NORD gratefully acknowledges Benjamin L. Shneider, MD, George Peterkin Endowed Chair, Professor of Pediatrics and Head of Section, Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine; Chief of Service, Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, for assistance in the preparation of this report.
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 appears to follow autosomal recessive inheritance in most patients. However, autosomal dominant inheritance may occur in some patients.
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), 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.
There is a spectrum of disease in PFIC3. At the severe end of the spectrum the disease is progressive and leads to liver transplantation in childhood. At the other end of the spectrum is a much milder disease that may be very responsive to UDCA.
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 mild abnormalities in liver blood tests, gallstones, jaundice and/or itching during pregnancy, or as scarring of the liver and/or yellowing of the eyes and skin.
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, pale 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) starting at about 9 months of age. 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 to properly absorb fat, fat soluble 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. Vitamin K deficiency can lead to severe even life-threatening problems with bleeding and as such careful monitoring of this issue is important. Rickets is a bone disorder with characteristic growth plate abnormalities and progressive softening of the bone structure. It can lead to a predisposition to fractures.
MDR3 deficiency eventually progresses to cause serious life-threatening complications including high blood pressure of the vein of that carries blood from the intestines 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 and stones found within the liver (as opposed to the usual location in the gallbladder) is fairly specific to MDR3 deficiency.
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 some cases the liver disease may look like sclerosing cholangitis a disease often seen in individuals with inflammatory bowel disease. In the setting of MDR3 disease the bile duct injury is mostly inside the liver.
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). In this condition there is a predisposition to the development of stones within the liver itself, which is different than the typical situation where the stones develop in the gallbladder. Because the problem is not localized to the gallbladder, problems can persist 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.
MDR3 deficiency occurs due to disruption or changes (mutations) of the ABCB4 gene. This mutation is thought to be 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. In general MDR3 disease behaves as an autosomal recessive condition, requiring the presence of mutations in both copies of the gene.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some cases, MDR3 related disease process occur in individuals with only one altered ABCB4 gene. Therefore, in some people, MDR3 deficiency can act like an autosomal dominant disease. This is not common but has been described.
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 enzyme leading to decreased level of phospholipids in bile and an abnormality in 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.
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 and/or chronic liver disease when the serum gGTP levels are elevated. 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 (GGT). Molecular genetic testing for mutations in the ABCB4 gene 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 could be performed. The decrease in biliary phospholipid supports the diagnosis and the level of the residual concentration is helpful for prognosis.
Ursodeoxycholic acid (udca) therapy is effective in some patients (especially those with milder disease) and should be part of the initial treatment options for affected individuals. Restoring vitamins and nutrients lost through malabsorption may also be necessary. At a minimum fat-soluble vitamin levels should be monitored to identify deficiency in affected individuals. 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 surgery (e.g. cholecystectomy [gallbladder removal]), but this may not be completely effective due to the on-going risk of stone formation within the liver.
Some individuals do not respond to ursodeoxycholic acid therapy and may require a liver transplant. Nearly all 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 transplant, affected individuals will be required to take medication life-long for immunosuppression.
Genetic counseling is recommended for affected individuals and their families.
In the future, cell, gene or targeted mutation-specific pharmacological therapies might be useful tools for the management of patients with PFIC3.
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