ORIGINAL ARTICLE: HEPATOLOGY
Byler Disease: Early Natural History
Amy L. Morris, yKathryn Bukauskas, Rachel E. Sada, and yBenjamin L. Shneider
ABSTRACT Objectives: Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease. Methods: This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children’s Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion. Results: Six childrenpresented between1 and 135 days of life:2 presented with newborn direct hyperbilirubinemia, 2 had complications ofcoagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas g-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children. Conclusions: Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life. Key Words: bile acid, cholestasis, liver disease, pruritus, vitamin
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B
yler disease was first described in the mid 1960s in Amish children who were descendants of Jacob Byler (1–4). The clinical courses of 11 children from 6 families have been reported. One child had significant xanthomas raising a question of whether this child had Byler disease. Interestingly, this child may have been responsive to biliary diversion (4). In the other children, the Received September 25, 2014; accepted November 25, 2014. From the Children’s Hospital of Pittsburgh of UPMC, and the yUniversity of Pittsburgh School of Medicine, Pittsburgh, PA. Address correspondence and reprint requests to Benjamin L. Shneider, MD, Texas Children’s Hospital, 6701 Fannin St, CCC 1010.00, Houston, TX 77030 (e-mail: [email protected]). B.L.S. has received grants from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases to study Byler disease (DK062466 and DK080808) and an investigator-initiated grant from Hyperion Therapeutics (Brisbane, CA) to study the treatment of Byler disease. He is study chair for an National Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases study of the treatment of Alagille syndrome, which involves a cooperative research and development agreement with Lumena Pharmaceuticals/ Shire, and has applied to participate in research in progressive familial intrahepatic cholestasis supported by Lumena Pharmaceuticals/Shire. The other authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000650
reported onset of disease was typically in the first year of life with pruritus (as early as 3 months), loose stools, and failure to thrive. Jaundice and direct hyperbilirubinemia were common but not universal. Rickets was reported in many cases along with vitamin K–responsive coagulopathy. Attacks of cholestasis are commented upon but not carefully delineated. Variable responses to mediumchain triglyceride-based formulas, cholestyramine, and phenobarbital are briefly described. Death is reported at a mean age of 70 months in 8 of these children (range 17–180 months; 17 months because of seizures and 180 months in the child with xanthomas). Death was typically attributed to gastrointestinal bleeding with variable evidence of coma. The natural history of Byler disease and our clinical understanding of its phenotype have evolved during the last 4 decades. Review of the existing clinical literature is complicated by a confusing and nonspecific nomenclature. Subsequent to the initial description of Byler disease in Amish kindred, other children were identified with intrahepatic cholestasis, and a general terminology evolved referring to the disorder as progressive familial intrahepatic cholestasis (PFIC) (5,6). PFIC was subdivided by clinical phenotype with a suggestion that PFIC1 was akintothe diseaseinitiallydescribedintheAmish,with the presumption of a common genetic basis (7,8). The relatively consistent clinical phenotype and founder effect in the Amish patients permitted the genetic basis of Byler disease to be elucidated as changes in the gene encoding the membrane protein, ATPase Class I Type 8b Member 1 (ATP8b1) (9). The exact molecular pathophysiology for the systemic manifestations of disease associated with mutations in ATP8b1 is under active investigation (10–23). It has become clear that not all individuals with ‘‘PFIC1’’ have mutations in ATP8b1, and thus the precise clinical phenotype of the liver disease reported in the existing literature is not clear. In addition, the nomenclature for the disease has evolved but remains confusing. PFIC1 is utilized by some for an ill-defined disease process. FIC1 disease/deficiency is used by others for disease related to defects in ATP8b1, whereas the term Byler disease remains entrenched in common parlance. Individuals may have heterozygous and compound mutations in multiple genes adding to the contextual confusion. For the purpose of this investigation, the term Byler disease is reserved for individuals who are proven to have homozygous changes in ATP8b1, which are predicted to yield a G308V missense mutation. It is of note that since the original descriptions of this disease in the late 1960s and early 1970s there has not been a detailed clinical report of the manifestations of the liver disease in the Amish. Information is embedded in other case series but difficult to tease out. As pharmacologic and surgical therapies for intrahepatic cholestasis evolve, a detailed understanding of natural history is critical for an accurate assessment of the effect of those therapies. In that context, this analysis of the early natural history of Byler disease was undertaken.
METHODS This report described routine clinical practice in the care of these children. Testing for the ATP8b1 c.923G>T mutation (p.G308V) was performed as part of clinical care through the
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laboratory of the Clinic for Special Children (Strasburg, PA). Collection of clinical information and review of records was part of a University of Pittsburgh Institutional Review Board approved protocol, with signed consent by the families or guardians of the children. This analysis focused on the early course of the liver disease, namely, up to 24 months of age or the time of partial external biliary diversion (PEBD). The clinical course after PEBD will be the subject of a distinct analysis. Only children whose clinical presentation and diagnosis occurred at the Children’s Hospital of Pittsburgh of UPMC since January 1, 2007 were potential subjects for review. Follow up was done potentially until October 31, 2014. The diagnosis of Byler disease was made upon the finding of homozygous changes in ATP8b1 that were predicted to lead to the G308V missense change in FIC1.
RESULTS Clinical Approach Protocols were not followed per se and practice evolved over time based upon the best estimates of optimal approaches. The general approach to the care of these infants in the first 2 years of life had a focus on nutritional issues and complications of cholestasis. When breast-feeding was not chosen or there was failure to thrive, a medium-chain triglyceride-enriched formula was typically recommended or there was caloric supplementation with mediumchain triglycerides. Social and cultural issues factored into a decision to exclusively use oral feeding in these patients. Fat-soluble vitamin deficiencies were tested for and generally treated using approaches that have been used for infants with biliary atresia (24). Tocopherol polyethylene glycol succinate (TPGS) was used as an adjunct to enhance the absorption of fat-soluble vitamins (25,26). Scratching behavior was presumed to be related to pruritus and was treated with antihistamines, ursodeoxycholic acid, and/or rifampin (27). Scratching that was persistently refractory to these interventions was typically an indication for consideration of PEBD (28). Ursodeoxycholic acid was also used as a potential choleretic agent.
