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.
The age of onset, severity and specific symptoms of low GGT familial intrahepatic cholestasis may vary from one individual to another, even among members of the same family. Although these disorders are generally described as being either mild or severe, cases have been identified that appear to fall in between these extremes (intermediate types), leading researchers to classify these disorders as a spectrum of disease. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS
The symptoms of PFIC types 1 and 2 are extremely similar. Symptoms are often present at birth or during the first few months of life (congenital). Progression may vary dramatically. Some individuals may develop severe symptoms early during infancy; others may not develop symptoms until later in childhood.
The major finding associated with all forms of PFIC is interruption or suppression of the flow of bile from the liver (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.
The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and 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, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. 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 PFIC may be foul smelling, greasy stools or watery diarrhea, which are often present at birth (congenital). Affected infants may also experience intense, often persistent, itching (pruritus). Itching can cause irritability and skin abrasions due to constant scratching. Itching can be resistant to treatment and have tremendously adverse effects on children and their families. Itching may occur with or without excessive bilirubin in the body (hyperbilirubinemia), resulting in yellowing of the skin, mucous membranes and whites of the eyes (jaundice). 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 common finding associated with PFIC 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).
PFIC types 1 and 2 eventually progress to cause serious life-threatening complications including the formation of fibrous tissue (fibrosis) and liver regeneration with scarring (cirrhosis) in the liver, eventually resulting in liver failure. Without surgical intervention, these complications may develop by the end of the first decade of life.
Additional symptoms have been reported in some cases including repeated infections and hearing impairment due to abnormalities of the inner ear (sensorineural deafness).
Children with PFIC2 (BSEP deficiency) may have a greater risk than the general population of developing a form of liver cancer known as hepatocellular carcinoma, potentially before the age of one. Some studies have noted that cases of PFIC2 generally have more severe abnormalities affecting the liver and biliary tract (hepatobiliary disease), while cases of PFIC1 generally are more likely to have abnormalities outside of the liver (extrahepatic disease). Some individuals with PFIC1 may have inflammation of the pancreas (pancreatitis), short stature and watery diarrhea, all of which can persist even after a liver transplant. In addition, PFIC1 after liver transplant may be associated with abnormal fat accumulation and associated inflammation within the liver (steatohepatitis). PFIC2 after liver transplant sometimes returns; this has been traced to formation of antibodies against BSEP that block BSEP function.
BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS
The milder forms of low GGT familial intrahepatic cholestasis are known as benign recurrent intrahepatic cholestasis (BRIC) types 1 and 2. Onset of BRIC can be at any age, but in most cases occurs during the first decade.
Affected individuals have prolonged recurrent attacks of cholestasis lasting from a few weeks to several months. The stimulus that brings on an attack is usually unclear. Generally, cholestasis associated with BRIC types 1 and 2 is self-limiting and not progressive. Chronic liver damage does not develop. Months or years may separate attacks of cholestasis. Symptoms usually begin in childhood or adolescence and may occur with regularity. Attacks typically begin with tiredness, weakness, and loss of appetite. Intense itchiness and yellowing of the skin, mucous membranes and whites of the eye may follow. The liver may be enlarged. Excessive fat in the feces and unintended weight loss may also occur. Affected individuals may experience impaired absorption of essential vitamins and nutrients in the digestive system (malabsorption). Hearing loss may occur in patients with BRIC1. In some cases, individuals with mild symptoms during childhood (BRIC) may develop more serious complications as an adult, with their condition being better classified as PFIC.
INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Some females with mutations in the genes that cause low GGT familial intrahepatic cholestasis 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. Some females with ICP also are sensitive to hormonal contraceptive agents. Contraceptive-associated intrahepatic cholestasis and ICP can be viewed as forms of BRIC in which the stimulus to an attack is known.
Low GGT familial intrahepatic cholestasis is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent.
Some affected individuals have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Investigators have determined that PFIC1 (FIC1 deficiency) occurs due to disruptions or changes (mutations) in ATP8B1, a gene that encodes a protein that is involved in maintaining differences in composition among different portions of cell membranes. Its function permits the secretion and transport of bile acids from the liver to the digestive tract. It is expressed not only in the liver, but other areas of the body as well, where its function permits other transporter proteins to work correctly. Its absence or dysfunction thus leads to problems like pancreatic inflammation and loss of hearing.
ATP8B1 is located on the long arm of chromosome 18 (18q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 18q21” refers to band 21 on the long arm of chromosome 18. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Investigators have determined that PFIC2 (BSEP deficiency) occurs due to disruptions or changes (mutations) in ABCB11, located on the long arm of chromosome 2 (2q24). It encodes a protein known as bile salt export pump (BSEP), which is involved in transporting bile salts from the liver to the digestive tract. BSEP is only expressed in the liver.
Cases of BRIC1 are due to mutations in ATP8B1. Cases of BRIC2 are due to mutations in ABCB11. Researchers believe individuals with mild forms of low GGT familial intrahepatic cholestasis have more residual protein activity than individuals with severe or intermediate forms.
