Primary biliary cirrhosis
Encyclopedia
Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease
of the liver
marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. When these ducts are damaged, bile
builds up in the liver (cholestasis
) and over time damages the tissue. This can lead to scarring, fibrosis
and cirrhosis
. It was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3-4,000 people; the sex ratio
is at least 9:1 (female to male).
or primary sclerosing cholangitis
(PSC).
Diagnostic blood test
s include:
Abdominal ultrasound
or a CT scan is usually performed to rule out blockage to the bile ducts. Previously most suspected sufferers underwent a liver biopsy
, and - if uncertainty remained - endoscopic retrograde cholangiopancreatography
(ERCP, an endoscopic
investigation of the bile duct
). Now most patients are diagnosed without invasive investigation since the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) liver function 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 progression toward end stage liver failure. Anti-centromere antibodies
correlate with developing portal hypertension. Anti-np62 and anti-sp100 are also found in association with PBC.
, making it an autoimmune disorder. Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. In addition, a more specific test to confirm this disease from a bone disorder such as Paget's disease which also has increases in Alkaline phosphatase is the Gamma-glutamyl transpeptidase
test (GGT). An increase in GGT could indicate presence of Primary Biliary Cirrhosis.
57% of patients with acute liver failure have anti-transglutaminase antibodies
suggesting a role of gluten sensitivity
in primary biliary cirrhosis, and primary biliary cirrhosis is considerably more common in gluten sensitive enteropathy than the normal population. 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. 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 genome scan of PBC patients. 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, suggesting future therapeutic targets.
As in all liver diseases, alcoholic beverage
s are contraindicated.
In advanced cases, a liver transplant, if successful, results in a favourable prognosis.
Obeticholic acid is in phase III clinical trials for PBC.
level is an indicator of the prognosis of primary biliary cirrhosis, with levels of 2–6 mg/dL having a mean survival time of 4.1 years, 6–10 mg/dL having 2.1 years and those above 10 mg/dL having a mean survival time of 1.4 years.
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.
Patients with primary biliary cirrhosis have an increased risk of hepatocellular carcinoma
.
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
of the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. When these ducts are damaged, bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
builds up in the liver (cholestasis
Cholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
) and over time damages the tissue. This can lead to scarring, fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
and cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
. It was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3-4,000 people; the sex ratio
Sex ratio
Sex ratio is the ratio of males to females in a population. The primary sex ratio is the ratio at the time of conception, secondary sex ratio is the ratio at time of birth, and tertiary sex ratio is the ratio of mature organisms....
is at least 9:1 (female to male).
Signs and symptoms
The following signs may present in PBC:- FatigueFatigue (physical)Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
- Pruritus (itchy skin)
- JaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
(yellowing of the eyes and skin), due to increased bilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
in the blood. - XanthomaXanthomaA xanthoma , from Greek xanthos, ξανθος, "yellow", is a deposition of yellowish cholesterol-rich material in tendons or other body parts in various disease states...
(local collections of cholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
in the skin, especially around the eyes (XanthelasmaXanthelasmaXanthelasma is a sharply demarcated yellowish deposit of cholesterol underneath the skin, usually on or around the eyelids. Although not harmful or painful, these minor growths may be disfiguring and can be removed...
)) - Complications of cirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
and portal hypertensionPortal hypertensionIn medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
:- Fluid retention in the abdomen (ascitesAscitesAscites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
) - Hypersplenism
- Esophageal varicesEsophageal varicesIn medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus...
- Hepatic encephalopathyHepatic encephalopathyHepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
, up to coma, in extreme cases.
- Fluid retention in the abdomen (ascites
- Association with an extrahepatic autoimmune disorder such as Rheumatoid arthritisRheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
or Sjögren's syndromeSjögren's syndromeSjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....
(up to 80% incidence).
Diagnosis
To diagnose PBC, distinctions should be established from other conditions with similar symptoms, such as autoimmune hepatitisAutoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
or primary sclerosing cholangitis
Primary sclerosing cholangitis
Primary sclerosing cholangitis is a chronic liver disease caused by progressive inflammation and scarring of the bile ducts of the liver. The inflammation impedes the flow of bile to the gut, which can ultimately lead to liver cirrhosis, liver failure and liver cancer...
(PSC).
Diagnostic blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s include:
- Deranged liver function tests (elevated gamma-glutamyl transferase and alkaline phosphataseAlkaline phosphataseAlkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
) - Presence of certain antibodies: antimitochondrial antibody(AMA), antinuclear antibody(ANA)
Abdominal ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
or a CT scan is usually performed to rule out blockage to the bile ducts. Previously most suspected sufferers underwent a liver biopsy
Liver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
, and - if uncertainty remained - endoscopic retrograde cholangiopancreatography
Endoscopic retrograde cholangiopancreatography
Endoscopic retrograde cholangiopancreatography is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal systems...
(ERCP, an endoscopic
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
investigation of the bile duct
Bile duct
A bile duct is any of a number of long tube-like structures that carry bile.Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine.The...
). Now most patients are diagnosed without invasive investigation since the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) liver function tests are considered diagnostic. However, a liver biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
is necessary to determine the stage of disease.
Anti-nuclear antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210 antibodies
Anti-glycoprotein-210 antibodies
Anti-glycoprotein-210 antibodies are directed at gp210 and are found within primary biliary cirrhosis patients in high frequency. AGPA recognize the cytoplasmic oriented carboxyl terminus of the protein...
