NORD gratefully acknowledges Angela C. Cheung, MD, FRCPC, Research Fellow, Mayo Clinic, Rochester, MN, and the Canadian PBC Society, for assistance in the preparation of this report.
Primary biliary cholangitis (PBC) is a chronic, or long lasting, progressive liver disorder that mostly affects women and usually appears during middle age. PBC leads to inflammation and scarring of the small bile ducts (the plumbing system of the liver which transports bile, the substance that helps digest fat). When PBC is very severe, it can lead to yellow discoloration of the skin (jaundice). If PBC is untreated, it can lead to cirrhosis, or scarring of the entire liver, which can lead to liver failure. PBC is divided into four stages, with stage 1 being early disease, where this is no significant scarring, to stage 4, or which is defined by cirrhosis. Although the exact cause of PBC is unknown, it is thought that it is likely due to a combination of factors such as autoimmune (when a person’s own immune system attacks their body), genetic, and environmental factors.
The most common symptoms of PBC are:
The cause of fatigue in PBC is unknown and can be very debilitating. Unfortunately, there are no accepted drug treatments for the fatigue in PBC, though research for medicines that can help fatigue is ongoing. Since fatigue is very common, it is important to rule out other causes of fatigue. The fatigue in PBC is not linked to the severity of the liver disease. Patients can have early disease but still have profound fatigue, while others with more advanced disease may have no fatigue at all. The fatigue is also not linked to how quickly the disease will get worse.
Like fatigue, the cause of pruritus in PBC is unknown and it is not always linked to the severity of the liver disease. It is likely that the pruritus is caused by substances in the blood, rather than in the skin, unlike pruritus caused by allergies. Fortunately, unlike fatigue, there are a number of drug treatments for pruritus that work for most people (see below under Standard Therapies).
As mentioned above, jaundice occurs when PBC is very severe. Sometimes, it can be reversed with treatment of the PBC, but sometimes, patients who have jaundice will require a liver transplant. Jaundice usually happens when the liver is so damaged that the normal function of the liver is impaired.
Complications of PBC:
•Portal hypertension (ascites, varices, hepatic encephalopathy)
Portal hypertension usually occurs after a patient develops cirrhosis. It can lead to fluid build-up in the abdomen (ascites), or big veins in the esophagus (the structure where food goes when you swallow), or confusion (due to a build-up of toxins that are not removed by the liver).
Fat malabsorption occurs only when PBC is very advanced, and it is very rare. If it does happen, it will cause diarrhea, oily stool and weight loss. Fat deposits under the skin are more common, as there is a higher amount of cholesterol in the blood of people with PBC. These fat deposits appear as yellow bumps beneath the skin, usually under the eyes or over joints.
Osteoporosis is the most common complication in PBC, though it is also very common in people without PBC. It leads to thinning of the bones and can be treated with medicines for the bones.
Other autoimmune diseases are also associated (occur more commonly) with PBC. Some examples of these other diseases include:
•Sjogren’s syndrome: A disease that causes dry eyes and dry mouth
•Celiac disease: A disease that affects the small intestine, causing an allergy to gluten (i.e. which is contained in products with wheat, rye, bran)
The exact cause of PBC is unknown. Possible immunological, autoimmune, genetic, and/or environmental factors are under investigation as potential causes of the disorder.
Immunological abnormalities may be an important contributing factor in the development of PBC. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). Individuals with PBC have unusually decreased numbers of circulating T cells in the blood and abnormalities in T cell function and regulation (i.e., helper and suppressor T cells). The role of T cell abnormalities in potentially contributing to the symptoms associated with PBC is not yet known.
Autoimmune factors may also play a contributing role in causing PBC. Autoimmune disorders are caused when the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. For example, antibodies typically directly kill “invaders” (e.g., microorganisms, toxins, and other foreign substances) or coat them so they are more easily destroyed by white blood cells. (The white blood cells [leukocytes] are part of the body’s system of defenses, playing an essential role in protecting against infection as well as fighting infection once it occurs.) However, in some patients, antibodies may improperly form against certain of the body’s own tissues, causing autoimmune disease.
Approximately 95 percent of people with PBC produce antibodies (known as “autoantibodies”) that act upon certain of the body’s own mitochondria (mitochondrial autoantigens, e.g., E2 component of pyruvate dehydrogenase complex [PDC-E2], E2 component of branched chain 2-oxo-acid dehydrogenase complex [BCOADC-E2]). Mitochondria are found by the hundreds within cells in the body and carry the blueprints for making energy. They have their own genetic instructions (mtDNA) and are located outside of the nucleus of the cell (cytoplasm). The role of anti-mitochondrial antibodies in potentially causing the symptoms associated with PBC is not clearly understood.
