FIC1 Disease: A Spectrum of Intrahepatic Cholestatic Disorders
FIC1 Disease: A Spectrum of Intrahepatic Cholestatic Disorders
FIC1 disease collectively refers to a group of autosomal-recessive familial liver disorders characterized by intrahepatic cholestasis due to mutations in the ATP8B1 gene (initially named FIC1). Classically, FIC1 disease comprises two different disorders: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). However, we now view these two disorders as two ends of a continuum. Current therapeutic strategies for FIC1 disease, both medical and surgical, may relieve symptoms, but are presently insufficiently evaluated. ATP8B1 encodes a protein belonging to a recently defined subfamily of P-type ATPases. The biochemical and cellular functions of its product, FIC1, and the mechanisms by which its absence or dysfunction leads to cholestasis are currently elusive. Further studies to elucidate FIC1's function will be essential to unravel the pathogenesis of FIC1 disease. Such studies will also have a general impact on our understanding of the molecular mechanisms of bile formation and may therefore improve clinical management of both hereditary and acquired forms of cholestasis.
Objectives: Upon completion of this article, the reader should (1) be able to make a differential diagnosis of a patient with low g-glutamyl transpeptidase cholestasis, (2) have some knowledge of the current understanding of FIC physiology, and (3) be aware of the natural course of this disease and the medical and surgical alternatives for treatment.
Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. TUSM takes full responsibility for the content, quality, and scientific integrity of this continuing education activity.
Credit: Tufts University School of Medicine designates this education activity for a maximum of 1.0 hour credit toward the AMA Physicians Recognition Award in category one. Each physician should claim only those hours that he/she actually spent in the educational activity.
Cholestasis is a frequent, prominent, and severe manifestation of liver disease. It is defined as an impairment of normal bile flow secondary to structural or biochemical abnormalities of the liver and biliary tree. Both acquired and hereditary forms of cholestasis have been described. Here we review one of the forms of hereditary cholestasis, FIC1 disease (familial intrahepatic cholestasis type 1), which is thought to result from a defect in bile acid secretion. FIC1 disease is defined on genetic rather than clinical criteria: these patients have recessive mutations in the ATP8B1 gene on chromosome 18q21. In fact, the disorder comprises at least three previously separate clinical entities: progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC) and Greenland familial cholestasis (GFC). Patients with PFIC, BRIC, and GFC all present with jaundice and pruritus, which is episodic in BRIC, but progresses to chronic liver disease in PFIC and GFC. A distinguishing biochemical hallmark of these disorders associated with mutations in ATP8B1 is the serum g-glutamyl transpeptidase (GGT) activity that is low for the degree of hyperbilirubinemia.
Genetic studies revealed that locus heterogeneity exists in PFIC and BRIC patients, whereas GFC is defined by a specific mutation in ATP8B1. PFIC can be caused by mutations in ATP8B1 encoding the FIC1 protein (PFIC1), as well as by mutations in the ABCB11 gene encoding the bile salt export protein (BSEP) PFIC2. The function of BSEP in relation to PFIC2 has been reviewed before and elsewhere in this issue (Thompson). Currently there are no clinical criteria or routine diagnostic laboratory tests that definitively distinguish between PFIC1 and PFIC2. Congenital cholestasis with low GGT activity also may be caused by inherited defects in the bile acid biosynthesis pathway. These diseases can be distinguished from PFIC1 and -2 because the serum bile acid concentrations are low. Yet another progressive liver disorder exists: PFIC3 (reviewed in this issue by Jacquemin), which is caused by the absence or dysfunction of multidrug resistance protein 3 (MDR3), encoded by the ABCB4 gene. Both clinically and with respect to biochemical parameters, PFIC3 differs substantially from PFIC1 and PFIC2. Most notably this disorder is characterized by markedly elevated serum GGT activities.
Genes underlying forms of familial intrahepatic cholestasis other than those described above, have yet to be discovered; these include Aegenaes syndrome and North American Indian childhood cirrhosis. There is evidence that BRIC is also characterized by locus heterogeneity. Two research groups separately reported BRIC families in which the disorder did not map to chromosome 18q21, but the alternative loci still need to be defined. Interestingly, in one of these families the disorder appeared to show an autosomal-dominant mode of transmission. With regard to PFIC, it is not yet known whether mutations in a gene or genes other than ATP8B1 and ABCB11 also can lead to either low-GGT PFIC or high-GGT PFIC.
The mutated genes associated with PFIC and BRIC encode membrane transport proteins, which are presumably involved in bile formation. The recent cloning and characterization of these and other hepatocyte transporter proteins provide the molecular tools to address the mechanisms of bile formation as well as the pathophysiology of hereditary and acquired types of cholestasis. These studies also reemphasize that in-depth studies of these relatively rare genetic disorders can increase our understanding of more common acquired diseases. This review particularly focuses on recent clinical, biochemical, histopathological, and genetic findings in patients with FIC1 disease.
