American Journal of Health-System Pharmacy · 2007 · 37 citations
Treatment of cholestatic pruritus in children
AbstractPURPOSE: The treatment of cholestatic pruritus in children is reviewed. SUMMARY: Cholestasis is characterized by an accumulation of substances that are normally secreted in the bile. Pruritus is a well-known feature of chronic cholestasis in both adults and children and has been reported as the most incapacitating symptom in children with chronic liver disease. Traditional agents, such as antihistamines, are typically ineffective as monotherapy in controlling cholestatic pruritus. As a result, clinicians have looked to other agents, such as rifampin, phenobarbital, ursodiol, opioid antagonists, and bile-binding resins, for attaining better control of pruritic symptoms. Each agent demonstrates different levels of efficacy in pediatric and adult literature. There are no guidelines or algorithms to guide therapy with these agents for children. As a result, an agent should be selected based on the patient's concurrent diseases and current medication regimen. Cholestyramine and ursodiol are both safe and inexpensive, with documented efficacy for cholestatic pruritus in children. Because cholestatic pruritus is likely a result of multiple mechanisms, combination therapy with agents that have differing mechanisms of action might be beneficial and could capitalize on potential synergy between the agents used. Future therapy for cholestatic pruritus may include serotonin antagonists, selective serotonin-reuptake inhibitors, and leukotriene antagonists. CONCLUSION: Depending on the underlying disease state resulting in cholestasis, phenobarbital, ursodiol, bile sequestering agents, and opioid antagonists appear to be most effective for treating pruritus related to intrahepatic cholestasis. Alternatively, rifampin appears to be the only agent with reported treatment efficacy for pruritus related to extrahepatic cholestasis.
https://doi.org/10.2146/ajhp060453Journal of Pediatric Gastroenterology and Nutrition · 1999 · 26 citations
Genetic Cholestasis Syndromes
AbstractIt has been recognized for many years that some forms of cholestatic liver disease have an increased prevalence in selected families and are apparently inherited diseases. In addition, many children without similarly affected family members have chronic cholestatic diseases, the exact cause of which defies characterization. These children may also have specific genetic abnormalities as the basis for their condition. As an aggregate these "genetic" cholestasis syndromes are not uncommon in pediatric hepatology and cause significant morbidity and mortality. The approach to the analysis of children with genetic cholestasis syndromes has included careful clinical characterization, gene-linkage analysis, and molecular investigations of the basic mechanisms involved in bile formation. This review summarizes many of the recent breakthroughs that have permitted the beginning of a new chapter in the investigation of genetic cholestasis. Recognition in the late 1950s and 1960s of familial cases of cholestatic liver disease was one of the first clues that there might be a primary genetic basis for these diseases (1-8). New descriptions of familial cholestasis continue to be reported into the present era (9-11). One of the critical issues in analyzing children with familial cholestasis is whether the clinical heterogeneity of their liver diseases and related morbidity indicates multiple causes or varying expression of a complex gene. Clinicians have developed a complex and confusing terminology that is associated with equally complicated associated clinical criteria. This has resulted in a bewildering array (Table 1) of diagnostic terms (syndromic bile duct paucity, nonsyndromic bile duct paucity, Alagille syndrome, Byler's disease, Byler's syndrome, progressive familial intrahepatic cholestasis, intrahepatic biliary atresia, Aagenes syndrome, and others [12]). These diagnostic terms have been developed in part in an attempt to bring clinical order to a complex set of clinical syndromes.TABLE 1: Nomenclature and the genetic basis of cholestasisThese clinical descriptions suggest important clinical characteristics of children with genetic cholestasis and appear to indicate that there are multiple causes of genetic cholestasis. For example, serum levels of γ-glutamyl transpeptidase (γ-GTP) seem to differentiate two forms of intrahepatic cholestasis, with a poorer prognosis in those children with normal γ-GTP levels (13). The presence and severity of pruritus may also distinguish different forms of genetic cholestasis, with an absence of pruritus being characteristic of abnormalities in bile acid synthesis (14). Associated malformations and syndromic features have been very important in the analysis of genetic cholestasis, with Alagille syndrome being one of the most important examples. ALAGILLE SYNDROME As early as 1965, features of what is now known as Alagille syndrome were described (5); more definitive characterization was detailed in subsequent reports (15,16). The