Primary Biliary Cholangitis Flashcards
PBC
is an autoimmune liver disease that generally affects middle-aged women and is the most common chronic cholestatic liver disease in adults in the USA.
PBC
PBC is characterized by progressive intrahepatic bile duct destruction, which leads to cholestasis, complications, and symptoms related to cholestasis, cirrhosis, and portal hypertension.
highly characteristic of the PBC
The presence of an elevated alkaline phosphatase level and AMA in the serum
PBC treatment
UDCA is the only medication shown to improve LT-free survival.
Obeticholic acid (OBA) was approved for patients intolerant of UDCA or those who do not have an adequate biochemical response to UDCA.
epidemiology
PBC occurs worldwide and predominantly in women, with a female-to-male ratio of 9:1. The diagnosis of PBC usually is made between the ages of 40 and 60 years.
PATHOGENESIS
immune-mediated process that occurs as a result of complex interactions between the environment and genetically susceptible individuals.
PBC seems to be triggered by an immune-mediated response to one or more allo- or autoantigens, which leads to progressive destruction of bile ducts, chronic cholestasis, and eventual biliary cirrhosis.
regarded as the most sensitive and specific immunologic hallmark of the disease
AMA
AMA are directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), the E2 unit of the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the E2 subunit of the 2-oxoglutarate dehydrogenase complex (OGDC-E2).
AMA do not appear to be cytotoxic
(1) They persist after LT without evidence of disease recurrence;
(2) disease severity is unrelated to antibody titer;
(3) they are not always present in PBC; and (4) they develop in animal models after the injection of recombinant PDC-E2 protein, but without resulting bile duct destruction or inflammation
Symptomatic Disease
The typical patient with symptomatic disease is a middle-aged woman with a complaint of fatigue or pruritus.
Symptomatic pruritus
Pruritus may occur at any point, early or late, or intermittently in the course of the disease.
Pruritus generally is intermittent during the day and is most troublesome in the evening and at night.
Pruritus often resolves as the disease progresses, but in some patients, severe, intractable pruritus can develop in earlier stages of the disease and may require LT for effective management.
Pruritus in cholestatic liver disease may be partially mediated by lysophosphatidic acid and the enzyme autotaxin, which mediates the production of lysophosphatidic acid from lysophosphatidylcholine.
Serum levels of lysophosphatidic acid and activity of autotaxin correlate with the severity of pruritus.
DIAGNOSIS
The diagnosis of PBC is established when 2 out of 3 of the following criteria are met: chronic cholestatic liver test elevation (typically with alkaline phosphatase ≥1.5 times the upper limit of normal [ULN]), elevated serum AMA (titers ≥1:40), or a liver biopsy specimen consistent with PBC. A liver biopsy is typically not required (see later).
Biochemical features
all patients have increased serum levels of alkaline phosphatase and GGTP.
Serum aminotransferase (AST, ALT) levels are mildly elevated (usually less than 3 times the ULN); marked elevations (more than 5 times the ULN) are distinctly unusual and may suggest PBC-autoimmune hepatitis overlap syndrome
Histopathology
One of the earliest histologic changes associated with PBC may be a loss of the canals of Hering, which can be demonstrated by biliary cytokeratin 19 staining.
The most important and only diagnostic clue
The most important and only diagnostic clue in many cases is ductopenia, defined as the absence of interlobular bile ducts in greater than 50% of portal tracts.
The florid duct lesion
The florid duct lesion, in which the epithelium of the interlobular and segmental bile ducts degenerates segmentally, with formation of poorly defined, noncaseating epithelioid granulomas, is nearly diagnostic of PBC but is found in a relatively small number of cases, mainly in early stages.
The 2 most popular histologic staging systems are those proposed by Ludwig and colleagues and by Scheuer that classify the disease in 4 stages.
Ludwig stage 1 disease is characterized by inflammatory destruction of the intrahepatic septal and interlobular bile ducts that range up to 100 μm in diameter.
These lesions often are focal and described as florid duct lesions, characterized by marked inflammation and necrosis around a bile duct. The portal tracts usually are expanded by lymphocytes, with only sparse neutrophils or eosinophils seen.
In stage 2 disease
the inflammation extends from the portal tract into the hepatic parenchyma, a lesion called interface hepatitis, or formerly, piecemeal necrosis. Destruction of bile ducts with proliferation of bile ductules can be seen.
stage 3 disease
characterized by scarring and fibrosis.
Lymphocytic involvement of the portal and periportal areas, as well as the hepatic parenchyma, can be seen, but the hallmark of this stage is the presence of fibrosis without regenerative nodules.
Stage 4 disease
characterized by cirrhosis with fibrous septa and regenerative nodules
highly predictive for a diagnosis of PBC.
In a person with AMA, the combination of a serum alkaline phosphatase level greater than 1.5 times the ULN and a serum AST level less than 5 times the ULN
Imaging
Cross-sectional imaging with US, CT, or MRI is useful for excluding biliary obstruction and plays a key role in the diagnostic evaluation of persons who present with cholestatic liver biochemical test elevations and those who require surveillance for HCC because of cirrhosis.
Imaging of PBC
increased liver echogenicity and signs of portal hypertension, several imaging find- ings appear to be common in persons with PBC.
Nearly two thirds can have a periportal “halo” sign (T1-and T2-weighted hypointensity centered around portal venous branches) on MRI and intraabdominal lymphadenopathy
Independent Predictors of Survival in Patients with PBC in Various Clinical Studies
CLINICAL
Age
Ascites
Edema Hepatomegaly Variceal bleeding
LABORATORY
Serum albumin level
Serum alkaline phosphatase level Serum bilirubin level
Prothrombin time
LIVER HISTOLOGY
Cholestasis Cirrhosis Fibrosis Mallory’s hyaline
ANTIMITOCHONDRIAL ANTIBODY-NEGATIVE
PRIMARY BILIARY CHOLANGITIS
AMA-negative PBC is the designation for those patients who clinically, biochemically, and histologically appear to have the classic features of PBC but are found not to have AMA in serum by IIF or immunoblotting techniques.
The absence of AMA makes liver biopsy mandatory to look for features of PBC and exclude other liver diseases.
Patents with AMA-negative PBC
Patents with AMA-negative PBC tend to follow a clinical course, and to demonstrate a therapeutic response to UDCA, similar to those in AMA-positive patients.
Patients with AMA- negative PBC should be treated with UDCA in a dose of 13 to 15 mg/kg/day
TREATMENT
UDCA, the 7-β epimer of chenodeoxycholic acid, occurs naturally in small quantities in human bile (less than 4% of total bile acids).
The most cost-effective dose of UDCA in patients with PBC is 13 to 15 mg/kg/day, which can be given in divided doses taken with meals.
Obeticholic Acid
OBA was granted approval for use in patients with PBC who are intolerant of UDCA or who do not achieve an adequate response to UDCA after one year.
Obeticholic acid (OBA) is a first-in-class farnesoid X receptor (FXR) agonist.
FXR is a nuclear receptor expressed in the liver, kidneys, adrenal glands, and intestine and plays a key role in bile acid metabolism, liver regeneration, and inflammation.
OBA is 100 times more potent than the natural FXR ligand, chenodeoxycholic acid.