In addition, in some individuals with PBC, specialized laboratory tests conducted on the fluid portion of the blood (serum) have revealed the presence of certain antibodies typically produced in response to certain viruses (i.e., retroviral antigens). Antigens are those substances, such as microorganisms, toxins, or other foreign substances, that may trigger production of particular antibodies as part of an immune response. This suggests that in individuals with PBC, certain antibodies may be mistakenly reacting to one or more of the body’s own proteins that are very similar to protein fragments from certain invading viruses (i.e., the immune system is unable to distinguish between the “mimic” protein on the surface of certain viruses and the body’s own proteins). On the other hand, such findings may provide evidence that PBC may be due, at least in part, to an underlying viral infection, a finding that has been demonstrated in other autoimmune disorders.
Because a number of familial cases of PBC have been reported in the medical literature, it is also suspected that certain genetic factors may play some role in the development of PBC. Environmental or other factors may trigger symptoms in those with a genetic predisposition to the disorder.
Further studies are needed to determine the potential role(s) that immunological, autoimmune, genetic, environmental, and/or other factors may play in causing PBC.
PBC affects mostly women, but more men are now being diagnosed. The disorder usually becomes apparent during middle age, initially affecting most individuals between the ages of 45 to 65 years. However, the disorder has been diagnosed in females as young as 22 years of age and in females in their early 90s. It has been estimated that PBC is one of the most common autoimmune diseases, affecting nearly 1 in 1000 women over the age of 40.
The diagnosis of PBC requires the presence of:
1)High alkaline phosphatase (ALP, a liver blood test) along with
2)Positive anti-mitochondrial antibody (+AMA)
If AMA testing is negative, then a patient would need a liver biopsy to confirm the diagnosis of PBC, since a number of diseases can cause a high ALP.
In 2004, the drug ursodiol (Urso), also known as ursodeoxycholic acid (UDCA), was approved by the Food and Drug Administration (FDA) for the treatment of PBC. Ursodiol is manufactured by Axan Pharma and Schwarz Pharma US.
In 2016, the drug obeticholic acid (Ocaliva) was approved for the treatment of PBC in combination with UDCA in adults with inadequate response to UDCA (i.e. lack of significant improvement or normalization of ALP), or as a single therapy in adults unable to tolerate UDCA. Obeticholic acid is manufactured by Intercept Pharmaceuticals Inc. For more information, contact:
Other treatments for PBC are for the symptoms.
The treatment of pruritus requires medications in addition to UDCA, as UDCA doesn’t usually treat the itch in PBC. The drugs cholestyramine or colestipol hydrochloride are usually the first drug that is tried because it stops itching in many people, and has limited side effects, the most common one being constipation. Other drugs for pruritus include rifampin (an old antibiotic that is no longer used as an antibiotic because there are better antibiotics on the market), gabapentin, sertraline, naltrexone, fibrates. Anti-itch medications such as anti-histamines do not usually work.
Very rarely, treatments such as UV therapy and plasmapheresis (an invasive medical procedure that filters the blood) are needed. Sometimes, none of these treatments work and patients require a liver transplant. This is very rarely done.
Malabsorption of fat-soluble vitamins may be treated with vitamin K 1, A, D, and calcium supplementation. Iron deficiency anemia responds to oral iron supplements. Additional folic acid can be given to individuals taking cholestyramine because this drug can sometimes cause a folic acid deficiency. Folic acid and cholestyramine should be taken several hours apart since they may react and prevent folic acid absorption when taken together. Loss of fat in the stools (steatorrhea) may be treated by a low-fat diet supplemented with medium-chain triglycerides to maintain high caloric intake.
The treatments for portal hypertension depend on the severity of the complications. For mild ascites, salt restriction may be the only treatment that is needed. When the ascites is severe, it may be necessary to take diuretics (water pills that make patients urinate more in order to decrease the fluid retention). Treatment of varices is either medical (ie. beta blockers to reduce the pressure in the varices) or endoscopic (ie. a very small camera that enters the esophagus and is used for banding, which is a procedure that shrinks the varices). Hepatic encephalopathy can be treated with a specific laxative called lactulose, or rifaximin, a non-absorbable antibiotic.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Beers MH, Porter RS, Jones TV, Kaplan JL, Berkwits M. eds. The Merck Manual, 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:218-19.
Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:799-800.
Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill Companies. New York, NY; 2005:1860-61.
Yamada T, Alpers DH, Kaplowitz N, Laine L, et al. Eds. Textbook for Gastroenterology. 4th ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2003:2374-85.
O’Leary JG, Pratt DS. Cholestasis and cholestatic syndromes. Curr Opin Gastroenterol. 2007;23:232-6.
Lazaridis KN, Talwalkar JA. Clinical epidemiology of primary biliary cirrhosis: incidence, prevalence, and impact of therapy. J Clin Gastroenterol. 2007;41:494-500.
He XS, Ansari AA, Ridgway WM, Coppel RL, Gershwin ME. New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol. 2006 Jan;239(1):1-13.
Leung PS, Coppel RL, Gershwin ME. Etiology of primary biliary cirrhosis: the search for the culprit. Semin Liver Dis. 2005;25:327-36.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Biliary Cirrhosis, Primary; PBC. Entry Number; 109720: Last Edit Date; 04/02/2014. http://omim.org/entry/109720 Accessed April 14, 2016.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100