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.