Transcript Cholestatic Liver Disease

Prof. Ziv Ben-Ari
Liver Institute
Rabin Medical Center
Cholestatic Liver Diseases
• Primary Biliary Cirrhosis (PBC)
• Primary Sclerosing Cholangitis
(PSC)
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
crohn’s disease
Case Presentation 1 cont
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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
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 intraand/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
Annual incidence rates between 0.9 and 1.3 cases per 100,000 population
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 Crohn’s 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
Pathogenesis
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
The gold standard for the diagnosis of PSC is ERCP
Normal ERCP
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
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
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
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
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
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
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
Natural history of PSC
Survival in PSC
PSC and IBD
• 70% patients with PSC have IBD as well, typically UC
and less commonly Crohn’s 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
Colonic neoplasia
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
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
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 bileducts
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 (20–30 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
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
PSC patient’s survival after liver transplantation
In our patient
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Previous diagnosis of IBD
Increased cholestatic liver enzymes
Hepatomegaly
Proceed to ERCP/MRCP (preferable)
No need for a liver biopsy for diagnosing
PSC
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)
Case Presentation 2
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46 years old female
Born in Ucreinia, 32 years in Israel
Medical history: rec UTI’s
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
Case Presentation 1
cont
• Medical history: no pruritus, rec UTI due to
E. coli, no drugs, mother had hypothyroidism
• Laboratory tests: autoAb’s
(ANA,AMA,ANCA), Ig’s (IgG&IgM), r/o other
etiologies, serology for hepatitis C and B
• Imaging – abdominal U/S
Primary Biliary Cirrhosis
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A slowly progressive autoimmune disease, primarily affects
women
Peak incidence in the fifth decade of life, uncommon < 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
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-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
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-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
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
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 endstage liver disease, characterized by cirrhosis
with regenerative nodules
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
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
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
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
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
•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
Clinical findings
• Hyperlipidemia, osteopenia/osteophorosis, and
coexisting autoimmune diseases, including Sjogren’s
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
•Other diseases associated with PBC
include interstitial pneumonitis,
celiac disease, sarcoidosis, renal
tubular acidosis, hemolytic anemia, and
autoimmune thrombocytopenia
Physical Examination
• Normal in early disease stage
• Might be later: jaundice, hyperpigmentation,
xanthelasmas, tendinous & planar
xanthomas, hepatomegaly, splenomegaly,
clubbing, bone tenderness, ecchymoses
Biochemical tests
• ALP and GGT and bilirubin
• Cholesterol
• IgM
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
In Our Patient
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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
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
Survival of PBC patients asymptomatic and
symptomatic
Treatment of symptoms and complications
pruritus
• 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
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,Azathioprine,
mycophenolate, Penicillamine , Chlorambucil
Thalidomide, Silymarin
Effect on UDCA on survival
UDCA-treated
Placebo group
Predicted group
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
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
In Our Patient
• URSO in a dosage up to 15 mg/kg
until normalization of ALP & GGT achieved
• Bone densitometry
• Serum cholesterol control