classical features of Alagille syndrome include peculiar facies, chronic cholestasis (with intrahepatic bile duct paucity), posterior embryotoxon, butterflylike vertebral arch defects, and cardiovascular malformations (17). This very distinctive syndrome, coupled with the high prevalence of the disease within families, made it a natural choice for analysis at the level of the human genome. The initial studies demonstrating an interstitial deletion of the short arm of chromosome 20 in children with Alagille syndrome suggested two distinct possibilities (18,19). One was that Alagille syndrome was a contiguous gene syndrome, which was the consequence of the deletion of multiple genes, thereby generating the multiple features of the syndrome. The rarity of gross deletions in children with Alagille syndrome made this unlikely. The more likely possibility was that the deletion disrupted an important gene involved in normal development. The deletion served to identify the locus of the gene of interest to chromosome 20. The finding of a translocation associated with Alagille syndrome further defined the region on chromosome 20 that was involved (20) and expedited the ultimate identification of the genetic abnormality in Alagille syndrome (21,22). Contigs of bacterial and yeast artificial chromosomes and P1 clones were used to identify candidate genes in the critical region of chromosome 20 implicated in Alagille syndrome. Two separate groups identified a number of mutations in a human gene referred to as JAG1. This gene encodes a transmembrane protein that is presumed to be the ligand for a transmembrane receptor protein called NOTCH1. The interaction between JAG1 and NOTCH1 is thought to play a crucial role in early cell fate determinations (23). Thus it has the potential to account for many of the phenotypic features observed in Alagille syndrome. Apparently JAG1 plays an important role in bile duct development, and thus further analysis of its physiology and pathophysiology is of critical importance. That there is no consistent genotype-phenotype association between defects in JAG1 and clinical features of Alagille syndrome highlights how much more there is to learn about this disease and the role that this gene plays in its development (24). The investigative ability to document defects in JAG1 will permit clarification of the basis of cholestatic liver disease in children who have atypical or incomplete syndromes. This diagnosis may become relevant in children who do not have apparent liver disease, but instead are primarily affected by cardiac problems (25). BYLER'S DISEASE Byler's disease is another example of a relatively homogenous clinical entity that has been successfully explored with modern genetic techniques. This disease was first described in the Amish community in direct descendants of Jacob Byler and Nancy Kauffman (26). The clinical features of the disease usually include progressive and sometimes episodic intrahepatic cholestasis, low serum γ-GTP levels, characteristic transmission electron microscopic appearance of canalicular bile, and pruritus (27). Other less consistently reported findings include unexplained diarrhea that does not necessarily respond to liver transplantation, pancreatic insufficiency, elevated sweat chloride concentration, and wheezing (28-30). A broader term of Byler's syndrome or progressive familial intrahepatic cholestasis has been used to describe children of non-Amish origin who have a similar disease (27,30). Early investigations of bile salt metabolism in these patients suggested an abnormality in canalicular excretion of bile salts (31). This disease seems to be responsive to partial biliary diversion, implying abnormalities in the regulation of the enterohepatic circulation of toxic bile salts (32,33). The relatively homogenous clinical phenotype of Byler's disease coupled with its high incidence in an endogamous community made it a particularly good candidate for analysis by genome screening by searching for shared segments (34). This approach assumes that those affected with a given inherited condition are related to a common ancestor with a founder mutation. Analysis of genetic haplotypes for informative markers across the human genome allows for identification of a specific chromosomal region that has a high probability of being responsible for the disease in question. This approach recently lead to the identification of 18q21-q22 as a potential locus for Byler's disease (35). Of interest, this turns out to be the same locus that was identified for benign recurrent intrahepatic cholestasis (34,36). A narrowed region of chromosome 18 was analyzed for candidate genes by screening a human liver cDNA library. A P-type adenosine triphosphatase (ATPase), referred to as FIC1, was identified and found to be mutated in a number of patients with progressive familial intrahepatic cholestasis and in patients with benign recurrent intrahepatic cholestasis (37). Mutations in the patients with benign recurrent intrahepatic cholestasis occur in regions of the FIC1 protein that are thought to be less