Demographics, Presentation, and Diagnosis Between January 1, 2007, and October 31, 2014, six children presented to the Children’s Hospital of Pittsburgh of UPMC and were subsequently diagnosed as having Byler disease (Table 1). The age of presentation ranged from the immediate newborn period to
135 days of age. The newborn, who was a sibling of another affected child, was diagnosed on the basis of testing of cord blood at a time when there were no obvious manifestations of liver disease or cholestasis. Two infants presented with jaundice at approximately 1 month of age. Bleeding or bruising was the primary manifestation of disease in 2 infants who presented at 54 and 135 days of age. One infant presented at 133 days of age primarily with failure to thrive and rickets related to vitamin D deficiency. This infant had a question of scratching behavior at the time of presentation. The presenting laboratory parameters were variable in nature. Total bilirubin (TB) was >2 mg/dL in 3 infants, although only 2 of these infants had direct hyperbilirubinemia. Alanine aminotransferase (ALT) levels were normal or near normal in all cases. As expected, g-glutamyltranspeptidase (gGTP) levels were not elevated in the 5 cases when measured (mean 30 IU/L, SD 4.5 IU/L). Alkaline phosphatase was elevated in 4 of the 6 infants. Significant coagulopathy was identified in 3 infants, all of whom responded to parenteral vitamin K administration. In all 3 of these infants, there were clinical manifestations of coagulopathy at presentation. Home birth without vitamin K administration along with breast-feeding is common in this group of patients. Diagnosis was made in these infants primarily on the basis of history (eg, Amish descent and/or family history of disease), preliminary biochemical laboratory findings (low gGTP cholestasis), and subsequent directed genetic testing. Some infants underwent other negative or unremarkable investigations for other causes of cholestasis, but over time the evaluations became more streamlined. The average time from presentation to obtaining blood for genetic testing was 33.7 days, with samples being obtained in 12 ND
N N N
1 32 227
0 4 94
0.7 10.8 1.9
ND 6.4 0.4
10 24 44
ND 24 35
235 836 944
16.6 1.0 7.0
N N N
137 45 150
83 6 15
Alk Phos ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase; DB ¼ direct bilirubin; gGTP ¼ g-glutamyltranspeptidase; INR ¼ international normalized ratio; OH ¼ hydroxy; TB ¼ total bilirubin. Liver biopsy performed as part of initial diagnostic investigations—Y ¼ yes, N ¼ no. y Day of life when genetic testing initiated. z Time interval between day of presentation and initiation of genetic testing.
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SBA (uM), ALT and gGTP (IL/L)
SBA (uM), ALT and gGTP (IL/L)
FIGURE 1. A–F, Clinical course for patients 1 to 6. Graphic depiction of the pattern of key laboratory values over time. The first data point represents the time of initial clinical presentation, whereas the last is either the last follow-up during the study period or just before PEBD. All of the laboratory results obtained are plotted. Timing of the samples is directed by clinical care and not by protocol. Inset box summarizes key events and age at initiation of pharmacologic and nutritional interventions. Interventions were ongoing from the time of initiation until the end of the study period. (In panel A, ? indicates unclear symptoms.) ALT ¼alanine aminotransferase, gGTP ¼ g-glutamyltranspeptidase, MCT ¼ medium-chain triglyceride, MVI ¼ multivitamin, PEBD ¼ partial external biliary diversion, po ¼ by mouth, SBA ¼ total serum bile acid, sq ¼ subcutaneous, TB ¼ total bilirubin, TPGS ¼ tocopherol polyethylene glycol succinate, UDCA ¼ ursodeoxycholic acid.
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Byler Disease: Early Natural History
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observed in all infants with an onset between 5 and 11 months of age. The pruritus was typically unresponsive to the medical regimens used and led to biliary diversion surgery in 4 of the 6 infants at 13 to 21 months of age (patients 1, 3, 4, and 5). In 2 patients (2 and 6), a marked drop in hyperbilirubinemia was noted after the initiation of rifampin therapy that was associated with a resolution of pruritus. Diarrhea was an issue for many of the infants but was self-resolving or manageable in all. A few special issues related to the clinical course were noted. Patient 1 was diagnosed as a newborn on the basis of an affected sibling. Fat-soluble vitamin supplementation was started in the newborn period. Laboratory parameters at 1 and 2 months of age did not show evidence of liver injury or direct hyperbilirubinemia. Patient 2 was diagnosed as having sensorineural hearing loss at 5 months of age. This infant also had marked failure to thrive. Patient 3 had a femur fracture at 8 months of age. Patient 4 had recurrent subdural bleeding. The initial presentation was not recognized to be a manifestation of cholestasis in part because of unremarkable liver biochemistries. Patient 6 had a persistent amelioration of pruritus in response to medical therapy until 24 months of age. Evidence of progressive liver disease manifest by features of portal hypertension and/or uncorrectable coagulopathy was not identified in this cohort. At the last follow-up, none of the patients had splenomegaly on physical examination, and platelet counts ranged from 235 to 525 109/L.
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Failure to thrive was an issue that evolved in many of the infants (Fig. 2 and Table 2). Growth trajectories were generally at the low end of percentiles and did not reflect parental size (data not shown). Diminished weight gain velocity was typically responsive to supplementation with medium-chain triglyceride-based formula and/or use of 30 calorie per ounce formulae that are designed for young children. Higher caloric density formulae were generally
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mo FIGURE 2. Composite weight growth curve. Weight in kilograms is plotted relative to age in months. Each patient’s growth is depicted by a distinct line. For point of reference, Centers for Disease Control and Prevention standard values are plotted for a boy at the 50th percentile and a girl at the 3rd percentile.
