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Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in
biliary A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
epithelial transporters. The clinical presentation usually occurs first in
childhood A child (plural, : children) is a human being between the stages of childbirth, birth and puberty, or between the Development of the human body, developmental period of infancy and puberty. The legal definition of ''child'' generally refers ...
with progressive
cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malig ...
. This usually leads to
failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
,
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
, and the need for
liver transplant Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...
ation.


Types

Types of progressive familial intrahepatic cholestasis are as follows: * Type 1 (OMIM #211600), also called Byler disease * Type 2 (OMIM #601847), also called
ABCB11 ATP-binding cassette, sub-family B member 11 also known as ABCB11 is a protein which in humans is encoded by the gene. Function The product of the ''ABCB11'' gene is an ABC transporter named BSEP (bile salt export pump), or sPgp (sister of ...
deficiency or BSEP deficiency * Type 3 (OMIM #602347), also called
ABCB4 The ATP-binding cassette 4 gene encodes the Multidrug resistance protein 3. ABCB4 is associated with progressive familial intrahepatic cholestasis type 3 and intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP), also ...
deficiency or MDR3 deficiency * Type 4 (OMIM #615878), from mutation in '' TJP2''


Signs and symptoms

The onset of the
disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
is usually before age 2, but patients have been diagnosed with PFIC even into
adolescence Adolescence () is a transitional stage of physical and psychological development that generally occurs during the period from puberty to adulthood (typically corresponding to the age of majority). Adolescence is usually associated with the ...
. Of the three entities, PFIC-1 usually presents earliest. Patients usually present in early childhood with
cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malig ...
,
jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
, and
failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
. Intense
pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
is characteristic; in patients who present in adolescence, it has been linked with
suicide Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...
. Patients may have fat
malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
, leading to fat soluble
vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
deficiency, and complications, including
osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
.


Pathogenesis

PFIC-1 is caused by a variety of
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in ATP8B1, a
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
coding for a P-type
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, FIC-1, that is responsible for
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
translocation across membranes. It was previously identified as clinical entities known as Byler's disease and Greenland-Eskimo familial cholestasis. Patients with PFIC-1 may also have watery
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
, in addition to the clinical features below, due to FIC-1's expression in the
intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
. How ATP8B1 mutation leads to cholestasis is not yet well understood. PFIC-2 is caused by a variety of
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in
ABCB11 ATP-binding cassette, sub-family B member 11 also known as ABCB11 is a protein which in humans is encoded by the gene. Function The product of the ''ABCB11'' gene is an ABC transporter named BSEP (bile salt export pump), or sPgp (sister of ...
, the
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
that codes for the ''bile salt export pump'', or BSEP. Retention of bile salts within hepatocytes, which are the only cell type to express BSEP, causes hepatocellular damage and cholestasis. PFIC-3 is caused by a variety of
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in
ABCB4 The ATP-binding cassette 4 gene encodes the Multidrug resistance protein 3. ABCB4 is associated with progressive familial intrahepatic cholestasis type 3 and intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP), also ...
, the gene encoding multidrug resistance protein 3 (MDR3), which codes for a
floppase Flippases (rarely spelled flipases) are transmembrane lipid transporter proteins located in the membrane which belong to ABC transporter or P4-type ATPase families. They are responsible for aiding the movement of phospholipid molecules between t ...
responsible for
phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybea ...
translocation. The defective phosphatidylcholine translocation leads to a lack of phosphatidylcholine in bile. Phosphatidylcholine normally chaperones bile acids, preventing damage to the biliary epithelium. The free or "unchaperoned" bile acids in bile of patients with MDR3 deficiency cause a cholangitis. Biochemically, this is of note, as PFIC-3 is associated with a markedly elevated GGT. The
inheritance Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Of ...
pattern of all three forms of PFIC defined to date is
autosomal recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...
. Liver biopsies typically show evidence of
cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malig ...
(including bile plugs and bile infarcts), duct hypoplasia, hepatocellular injury, and Zone 3
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. Giant cell change and other features of hepatocellular injury are more pronounced in PFIC-2 than in PFIC-1 or PFIC-3. End-stage disease in all forms of PFIC defined to date is characterized by bridging fibrosis with duct proliferation in peri-portal regions.


Diagnosis

Biochemical markers include a normal GGT for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum
bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primar ...
levels are grossly elevated. Serum
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
levels are typically not elevated, as is seen usually in cholestasis, as the
pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
is due to a transporter as opposed to an anatomical problem with biliary cells.


Treatment

Initial treatment is supportive, with the use of agents to treat
cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malig ...
and
pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
, including the following: *
Ursodeoxycholic acid Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of ...
*
Cholestyramine Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, wh ...
*
Rifampin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...
*
Naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...
, in refractory cases The partial external biliary diversion (PEBD) procedure is a surgical approach that diverts bile from the gallbladder externally into an ileostomy bag. Patients should be supplemented with fat-soluble vitamins, and occasionally medium-chain triglycerides in order to improve growth. When liver synthetic dysfunction is significant, patients should be listed for transplantation. Family members should be tested for PFIC mutations, in order to determine risk of transmission.


Prognosis

The disease is typically progressive, leading to fulminant
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
failure and death in childhood, in the absence of
liver transplantation Liver transplantation or hepatic transplantation is the replacement of a Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...
.
Hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...
may develop in PFIC-2 at a very early age; even toddlers have been affected.


Epidemiology

*
Consanguinity Consanguinity ("blood relation", from Latin '' consanguinitas'') is the characteristic of having a kinship with another person (being descended from a common ancestor). Many jurisdictions have laws prohibiting people who are related by blood fr ...
is believed to be a major risk factor. * Similar transport protein mutations are believed to pose a higher risk for
intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, cholestasis of pregnancy, jaundice of pregnancy, and prurigo gravidarum, is a medical condition in which cholestasis occurs during pregnancy. It typically presents wi ...
.


See also

*
Alagille syndrome Alagille syndrome is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and ...
*
Intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, cholestasis of pregnancy, jaundice of pregnancy, and prurigo gravidarum, is a medical condition in which cholestasis occurs during pregnancy. It typically presents wi ...
*
Liver transplantation Liver transplantation or hepatic transplantation is the replacement of a Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...


References


External links


GeneReview/NIH/UW entry on Low γ-GT Familial Intrahepatic Cholestasis

OMIM entry on CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 1; PFIC1
{{ABC transporter disorders Diseases of liver Congenital disorders Membrane transport protein disorders Hepatology