Some individuals with low GGT familial intrahepatic cholestasis cannot be shown to have mutations in either ATP8B1 or ABCB11. In these cases, different, unidentified genes may cause the disorder. These cases are sometimes referred to as genetically undetermined PFIC or BRIC.
Low GGT familial intrahepatic cholestasis affects males and females in equal numbers. The exact incidence is unknown, but these disorders are extremely rare. However, because particularly in their milder forms these disorders often go unrecognized or misdiagnosed, they may be under-diagnosed, making it difficult to determine their true frequency in the general population.
PFIC1 was first described in a large kindred in the Amish community and was referred to as Byler disease after the family in which the disorder was observed. A second cluster of individuals with PFIC1 was identified among the Greenland Inuit people and has been referred to as Greenland familial cholestasis. Since its original description PFIC has been described in individuals of every race and various ethnicities.
A diagnosis of low GGT familial intrahepatic cholestasis should be suspected in infants and children with evidence of cholestasis. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, and a variety of tests. These tests include measuring serum levels of bilirubin, bile salts, and gamma-glutamyltransferase. Surgical excision and microscopic examination of liver tissue (biopsy) may be performed to aid in diagnosis and to detect the presence of cirrhosis. Molecular genetic testing is available on a clinical basis.
No specific therapy exists for individuals with low GGT familial intrahepatic cholestasis. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment options include drug therapy, various surgical procedures, and in severe cases liver transplantation. Restoring vitamins and nutrients lost through malabsorption is necessary in many cases.
Various drug therapies have been tried in individuals with PFIC, with moderate success. Ursodeoxycholic acid is often the initial treatment option for affected individuals and may be effective in some cases. Additional drug therapies that have been used to treat individuals with PFIC include phenobarbital, rifampin, cholestyramine, and antihistamines. These therapies can alleviate or improve some of the clinical symptoms such as intense itching. However, they are not effective in all cases and there is no conclusive evidence that demonstrates that they stop the progression of liver disease.
Some affected infants and children with PFIC types 1 or 2 may be treated by a surgical procedure known as partial biliary diversion. This surgical procedure is used to disrupt or divert recirculation of bile acids between the liver and the gastrointestinal tract. Researchers believe that these acids abnormally accumulate within the liver in individuals with PFIC. Initial studies of this therapy have demonstrated that, in some cases, this therapy has slowed the progression of the disease, reduced itchiness, and reversed connective tissue growth (fibrosis) in the liver. Reports of the value of various forms of partial biliary diversion are, with rare exceptions, flawed because they do not classify results in terms of underlying genetic defect.
A similar procedure called nasobiliary drainage has been used to treat some individuals with mild disease due to mutations in ATP8B1 (BRIC1). During this procedure, a thin, flexible tube (catheter) is run from the nose to the common bile duct, allowing for the drainage of excess bile acids via the catheter. This lowers body levels of bile acids and of other substances in bile. In the cases reported, individuals demonstrated rapid and long-lasting remission of cholestatic episodes and relief from associated itching. This procedure is being studied in individuals with mild familial intrahepatic cholestasis due to mutations of ABCB11 (BRIC2).
In severe cases (i.e., cases that have progressed to cirrhosis or liver failure or in which biliary diversion or ileal exclusion was unsuccessful), liver transplantation may be required. Some affected individuals who have undergone liver transplantation have demonstrated dramatic improvement of symptoms. In some cases of PFIC1, certain symptoms (e.g., malabsorption and diarrhea) may persist. In some cases of PFIC2, low GGT cholestasis may recur.
Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K. Calcium, phosphate, and zinc supplementation may also be required. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with PFIC (i.e., independent of bile flow).
Genetic counseling may be of benefit for affected individuals and their families. Affected individuals should receive regular follow-up examinations, especially screening for individuals with severe disease because of the increased risk of hepatobiliary carcinoma.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Overview of the physiology of PFIC1 and BRIC1.
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Overview of the physiology of PFIC2 and BRIC2.
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Clinical distinctions between PFIC1 and PFIC2.
Pawlikowska L, Strautnieks S, Jankowska I, et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53:170-78.
Histopathologic and clinical distinctions between PFIC1 and PFIC2.
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First report of results of non-transplant surgery analyzed in terms of genetic cause of disease for more than one instance of PFIC.
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First description of specific problem to be expected after liver transplantation in PFIC2.
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Overview of approaches; prognostic value reduced because no analysis conducted in terms of genetic cause of disease.
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Overview of the genetics of PFIC2 and BRIC2.
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First description of hepatobiliary malignancy in PFIC2.
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First description of use of this treatment in BRIC1 patients.
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First description of BRIC2.
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Overview of the genetics of PFIC1 and BRIC1.
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First description of specific problems to be expected after liver transplantation in PFIC1.
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Summary of the history of PFIC.
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Identification of the gene responsible for PFIC2 (and, later identified, BRIC2).
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Identification of the gene responsible for PFIC1 and BRIC1.
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First demonstration that PFIC is caused by defects in more than one gene, and that biopsy findings can help tell apart different kinds of PFIC.
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FROM THE INTERNET
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