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TABLE 2. Growth parameters
Age, mo
Patient 1
Patient 2
Wt Ht BMI Wt Ht 0.67 2.02 0.67 2.38 1.28 1.34 2.04 0.19 3.40 2.89 1.90 3.50 0.36 3.68 3.02 — — — 3.66 4.44 — — — — —
2 6 12 18 24
Patient 3
Patient 4
BMI Wt Ht BMI Wt Ht 2.40 — — — 0.49 0.28 2.34 3.12 3.71 1.13 0.78 0.17 2.71 2.48 3.61 0.30 0.92 0.38 1.19 — — — 1.01 1.26 — — — — — —
Patient 5
Patient 6
BMI Wt Ht BMI Wt Ht BMI 0.82 1.90 2.56 0.58 0.97 0.77 2.84 1.10 3.40 3.19 1.97 1.14 1.34 0.69 1.00 1.56 2.70 0.10 1.90 2.02 0.72 0.34 — — — 1.16 0.78 0.98 — — — — 1.64 0.84 1.28
BMI ¼ body mass index expressed as sex-specific z score for age; Ht ¼ height; Wt ¼ weight. Closest time at or beyond this age.
taken better (presumed to be related to taste) and used in infants >9 months of age. Fat-soluble vitamin insufficiencies were universal in this cohort (Table 3). A TPGS vitamin E–based multivitamin preparation was not adequate to prevent insufficiency. Supplementation with vitamin A was rarely required, and 2 infants had levels greater than recommended despite no active supplementation. On the contrary, vitamins D, E, and K insufficiency were nearly universal and required supplemental administration, which was significant.
Course of Disease: Biochemistries Liver biochemistries were variable in their consistency. Almost by definition, gGTP levels were on the low end of normal throughout the monitored course of disease. Amongst 50 measurements in this cohort, the mean level was 19.7 IU/L (standard deviation 6.4, standard error of the mean 0.9, and range 11–35). In general, ALT levels were normal or modestly elevated with a mean level of 49.5 IU/L amongst 66 measurements (standard deviation 24.0, standard error of the mean 3.0, and range 11–135). TB levels were variable. TB and direct bilirubin (DB) (not shown) levels fluctuated during the first 12 to 24 months of age without an apparent relation between disease state or medication administration. In patient 1, the hyperbilirubinemia was indirect in the first 2 months of life (2 weeks TB 6.1, DB 0.2; 1 month TB 3.2, DB 0.2; 2 months TB 0.6, DB 0.3). This indirect hyperbilirubinemia was supplanted by direct hyperbilirubinemia beginning at 3 months of age (3 months TB 3.0, DB 2.0). In patients 2 and 5, the course was one of early hyperbilirubinemia,
whereas in patients 3, 4, and 6, the bilirubin elevations were more modest. Diminishing hyperbilirubinemia despite persistent cholestasis was a common finding in the second year of life. Serum bile acids were sporadically measured and typically in excess of 100 mmol/L. It is noteworthy that in patient 4, levels were minimally elevated in the context of coagulopathy.
DISCUSSION This detailed analysis of the early clinical course of Byler disease provides new insights into this systemic disorder. Despite the homogeneity of the specific genetic change in ATP8b1, there is significant variability in the mode of presentation. This initial presentation is somewhat dichotomous with regard to the issue of neonatal jaundice, in some ways akin to what has been observed with a-1 antitrypsin deficiency (29,30). The presence of early direct hyperbilirubinemia highlights the presence of liver disease and enhances early identification of the disease. In contrast, 3 infants did not have marked direct hyperbilirubinemia early in their course. In the context of normal serum aminotransferase and gGTP levels, liver disease was not apparent and delay in diagnosis occurred. Complications of fat-soluble vitamin deficiencies, namely rickets related to vitamin D and coagulopathy related to vitamin K, became the mode of presentation. Cholestasis may only be identified by careful review of laboratory studies and/or by the measurement of serum bile acids. DB levels in 2 cases were abnormal, 0.7 and 0.4 mg/dL, although these levels may not be considered clinically relevant by some. Bleeding diathesis is a particular issue in the Amish community where home delivery is common and vitamin K
TABLE 3. Vitamin nutriture Vitamin A No. MVI Range of levelsy 1 2 3 4 5 6
Y Y Y Y Y
8–56 51–74 56 30–65 32 29–115
Vitamin D
Range of dosesz
Last levely
Last dosez
Range of levels§
Range of dosesjj
Last level§
2000–6000 0 0 0 0 0
56 74 56 30 32 115
6000–>2000 0 0 0 0 0
5–40 7–44 9–27 15–33 4–24 10–44
8000–16000 2000–16000 5000–16000 2000–16000 2000–16000 2000–20000
40 35 10 18 24 10
Vitamin E Last dosejj
Range of levelsô
Range of doses#
16000 5.0–8.7 80–107 16000 0.0–8.0 27–80 16000 1.9–5.0 25–133 16000 2.0–3.0 80–160 16000 0.0–6.0 160 –187 20000 2.4 – 12.5 80 – 300
Last Last MVI levelô dose# 7.0 5.0 1.9 3.0 2.0 8.8
107 80 133 160 187 300
N Y Y Y Y N
MVI ¼ multivitamin; TPGS ¼ tocopherol polyethylene glycol succinate. Doses are supplementation in addition to 1–2 mL/day of ADEKs or AquADEKs (Yasoo Health, Johnson City, TN), yes (Y) or no (N) at beginning and end of time period. y Retinol—mg/dL (reference range 19–77). z IU/day of retinol. § 25-OH vitamin D—ng/mL (reference range 20–45). jj IU/day of cholecalciferol. ô Tocopherol—mg/mL (reference range 3.8–20.3).
