lowed by cell death and permanent disability [31, 50, 59]. Crigler and Najjar first characterized fatal hereditary non- hemolytic jaundice in 1952 [19]. They described six infants in three families; five children died of kernicterus by 15 months of age, and the remaining patient died at age 15 years, several months after suffering devastating brain injury. Crigler-Najjar disease is rare in most populations, but a loss-of-function (type I) UGT1A1 mutation is prevalent among the Amish and Mennonite groups of Pennsylvania and the Midwestern United States. While the development of effective phototherapy systems has altered the course of this previously lethal disease [18, 34], CND patients remain vulnerable to brain injury throughout their life span [14], and the high disease incidence within our local Plain commu- nities necessitated the development of a systematic treatment protocol. We report here uniformly good neurological outcomes for all CND patients managed under this protocol over the last 16 years. Patients and methods Patients Twenty CND patients, ages 0.8–21 years, were managed over a 16-year period and represent 200 patient-years of follow-up (Table 1). Over this same time period, we were consulted about additional children (not included in the 20- patient cohort) who suffered kernicterus. Data from these cases are included under the section Case summaries to illustrate various concepts. For the 17 patients from Amish or Mennonite communities, only exon 1 of UGT1A1was sequenced to determine the homozygous 222C→A genotype. For the three remaining patients, all five exons of UGT1A1 were sequenced according to previously described methods [40]. Written informed consent to DNA testing was obtained from the parents of all patients. Clinical management The mainstay of therapy was an overhead array of ten Philips 40 W special blue (BB) fluorescent tubes3. In recent years, two other phototherapy systems were used: portable light emitting diode (LED)-based panels (Stanford PortaBed system [55]) and a custom-made “lightbox” housing 24 fluorescent tubes (combined TL52 and BB). For newborns, a BB- or LED-based light source was placed 10–15 cm from the skin for 15–20 h/day with 60–70% of the body surface exposed. For older children and adults using the BB panel and PortaBed systems, light was positioned 15–30 cm from the skin and delivered at night for 8–12 h with 35–50% of the skin exposed. Mirrors were placed at the sides and head of the bed, and all patients used white sheets. Lightbox therapy was provided for shorter daytime intervals (2–3 h) with about 80% of skin exposed. Ursodiol (15–30 mg/kg/day) and a lipid-rich bedtime snack were used to stimulate bile acid-dependent bile flow and increase hepatic clearance of lumirubin, the water-soluble hepatically-excreted bilirubin photoproduct [21]. Irradiance was measured at the skin surface using three different instruments: the BiliBlanket Meter II (Ohmeda Medical, Laurel, Md.), Joey Dosimeter (Respironics, Pittsburgh, Pa.), and a relatively inexpensive light meter (model LM631, Meterman Test Tools, Everett, Wash.) adapted at Stanford University and calibrated against the BiliBlanket Meter II [55]. The dose of light in watt-hours per nanometer (W-h/nm) was estimated as the product of skin- level irradiance (μW/cm2/nm), surface area exposed (cm2), Table 1 Clinical and biochemical summary of 20 patients with Crigler-Najjar disease Patient information Mean (range) Current age (years) 11 (0.8–21) Age treatment started (days) 6 (2–14) Number of non-surgical hospitalizationsa 1.2 (0–5) Clinical parameters Percentage of patients (n=20) Exchange transfusionb 10 Ursodiol therapy 80 Cholecystectomy 50 Liver transplantation 20 Neurological impairment 0 Visual impairment 0 Biochemical parameters Means, SD (range) Reference range Bilirubin (mg/dl)c 16±5 (7–28) 0.2–1.0 Albumin (g/dl) 4.3±0.3 (3.6–4.7) 3.5–5.2 Bilirubin:albumin (mol:mol) 0.44±0.15 (0.17–0.75) Not applicable Alanine transaminase (IU/l) 75±36 (28–167) 8–50 Alkaline phosphatase (IU/l) 195±68 (38–282) 34–125 γ-Glutamyl transpeptidase (IU/l) 23±21 (14–108) 6–42 aOver 50% of non-surgical hospitalizations were for neonatal hyper- bilirubinemia, the remainder were for infectious illnesses. Overall hospitalization rate was 0.12 hospitalizations per patient per year bExchange transfusions were performed on two patients during the newborn period, before they came under our care in 1989. No exchange procedures were performed within the cohort after 1989 cBilirubin in mg/dl×17.1 = bilirubin in μmol/l; albumin in g/dl×152 = albumin in μmol/l 3 Overhead BB