critical (i.e. less highly conserved) to the function of FIC1. The exact function of FIC1 is unknown at this time, although related genes appear to play a role in the transfer of aminophospholipids from the outer to the inner hemileaflet of the phospholipid bilayer (38). Also of interest, abnormalities in MDR 3, a gene with phosphatidylcholine transferase activity, have been recently determined to cause intrahepatic cholestasis (see later discussion). FIC1 transcripts are expressed in a wide range of tissues including liver, intestine, and pancreas. Thus Byler's disease may be a systemic disorder, and this may explain some of the clinical problems that persist even after successful liver transplantation. Future genetic analysis of children who apparently have Byler's syndrome (PFIC1) will clarify whether they have the same genetic defect that affected the descendants of Jacob Byler. CANALICULAR BILE ACID TRANSPORT DEFECTS Genetic analysis of groups of patients with progressive familial intrahepatic cholestasis has excluded the FIC1 locus in certain populations including children from Saudi Arabia, Sweden, and Eastern Greenland (9,11). Therefore, at least one alternative cause of genetic cholestasis exists. Many clinicians and investigators have been convinced that some forms of pediatric cholestasis are the result of inherited abnormalities in canalicular excretion of bile salts (39,40). An alternative to genetic analysis of these patients has been to try to identify the protein or proteins involved in canalicular excretion of bile salts and then to search for defects in those proteins in selected cases of pediatric cholestasis. This approach relies on a relatively complete understanding of the mechanisms involved in the vectorial transport of bile acids from blood to the bile (Fig. 1). Sodium-dependent and -independent transport processes have been identified at the basolateral surface of the hepatocyte and are the primary mechanisms responsible for the hepatic extraction of bile salts from the systemic circulation. At least three proteins (sodium taurocholate cotransporting polypeptide [41], organic anion transporting polypeptide [42], and microsomal epoxide hydrolase [43]) have been shown, by various techniques, to be involved in the process of uptake of bile acids at the hepatic sinusoidal membrane. Once within the hepatocyte, bile salts appear to bind to specific cytosolic proteins, including dihydrodiol dehydrogenase in the human liver (44). These intracellular binding proteins presumably help prevent reflux of bile acids across the sinusoidal membrane, sequester them to reduce their detergent properties, and may play a role in intracellular transport of bile salts. There is controversy about the mechanisms involved in the movement of bile salts from the basolateral to the canalicular membrane, with passive diffusion and microtubule-dependent vesicular pathways proposed. Once at the canalicular membrane, potential-driven and adenosine triphosphate (ATP)-dependent processes appear to be involved in the excretion of bile salts into the canaliculus. In the rat, the 100 kDa ecto-ATPase protein has been found to be involved in potential-driven canalicular excretion of bile salts (45). Given the high gradient in bile salt concentrations that exists between the canalicular lumen and the inside of the hepatocyte, most investigators believe that the ATP-dependent transport processes are physiologically the most important in bile salt excretion.FIG. 1: Diagram of the pathways of vectorial translocation of bile acids and other components of bile. Bile acids (BA) are transported from the systemic and portal circulation into the hepatocyte by one of at least three proteins, sodium taurocholate cotransporting polypeptide (NTCP), organic anion transporting polypeptide (OATP), and microsomal epoxide hydrolase (MEH). Once within the hepatocyte, they bind to intracellular binding proteins and may passively diffuse through the cytosol or are transported through the Golgi/endoplasmic reticulum network through a microtubular-dependent process. Finally, at the canaliculus at least four proteins appear to be involved in canalicular excretion of bile: canalicular multispecific organic anion transporter (cMOAT), sister gene of P-glycoprotein (SPGP), multidrug resistance proteins (MDR), and EctoATPase. SPGP and EctoATPase have been shown to be involved directly in bile acid excretion. In contrast, MDR 3 is involved in canalicular excretion of phospholipids (PL), whereas cMOAT transports conjugated bilirubin (BIL). Molecular defects in SPGP, cMOAT, and MDR 3 lead to the distinct clinical diseases that are discussed in this review.Cloning of transport proteins involved in efflux is much harder than identifying those proteins involved in uptake, and thus, characterization of the ATP-dependent canalicular bile acid transporter has been difficult. It was not until recently that it was appreciated that canalicular transport of bile salts was an ATP-dependent process (46,47). Adenosine triphosphate-dependent transport processes are often mediated by ATP