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may not be administered perinatally. Historically, child abuse has been inappropriately suspected in some circumstances because of concerns for bruising and/or skeletal fractures. Diagnosis of Byler disease can be straightforward, efficient, and cost-effective in the context of a heightened index of suspicion and presently available molecular diagnostics. Neonatal cholestatic liver disease in the setting of an Amish background or family history of Byler disease, coupled with the finding of a low gGTP level, is highly suspicious for Byler disease. In this circumstance, specific genetic testing for the ATP8b1 c.923G>T mutation is recommended. Additional standard evaluations of neonatal cholestasis are probably not warranted (31). Liver biopsy was not necessary as part of the diagnostic evaluation in any of these children, despite the potential relevance of the histologic and ultrastructural findings (3,8). Genetic testing, may in fact, be the most cost-effective way to screen newborn siblings of affected individuals. This approach worked well in the present series and identified an individual with Byler disease who did not have biochemical or clinical evidence of liver disease in the first 2 months of life. Early identification of Byler disease may prevent complications of cholestasis, in particular life-threatening intracranial hemorrhage. Later presentations of Byler disease may require a heightened index of suspicion to lead to a rapid molecular diagnosis and proper therapeutic interventions. Just as the mode of presentation was variable so was the ensuing clinical course. Diarrhea was commonly reported in this cohort, although it did not seem to be as problematic as was described in earlier reports. Jaundice and hyperbilirubinemia were variable, without a ready explanation for the variability. In some cases, there were apparent discrepancies between the degree of hyperbilirubinemia and the degree of cholestasis, the latter manifest by either scratching behavior and/or serum bile acid levels. TB levels may actually fall in the context of more intense pruritus and high serum bile acid levels. Bile acids are unlikely to be a direct pruritogen but serve as a biomarker of cholestasis (32,33). It is worth noting the relatively minimal abnormality in serum ALT levels measured in this cohort. Even more remarkable are the persistent and almost pathognomonic low normal gGTP levels. The pattern of biochemistries becomes relevant for both diagnosis and assessment of clinical course. A marked increase in ALT may indicate an additional pathologic process including potential druginduced liver injury, whereas interpretation of changes in TB may not be as clear. Despite the profound cholestasis, progressive liver disease was not observed in this cohort. This is a relevant issue in consideration of PEBD as a therapeutic intervention. Cirrhosis and portal hypertension can be problematic for the use of PEBD as an intervention—this issue does not appear to be relevant in the first 2 years of life for most children with Byler disease. Scratching behavior became apparent in the second half of the first year of life and, in general, was refractory to medical therapy. Given the generally favorable response to PEBD, this approach was recommended in the setting of weeks of intractable pruritus. In 2 patients, there was a more pronounced response to rifampin that included a change in TB level in addition to an amelioration in pruritus. In selected individuals, rifampin therapy may be a treatment for hepatocellular secretory failure (34). Medical issues related to growth and nutrition are paramount in the early course of Byler disease. As noted above, vitamin K deficiency can be lethal and requires constant monitoring and supplementation. Vitamin D and E insufficiency are common and also require monitoring and supplementation. The amount of supplementation can be significant, and in some circumstances, consideration for the use of 1,25-hydroxyvitamin D is warranted. It is curious that vitamin A insufficiency was uncommon and elevated levels were observed without specific supplementation. The pathophysiology and significance of this are uncertain. Growth issues are www.jpgn.org
Byler Disease: Early Natural History prominent in Byler disease and in part related to diminished luminal absorption of long-chain fatty acids. It is also possible that there may be a component of somatic growth restriction in Byler disease. It is not certain whether nasogastric or gastrostomy feeding will help ameliorate some of the growth issues in these children. Careful attention to growth and nutrition in Byler disease is critical in the early management of this disorder. The biologic basis for the variability of the disease presentation and course in Byler disease is not known. Given the endogamous nature of the Amish community, confounding inherited disorders or modifiers are certainly possible (35–37). Additional distinct etiologies for cholestasis have been identified in the Amish community (38). Systematic examination of bile acid coenzyme A: amino acid N-acyltransferase and tight junction protein 2 has not been reported in children with Byler disease. The latter of these proteins has recently been described in another cohort of individuals with cholestatic liver disease (39). Heterozygote mutations for either of the genes may impact bile flow and thereby influence the early course of the disease. One child in this cohort had early onset of sensorineural hearing loss. This particular manifestation of this disease is variable and understanding of that variability may yield new insights into hearing disorders in general (18). This contemporary clinical description of Byler disease adds to the most recent similar reports from 40 years ago. There are striking similarities in the descriptions, although the present report provides contemporary details not available in those initial contributions. This detailed analysis has uncovered an unappreciated heterogeneity to the hepatic manifestations of Byler disease. In particular, there seems to be a dichotomy in the degree of neonatal hyperbilirubinemia, which has a distinct impact on the mode of presentation and the timing of recognition and diagnosis of the disease. Further detailed investigations of the underpinning of the heterogeneity are warranted as are descriptions of the course of disease after PEBD. The early manifestations of Byler disease include growth and nutrition issues coupled with severe and incapacitating pruritus. Particular attention to nutritional issues is key to avoid morbidity and mortality.
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Shneider et al 11. Chen F, Ananthanarayanan M, Emre S, et al. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology 2004;126:756–64. 12. Pawlikowska L, Groen A, Eppens EF, et al. A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. Hum Mol Genet 2004;13:881–92. 13. Paulusma CC, Groen A, Kunne C, et al. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology 2006;44:195– 204. 14. Groen A, Kunne C, Paulusma CC, et al. Intestinal bile salt absorption in Atp8b1 deficient mice. J Hepatol 2007;47:114–22. 15. Frankenberg T, Miloh T, Chen FY, et al. The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 2008;48:1896– 905. 16. Cai SY, Gautam S, Nguyen T, et al. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology 2009;136: 1060–9. 17. Chen F, Ellis E, Strom SC, et al. ATPase Class I Type 8B Member 1 and protein kinase C zeta induce the expression of the canalicular bile salt export pump in human hepatocytes. Pediatr Res 2010;67:183–7. 18. Stapelbroek JM, Peters TA, van Beurden DH, et al. ATP8B1 is essential for maintaining normal hearing. Proc Natl Acad Sci U S A 2009; 106:9709–14. 19. Ray NB, Durairaj L, Chen BB, et al. Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. Nat Med 2010;16:1120–7. 20. Shah S, Sanford UR, Vargas JC, et al. Strain background modifies phenotypes in the ATP8B1-deficient mouse. PLoS One 2010;5:e8984. 21. Verhulst PM, van der Velden LM, Oorschot V, et al. A flippaseindependent function of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1, is required for apical protein expression and microvillus formation in polarized epithelial cells. Hepatology 2010;51:2049–60. 22. Groen A, Romero MR, Kunne C, et al. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology 2011;141:1927–37e1–4. 23. Chen F, Ghosh A, Shneider BL. Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1. J Lipid Res 2013;54:379–85. 24. Shneider BL, Magee JC, Bezerra JA, et al. Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia. Pediatrics 2012;130:e607–14.
