Download Presentation of Case - Sheba Hungary Student

A case of Primary Biliary
Cirrhosis (PBC) in antiphospholipid
syndrome (APS) patient
Department of Medicine 'B' & Center of Autoimmune Diseases,
Sheba Medical Center
Dana Ben-Ami
[email protected]
November 2009
Presentation of Case
• A 36-year-old woman was admitted to the hospital because of pruritus.
• The patient had been well until 7 days earlier, when she developed
pruritus, fever, malaise, diffuse myalgias, arthralgias without joint swelling
or erythema, frontal headache and dark urine. She denied steatorrhea.
• One month before her admission she quitted her job due to chronic fatigue.
• She was exposed to her son, who had viral gastroenteritis 2 weeks earlier
• There is no history of weight loss, recent travel, exposure to animals. She
denies alcohol or drug abuse, and was vaccinated against HBV.
Presentation of Case
• The patient has a history of antiphospholipid syndrome (APS),
treated with coumadin, S/P MI, S/P PTCA W stent to LAD (2006).
• There is no history of allergies.
• Family history: Rheumatoid arthritis to her niece, Ischemic heart
disease to her parents.
• Her medications comprise COUMADIN, LIPITOR, ASPIRIN,
FOLIC ACID and IRON.
• 3 weeks ago treatment with SIMOVIL was replaced with
LIPITOR.
Presentation of Case
Suspected APS in the presented patient:
• an event of emboli to the LAD
• elevated titers of anticardiolipin antibodies and Lupus anticoagulant (LAC)
Sapporo criteria:
A. At least one autoantibody (LAC, anticardiolipin Abs, anti-β2
glycoprotein-I) on two or more occasions at least 12 weeks apart.
B. One or more episodes of venous, arterial, or small vessel thrombosis
and/or morbidity with pregnancy (unexplained death at >10 weeks
gestation of a morphologically normal fetus / one or more premature
birth before 34 weeks of gestation / three or more embryonic
pregnancy loss before 10 week gestation)
Presentation of Case
Physical examination:
• The temperature was 36.7, the pulse was 76, and the
respirations were 16. The blood pressure was 95/69.
• The patient had sclera jaundice, abdominal examination
revealed splenomegaly with no evidence of tenderness or
ascites. Ecchymoses and hematomas on her thighs and also
excoriations with multiple abrasions on both legs and arms.
Presentation of Case
• Hematologic laboratory values:
Presentation of Case
• Blood chemical values:
Presentation of Case
• Coagulation test results:
Presentation of Case
• Radiographs of the chest & the abdomen were without
significant findings.
• Abdominal ultrasound ruled out portal vein thrombosis
and demonstrated enlarged spleen up to 15 cm length,
normal liver, no pathology of the bile ducts or gallbladder,
no evidence for ascites. A small lymph node , size of 1.6
cm was seen next to the liver.
Presentation of Case
Classification of jaundice according to type of bile pigment and mechanism
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Unconjugated hyperbilirubinemia
Conjugated hyperbilirubinemia
Increased bilirubin production
Extravascular hemolysis
Extravasation of blood into tissues
Intravascular hemolysis
Dyserythropoiesis
Impaired hepatic bilirubin uptake
Congestive heart failure
Portosystemic shunts
Some patients with Gilbert's syndrome
Certain drugs - rifampin, probenecid flavaspadic acid,
bunamiodyl
Impaired bilirubin conjugation
Crigler-Najjar syndrome type I and II
Gilbert's syndrome
Neonates
Hyperthyroidism
Ethinyl estradiol
Liver diseases - chronic persistent hepatitis, advanced
cirrhosis, Wilson's disease
Extrahepatic cholestasis (biliary obstruction)
Choledocholithiasis
Intrinsic and extrinsic tumors - eg, cholangiocarcinoma
Primary sclerosing cholangitis
AIDS cholangiopathy
Acute and chronic pancreatitis
Strictures after invasive procedures
Certain parasitic infections-eg, Ascaris lumbricoides, liver flukes
Intrahepatic cholestasis
Viral hepatitis
Alcoholic hepatitis
Nonalcoholic steatohepatitis
Primary biliary cirrhosis
Drugs and toxins - eg, alkylated steroids, chlorpromazine, herbal
medications (eg, Jamaican bush tea), arsenic
Sepsis and hypoperfusion states
Infiltrative diseases - eg, amyloidosis, lymphoma, sarcoidosis,
tuberculosis
Total parenteral nutrition
Postoperative patient
Following organ transplantation
Hepatic crisis in sickle cell disease
Pregnancy
End-stage liver disease
Hepatocellular injury
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Presentation of Case
• Additional laboratory results:
Review Article
Primary Biliary Cirrhosis
Marshall M. Kaplan, M.D., and M. Eric Gershwin, M.D.
