Progressive intrahepatic cholestasis type 1, 2 and 3 (Progressive Familial Intrahepatic cholestasis types 1, 2 and 3 -PFIC1, PFIC2 and PFIC3-) - Genes ATP8B1 (PFIC1), ABCB11 (PFIC2) and ABCB4 (PFIC3)
Intrahepatic cholestasis progressive family the (PFIC: Progressive Familial Intrahepatic cholestasis) are a group of progressive liver diseases that cause liver failure. These diseases are due to decreased secretory capacity of hepatocytes to some of the components of bile. The accumulation of these components in the hepatocyte causes damage of these cells and expression of liver disease starting in the early stages of life. Those affected suffer from severe itching, jaundice, decreased development, portal hypertension and hepatosplenomegaly. Three types of PFIC: PFIC1, PFIC2 and PFIC3, each of them caused by the decreased synthesis, or absence, of a particular protein required for normal hepatocyte secretory function.
The PFIC1, PFIC2 and PFIC3, are caused by mutations in the ATP8B1 (or FIC1) genes, ABCB11 and ABCB4 (or MDR3), respectively. In some cases they have not found mutations of these genes and processes are considered unknown cause.
Progressive familial intrahepatic cholestasis type 1 (PFIC1: Progressive Familial Intrahepatic cholestasis type 1; Byler 's Disease) - Gen ATP8B1 (FIC1).
Familial intrahepatic cholestasis progressive type 1 (PFIC1) is characterized clinically, in addition to the common signs and symptoms listed, by short stature, deafness, diarrhea, pancreatitis, and decreased blood levels of fat soluble vitamins (A, D, E and K). Those affected come to liver failure before adulthood.
This disease is caused by mutations in the ATP8B1 (or FIC1) gene, located on the long arm of chromosome 18 (18q21-q22), encoding a carrier protein (aminophospholipid translocase) of some fat molecules (aminophospholipids) through cell membrane, helping to maintain a proper balance of bile acids in bile. The ATP8B1 gene belongs to the family of ATP (superfamily ATPase) gene, and described more than 50 different mutations in it. ATP8B1 gene mutations have been associated with other forms of liver disease called "benign recurrent intrahepatic cholestasis" (BRIC: Benign Recurrent Intreahepatic cholestasis) - see intrahepatic cholestasis benign recurrent -.
Most mutations in the gene responsible for PFIC1 ATP8B1 remove large portions of the gene or coding result of an abnormally short protein. These mutations severely alter the structure or function of the protein ATP8B1 causing bile acids accumulate in liver cells, damaging these cells and leading to liver disease. Although the ATP8B1 protein found throughout the body, it is not clear how this functional protein deficiency causes short stature, deafness, diarrhea and other signs and symptoms of PFIC1.
Intrahepatic cholestasis type progressive family 2 (PFIC2: Progressive Familial Intrahepatic cholestasis type 2) - Gen ABCB11.
Family intrahepatic cholestasis progressive type 2 (PFIC2) is clinically characterized by expressing only the common signs and symptoms mentioned, although they are more intense than in the PFIC1 and develop liver failure in the early stages of life. In addition, those affected are at increased risk of developing hepatocellular carcinoma.
This disease is due to mutations in the gene ABCB11 (ATP-binding cassette, subfamily B-MDR / TAP, member 11), located on the long arm of chromosome 2 (2q24). The ABCB11 gene belongs to the family of ABC genes (ATP-Binding Cassette tranporters), and the family of ATP (superfamily ATPase) gene. This gene encodes a bile salt export protein (BSEP: Bile Salt Export Pump) that moves bile salts of hepatocytes.
They described over 100 mutations in the gene ABCB11 in people with PFIC2. Mutations in this gene result in a reduction of 70% or complete absence of bile salt transport outside the liver, which makes bile salts accumulate in the liver cells, causing liver disease and signs and symptoms PFIC2 associated. Mutations which lead to a short protein coding, non - functional or that inhibit protein coding tend to be associated with serious liver disease with an earlier start. People with no functional protein also appear to be at increased risk of developing hepatocellular carcinoma.
ABCB11 gene mutations have been associated with other forms of liver disease called "benign recurrent intrahepatic cholestasis" (BRIC: Benign Recurrent Intreahepatic cholestasis) - see intrahepatic cholestasis benign recurrent -. ABCB11 gene mutations have also been found in the "intrahepatic cholestasis of pregnancy" (ICP: Intrahepatic Cholestacis of Pregnancy) - see Intrahepatic cholestasis a gestation -.
Progressive familial intrahepatic cholestasis type 3 (PFIC3: Progressive Familial Intrahepatic cholestasis type 3) - Gen ABCB4 (MDR3).
Family progressive intrahepatic cholestasis type 3 (PFIC3) is clinically characterized by expressing only the common signs and symptoms mentioned, but these do not appear until late childhood or early childhood. Rarely, people are diagnosed in early adulthood.
This disease is caused by mutations in the gene ABCB4 (aka MDR3) (ATP-binding cassette, subfamily B-MDR / TAP, member 4), located on the long arm of chromosome 7 (7q21.1). This gene belongs to the family of ABC genes (ATP-Binding Cassette Transporters) or family of genes ATP (superfamily ATPase), and encodes a protein that moves phospholipids through the cell membrane of hepatocytes. Outside of hepatocytes, phospholipids bind bile acids. When there is an excess of free bile acids, without being bound to phospholipids not secreted by hepatocytes, can be toxic.
They have identified more than 45 mutations in the gene ABCB4 in people with familial intrahepatic cholestasis type 3 progressive (PFIC3). These genetic changes usually cause liver failure. Mutations which lead to a short protein coding, non - functional or that inhibit protein coding tend to be associated with serious liver disease with an earlier start. Mutations in this gene alter movement of the phospholipids of cell membranes, leading to a deficiency of available phospholipids to bind bile acids. An accumulation of bile acids damaged liver cells, causing the signs and symptoms associated with the disease.
Progressive familial intrahepatic cholestasis the inherited with an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with progressive familial intrahepatic cholestasis, by complete PCR amplification of the exons of the ATP8B1 (PFIC1), ABCB11 (PFIC2) and ABCB4 (PFIC3) genes, respectively, and subsequent sequencing. To reduce costs is recommended to clarify the clinical suspicion of each of the types of PFIC, so you can direct the genetic study into the gene involved, depending on the type of PFIC.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).