, and to a lesser degree anti-p62 antibodies
Anti-p62 antibodies
Anti-p62 antibodies are found in a primary biliary cirrhosis. p62 is also more frequent in Stage IV primary biliary cirrhosis and is prognostic for severe disease. The autoantigen is the nucleoporin 62kDA protein....
correlate with progression toward end stage liver failure. Anti-centromere antibodies
Anti-centromere antibodies
Anti-centromere antibodies occur in auto immune disorders; frequently in limited systemic scleroderma, , and, occasionally are found in the diffuse form of scleroderma...
correlate with developing portal hypertension. Anti-np62 and anti-sp100 are also found in association with PBC.
Biopsy
Primary biliary cirrhosis is characterized by interlobular bile duct destruction. Histopathologic findings of primary biliary cirrhosis include:- Inflammation of the bile ducts, characterized by intraepithelial lymphocyteLymphocyteA lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s, and - Periductal epithelioidEpithelioidAn epithelioid cell is a cell that resembles epithelial cells in that it directly contacts its neighboring cells via cell surface molecules or junctions. Unlike epithelial cells, however, epithelioid cells make contacts over their entire surface, rather than at restricted portions. The term...
granulomata.
Summary of stages
- Stage 1 - Portal Stage: Normal sized triads; portal inflammation, subtle bile ductBile ductA bile duct is any of a number of long tube-like structures that carry bile.Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine.The...
damage. Granulomas are often detected in this stage.
- Stage 2 - Periportal Stage: Enlarged triads; periportal fibrosisFibrosisFibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
and/or inflammationInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. 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
Etiology
The cause of the disease is unknown at this time, but research indicates that there is an immunological basis for the diseaseDisease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, making it an autoimmune disorder. Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. In addition, a more specific test to confirm this disease from a bone disorder such as Paget's disease which also has increases in Alkaline phosphatase is the Gamma-glutamyl transpeptidase
Gamma glutamyl transpeptidase
Gamma-glutamyltransferase or gamma-glutamyl transpeptidase is an enzyme that transfers gamma-glutamyl functional groups...
test (GGT). An increase in GGT could indicate presence of Primary Biliary Cirrhosis.
57% of patients with acute liver failure have anti-transglutaminase antibodies
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
suggesting a role of gluten sensitivity
Gluten sensitivity
Gluten sensitivity belongs to a spectrum of disorders in which gluten has an adverse effect on the body. It can be defined as a non-allergic and non-autoimmune condition in which the consumption of gluten can lead to symptoms similar to those observed in coeliac disease or wheat allergy .Gluten...
in primary biliary cirrhosis, and primary biliary cirrhosis is considerably more common in gluten sensitive enteropathy than the normal population. In some cases of disease protein expression may cause an immune tolerance
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
failure, as might be the case with gp210
Nucleoporin 210kDa
Nuclear pore glycoprotein-210 is an essential trafficking regulator in the eukaryotic nuclear pore complex. Gp-210 anchors the pore complex to the nuclear membrane...
and p62
Nucleoporin 62
Nucleoporin p62 is a protein complex associated with the nuclear envelope. The p62 protein remains associated with the nuclear pore complex-lamina fraction. p62 is synthesized as a soluble cytoplasmic precursor of 61 kDa followed by modification that involve addition of N-acetylglucosamine residues...
, nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients. 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 genome scan of PBC patients. 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, suggesting future therapeutic targets.
Therapy
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. However, specific treatment for fatigue, which may be debilitating in some patients, is unavailable.- Ursodeoxycholic acid (UrsodiolUrsodiolUrsodiol, also known as ursodeoxycholic acid and the abbreviation UDCA, is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.-Endogenous effects:...
) is the most frequently used treatment. This helps reduce the cholestasis and improves blood test results (liver function testsLiver function testsLiver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
). It has a minimal effect on symptoms and whether it improves prognosis is controversial.
- To relieve itching caused by bile acids in circulation, which would normally be removed by the liver, cholestyramineCholestyramineCholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
(a bile acid sequestrantBile acid sequestrantThe bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic...
) may be prescribed to absorb bile acids in the gut and be eliminated, rather than re-enter the blood stream.
- Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K. Multivitamins (esp. Vitamin D) and calcium are recommended.
As in all liver diseases, alcoholic beverage
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
s are contraindicated.
In advanced cases, a liver transplant, if successful, results in a favourable prognosis.
Obeticholic acid is in phase III clinical trials for PBC.
Epidemiology
The female:male ratio is at least 9:1. 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.Prognosis
The serum bilirubinBilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
level is an indicator of the prognosis of primary biliary cirrhosis, with levels of 2–6 mg/dL having a mean survival time of 4.1 years, 6–10 mg/dL having 2.1 years and those above 10 mg/dL having a mean survival time of 1.4 years.
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.
Patients with primary biliary cirrhosis have an increased risk of hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
.
External links
- Primary Biliary Cirrhosis page from the National Digestive Diseases Information ClearinghouseNational Digestive Diseases Information ClearinghouseThe National Digestive Diseases Information Clearinghouse is an information dissemination service of the National Institute of Diabetes and Digestive and Kidney Diseases . The NIDDK is part of the National Institutes of Health, which is under the U.S...
- Primary Biliary Cirrhosis page from the American Liver FoundationAmerican Liver FoundationThe American Liver Foundation is a non-profit organization that promotes liver health and disease prevention. The mission of the ALF is to facilitate, advocate and promote education, support and research for the prevention, treatment and cure of liver disease....
- PBCers.org - patients' organisation
- PBC-Society.ca - Canadian PBC patient and research support
- PBC Foundation UK