binding cassette (ABC) proteins. This fact was used to clone a rat canalicular ATP-dependent bile acid transport protein (48). Endogenous efflux mechanisms made assessment of the function of this gene product in oocytes problematic (49). Therefore, ATP-dependent bile acid transport studies were performed in membrane vesicles prepared from insect cell lines that were transduced with this newly cloned gene. The cloned gene is identical to a liver-specific ABC protein referred to as the sister gene of P-glycoprotein (SPGP), which had been previously predicted to be a canalicular bile acid transporter (50). Genome-wide screening of six consanguineous Middle Eastern families has localized another form of genetic cholestasis, which some have referred to as PFIC 2 (51), to 2q24 (52). Children with PFIC 2 appear to have a more progressive disease that leads to end-stage liver disease more quickly than children with FIC1 abnormalities. Genetic analysis of 41 patients from 35 families using a variety of informative markers pinpointed the region of abnormality in these patients to 870 kb of chromosome 2. Given the bile acid-transporting properties of SPGP, its gene was a logical candidate to be tested (48). Ten different mutations have been reported in SPGP in this patient population (53). Although none of the mutations have been shown in vitro to result in bile acid-transport abnormalities, the evidence is compelling that this is the cause of cholestasis in children with PFIC 2. Absence of the SPGP protein in patients with PFIC 2 has also been observed (54). This is a wonderful example in which investigators approaching a problem from different directions (genetics and physiology) have arrived at the same predicted answer. MULTIDRUG RESISTANCE PROTEINS Some of the advances in our understanding of genetic cholestasis have stemmed from initially unrelated endeavors, with the most notable recent example being analysis of the multidrug resistance gene MDR3. The multidrug resistance genes have been the subject of intense investigation by oncologist because of their ability to impart resistance to chemotherapeutic agents. The function of one of these multidrug resistance proteins, known as mdr2 in mice and MDR3 in humans, had eluded identification for many years. Knockout mice were created in an effort to understand the function of mdr2, and unexpectedly, the major manifestation in these mice was nonsuppurative inflammatory cholangitis (55,56). Physiologic analysis of these knockout mice revealed the absence of phospholipids in their bile and suggested that the mdr2 protein was involved in phospholipid transport. Studies of normal rat canalicular plasma membrane vesicles revealed the presence of ATP-dependent phosphatidylcholine flippase activity, which is presumed to represent the exact function of the mdr2 protein (57). Ultrarapid cryofixation ultrastructural studies of mouse liver have convincingly shown that the mdr2 protein is crucial for phosphatidylcholine flipping from the inner to outer hemileaflet at the canaliculus. This ultimately results in vesicular-mediated excretion of phospholipid from the liver into bile (58). Interruption of this process can lead to impaired phospholipid excretion into bile. This yields bile with a of bile salts. The detergent properties of the salts are presumed to cause the canalicular in the The finding of a in the mdr2 knockout mice a search for a defect in the human MDR3 in children with familial cholestasis. Children with relatively progressive cholestasis by elevated γ-GTP levels have been found to have mutations in the MDR3 gene (Fig. 1). This is associated with an absence of MDR3 protein In selected patients in it has been biliary phospholipid levels are similar to that observed in the knockout investigations at understanding a potential resistance gene have lead to the of a new of genetic cholestatic liver in two other are important to in the of genetic forms of cholestasis. The first is the role of of bile acid synthesis in progressive cholestasis. A variety of of bile salt synthesis have been and they often have cholestasis as one of their major clinical features analysis of excretion of bile acid by and in children with progressive intrahepatic cholestasis the of in children (14). In addition, four of the of these children were ultimately found to have the same The clinical features of these children are distinct in that they have cholestasis without significant pruritus and they have low serum levels of primary bile and of a liver canalicular cholestasis with or These children seem to have very to acid its to reduce primary bile acid major recent related to genetic cholestasis is the identification of a defect in the multispecific organic anion multidrug resistance as the cause of syndrome (Fig. 1). syndrome is a disease primarily by impaired canalicular excretion of conjugated which with the function of As with these were initially by in a of syndrome, the In of the recent advances described in this the diagnostic of the with cholestasis has become even more complex for the pediatric An approach