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25. Sokol RJ, Butler-Simon N, Conner C, et al. Multicenter trial of d-alphatocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis. Gastroenterology 1993;104:1727–35. 26. Argao EA, Heubi JE, Hollis BW, et al. d-Alpha-tocopheryl polyethylene glycol-1000 succinate enhances the absorption of vitamin D in chronic cholestatic liver disease of infancy and childhood. Pediatr Res 1992;31: 146–50. 27. Yerushalmi B, Sokol RJ, Narkewicz MR, et al. Use of rifampin for severe pruritus in children with chronic cholestasis. J Pediatr Gastroenterol Nutr 1999;29:442–7. 28. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988;95:130–6. 29. Psacharopoulos HT, Mowat AP, Cook PJ, et al. Outcome of liver disease associated with alpha 1 antitrypsin deficiency (PiZ). Implications for genetic counselling and antenatal diagnosis. Arch Dis Child 1983;58: 882–7. 30. Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316–21. 31. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004;39:115–28. 32. Kremer AE, Martens JJ, Kulik W, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010;139: 1008–18. 33. Vaz FM, Paulusma CC, Huidekoper H, et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 2015;61:260–7. 34. van Dijk R, Kremer AE, Smit W, et al. Characterization and treatment of persistent hepatocellular secretory failure. Liver Int 2014[Epub ahead of print]. 35. Knisely AS. Progressive familial intrahepatic cholestasis: a personal perspective. Pediatr Dev Pathol 2000;3:113–25. 36. Payne M, Rupar CA, Siu GM, et al. Amish, Mennonite, and Hutterite genetic disorder database. Paediatr Child Health 2011;16:e23–4. 37. Morton DH, Morton CS, Strauss KA, et al. Pediatric medicine and the genetic disorders of the Amish and Mennonite people of Pennsylvania. Am J Med Genet C Semin Med Genet 2003;121C:5–17. 38. Carlton VE, Harris BZ, Puffenberger EG, et al. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet 2003;34:91–6. 39. Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 2014;46:326–8.
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Byler Disease: Early Natural History
Amy L. Morris, yKathryn Bukauskas, Rachel E. Sada, and yBenjamin L. Shneider
ABSTRACT Objectives: Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease. Methods: This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children’s Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion. Results: Six childrenpresented between1 and 135 days of life:2 presented with newborn direct hyperbilirubinemia, 2 had complications ofcoagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas g-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children. Conclusions: Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life. Key Words: bile acid, cholestasis, liver disease, pruritus, vitamin
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B
yler disease was first described in the mid 1960s in Amish children who were descendants of Jacob Byler (1–4). The clinical courses of 11 children from 6 families have been reported. One child had significant xanthomas raising a question of whether this child had Byler disease. Interestingly, this child may have been responsive to biliary diversion (4). In the other children, the Received September 25, 2014; accepted November 25, 2014. From the Children’s Hospital of Pittsburgh of UPMC, and the yUniversity of Pittsburgh School of Medicine, Pittsburgh, PA. Address correspondence and reprint requests to Benjamin L. Shneider, MD, Texas Children’s Hospital, 6701 Fannin St, CCC 1010.00, Houston, TX 77030 (e-mail: [email protected]). B.L.S. has received grants from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases to study Byler disease (DK062466 and DK080808) and an investigator-initiated grant from Hyperion Therapeutics (Brisbane, CA) to study the treatment of Byler disease. He is study chair for an National Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases study of the treatment of Alagille syndrome, which involves a cooperative research and development agreement with Lumena Pharmaceuticals/ Shire, and has applied to participate in research in progressive familial intrahepatic cholestasis supported by Lumena Pharmaceuticals/Shire. The other authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000650
reported onset of disease was typically in the first year of life with pruritus (as early as 3 months), loose stools, and failure to thrive. Jaundice and direct hyperbilirubinemia were common but not universal. Rickets was reported in many cases along with vitamin K–responsive coagulopathy. Attacks of cholestasis are commented upon but not carefully delineated. Variable responses to mediumchain triglyceride-based formulas, cholestyramine, and phenobarbital are briefly described. Death is reported at a mean age of 70 months in 8 of these children (range 17–180 months; 17 months because of seizures and 180 months in the child with xanthomas). Death was typically attributed to gastrointestinal bleeding with variable evidence of coma. The natural history of Byler disease and our clinical understanding of its phenotype have evolved during the last 4 decades. Review of the existing clinical literature is complicated by a confusing and nonspecific nomenclature. Subsequent to the initial description of Byler disease in Amish kindred, other children were identified with intrahepatic cholestasis, and a general terminology evolved referring to the disorder as progressive familial intrahepatic cholestasis (PFIC) (5,6). PFIC was subdivided by clinical phenotype with a suggestion that PFIC1 was akintothe diseaseinitiallydescribedintheAmish,with the presumption of a common genetic basis (7,8). The relatively consistent clinical phenotype and founder effect in the Amish patients permitted the genetic basis of Byler disease to be elucidated as changes in the gene encoding the membrane protein, ATPase Class I Type 8b Member 1 (ATP8b1) (9). The exact molecular pathophysiology for the systemic manifestations of disease associated with mutations in ATP8b1 is under active investigation (10–23). It has become clear that not all individuals with ‘‘PFIC1’’ have mutations in ATP8b1, and thus the precise clinical phenotype of the liver disease reported in the existing literature is not clear. In addition, the nomenclature for the disease has evolved but remains confusing. PFIC1 is utilized by some for an ill-defined disease process. FIC1 disease/deficiency is used by others for disease related to defects in ATP8b1, whereas the term Byler disease remains entrenched in common parlance. Individuals may have heterozygous and compound mutations in multiple genes adding to the contextual confusion. For the purpose of this investigation, the term Byler disease is reserved for individuals who are proven to have homozygous changes in ATP8b1, which are predicted to yield a G308V missense mutation. It is of note that since the original descriptions of this disease in the late 1960s and early 1970s there has not been a detailed clinical report of the manifestations of the liver disease in the Amish. Information is embedded in other case series but difficult to tease out. As pharmacologic and surgical therapies for intrahepatic cholestasis evolve, a detailed understanding of natural history is critical for an accurate assessment of the effect of those therapies. In that context, this analysis of the early natural history of Byler disease was undertaken.