panels were constructed by Floyd Martin under the guidance of DHM. The BiliBlanket II Meter-based light meter and LED-based PortaBed system were designed and constructed by HJV and colleagues. The LED light panel research and development was financed by a grant from the Dutch Crigler-Najjar Association. The upright lightbox was originally designed and built by Alex Carmichael (Australia) utilizing TL52 tubes. A modified BB tube- based lightbox unit, used for this study, was constructed by FM. 307 Hue test [22]. Five of these subjects were from our cohort (ages 11–19 years) and five were managed at the Sophia Children’s Hospital in Rotterdam, The Netherlands (ages 12–18 years). None of the CND patients tested wore eye shields during phototherapy. Three age-matched healthy siblings (ages 13–15 years) were used as controls. Results Diagnosis All seventeen patients of Amish or Mennonite descent were homozygous for a 222C→A mutation in exon 1 of the UGT1A1 gene that resulted in a stop codon (Y74X) and complete absence of transferase activity. Among the remain- ing patients, two had severe phenotypes (with genotypes c. [1069C→T] + [1069C→T] and c. [1305-1G→A] + [877_ 890delinsT]) and one had a milder CN variant (with genotype c. [992A→G] + [992A→G]). Patients for whom records were available began receiving phototherapy at 6±5 days of age, before molecular confirmation of the CND diagnosis. In the newborn period, no patient had evidence of infection, hepatopathy, or hemolysis. Bilirubin rose 3– 6 mg/dl/day4, and the hour-specific bilirubin at presenta- tion was equal to or greater than the 75th percentile for healthy term neonates [6] (Fig. 1a). For high-risk neonates (e.g. sibling affected with CND or parents known to be carriers), mutation detection from cord blood was typically completed within the first 72 h of life. Phototherapy We detected no serious health consequences for individuals exposed to >75,000 lifetime hours of high-intensity blue light. For patients homozygous for the Y74X mutation, phototherapy maintained total bilirubin at a mean value of 16±5 mg/dl (range: 7–28 mg/dl)5 and a bilirubin:albumin molar concentration ratio of 0.44±0.15 (range: 0.17–0.75). Major determinants of individual bilirubin values were the total light dose (irradiance × treated surface area × time)5 and patient age. Despite consistent light dosing, baseline total bilirubin increased at a rate of 0.8 mg/dl/year (r=0.85, Fig. 1b), such that the bilirubin:albumin molar ratio approached 0.7 by age 20 years. Daily illumination time (8–12 h) and percentage body surface treated (35–50%) were similar among children and adults with CND, whereas irradiance varied considerably. Using the Ohmeda BiliBlanket II Meter, an overhead bank with ten fresh 40 W BB tubes irradiated skin with 95– 115 μW/cm2/nm at a distance of 20 cm. The Joey Dosimeter measured considerably higher irradiance values from a common light source at a similar distance (Fig. 2a). For fluorescent BB systems, major determinants of skin- level irradiance were source distance, hours of use (tube “freshness”), and the nature of surrounding materials. Energy output was also influenced by the length (2–foot vs. 4 foot) and number of tubes in the array, their axis of orientation to the body, and tube temperature; irradiance was highest when a large number of 40 W (4-foot) tubes were oriented parallel to the long axis of the body and kept cool by a separate system of fans. Tube irradiance diminished by 35–40% after about 1,200 h (4 months) of use, but this was not visually detectable. Families that used light meters on a regular basis more effectively controlled the many variables influencing light dose. Irradiance provided by the PortaBed (96–105 μW/cm2/ nm) was roughly equivalent to overhead BB light banks. Major advantages of the LED panels were portability, source longevity, and sleep under cover, but the system remains prohibitively expensive at this time. The upright “light box” was most effective, delivering a uniform circumferential irradiance that was 1.5- to 2-fold higher than that achieved with either the overhead BB panel or PortaBed (Fig. 2b). Advantages of the light box system were a high surface area exposure, capacity for a large number of tubes, close proximity of light source to skin, and controlled use of reflective surfaces. Because it constrained the patient during waking hours, it was only practical for about 2 h of use per day. All three systems generated considerable heat, necessitating the use of cooling fans and warranting special attention to patient hydration. Hospitalizations The overall