Primary biliary cirrhosis

PBC (Primary biliary cholangitis or primary

biliary cirrhosis)

Micrograph of PBC showing bile

ductinflammation and injury. H&E stain.
Classification and external resources
ICD-10

K74.3

ICD-9

571.6

OMIM

109720

DiseasesDB

10615

MedlinePlus

000282

eMedicine

med/223

Patient UK

Primary biliary cirrhosis

MeSH

D008105

The condition known by its abbreviation PBC, standing for primary biliary cirrhosis, is
an autoimmune disease of the liver.[1][2] It is marked by slow progressive destruction of the
small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the
disease.[3] When these ducts are damaged, bile and other toxins build up in the liver (cholestasis)
and over time damages the liver tissue in combination with ongoing immune related damage.

This can lead to scarring, fibrosis and cirrhosis. As cirrhosis is only a feature of advanced
disease, a change of name to primary biliary cholangitis was proposed in 2014.[4] This retains
the initials of PBC but reflects more accurately the nature of the disease. It has not yet (April
2015) been adopted in scientific publications.
PBC was previously thought to be a rare disease, but more recent studies have shown that it may
affect up to 1 in 34,000 people; the sex ratio is at least 9:1 female to male.[5]
Contents
[hide]

1 Signs and symptoms

2 Causes

3 Diagnosis
o 3.1 Biopsy
o 3.2 Summary of stages

4 Therapy

5 Epidemiology

6 Prognosis

7 History

8 Name Change

9 Additional images

10 References

11 External links

Signs and symptoms[edit]

Individuals with PBC with disease may present with the following:

Fatigue

Pruritus (itchy skin)

Jaundice (yellowing of the eyes and skin), due to increased bilirubin in the blood in more
advanced disease.

Xanthoma (local collections of cholesterol in the skin, especially around the eyes
(xanthelasma))

Complications of cirrhosis and portal hypertension: in more advanced disease

Fluid retention in the abdomen (ascites) in more advanced disease

Enlarged spleen in more advanced disease

Oesophageal varices in more advanced disease

Hepatic encephalopathy, including coma in extreme cases in more advanced

disease.

Association with an extrahepatic autoimmune disorder such as rheumatoid

arthritis or Sjgren's syndrome (in up to 80% of cases).

Causes[edit]
The cause of the disease is attributed to an immunological basis for the disease, making it
an autoimmune disorder. Most of the patients (>90%) have anti-mitochondrial antibodies
(AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found
in the mitochondria.
Many PBC patients have a concomitant autoimmune disease, including rheumatological,
endocrinological, gastrointestinal, pulmonary, or dermatological conditions, which suggests
shared genetic and immune abnormalities.[6] Common associations include Sjgren's
syndrome, systemic sclerosis, rheumatoid arthritis, SLE, hypothyroidism and gluten sensitive
enteropathy.[6][7][8][9] In some cases of disease, protein expression may cause an immune
tolerance failure, as might be the case with gp210 and p62, nuclear pore proteins. Gp210 has
increased expression in the bile duct of anti-gp210 positive patients.[10] Both proteins appear to be
prognostic of liver failure relative to anti-mitochondrial antibodies.
A genetic predisposition to disease has been thought important for some time, as evident by cases
of PBC in family members, concordance in identical twins, and clustering of autoimmune
diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of
Medicine results from the first PBC genome-wide association study.[11][12] This research revealed
parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be
important in the etiology of the disease in addition to the HLA region. In 2012, two independent
PBC association studies increased the total number of genomic regions associated to 26,

implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.[13]
[14]

In 2003 it was reported that an environmental Gram negative alphabacterium

Novosphingobium aromaticivorans[15] was strongly associated with this disease. Subsequent
reports appear to have confirmed this finding suggesting an aetiological role for this organism.[16]
[17][18]
The mechanism appears to be a cross reaction between the proteins of the bacterium and
the mitochondrial proteins of the liver cells.[19] The gene encoding CD101 may also play a role in
host susceptibility to this disease.[20]
Diagnosis[edit]

Intermediate magnificationmicrograph of PBC showing bile duct inflammation and

periductalgranulomas. Liver biopsy. H&E stain.

Immunofluorescence staining pattern of sp100 antibodies (nuclear dots) and AMA.

To diagnose PBC, distinctions should be established from other conditions with similar
symptoms, such as autoimmune hepatitis or primary sclerosing cholangitis (PSC).

Diagnostic blood tests include:

Elevated liver enzyme tests (elevated gamma-glutamyl transferase and alkaline

phosphatase)

Presence of certain antibodies: antimitochondrial antibody (AMA), antinuclear

antibody (ANA)

Abdominal ultrasound, MR scanning (MRCP) or a CT scan is usually performed to rule out

blockage to the bile ducts. Most suspected cases have a liver biopsy performed, and if
uncertainty remains an is some patients, endoscopic retrograde cholangiopancreatography or
ERCP, where an endoscopic investigation of the bile ductis performed. Most patients are
diagnosed without invasive investigation, as the combination of anti-mitochondrial antibodies
(see below) and typical (cholestatic) liver enzyme tests are considered diagnostic. However, a
liver biopsy is necessary to determine the stage of disease.
Anti-nuclear antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210
antibodies, and to a lesser degree anti-p62 antibodies, correlate with the disease's progression
toward end stage liver failure. Anti-centromere antibodies often correlate with developing portal
hypertension.[21] Anti-np62[22] and anti-sp100 are also found in association with PBC.
Biopsy[edit]
PBC is characterized by interlobular bile duct destruction. Histopathologic findings of primary
biliary cholangitis include the following:[23]

Inflammation of the bile ducts, characterized by intraepithelial lymphocytes, and

Periductal epithelioid granulomata.