N Engl J Med
Volume 353:1261-1273, September 22, 2005, Number 12
Primary biliary cirrhosis (PBC)
• A slowly progressive autoimmune disease with portal
inflammation and destruction of the intrahepatic bile ducts
• Decreased bile secretion and retention of toxic substances
within the liver, resulting in further hepatic damage, fibrosis and
cirrhosis
• Antimitochondrial antibodies (AMA) are present in 90-95% of
patients and are often detectable years before clinical signs
• Nearly every patient with PBC has an elevated serum IgM level
• Autoantibodies directed at nuclear antigens (ANA) are found in
approximately 50% of patients (nuclear-rim and nuclear-dot
patterns are highly specific)
Primary biliary cirrhosis
• PBC is now diagnosed earlier than it was in the past; Its peak
incidence occurs in the fifth decade of life
• 50-60% of patients are asymptomatic at diagnosis
• Presenting symptoms: fatigue (21%) & pruritus (19%)
• Fatigue has been noted in up to 78% of patients and pruritus
occurs in 20-70%
• The onset of the prurutus usually precedes the onset of jaundice
by months to years, can be local or diffuse, usually worse at night
and is often exacerbated by contact with wool or heat. Its cause is
unknown, but endogenous opioids may have a role
Primary biliary cirrhosis
• Hyperlipidemia, hypothyroidism, osteopenia, coexisting
autoimmune diseases (Sjögren's syndrome & scleroderma)
• Portal hypertension - later in the course of the disease
• Malabsorption, deficiencies of fat-soluble vitamins, and
steatorrhea are uncommon except in advanced disease
• Rare: ascites, hepatic encephalopathy, hemorrhage from
esophageal varices
• The incidence of hepatocellular carcinoma is elevated
Primary biliary cirrhosis
• More common in first-degree relatives of patients
• 1-6% of all patients have at least one affected family
member (mother–daughter / sister–sister )
• The ratio of women to men is 10 : 1
• The prevalence differs considerably in different geographic
areas, ranging from 40 to 400 per million, Most prevalent in
northern Europe
• Higher risk in persons with a polymorphism of the gene for
the vitamin D receptor
Physical examination
• Often normal in the asymptomatic patient
• Melanin pigmentation in the skin, spider nevi, and
excoriations occur as the disease progresses
• Xanthelasmas – 5-10% of patients
• Hepatomegaly – 70% of patients
• Late manifestations: splenomegaly, jaundice , temporal
and proximal limb muscle wasting,
ascites, edema
Pathological findings
• The characteristic lesion of PBC is
symmetric destruction of the bile ducts
within the portal triads
Four possible histologic stages:
• Stage 1 - localization of inflammation to the portal
triads
• Stage 2 - the number of normal bile ducts is
reduced and inflammation extends beyond
the portal triads into the surrounding parenchyma
• Stage 3- fibrous septa link adjacent portal triads
• Stage 4 - end-stage liver disease, characterized by
frank cirrhosis with regenerative nodules
PBC and major-histocompatibility-complex (MHC)
Once thought:
that there is little, if any, association between PBC and the presence of any
particular major-histocompatibility-complex alleles
Primary Biliary Cirrhosis Associated with HLA,
IL12A, and IL12RB2 Variants
Gideon M. et al., NEJM, Vol. 360(24):2544-2555, June 11, 2009
This study results show significant associations
between PBC and common genetic variants at the
HLA class II, IL12A, and IL12RB2 loci and suggest
that the interleukin-12 immunoregulatory signaling axis
is relevant to the pathophysiology of PBC.