METHODS This report described routine clinical practice in the care of these children. Testing for the ATP8b1 c.923G>T mutation (p.G308V) was performed as part of clinical care through the
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laboratory of the Clinic for Special Children (Strasburg, PA). Collection of clinical information and review of records was part of a University of Pittsburgh Institutional Review Board approved protocol, with signed consent by the families or guardians of the children. This analysis focused on the early course of the liver disease, namely, up to 24 months of age or the time of partial external biliary diversion (PEBD). The clinical course after PEBD will be the subject of a distinct analysis. Only children whose clinical presentation and diagnosis occurred at the Children’s Hospital of Pittsburgh of UPMC since January 1, 2007 were potential subjects for review. Follow up was done potentially until October 31, 2014. The diagnosis of Byler disease was made upon the finding of homozygous changes in ATP8b1 that were predicted to lead to the G308V missense change in FIC1.
RESULTS Clinical Approach Protocols were not followed per se and practice evolved over time based upon the best estimates of optimal approaches. The general approach to the care of these infants in the first 2 years of life had a focus on nutritional issues and complications of cholestasis. When breast-feeding was not chosen or there was failure to thrive, a medium-chain triglyceride-enriched formula was typically recommended or there was caloric supplementation with mediumchain triglycerides. Social and cultural issues factored into a decision to exclusively use oral feeding in these patients. Fat-soluble vitamin deficiencies were tested for and generally treated using approaches that have been used for infants with biliary atresia (24). Tocopherol polyethylene glycol succinate (TPGS) was used as an adjunct to enhance the absorption of fat-soluble vitamins (25,26). Scratching behavior was presumed to be related to pruritus and was treated with antihistamines, ursodeoxycholic acid, and/or rifampin (27). Scratching that was persistently refractory to these interventions was typically an indication for consideration of PEBD (28). Ursodeoxycholic acid was also used as a potential choleretic agent.
Demographics, Presentation, and Diagnosis Between January 1, 2007, and October 31, 2014, six children presented to the Children’s Hospital of Pittsburgh of UPMC and were subsequently diagnosed as having Byler disease (Table 1). The age of presentation ranged from the immediate newborn period to
135 days of age. The newborn, who was a sibling of another affected child, was diagnosed on the basis of testing of cord blood at a time when there were no obvious manifestations of liver disease or cholestasis. Two infants presented with jaundice at approximately 1 month of age. Bleeding or bruising was the primary manifestation of disease in 2 infants who presented at 54 and 135 days of age. One infant presented at 133 days of age primarily with failure to thrive and rickets related to vitamin D deficiency. This infant had a question of scratching behavior at the time of presentation. The presenting laboratory parameters were variable in nature. Total bilirubin (TB) was >2 mg/dL in 3 infants, although only 2 of these infants had direct hyperbilirubinemia. Alanine aminotransferase (ALT) levels were normal or near normal in all cases. As expected, g-glutamyltranspeptidase (gGTP) levels were not elevated in the 5 cases when measured (mean 30 IU/L, SD 4.5 IU/L). Alkaline phosphatase was elevated in 4 of the 6 infants. Significant coagulopathy was identified in 3 infants, all of whom responded to parenteral vitamin K administration. In all 3 of these infants, there were clinical manifestations of coagulopathy at presentation. Home birth without vitamin K administration along with breast-feeding is common in this group of patients. Diagnosis was made in these infants primarily on the basis of history (eg, Amish descent and/or family history of disease), preliminary biochemical laboratory findings (low gGTP cholestasis), and subsequent directed genetic testing. Some infants underwent other negative or unremarkable investigations for other causes of cholestasis, but over time the evaluations became more streamlined. The average time from presentation to obtaining blood for genetic testing was 33.7 days, with samples being obtained in 12 ND
N N N
1 32 227
0 4 94
0.7 10.8 1.9
ND 6.4 0.4
10 24 44
ND 24 35
235 836 944
16.6 1.0 7.0
N N N
137 45 150
83 6 15
Alk Phos ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase; DB ¼ direct bilirubin; gGTP ¼ g-glutamyltranspeptidase; INR ¼ international normalized ratio; OH ¼ hydroxy; TB ¼ total bilirubin. Liver biopsy performed as part of initial diagnostic investigations—Y ¼ yes, N ¼ no. y Day of life when genetic testing initiated. z Time interval between day of presentation and initiation of genetic testing.
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SBA (uM), ALT and gGTP (IL/L)
FIGURE 1. A–F, Clinical course for patients 1 to 6. Graphic depiction of the pattern of key laboratory values over time. The first data point represents the time of initial clinical presentation, whereas the last is either the last follow-up during the study period or just before PEBD. All of the laboratory results obtained are plotted. Timing of the samples is directed by clinical care and not by protocol. Inset box summarizes key events and age at initiation of pharmacologic and nutritional interventions. Interventions were ongoing from the time of initiation until the end of the study period. (In panel A, ? indicates unclear symptoms.) ALT ¼alanine aminotransferase, gGTP ¼ g-glutamyltranspeptidase, MCT ¼ medium-chain triglyceride, MVI ¼ multivitamin, PEBD ¼ partial external biliary diversion, po ¼ by mouth, SBA ¼ total serum bile acid, sq ¼ subcutaneous, TB ¼ total bilirubin, TPGS ¼ tocopherol polyethylene glycol succinate, UDCA ¼ ursodeoxycholic acid.