Summary of stages[edit]

Stage 1 Portal Stage: Normal sized triads; portal inflammation, subtle bile
duct damage. Granulomas are often detected in this stage.

Stage 2 Periportal Stage: Enlarged triads; periportal fibrosis and/or inflammation.

Typically characterized by the finding of a proliferation of small bile ducts.

Stage 3 Septal Stage: Active and/or passive fibrous septa.

Stage 4 Biliary Cirrhosis: Nodules present; garland or jigsaw puzzle pattern.

Therapy[edit]

There is no known cure, but medication may slow the progression so that a normal lifespan and
quality of life may be attainable for many patients.[24][25]

Ursodeoxycholic acid (Ursodiol) is the most frequently used treatment. This helps reduce
the cholestasis and improves blood test results (liver function tests). It has a minimal
effect on symptoms and whether it improves prognosis is controversial.[26]

To relieve itching caused by bile acids in circulation, which would normally be removed
by the liver, cholestyramine (abile acid sequestrant) may be prescribed to absorb bile
acids in the gut and be eliminated, rather than re-enter the blood stream. Alternative
agents include naltrexone and rifampicin.[24][25]

Specific treatment for fatigue, which may be debilitating in some patients, is limited and
undergoing trials.[27] Some studies indicate that Provigil (modafinil) may be effective
without damaging the liver.[28] Though off-patent, the limiting factor in the use of
modafinil in the U.S. is cost. The manufacturer, Cephalon, has made agreements with
manufacturers of generic modafinil to provide payments in exchange for delaying their
sale of modafinil.[29] The FTC has filed suit against Cephalon alleging anti-competitive
behavior.[30]

Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.

[31]
Appropriate supplementation is recommended when bilirubin is elevated.[32]

Patients with PBC are at elevated risk of developing osteoporosis[33] and esophageal
varices[34] as compared to the general population and others with liver disease. Screening
and treatment of these complications is an important part of the management of PBC.

As in all liver diseases, consumption of alcohol is contraindicated.

In advanced cases, a liver transplant, if successful, results in a favorable prognosis.[35]
Obeticholic acid is in phase III clinical trials for PBC.[36]
Epidemiology[edit]
PBC is a chronic autoimmune liver disease with a female gender predominance with
female:male ratio is at least 9:1 and a peak incidence in the fifth decade of life.[37] In some areas
of the US and UK the prevalence is estimated to be as high as 1 in 4000. This is much more
common than in South America or Africa, which may be due to better recognition in the US and
UK. First-degree relatives may have as much as a 500 times increase in prevalence, but there is
debate if this risk is greater in the same generation relatives or the one that follows.[5]
Prognosis[edit]

The serum bilirubin level is an indicator of the prognosis of PBC, with levels of 26 mg/dL
having a mean survival time of 4.1 years, 610 mg/dL having 2.1 years and those above
10 mg/dL having a mean survival time of 1.4 years.[38]
After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10
years. There is no consensus on risk factors for recurrence of the disease.[39]
Patients with PBC have an increased risk of hepatocellular carcinoma compared to the general
population, as is found in other cirrhotic patients. In patients with advanced disease, one series
found an incidence of 20% in men and 4% in women.[40]
History[edit]
Addison and Gull in 1851 described the clinical picture of progressive obstructive jaundice in the
absence of mechanical obstruction of the large bile ducts. Ahrens et al in 1950 coined the term
primary biliary cirrhosis for this disease. The association with anti-mitochondrial antibodies was
first reported in 1965[41] and their presence was recognised as a marker of early, pre-cirrhotic
disease.[42]
Name Change[edit]
A wave of activity to change the name of Primary Biliary Cirrhosis to Primary Biliary
Cholangitis, initiated in the patient community, has moved forward rapidly. This initiative and
momentum is justified as over 80% of patients at the time of diagnosis of PBC do not have
cirrhosis. Patients' organisations (PBCers.org, PBC Foundation UK) have been strong advocates
for this name change. The seed of this change was planted at the PBC meeting in London, prior
to EASL in 2014, with a panel of patient advocates and experts expressing support after the
meeting. At the EASL symposium in Milan in May 2014 of the PBC Foundation, many of the
presentations by experts embraced the name change, and the results of a global survey were
presented supporting this new moniker. This global survey, with over 1100 respondents from the
patient and provider community, reached a nearly unanimous vote in favor of this name
change and supported the name of Primary Biliary Cholangitis to preserve the PBC initials. The
United States PBCers group has been involved with this proposal for a name change from its
inception in April 2014 and this enthusiasm reached a crescendo of nearly universal support at
the PBCers convention in Las Vegas in July 2014.[4][43]
Additional images[edit]


Low magnificationmicrograph of PBC.H&E stain.
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