NORD gratefully acknowledges James E Squires, MD, MSc, Assistant Professor, Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh and 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. Advancements in understanding of bile transport physiology have led to the discovery of a variety of protein defects whose dysfunction leads to low GGT familial intrahepatic cholestasis. Children with defects in bile acid synthesis or conjugation, 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 primarily covers the two severe forms of low GGT familial intrahepatic cholestasis that have been classically described (PFIC1 aka FIC1 deficiency; and PFIC2 aka BSEP deficiency). Two milder forms, known as benign recurrent intrahepatic cholestasis (BRIC) 1 and 2 are also described. These less severe diseases result from defects in the same proteins which cause PFIC 1 and 2. Thus PFIC and BRIC lie at different ends of a spectrum of disease with common genetic basis. Newer forms of genetic based disorders which manifest as low GGT cholestasis (PFIC 4-6) will be presented in less detail given the relatively few patients known to be affected by these disorders. Some persons with low GGT familial intrahepatic cholestasis cannot be shown to have any of the disorders mentioned in this report. 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). Recently, additional proteins have been identified in whom mutations result in a phenotypic pattern that is similar to PFIC 1 and 2, mainly cholestasis presenting in the neonatal period. PFIC4 stems from loss of function mutations in TJP2 encoding the tight junction protein TJP2. PFIC5 results from mutations in NR1H4, which encodes the farnesoid X receptor (FXR), the nuclear receptor transcription factor which regulates BSEP expression. PFIC6 results in defects in MYO5B, on which BSEP depends to localize to the appropriate location within the cell. All forms of PFIC are inherited in an autosomal recessive pattern. Some affected individuals do not have mutations in any 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-glutamyl transferase (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 PFIC disorders, 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. Various names have been used for these disorders such as FIC1 deficiency and Byler’s Syndrome for PFIC1; and BSEP deficiency and Byler’s disease for PFIC2, adding to the confusion. The classification and grouping of these disorders may undergo further changes in the future as more becomes known about the genetic underpinnings driving disease development.
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 persistent 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, many 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 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, hearing impairment due to abnormalities of the inner ear (sensorineural deafness), profound diarrhea, and pancreatitis. These extrahepatic, or outside the liver, manifestations of disease are more commonly reported in individuals with PFIC1 as the FIC1 protein is expressed in many tissues throughout the body. This is in contrast to BSEP protein which is exclusive to the liver cell. Notably, the extrahepatic manifestations of PFIC1 can persist, or even worsen after 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.
PFIC1 (FIC1 deficiency) occurs due to disruptions or changes (mutations) in ATP8B1, a gene that encodes a protein that is thought to be involved in maintaining differences in composition among different portions of cell membranes. Its function has been proposed to permit 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.
PFIC2 (BSEP deficiency) occurs due to disruptions mutations in the ABCB11 gene. 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.
BRIC1 is caused by mutations in ATP8B1 and BRIC2 is caused by 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.
Mutations in TJP2 result in abnormalities in the tight junction protein 2, one of the intracellular anchors for tight junctions that bind liver cells together and protects them from damage from dangerous detergent bile salts which are meant to be excreted from the liver.
PFIC 5 and 6 result from mutations in NR1H4 and MYO5B respectively. The protein products from these genes assist in the proper localization of the BSEP protein. Therefore, when these genes are defective, BSEP is not able to properly situate within the cell, resulting in the inability to transport bile salts out of the liver cell and the ‘BSEP-like’ physical manifestations of low GGT cholestasis.
Low GGT familial intrahepatic cholestasis is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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.
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 syndrome 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, a comprehensive family 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. Increasingly, molecular genetic testing is available on a clinical basis and has emerged as a more prominent diagnostic tool. All children identified with low GGT cholestasis should undergo confirmatory genetic testing to identify the causative gene where applicable.
No specific therapy exists for individuals with low GGT familial intrahepatic cholestasis. Supportive measures are focused on improving nutritional deficiencies and managing complications of end stage liver disease. Additional 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, antihistamines, opiate antagonists (Naltrexone), and selective serotonin reuptake inhibitors (sertraline). 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.
When medical therapy is insufficient, surgical intervention may be considered with the goal of bypassing the enterohepatic circulation and/or decreasing reabsorption of bile salts. Researchers believe that these acids abnormally accumulate within the liver in individuals with PFIC. Procedures including partial external biliary diversion, partial internal biliary diversion, and ileal exclusion have generally, though not uniformly, resulted in sustained clinical improvement in PFIC patients. Notably, no single procedure has demonstrated definitive superiority with center-experience likely driving center-specific approaches. Reports of the value of various forms surgical intervention are, with rare exceptions, flawed because they do not classify results in terms of underlying genetic defect. Newer therapeutics including inhibitors of the ileal apical-sodium dependent bile acid transporter (ASBT) which effectively act as a ‘chemical’ biliary diversion are currently under investigation.
In certain cases, a procedure called nasobiliary drainage has been used to treat 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.
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 is recommended 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
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Paulusma CC, Oude Elferink RP, Jansen PL. Progressive familial intrahepatic cholestasis type 1. Semin Liver Dis. 2010;30:117-24.
Overview of the physiology of PFIC2 and BRIC2:
Lam P, Soroka CJ, Boyer JL. The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease. Semin Liver Dis. 2010;30:125-33.
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:
Davit-Spraul A, Fabre M, Branchereau S, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51:1645-55.
First report of results of non-transplant surgery analyzed in terms of genetic cause of disease for more than one instance of PFIC:
Arnell H, Papadogiannakis N, Zemack H, et al. Follow-up in children with progressive familial intrahepatic cholestasis after partial external biliary diversion. J Pediatr Gastroenterol Nutr. 2010;51:494-99.
First description of specific problem to be expected after liver transplantation in PFIC2:
Keitel V, Burdelski M, Vojnisek Z, et al. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology 2009;50:510-517.
Overview of approaches; prognostic value reduced because no analysis conducted in terms of genetic cause of disease:
Davis AR, Rosenthal P, Newman TB. Nontransplant surgical interventions in progressive familial intrahepatic cholestasis. J Pediatr Surg. 2009;44:821-27.
An explanation of hearing loss in PFIC1 and BRIC1:
Stapelbroek JM, Peters TA, van Beurden DH, et al. ATP8B1 is essential for maintaining normal hearing. Proc Natl Acad Sci USA. 2009;106:9709-14.
Overview of the genetics of PFIC2 and BRIC2:
Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe bile export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008;134:1203-1214.
First description of hepatobiliary malignancy in PFIC2:
Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006;44:478-86.
First description of use of this treatment in BRIC1 patients:
Stapelbroek JM, van Erpecum KJ, Klomp LW, et al. Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis. Hepatology. 2006;43:51-53.
First description of BRIC2:
van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology. 2004;127:379-84.
Overview of the genetics of PFIC1 and BRIC1:
Klomp LW, Vargas JC, van Mil SW, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology. 2004;40:27-38.
First description of specific problems to be expected after liver transplantation in PFIC1:
Lykavieris P, van Mil S, Cresteil D, et al. Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. J Hepatol. 2003;39:447-52.
Summary of the history of PFIC:
Knisely AS. Progressive familial intrahepatic cholestasis: a personal perspective. Pediatr Dev Pathol. 2000;3:113-25.
Identification of the gene responsible for PFIC2 (and, later identified, BRIC2):
Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998;20:233-8.
Identification of the gene responsible for PFIC1 and BRIC1:
Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998;18:219-24.
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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