FIC1 disease collectively refers to a group of autosomal-recessive familial liver disorders characterized by intrahepatic cholestasis due to mutations in the ATP8B1 gene (initially named FIC1). Classically, FIC1 disease comprises two different disorders: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). However, we now view these two disorders as two ends of a continuum. Current therapeutic strategies for FIC1 disease, both medical and surgical, may relieve symptoms, but are presently insufficiently evaluated. ATP8B1 encodes a protein belonging to a recently defined subfamily of P-type ATPases. The biochemical and cellular functions of its product, FIC1, and the mechanisms by which its absence or dysfunction leads to cholestasis are currently elusive. Further studies to elucidate FIC1's function will be essential to unravel the pathogenesis of FIC1 disease. Such studies will also have a general impact on our understanding of the molecular mechanisms of bile formation and may therefore improve clinical management of both hereditary and acquired forms of cholestasis.
Objectives: Upon completion of this article, the reader should (1) be able to make a differential diagnosis of a patient with low g-glutamyl transpeptidase cholestasis, (2) have some knowledge of the current understanding of FIC physiology, and (3) be aware of the natural course of this disease and the medical and surgical alternatives for treatment.
Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. TUSM takes full responsibility for the content, quality, and scientific integrity of this continuing education activity.
Credit: Tufts University School of Medicine designates this education activity for a maximum of 1.0 hour credit toward the AMA Physicians Recognition Award in category one. Each physician should claim only those hours that he/she actually spent in the educational activity.
Cholestasis is a frequent, prominent, and severe manifestation of liver disease. It is defined as an impairment of normal bile flow secondary to structural or biochemical abnormalities of the liver and biliary tree. Both acquired and hereditary forms of cholestasis have been described. Here we review one of the forms of hereditary cholestasis, FIC1 disease (familial intrahepatic cholestasis type 1), which is thought to result from a defect in bile acid secretion. FIC1 disease is defined on genetic rather than clinical criteria: these patients have recessive mutations in the ATP8B1 gene on chromosome 18q21. In fact, the disorder comprises at least three previously separate clinical entities: progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC) and Greenland familial cholestasis (GFC). Patients with PFIC, BRIC, and GFC all present with jaundice and pruritus, which is episodic in BRIC, but progresses to chronic liver disease in PFIC and GFC. A distinguishing biochemical hallmark of these disorders associated with mutations in ATP8B1 is the serum g-glutamyl transpeptidase (GGT) activity that is low for the degree of hyperbilirubinemia.
Genetic studies revealed that locus heterogeneity exists in PFIC and BRIC patients, whereas GFC is defined by a specific mutation in ATP8B1. PFIC can be caused by mutations in ATP8B1 encoding the FIC1 protein (PFIC1), as well as by mutations in the ABCB11 gene encoding the bile salt export protein (BSEP) PFIC2. The function of BSEP in relation to PFIC2 has been reviewed before and elsewhere in this issue (Thompson). Currently there are no clinical criteria or routine diagnostic laboratory tests that definitively distinguish between PFIC1 and PFIC2. Congenital cholestasis with low GGT activity also may be caused by inherited defects in the bile acid biosynthesis pathway. These diseases can be distinguished from PFIC1 and -2 because the serum bile acid concentrations are low. Yet another progressive liver disorder exists: PFIC3 (reviewed in this issue by Jacquemin), which is caused by the absence or dysfunction of multidrug resistance protein 3 (MDR3), encoded by the ABCB4 gene. Both clinically and with respect to biochemical parameters, PFIC3 differs substantially from PFIC1 and PFIC2. Most notably this disorder is characterized by markedly elevated serum GGT activities.
Genes underlying forms of familial intrahepatic cholestasis other than those described above, have yet to be discovered; these include Aegenaes syndrome and North American Indian childhood cirrhosis. There is evidence that BRIC is also characterized by locus heterogeneity. Two research groups separately reported BRIC families in which the disorder did not map to chromosome 18q21, but the alternative loci still need to be defined. Interestingly, in one of these families the disorder appeared to show an autosomal-dominant mode of transmission. With regard to PFIC, it is not yet known whether mutations in a gene or genes other than ATP8B1 and ABCB11 also can lead to either low-GGT PFIC or high-GGT PFIC.
The mutated genes associated with PFIC and BRIC encode membrane transport proteins, which are presumably involved in bile formation. The recent cloning and characterization of these and other hepatocyte transporter proteins provide the molecular tools to address the mechanisms of bile formation as well as the pathophysiology of hereditary and acquired types of cholestasis. These studies also reemphasize that in-depth studies of these relatively rare genetic disorders can increase our understanding of more common acquired diseases. This review particularly focuses on recent clinical, biochemical, histopathological, and genetic findings in patients with FIC1 disease.
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