NORD gratefully acknowledges Alex Knisely, MD, Institute of Liver Studies/Histopathology, King's College Hospital, London, UK, for assistance in the preparation of this report.
Low gamma-GT (GGT) familial intrahepatic cholestasis refers to a spectrum of disease, ranging from mild to severe cases. This spectrum of disease predominantly affects the liver. A variety of disorders leads to low GGT familial intrahepatic cholestasis. Children with defects in bile acid synthesis or conjugation, children with abnormalities of contact between liver cells, children with abnormalities of cell organization manifest as arthrogryposis-renal dysfunction-cholestasis syndrome, and children with "neonatal hemochromatosis" all may have low GGT familial intrahepatic cholestasis. These disorders are not covered in this report.
This report covers the two severe and two mild forms of low GGT familial intrahepatic cholestasis that have been generally recognized, although researchers have begun to identify cases that fall in between these two extremes. The severe forms are known as progressive familial intrahepatic cholestasis (PFIC) 1 and 2 and the two milder forms are known as benign recurrent intrahepatic cholestasis (BRIC) 1 and 2. PFIC and BRIC thus lie at different ends of a spectrum. Some persons with low GGT familial intrahepatic cholestasis cannot be shown to have any of the disorders mentioned in this paragraph or in the preceding paragraph. The search continues for causes for these persons' illness or illnesses.
The main symptom of this spectrum of disease is interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis in these disorders occurs due to defects within the liver (intrahepatic) rather than within the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets, and persistent, severe itchiness (pruritus). In many cases, symptoms or signs are present at birth or during the newborn period. The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.
PFIC1 and BRIC1 are caused by mutations in a gene named ATP8B1. ATP8B1 encodes a protein named familial intrahepatic cholestasis 1 (FIC1). PFIC2 and BRIC2 are caused by mutations in a gene named ABCB11. ABCB11 encodes a protein named bile salt export pump (BSEP). All forms of PFIC are inherited as an autosomal recessive trait. Some affected individuals do not have mutations in either of these genes, suggesting that additional, as of yet unidentified, forms of these disorders may exist.
These disorders have normal or low serum levels of an enzyme known as gamma-glutamyltransferase (GGT) and, therefore, may be collectively known as low GGT familial intrahepatic cholestasis. Most children with severe cholestasis have elevated levels of this enzyme, enabling physicians to distinguish these disorders from other causes of cholestasis.
Researchers have also identified a disorder known as PFIC type 3 or multidrug resistance protein 3 (MDR3) deficiency. Although this disorder is often grouped with PFIC1 and PFIC2, it is associated with high levels of GGT enzyme activity and the underlying defects causing this disorder are different. MDR3 deficiency is not covered in this report.
The classification of these disorders is complicated and has continually changed as more about these disorders has become known. The classification and grouping of these disorders may undergo further changes in the future. Both these disorders were called "Byler disease" at one time, until their different genetic basis became clear. Various other names have been used for these disorders such as FIC1 deficiency for PFIC1 and BSEP deficiency for PFIC2, adding to the confusion.
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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