MDR3 Deficiency

NORD gratefully acknowledges Prof. Emmanuel Jacquemin and Dr Emmanuel Gonzales, Pediatric Hepatology Unit and Pediatric Liver Transplantation Unit, Reference Center for Children with Biliary Atresia, Bicêtre Hospital, Paris, France, for assistance in the preparation of this report.

Subdivisions of MDR3 Deficiency

  • Low Phospholipid Associated Cholelithiasis
  • Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3)

General Discussion


MDR3 deficiency is a rare genetic disorder that predominantly affects the liver. The disorder represents a spectrum of diseases that can range from mild to severe. The main symptom is interruption or suppression of the flow of bile from the liver (cholestasis). In addition, affected individuals may be prone to forming gallstones. Cholestasis in MDR3 deficiency occurs due to defects within the liver (intrahepatic) rather than within the bile ducts outside the liver (extrahepatic). Cholestasis can cause yellowing of the skin mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets and persistent itchiness. Symptoms may be present in the neonatal period rather than at birth (congenital) or, in mild cases, may not appear until middle age when the disorder manifests as intrahepatic cholestasis of pregnancy, gallstone disease, or jaundice and scarring of the liver (cirrhosis). MDR3 deficiency is caused by mutations of the ABCB4 gene and is inherited as an autosomal recessive trait.


The terminology used to describe MDR3 deficiency can be confusing. The term can be applied to several disorders including progressive familial intrahepatic cholestasis (PFIC) type 3, benign recurrent intrahepatic cholestasis (BRIC) type 3, low phospholipid associated cholelithiasis (LPAC) syndrome, adult biliary fibrosis or cirrhosis, and certain cases of intrahepatic cholestasis of pregnancy (ICP), of drug induced cholestasis (DIC) and of transient neonatal cholestasis (TNC). These disorders are all caused by mutations of the ABCB4 gene and resulting deficiency of MDR3.

Signs & Symptoms

The age of onset, severity and specific symptoms of MDR3 deficiency can vary greatly from one person to another. In some cases (mainly PFIC3, TNC3), cholestasis may be present in newborns (neonatal period). Individuals with mild forms of this disorder may not develop symptoms until young adulthood or middle age where MDR3 deficiency may manifest as gallstones, as intrahepatic cholestasis of pregnancy, or as cirrhosis and jaundice.

Cholestasis is the characteristic finding for MDR3 deficiency. Cholestasis is defined as an alteration of the flow of bile from the liver. The formation of bile is one of the main functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), lipids (bile salts, phospholipids, cholesterol), and other materials including an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, fat soluble vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. In MDR3 deficiency cholestasis, this interruption or suppression usually begins during the first few months of life. Affected infants have episodes of cholestasis followed by disease-free periods. However, eventually cholestasis progresses to become a permanent condition.

Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.

The initial symptoms associated with MDR3 deficiency may be jaundice, discolored stools and/or hepatomegaly, which can be present during the neonatal period rather than at birth (congenital). Affected infants may also experience mild or moderate itching (pruritus). Itching can cause irritability and skin abrasions due to constant scratching. Yellowing of the skin, mucous membranes and whites of the eyes (jaundice) is often present. Initially jaundice may come and go, but eventually it may continually persist. Additional symptoms common to liver disease such as an abnormally large liver and spleen (hepatosplenomegaly) may also occur.

Another symptom associated with MDR3 deficiency is impairment of the ability of the digestive system properly to absorb fat, vitamins and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and eventually results in failure to thrive, growth deficiency, bleeding episodes such as repeated nosebleeds, an abnormal susceptibility to bruising, and rickets. Rickets is a bone disorder with characteristic growth plate abnormalities and progressive softening of the bone structure. As a result, some children may be small for their age (short stature).

MDR3 deficiency eventually progresses to cause serious life-threatening complications including high blood pressure of the vein of that carries blood from the stomach to the liver (portal hypertension), scarring of the liver (cirrhosis) and, eventually, liver failure. This process can occur rapidly or more slowly, ranging from the neonatal period to before adulthood.

