ-specific, although the 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 that
• mitochondrial 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-histocompatibilit
  y
• -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

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Epidemiologic and genetic factors

• PBC is considerably more common in first-degree
  relatives of patients than in unrelated persons
• There is little association between PBC and the
  presence of any particular major-histocompatibilit
  y-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
  tract infections in patients with PBC and the
  highly conserved nature of the mitochondrial
  autoantigens autoantigens. Antibodies against the
  human pyruvate dehydrogenase complex react well
  against the E. coli pyruvate dehydrogenase
  complex
• Xenobiotic-metabolizing, gram-negative bacterium
  called
• Novosphingobium aromaticivorans. it has four
  lipoyl domains with striking homology with human
  lipoylated autoantigens

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Pathological findings
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
Stage 1 localization of inflammation to the
portal triads. In stage 2, the number of normal
bile ducts is reduced, and inflammation extends
beyond the portal triads into the surrounding
parenchyma. In stage 3, fibrous septa link
adjacent portal triads. Stage 4 represent
end-stage liver disease, characterized by
cirrhosis with regenerative nodules
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Diagnosis

• The diagnosis of PBC is based on three criteria
  the presence of detectable AMA in serum,
  elevation of liver enzymes (most commonly 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 to that in
  patients with AMA
• ANA are found in approximately 50 of patients
  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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These target antigens are located in the inner
mitochondrial membrane
The targets of the AMA are members of the family
of the pyruvate dehydrogenase complex (PDC)
The antigenic component specific for PBC is M2
Four M2 antigen polypeptides were identified, all
components of the PDC
The dominant epitope recognized by AMA is located
within the lipoyl domain
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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 many years
• 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 disability
• Pruritus occurs in 20-70 of patients, can be
  the most distressing symptom. Onset usually
  precedes the onset of jaundice by months to
  years. Endogenous opioids may have a role
• Discomfort in the right upper quadrant occurs in
  approximately 10 of patients

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Clinical findings

• Hyperlipidemia, osteopenia/osteophorosis, and
  coexisting autoimmune diseases, including
  Sjogrens syndrome, scleroderma and
  hypothyroidism
• Malabsorption, deficiencies of fat-soluble
  vitamins, and steatorrhea are uncommon except in
  advanced disease
• Portal hypertension does not usually occur until
  later in the course of the disease
• Rarely, patients present with ascites, hepatic
  encephalopathy, or hemorrhage from esophageal
  varices
• The incidnece of hepatocellular carcinoma is
  elevated among patients with long-standing
  histologically advanced disease

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• Other diseases associated with PBC include
  interstitial pneumonitis,
• celiac disease, sarcoidosis, renal tubular
  acidosis, hemolytic anemia, and autoimmune
  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 (ALPGGT)
• AMA (M2) positive (gt180)
• 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

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Natural history and prognosis

• The prognosis is much better now than it formerly
  was as a result of treatment in earlier stages of
  disease
• In at least 25-30 of patients with PBC who are
  treated with URSO, a complete response occurs,
  characterized by normal biochemical test results
  and stabilized or improved histologic findings in
  the liver
• In untreated patients, the median time until
  death or referral for liver transplantation is
  only 9.3 years

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Survival of PBC patients asymptomatic and
symptomatic
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Treatment of symptoms and complicationspruritus

• Ammonium resin cholestyramine, at a dose of 8 to
  24 g daily, will relieve 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

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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
  liver transplantation 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,Azathiopr
  ine, mycophenolate, Penicillamine , Chlorambucil
  Thalidomide, Silymarin

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Effect on UDCA on survival
UDCA-treated
Placebo group
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 liver function
  when used with URSO, but it may worsen osteopenia

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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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