hospitalization rate was 0.12 hospital admis- sions per patient per year, and six patients in the cohort (30%) were never hospitalized. Over 50% of all hospi- talizations were for neonatal hyperbilirubinemia and occurred within the first 2 weeks of life. Remaining hospitalizations were for various non-surgical and surgical indications. The major reason for non-surgical hospitaliza- tion was infectious illness, which was often associated with transiently increased bilirubin and decreased albumin. Daily light dose could be increased in the hospital by adding a second high-intensity unit and increasing expo- sure time to >20 h/day. However, given the high efficacy of home phototherapy units, patients were not hospitalized for any intensification of phototherapy per se, but for intrave- nous albumin therapy, more careful clinical and biochem- ical monitoring, and the treatment of complicating factors 4 Our hospital laboratory routinely reports bilirubin values in mg/dl and albumin in g/dl, whereas other laboratories use units of μmol/l. To interconvert these units: Bilirubin in mg/dl × 17.1 = bilirubin in μmol/l; albumin in g/dl × 152 = albumin in μmol/l. 5 Throughout the manuscript, calculated energy doses are based on direct light meter readings over the spectral range found effective toward photodegrading bilirubin (400–525 nm). This range encompasses the blue light absorption spectrum of bilirubin. These measurements are valid for comparing relative light energies. However, for more precise calculation of total light energy striking a biological material, such as the retina, we use “full width at half max” (FWHM), defined as the spectral width at half-maximal light intensity. This is also called the “bandwidth” and for practical purposes takes into account the Gaussian distribution of energy over the detectable range. 309 (e.g., vomiting, anorexia, dehydration, dysnatremia, etc.). There were no complications of albumin administration, and no patient received plasmapharesis while under our care. Ten of twenty patients (50%) developed cholelithiasis and underwent elective laproscopic cholecystectomy; eight of these patients were being treated with ursodiol prior to developing gallstones. Neurological outcome Serial neurological examinations of CND patients showed no evidence of hearing loss, cranial nerve injury, dystonia, cerebellar dysfunction, gait abnormalities, or peripheral neuromuscular disease. Children and adults with CND had normal intellectual function as assessed by school performance and social interactions. Visual acuity was 20/20–30 in both eyes for non-spectacled CND patients over 5 years of age and, compared to unaffected siblings, CND patients did not have an increased need for corrective lenses. The Farnsworth-Munsell color discrimination error score was 58±11 for CND patients and 39±15 for controls (p=0.39, non-significant), where error scores of <100 are consistent with normal color vision. Liver transplantation Four patients (ages 12, 14, 19, and 19 years) had whole orthotopic liver transplants performed under standard protocol at the Thomas E. Starzl Institute (Pittsburgh, Pa.). Mean post-transplantation follow-up time was 20 months (range: 12–48 months). Total bilirubin was normal within 24 h of allograft perfusion, but staining of skin and sclerae did not resolve completely for 1–2 weeks. The youngest of these patients had significant post- transplant complications, including CMV hepatitis, EBV viremia, acute and chronic allograft rejection, widespread opportunistic infection of the small bowel, and post- transplant lymphoproliferative disease. Case summaries Five clinical cases are grouped by clinical paradigm and briefly summarized. Cases 1, 3, and 5 are patients from the present cohort. Two additional cases (2 and 4) are Amish CND patients from Midwestern states managed elsewhere. Mechanisms of kernicterus are introduced for further discussion (see Figs. 3, 4). Fig. 1 a The rate of rise of bilirubin over the first 96 h of life may be normal in CND patients but continues to rise to dangerous levels by day of life 5. Using the 75th percentile hour-specific bilirubin [6] as a screening cutoff value for pre- dicting severe jaundice (peak bilirubin >17 mg/dl), all of these CND patients would have been identified for targeted follow-up and the early institution of pho- totherapy. b In our CND pa- tients the molar ratio of bilirubin to albumin is elevated from 0.37 to 0.6 during the neonatal peri- od, reaches a nadir by age 4 years, and then rises progres- sively to adulthood at a rate of 0.022 mol:mol/year (r=0.82). This