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3
observed in all infants with an onset between 5 and 11 months of age. The pruritus was typically unresponsive to the medical regimens used and led to biliary diversion surgery in 4 of the 6 infants at 13 to 21 months of age (patients 1, 3, 4, and 5). In 2 patients (2 and 6), a marked drop in hyperbilirubinemia was noted after the initiation of rifampin therapy that was associated with a resolution of pruritus. Diarrhea was an issue for many of the infants but was self-resolving or manageable in all. A few special issues related to the clinical course were noted. Patient 1 was diagnosed as a newborn on the basis of an affected sibling. Fat-soluble vitamin supplementation was started in the newborn period. Laboratory parameters at 1 and 2 months of age did not show evidence of liver injury or direct hyperbilirubinemia. Patient 2 was diagnosed as having sensorineural hearing loss at 5 months of age. This infant also had marked failure to thrive. Patient 3 had a femur fracture at 8 months of age. Patient 4 had recurrent subdural bleeding. The initial presentation was not recognized to be a manifestation of cholestasis in part because of unremarkable liver biochemistries. Patient 6 had a persistent amelioration of pruritus in response to medical therapy until 24 months of age. Evidence of progressive liver disease manifest by features of portal hypertension and/or uncorrectable coagulopathy was not identified in this cohort. At the last follow-up, none of the patients had splenomegaly on physical examination, and platelet counts ranged from 235 to 525 109/L.
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Failure to thrive was an issue that evolved in many of the infants (Fig. 2 and Table 2). Growth trajectories were generally at the low end of percentiles and did not reflect parental size (data not shown). Diminished weight gain velocity was typically responsive to supplementation with medium-chain triglyceride-based formula and/or use of 30 calorie per ounce formulae that are designed for young children. Higher caloric density formulae were generally
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mo FIGURE 2. Composite weight growth curve. Weight in kilograms is plotted relative to age in months. Each patient’s growth is depicted by a distinct line. For point of reference, Centers for Disease Control and Prevention standard values are plotted for a boy at the 50th percentile and a girl at the 3rd percentile.
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TABLE 2. Growth parameters
Age, mo
Patient 1
Patient 2
Wt Ht BMI Wt Ht 0.67 2.02 0.67 2.38 1.28 1.34 2.04 0.19 3.40 2.89 1.90 3.50 0.36 3.68 3.02 — — — 3.66 4.44 — — — — —
2 6 12 18 24
Patient 3
Patient 4
BMI Wt Ht BMI Wt Ht 2.40 — — — 0.49 0.28 2.34 3.12 3.71 1.13 0.78 0.17 2.71 2.48 3.61 0.30 0.92 0.38 1.19 — — — 1.01 1.26 — — — — — —
Patient 5
Patient 6
BMI Wt Ht BMI Wt Ht BMI 0.82 1.90 2.56 0.58 0.97 0.77 2.84 1.10 3.40 3.19 1.97 1.14 1.34 0.69 1.00 1.56 2.70 0.10 1.90 2.02 0.72 0.34 — — — 1.16 0.78 0.98 — — — — 1.64 0.84 1.28
BMI ¼ body mass index expressed as sex-specific z score for age; Ht ¼ height; Wt ¼ weight. Closest time at or beyond this age.
taken better (presumed to be related to taste) and used in infants >9 months of age. Fat-soluble vitamin insufficiencies were universal in this cohort (Table 3). A TPGS vitamin E–based multivitamin preparation was not adequate to prevent insufficiency. Supplementation with vitamin A was rarely required, and 2 infants had levels greater than recommended despite no active supplementation. On the contrary, vitamins D, E, and K insufficiency were nearly universal and required supplemental administration, which was significant.
Course of Disease: Biochemistries Liver biochemistries were variable in their consistency. Almost by definition, gGTP levels were on the low end of normal throughout the monitored course of disease. Amongst 50 measurements in this cohort, the mean level was 19.7 IU/L (standard deviation 6.4, standard error of the mean 0.9, and range 11–35). In general, ALT levels were normal or modestly elevated with a mean level of 49.5 IU/L amongst 66 measurements (standard deviation 24.0, standard error of the mean 3.0, and range 11–135). TB levels were variable. TB and direct bilirubin (DB) (not shown) levels fluctuated during the first 12 to 24 months of age without an apparent relation between disease state or medication administration. In patient 1, the hyperbilirubinemia was indirect in the first 2 months of life (2 weeks TB 6.1, DB 0.2; 1 month TB 3.2, DB 0.2; 2 months TB 0.6, DB 0.3). This indirect hyperbilirubinemia was supplanted by direct hyperbilirubinemia beginning at 3 months of age (3 months TB 3.0, DB 2.0). In patients 2 and 5, the course was one of early hyperbilirubinemia,
whereas in patients 3, 4, and 6, the bilirubin elevations were more modest. Diminishing hyperbilirubinemia despite persistent cholestasis was a common finding in the second year of life. Serum bile acids were sporadically measured and typically in excess of 100 mmol/L. It is noteworthy that in patient 4, levels were minimally elevated in the context of coagulopathy.
DISCUSSION This detailed analysis of the early clinical course of Byler disease provides new insights into this systemic disorder. Despite the homogeneity of the specific genetic change in ATP8b1, there is significant variability in the mode of presentation. This initial presentation is somewhat dichotomous with regard to the issue of neonatal jaundice, in some ways akin to what has been observed with a-1 antitrypsin deficiency (29,30). The presence of early direct hyperbilirubinemia highlights the presence of liver disease and enhances early identification of the disease. In contrast, 3 infants did not have marked direct hyperbilirubinemia early in their course. In the context of normal serum aminotransferase and gGTP levels, liver disease was not apparent and delay in diagnosis occurred. Complications of fat-soluble vitamin deficiencies, namely rickets related to vitamin D and coagulopathy related to vitamin K, became the mode of presentation. Cholestasis may only be identified by careful review of laboratory studies and/or by the measurement of serum bile acids. DB levels in 2 cases were abnormal, 0.7 and 0.4 mg/dL, although these levels may not be considered clinically relevant by some. Bleeding diathesis is a particular issue in the Amish community where home delivery is common and vitamin K
TABLE 3. Vitamin nutriture Vitamin A No. MVI Range of levelsy 1 2 3 4 5 6
Y Y Y Y Y
8–56 51–74 56 30–65 32 29–115
Vitamin D
Range of dosesz
Last levely
Last dosez
Range of levels§
Range of dosesjj
Last level§
2000–6000 0 0 0 0 0
56 74 56 30 32 115
6000–>2000 0 0 0 0 0
5–40 7–44 9–27 15–33 4–24 10–44
8000–16000 2000–16000 5000–16000 2000–16000 2000–16000 2000–20000
40 35 10 18 24 10
Vitamin E Last dosejj
Range of levelsô
Range of doses#
16000 5.0–8.7 80–107 16000 0.0–8.0 27–80 16000 1.9–5.0 25–133 16000 2.0–3.0 80–160 16000 0.0–6.0 160 –187 20000 2.4 – 12.5 80 – 300
Last Last MVI levelô dose# 7.0 5.0 1.9 3.0 2.0 8.8
107 80 133 160 187 300
N Y Y Y Y N
MVI ¼ multivitamin; TPGS ¼ tocopherol polyethylene glycol succinate. Doses are supplementation in addition to 1–2 mL/day of ADEKs or AquADEKs (Yasoo Health, Johnson City, TN), yes (Y) or no (N) at beginning and end of time period. y Retinol—mg/dL (reference range 19–77). z IU/day of retinol. § 25-OH vitamin D—ng/mL (reference range 20–45). jj IU/day of cholecalciferol. ô Tocopherol—mg/mL (reference range 3.8–20.3).