Additional symptoms that may affect individuals with MDR3 deficiency include the development of gallstones. Gallstones, also known as cholelithiasis, can cause obstruction and/or inflammation of the gallbladder (cholecystitis), which can result in cramping pain in the upper abdomen, fever and jaundice.

Although many cases of MDR3 deficiency occur during infancy or childhood, some individuals with mutations of the ABCB4 gene do not develop symptoms until young adulthood or middle age. For example, some adults may develop jaundice and scarring of the liver (fibrosis or cirrhosis) during middle age.

In other cases, some adults with mutations of the ABCB4 gene develop a specific type of cholesterol gallstone disease called low phospholipid associated cholelithiasis (LPAC). LPAC syndrome is characterized by inflammation of the gallbladder, inflammation of the bile ducts, intrahepatic gallstone disease and may result in inflammation of the pancreas (pancreatitis). Gallstone disease often persists even after the surgical removal of the gallbladder. Onset of symptoms is younger than 40 years of age.

Some females with mutations of the ABCB4 gene may develop a condition known as intrahepatic cholestasis of pregnancy (ICP). This condition is characterized by cholestasis, itching and, in some cases, jaundice that develops during pregnancy, usually during the third trimester. The symptoms resolve without treatment (spontaneously) after the pregnancy (postpartum). Generally, females who develop ICP do not exhibit symptoms before pregnancy and do not develop chronic liver damage.

It is important to note that individuals with MDR3 deficiency might experience during their life different features of the various MDR3 deficiency diseases.


Investigators have determined that MDR3 deficiency occurs due to disruption or changes (mutations) of the ABCB4 gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

Investigators have determined that the ABCB4 gene is located on the long arm of chromosome 7 (7q21.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 7q21.1” refers to band 21.1 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The ABCB4 gene creates (encodes) a protein known as multidrug resistance protein 3 (MDR3). Mutations in the ABCB4 gene result in absence or low levels of functional MDR3. This protein is involved in transporting phospholipids across the canalicular membrane of liver cells (hepatocytes). When this protein is absent or functions improperly it reduces the level of phospholipids in bile. Phospholipids are substances that come from the body’s fats (lipids) and within the bile they help to breakdown fat and vitamins to be absorbed by the body. In addition, the stability of lipid droplets (called mixed micelles) within bile is determined by a three-phase system, in which a proper proportion of bile salts and phospholipids are necessary to maintain solubility of cholesterol. The absence of phospholipids destabilizes these micelles and promotes lithogenicity (formation of stone) of bile with crystallization of cholesterol, which results in obstruction of small bile ducts. The lack of phospholipids ultimately has a toxic effect on the bile ducts. Individuals with no residual enzyme activity have severe forms of MDR3 deficiency. Individuals with mild forms of the MDR3 deficiency have varying degrees of enzyme activity and of subsequent phospholipid concentrations in bile. In all patients with MDR3 deficiency, serum GGT activity is elevated.

Affected Populations

MDR3 deficiency affects males and females in equal numbers. The exact incidence and prevalence of MDR3 deficiency is unknown. Concerning PFIC3, fewer than 100 cases have been reported in the medical literature. Because milder forms of MDR3 deficiency often go unrecognized or misdiagnosed, it is difficult to determine the disorder’s true frequency in the general population.


A diagnosis of MDR3 deficiency should be suspected in infants and children with evidence of cholestasis. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, and a variety of tests.

Clinical Testing and Work-Up

Tests used to help diagnose MDR3 deficiency include measuring serum levels of bilirubin, bile salts, and gamma-glutamyltransferase. Molecular genetic testing is available on a clinical basis and can confirm the diagnosis. Microscopic examination of liver tissue (biopsy) and MDR3 immunostaining may be performed to aid in diagnosis and to detect the presence of cirrhosis. If bile can be collected during ERCP or surgery, a biliary lipid analysis should be performed. The decrease in biliary phospholipid confirms the diagnosis and the level of the residual concentration is helpful for prognosis.