Antimitochondrial antibodies (AMA)
The targets of the AMA are members of the family of the 2-oxo-acid
dehydrogenase complexes:
• E2 subunits of the pyruvate dehydrogenase complex
• The branched-chain 2-oxo-acid dehydrogenase complex
• The ketoglutaric acid dehydrogenase complex
• The dihydrolipoamide dehydrogenase–binding protein
There is substantial homology among these four autoantigens,
and all participate in oxidative phosphorylation and share lipoic
acid moieties. These target antigens are located in the inner
mitochondrial matrix.
Role of the lipoyl domains in the metabolism of Pyruvic acid
The figure shows the presence
of two lipoyl domains and the
role of the pyruvate
dehydrogenase E2 complex
(PDC-E2) in the reduction of
flavin adenine dinucleotide
(FAD) to FADH2.
This reaction is an essential
metabolic step for oxidative
phosphorylation.
PBC appears to be the only
disease with autoreactive T cells
and B cells against PDC-E2
Kaplan M and Gershwin M. N Engl J Med 2005;353:1261-1273
PBC environmental facrors
• Molecular mimicry is the most widely proposed
mechanism for the initiation of autoimmunity in PBC
Escherichia coli
Lactobacilli & Chlamydia
MMTV (mouse mammary-tumor virus)
Novosphingobium aromaticivorans
Pesticides and detergents
The paradox of PBC
Mitochondrial proteins are present in
all nucleated cells, yet the
autoimmune attack is directed with
high specificity to the biliary
epithelium.
• In biliary epithelial cells, the pyruvate
dehydrogenase E2 complex (PDC-E2)
remains immunologically intact after
apoptosis
Lupus anticoagulant (LAC) &
International Normalized Ratio (INR)
Prothrombin time (PT) test & International
Normalized Ratio (INR)
• The prothrombin time (PT) test is used to monitor oral
anticoagulant treatment.
• The obvious advantages of this simple test have been
obscured for many years by the dependency of the clotting
time on the thromboplastin reagent used for testing.
• This problem has been solved since the adoption of a universal
scale to express PT results (in 1982), called the International
Normalized Ratio (INR).
• INR= Patient PT/mean normal PT
• This system is able to make results less dependent on the
reagent used for testing.
Lupus anticoagulant
• Lupus anticoagulant (LAC) was first described in
patients with systemic lupus erythemathosus (SLE),
although its occurrence is not limited to this disease
• LAC are auto-antibodies directed against phospholipids
or phospho-lipid binding proteins
• The presence of this anticoagulant has been associated
with an increased risk of venous and arterial
thromboembolism, yet it is detected in the laboratory as
a paradoxical prolongation of various clotting tests.
The problem..
• Because of the variable responsiveness of
thromboplastins to the presence of LAC, there is
confusion about the reliability of INR monitoring in
patients with LAC, who receive oral anticoagulant
treatment.
• In spite of anticoagulant treatment, recurrence of
thrombosis is frequent in patients with antiphospholipid
syndrome (APS). This fact may be in part explained by
unreliable INR values found when different test reagents
(thromboplastin) are used.
Controversy regarding the reliability of INR
measurement in patients with LAC
• In one study, it was reported that circulating
antiphospholipid antibodies greatly influenced INR results
when different reagents were used. INR values differed as
much as 6.5 in the same patient. Moll S, et al., Ann Intern Med,1997.
• Two other studies also reported INR discrepancies in
patients with antiphospholipid antibodies. Della Valle P, et al., Ann
de Med Int,1996. LowJ, et al., Thromb Haemost, 1997. Armando T, et al., British
Journal of Haematology, 2001.
However, similar studies in patients with LAC could not
confirm this finding. Nick R.B, et al., J-Thromb-Thrombolysis, 2000. Lawrie
AS, et al., Br J Haematol, 1997. Robert A, et al., ThrombHaemost, 1998.
Chromogenic factor X assay
• An independent measure of warfarin effect that avoids the
LAC clotting test artifact is the chromogenic factor X
assay.
• This assay is an enzymatic measure of the activity of
factor X, a vitamin K –dependent clotting factor.
• A study conducted on patients receiving warfarin showed
that at least 10% of patients with LAC receiving warfarin
therapy may have falsely high INR values. Monitoring the
chomogenic factor X activity avoids this INR artifact.
Terry k, et al., Pharmacotherapy, 2004.
Thank You..
Department of Medicine 'B' & Center of Autoimmune Diseases,
Sheba Medical Center
Dana Ben-Ami
[email protected]
November 2009