Progressive familial intrahepatic cholestasis
Encyclopedia
Progressive familial intrahepatic cholestasis (PFIC) refers to a group of familial cholestatic
conditions caused by defects in biliary
epithelial transporters. The clinical presentation usually occurs first in childhood
with progressive cholestasis
. This usually leads to failure to thrive
, hepatic failure
, and the need for liver transplantation.
PFIC-1 is caused by a variety of mutations in ATP8B1
, a gene
coding for a P-type ATPase
protein
, FIC-1, that is responsible for phospholipid
translocation
. 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
, in addition to the clinical features below, due to FIC-1's expression in the intestine
. How ATP8B1 mutation leads to cholestasis is not yet well understood.
PFIC-2 is caused by a variety of mutations in ABCB11
, the gene
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 ABCB4
, the gene encoding multidrug resistance protein 3 (MDR3), which codes for a flippase
responsible for phosphatidylcholine
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
pattern of all three forms of PFIC defined to date is autosomal recessive.
is usually before age 2, but patients have been diagnosed with PFIC even into adolescence
. Of the three entities, PFIC-3 usually presents earliest. Patients usually present in early childhood with cholestasis
, jaundice
, and failure to thrive
. Intense pruritus is characteristic; in patients who present in adolescence, it has been linked with suicide
. Patients may have fat
malabsorption
, leading to fat soluble vitamin
deficiency, and complications, including osteopenia
.
Biochemical markers include a normal GGT
for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum bile acid
levels are grossly elevated. Serum cholesterol
levels are typically not elevated, as is seen usually in cholestasis, as the pathology
is due to a transporter as opposed to an anatomical problem with biliary cells.
The disease is typically progressive, leading to fulminant liver
failure and death
in childhood, in the absence of liver transplantation
. Hepatocellular carcinoma
may develop in PFIC-2 at a very early age; even toddlers have been affected.
typically show evidence of cholestasis
(including bile plugs and bile infarcts), duct hypoplasia, hepatocellular injury, and Zone 3 fibrosis
. 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.
and pruritus, including the following:
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.
Cholestasis
In medicine, 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 such as can occur from a gallstone or malignancy and metabolic types of...
conditions caused by defects in biliary
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
epithelial transporters. The clinical presentation usually occurs first in childhood
Childhood
Childhood is the age span ranging from birth to adolescence. In developmental psychology, childhood is divided up into the developmental stages of toddlerhood , early childhood , middle childhood , and adolescence .- Age ranges of childhood :The term childhood is non-specific and can imply a...
with progressive cholestasis
Cholestasis
In medicine, 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 such as can occur from a gallstone or malignancy and metabolic types of...
. This usually leads to failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
, hepatic failure
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, and the need for liver transplantation.
Pathogenesis
ATP8B1
Probable phospholipid-transporting ATPase IC is an enzyme that in humans is encoded by the ATP8B1 gene. This protein is associated with progressive familial intrahepatic cholestasis type 1 as well as benign recurrent intrahepatic cholestasis.- Function :...
, a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding for a P-type ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, FIC-1, that is responsible for phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
translocation
Translocation
Translocation may refer to:* Chromosomal translocation, in genetics* Translocation in plants, transport of food or pesticides through phloem or xylem* Protein translocation or protein targeting, a process in protein biosynthesis...
. 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
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, in addition to the clinical features below, due to FIC-1's expression in the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
. How ATP8B1 mutation leads to cholestasis is not yet well understood.
PFIC-2 is caused by a variety of mutations in ABCB11
ABCB11
ATP-binding cassette, sub-family B member 11 also known as ABCB11 is a protein which in humans is encoded by the ABCB11 gene.- Function :...
, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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 ABCB4
ABCB4
Multidrug resistance protein 3 is a protein that in humans is encoded by the ABCB4 gene. ABCB4 is associated with progressive familial intrahepatic cholestasis type 3.-External links:...
, the gene encoding multidrug resistance protein 3 (MDR3), which codes for a flippase
Flippase
Flippases are a family of transmembrane lipid transporter enzymes located in the membrane responsible for aiding the movement of phospholipid molecules between the two leaflets that compose a cell's membrane...
responsible for phosphatidylcholine
Phosphatidylcholine
Phosphatidylcholines 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 soy beans from which they are mechanically extracted or chemically...
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
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
pattern of all three forms of PFIC defined to date is autosomal recessive.
Clinical presentation and natural history
The onset of the diseaseDisease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
is usually before age 2, but patients have been diagnosed with PFIC even into adolescence
Adolescence
Adolescence is a transitional stage of physical and mental human development generally occurring between puberty and legal adulthood , but largely characterized as beginning and ending with the teenage stage...
. Of the three entities, PFIC-3 usually presents earliest. Patients usually present in early childhood with cholestasis
Cholestasis
In medicine, 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 such as can occur from a gallstone or malignancy and metabolic types of...
, jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, and failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
. Intense pruritus is characteristic; in patients who present in adolescence, it has been linked with suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
. Patients may have fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
, leading to fat soluble vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
deficiency, and complications, including osteopenia
Osteopenia
Osteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
.
Biochemical markers include a normal GGT
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
levels are grossly elevated. Serum cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
levels are typically not elevated, as is seen usually in cholestasis, as the pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
is due to a transporter as opposed to an anatomical problem with biliary cells.
The disease is typically progressive, leading to fulminant liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
failure and death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
in childhood, in the absence of liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
. Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
may develop in PFIC-2 at a very early age; even toddlers have been affected.
Pathology
Liver biopsiesLiver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
typically show evidence of cholestasis
Cholestasis
In medicine, 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 such as can occur from a gallstone or malignancy and metabolic types of...
(including bile plugs and bile infarcts), duct hypoplasia, hepatocellular injury, and Zone 3 fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
. 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.
Treatment
Initial treatment is supportive, with the use of agents to treat cholestasisCholestasis
In medicine, 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 such as can occur from a gallstone or malignancy and metabolic types of...
and pruritus, including the following:
- Ursodeoxycholic acid
- CholestyramineCholestyramineCholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
- Rifampin
- NaloxoneNaloxoneNaloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
, in refractory cases
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.
Associations
- ConsanguinityConsanguinityConsanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
is believed to be a major risk factor. - Similar transport protein mutations are believed to pose a higher risk for intrahepatic cholestasis of pregnancyIntrahepatic Cholestasis of PregnancyIntrahepatic cholestasis of pregnancy in the United Kingdom, is a medical condition in which cholestasis occurs during pregnancy...
.
See also
- Alagille syndromeAlagille syndromeAlagille syndrome is a genetic disorder that affects the liver, heart, kidney, and other systems of the body. Problems associated with the disorder generally become evident in infancy or early childhood...
- Intrahepatic cholestasis of pregnancyIntrahepatic Cholestasis of PregnancyIntrahepatic cholestasis of pregnancy in the United Kingdom, is a medical condition in which cholestasis occurs during pregnancy...
- Liver transplantationLiver transplantationLiver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...