to these new potential is in 2. This approach may be by some as but it is through studies that and potential can be In addition, this of analysis is in our understanding of pediatric cholestasis. The initial approach to the with cholestasis is has been in many and as no cause for the cholestasis can be the approach is Alagille syndrome may be in children with cholestasis and syndromic it is not how many of the features of this syndrome be present to be Many of the characteristics as the posterior embryotoxon, and are relatively Therefore, diagnostic is common in many cholestatic children with an incomplete syndrome. of a diagnosis of Alagille syndrome may be important in genetic in the of as a and in the process of of potential liver Thus analysis for mutations in be in patients with cholestasis and incomplete for the approach to pediatric syndromic features are and there is no significant analysis of bile acid concentrations be in serum bile salts further for the patient described in the of normal serum bile acids be by analysis of bile acid by and using This analysis will permit identification of specific in bile salt and primary bile acid In those patients who have pruritus significant serum levels of γ-GTP can be in in which to γ-GTP is in children with defects in and the finding of low levels of biliary phospholipid be highly of this These patients are often to and liver be early in their Finally, in those patients with normal γ-GTP levels, the possibility of a defect in the FIC1 gene be of these patients by electron microscopic analysis of a liver can be very because these patients have bile (27). It is important that acid be the because it can the characteristic features of the bile. genetic analysis for defects in FIC1 be The of Byler's disease to partial biliary careful investigation to document this Finally, in those patients with normal γ-GTP levels and bile, the possibility of a defect in SPGP be It is not known how these patients will respond to biliary or to acid is to be given the expression of This be recognized as a in not into this time, the of clinical of the diseases described will become In addition, new genetic defects that cause pediatric cholestatic liver disease are to be The recent advances in understanding the molecular basis of pediatric cholestatic liver diseases have not the confusing that exists in this The terminology will most likely significant as more molecular defects are described and as a understanding of the phenotypic expression of these genetic abnormalities. PFIC familial intrahepatic cholestasis 1) be used to describe children with the disease previously referred to as Byler's disease or syndrome and may now be to children with defects in the FIC1 gene. The PFIC 2 has been suggested to describe children who appear to have a defect in the sister gene of investigators in this have to this the bile salt Some investigators have used PFIC 3 to to children with an abnormality in the MDR3 gene. The specific bile acid can be used to describe children with in primary bile acid The diagnosis of Alagille syndrome has been for patients who at least three of major clinical criteria. Future may be made in patients with different and may be on genetic (25). The for clinical and investigations into pediatric cholestatic liver disease is of potential with many important to be The of the mechanisms of bile that many more genetic abnormalities have to be identified a number of cholestatic with features can be the result of of other gene involved in the of bile development of the intrahepatic and biliary For Aagenes syndrome to be a distinct form of intrahepatic cholestasis that is associated with problems of cause and important genes that may be involved in bile and duct development may be affected in this example is an form of cholestasis that has recently been described in the Amish community and of elevated serum bile acid levels without significant This has been to be the result of an abnormality in hepatic of bile although the molecular basis of the One of the most important of investigation is the of the prevalence of these various genetic abnormalities in children with liver analysis of groups of children with cholestasis will for more understanding of genotype-phenotype and will important into the and function of these important components of the biliary The exact mechanisms by which the and genes cell fate be In addition, in the clinical in with identical genetic defects in unexplained and the of genes that have to be The function of the FIC1 protein of a of how defects in FIC1 lead to the clinical in Byler's disease and benign recurrent intrahepatic cholestasis is a high understanding of the mechanisms involved in the development of cholestasis in MDR3 defects has been by the of a knockout mouse these the prevalence of MDR3 defects in children with liver disease is unknown Finally, the recent of the role of SPGP in canalicular bile acid excretion will permit detailed analysis of the regulation of this important gene product in a variety of and
https://doi.org/10.1097/00005176-199902000-00005