Standard Therapies


No specific therapy exists for individuals with MDR3 deficiency. However, ursodeoxycholic acid is efficient in most cases and should be the initial treatment option for affected individuals. Some affected individuals including patients with a PFIC3 presentation have a favorable outcome with this therapy. Other treatments are directed toward the specific symptoms (e.g. itching) or complications (e.g. cirrhosis, gallbladder stone disease) that are apparent in each individual. Treatment options include drug therapy, surgery (e.g. cholecystecomy) and, in severe cases, liver transplantation. Restoring vitamins and nutrients lost through malabsorption may also be necessary.

Some individuals do not respond to ursodeoxycholic acid therapy and may require a liver transplantation. Some affected individuals who have undergone liver transplantation have demonstrated dramatic improvement of symptoms. However, a liver transplantation carries risk and may result in post-operative complications. Also, after a liver transplantation, affected individuals will be required to take medication life-long for immunosuppression. In the future, cell, gene or targeted mutation-specific pharmacological therapies might be useful tools for the management of patients with PFIC3.

Genetic counseling may be of benefit for affected individuals and their families.

Investigational Therapies

IInformation on current clinical trials is posted on the Internet at 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:

Toll-free: (800) 411-1222

TTY: (866) 411-1010


For information about clinical trials sponsored by private sources, in the main, contact:

For information about clinical trials conducted in Europe, contact:


Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

Supporting Organizations



Gautherot J, Durand-Schneider AM, Delautier D, Delaunay JL, Rada A, Gabillet J, Housset C, Maurice M, Aït-Slimane T. Effects of cellular, chemical, and pharmacological chaperones on the rescue of a trafficking-defective mutant of the ATP-binding cassette transporter proteins ABCB1/ABCB4. J Biol Chem. 2012 Feb 10;287(7):5070-8.

Gonzales E, Spraul A, Jacquemin E. Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 3. Eur J Hum Genet. 2013 Sep 4. doi: 10.1038/ejhg.2013.188. [Epub ahead of print]

Kubitz R, Bode J, Erhardt A, et al. Cholestatic liver diseases from child to adult: the diversity of MDR3 disease. Z Gastroenterol. 2011;49:728-736.

Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. The spectrum of liver disease related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin Liver Dis. 2010;30:136-146.

Gonzales E, Jacquemin E. Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: a new tool in a near future? J Hepatol. 2010 Aug;53(2):385-7.

Stapelbroek JM, van Erpecum KJ, Klomp LWJ, Houwen RHJ. Liver disease associated with canalicular transport defects: current and future therapies. J Hep. 2010;52:258-271.

Gonzales E, Davit-Spraul A, Baussan C, et al. Liver diseases related to MDR3 (ABCB4) gene deficiency. Front Biosci. 2009;14:4242-4256.

Jung C, Driancourt C, Baussan C, Zater M, Hadchouel M, Meunier-Rotival M, Guiochon-Mantel A, Jacquemin E. Prenatal molecular diagnosis of inherited cholestatic diseases. J Pediatr Gastroenterol Nutr. 2007 Apr;44(4):453-8.

Sundaram SS, Sokol RJ.The multiple facets of ABCB4 (MDR3) deficiency.Curr Treat Options Gastroenterol. 2007;10:495-503.

Fein F, Hermelin B, Becker MC, Felix S, Carbonnel F. Acute recurrent biliary pancreatitis associated with the ABCB4 gene mutation. GastroenterolClin Biol. 2007;31:106-109.

Jansen PL, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int. 2003;23:315-322.

Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001;120:1448-1458.


Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive Familial Intrahepatic Cholestasis. Orphanet encyclopedia, January 2009. Available at: Accessed Feb 12, 2014.

Rosmorduc O, Poupon R. Low Phospholipid Associated Cholestasis: Association with Mutation in the MDR3/ABCB4 gene. Orphanet encyclopedia, June 2007. Available at: Accessed Feb 12, 2014.

Friedman JR, Muir AB. Progressive Familial Intrahepatic Cholestasis. Medscape, Updated: Aug 15, 2013. Available at: Accessed Feb 12, 2014.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:602347; Last Update: 12/07/2012. Available at: Accessed Feb 12, 2014.


Years Published

2011, 2014

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