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may not be administered perinatally. Historically, child abuse has been inappropriately suspected in some circumstances because of concerns for bruising and/or skeletal fractures. Diagnosis of Byler disease can be straightforward, efficient, and cost-effective in the context of a heightened index of suspicion and presently available molecular diagnostics. Neonatal cholestatic liver disease in the setting of an Amish background or family history of Byler disease, coupled with the finding of a low gGTP level, is highly suspicious for Byler disease. In this circumstance, specific genetic testing for the ATP8b1 c.923G>T mutation is recommended. Additional standard evaluations of neonatal cholestasis are probably not warranted (31). Liver biopsy was not necessary as part of the diagnostic evaluation in any of these children, despite the potential relevance of the histologic and ultrastructural findings (3,8). Genetic testing, may in fact, be the most cost-effective way to screen newborn siblings of affected individuals. This approach worked well in the present series and identified an individual with Byler disease who did not have biochemical or clinical evidence of liver disease in the first 2 months of life. Early identification of Byler disease may prevent complications of cholestasis, in particular life-threatening intracranial hemorrhage. Later presentations of Byler disease may require a heightened index of suspicion to lead to a rapid molecular diagnosis and proper therapeutic interventions. Just as the mode of presentation was variable so was the ensuing clinical course. Diarrhea was commonly reported in this cohort, although it did not seem to be as problematic as was described in earlier reports. Jaundice and hyperbilirubinemia were variable, without a ready explanation for the variability. In some cases, there were apparent discrepancies between the degree of hyperbilirubinemia and the degree of cholestasis, the latter manifest by either scratching behavior and/or serum bile acid levels. TB levels may actually fall in the context of more intense pruritus and high serum bile acid levels. Bile acids are unlikely to be a direct pruritogen but serve as a biomarker of cholestasis (32,33). It is worth noting the relatively minimal abnormality in serum ALT levels measured in this cohort. Even more remarkable are the persistent and almost pathognomonic low normal gGTP levels. The pattern of biochemistries becomes relevant for both diagnosis and assessment of clinical course. A marked increase in ALT may indicate an additional pathologic process including potential druginduced liver injury, whereas interpretation of changes in TB may not be as clear. Despite the profound cholestasis, progressive liver disease was not observed in this cohort. This is a relevant issue in consideration of PEBD as a therapeutic intervention. Cirrhosis and portal hypertension can be problematic for the use of PEBD as an intervention—this issue does not appear to be relevant in the first 2 years of life for most children with Byler disease. Scratching behavior became apparent in the second half of the first year of life and, in general, was refractory to medical therapy. Given the generally favorable response to PEBD, this approach was recommended in the setting of weeks of intractable pruritus. In 2 patients, there was a more pronounced response to rifampin that included a change in TB level in addition to an amelioration in pruritus. In selected individuals, rifampin therapy may be a treatment for hepatocellular secretory failure (34). Medical issues related to growth and nutrition are paramount in the early course of Byler disease. As noted above, vitamin K deficiency can be lethal and requires constant monitoring and supplementation. Vitamin D and E insufficiency are common and also require monitoring and supplementation. The amount of supplementation can be significant, and in some circumstances, consideration for the use of 1,25-hydroxyvitamin D is warranted. It is curious that vitamin A insufficiency was uncommon and elevated levels were observed without specific supplementation. The pathophysiology and significance of this are uncertain. Growth issues are www.jpgn.org
Byler Disease: Early Natural History prominent in Byler disease and in part related to diminished luminal absorption of long-chain fatty acids. It is also possible that there may be a component of somatic growth restriction in Byler disease. It is not certain whether nasogastric or gastrostomy feeding will help ameliorate some of the growth issues in these children. Careful attention to growth and nutrition in Byler disease is critical in the early management of this disorder. The biologic basis for the variability of the disease presentation and course in Byler disease is not known. Given the endogamous nature of the Amish community, confounding inherited disorders or modifiers are certainly possible (35–37). Additional distinct etiologies for cholestasis have been identified in the Amish community (38). Systematic examination of bile acid coenzyme A: amino acid N-acyltransferase and tight junction protein 2 has not been reported in children with Byler disease. The latter of these proteins has recently been described in another cohort of individuals with cholestatic liver disease (39). Heterozygote mutations for either of the genes may impact bile flow and thereby influence the early course of the disease. One child in this cohort had early onset of sensorineural hearing loss. This particular manifestation of this disease is variable and understanding of that variability may yield new insights into hearing disorders in general (18). This contemporary clinical description of Byler disease adds to the most recent similar reports from 40 years ago. There are striking similarities in the descriptions, although the present report provides contemporary details not available in those initial contributions. This detailed analysis has uncovered an unappreciated heterogeneity to the hepatic manifestations of Byler disease. In particular, there seems to be a dichotomy in the degree of neonatal hyperbilirubinemia, which has a distinct impact on the mode of presentation and the timing of recognition and diagnosis of the disease. Further detailed investigations of the underpinning of the heterogeneity are warranted as are descriptions of the course of disease after PEBD. The early manifestations of Byler disease include growth and nutrition issues coupled with severe and incapacitating pruritus. Particular attention to nutritional issues is key to avoid morbidity and mortality.
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