is due to a progressive 0.82 mg/dl/year (range: 0.68– 0.96 mg/dl/year) rise of bilirubin unrelated to patient compliance. Based on the chemistry of bili- rubin-albumin binding in healthy individuals, we assign the “safe” bilirubin:albumin molar ratio at or below 0.7 in older children and adults (de- noted by the dashed line) [8] 310 Type I Crigler-Najjar disease in the newborn period Case 1. Prospective management of CND A Mennonite newborn had a sibling and several cousins homozygous for the Y74X mutation. Phototherapy with an overhead BB light bank was started at home when jaundice was apparent on day of life 3. Cord blood was sent to our clinic for targeted mutation testing, and the diagnosis of CND was confirmed on day of life 6, at which time total bilirubin was 13 mg/dl (222 μmol/l), albumin was 3.7 g/dl (562 μmol/l), and the bilirubin:albumin molar ratio was 0.39. She was managed throughout the first year of life with daily overhead phototherapy and ursodiol (20 mg/kg/day). During that time, total bilirubin ranged from 11.4 to 15.9 mg/dl (194– 270 μmol/l) and the bilirubin:albumin ratio ranged from 0.32–0.47. Growth and development were normal, and she had no hospitalizations. She is now 6 years of age, receiving phototherapy 10 h per day, and healthy. Case 2. Poor neonatal risk assessment, inadequate therapy, and kernicterus In 1997 an Amish infant from the Midwest (not in the 20-patient cohort) was delivered at Fig. 2 a Using two different light meters, the Ohmeda Bili- Blanket Meter II and the Respironics Joey Dosimeter, irradiance measurements were taken at 5-cm increments from an overhead bank of BB tubes (Philips 20 W, 2-foot long) used routinely at a community hos- pital Neonatal Intensive Care Unit (NICU). BB tubes in use were aged, putting out only about 50% of the power pro- vided by fresh tubes, irradiance decreased as a function of dis- tance from the source, and light meters which should yield roughly equivalent values dif- fered by as much as two- to threefold. b The graph displays hourly light power within the 400- to 525-nm bandwidth as the product of skin-level irradi- ance (μW/cm2/nm, BiliBlanket Meter II) and average treatable body surface area with each type of system, estimated for a pa- tient with total body surface area of 1 m2 (10,000 cm2). Because irradiance values from the same source vary considerably using different light meters, the graph displays a relative, rather than absolute, comparison of light power 311 home by a lay midwife. Jaundice was first apparent on day of life 3 but was not measured until he was hospitalized at 14 days of age with lethargy and severe hyperbilirubinemia (48 mg/dl, 821 μmol/l). Liver disease and hemolysis were excluded. Phototherapy decreased total bilirubin to 12 mg/dl over 96 h. He was discharged without phototherapy, and bilirubin again rose to a range of 24–39 mg/dl. He was first examined by us at 7 months of age, and found to be stuporous, irritable, and hypotonic. He had generalized axial dystonia, athetoid movements, poor head control, and feeding impairment. Muscle mass and power were normal, deep tendon reflexes were diminished, and ankle clonus was absent. Babinski reflexes were strongly plantarflexion. Brain stem auditory evoked potentials were absent. A brain MRI showed enlarged cerebrospinal fluid spaces over the frontal and temporal lobes and prominent sulci suggestive of diffuse cortical atrophy. The basal ganglia were normal in size. There were symmetric T2 signal hyperintensities in the internal and external pallidi, nucleus accumbens, substantia nigra, and hypothalamus. At present, he is deaf and has severe generalized dystonia. Hospital management Case 3. Prevention of kernicterus in a CND patient during an infectious illness A 7-year-old Amish girl with CND was admitted to our hospital with streptococcal pharyngitis, fever, vomiting, dehydration, rising total bilirubin (31 mg/dl, 530 μmol/l), and a high bilirubin:albumin molar ratio (0.88). She was managed according to an inpatient protocol (Table 1) over a 70-h period. Continuous phototherapy Fig. 3 Bilirubin in the cerebral circulation is bound to albumin and to a lesser extent red blood cells (RBC). Unbound bilirubin (b) is the fraction that interacts with cerebral membranes, moving continuously between intravascular and extravascular binding sites. Cumulative bilirubin deposition on endothelial membranes interferes with a variety of cellular processes, perhaps by altering the properties of membrane- associated and -embedded proteins such as ion pumps (NaK-ATPase), nutrient transporters (e.g.,GLUT1, LAT1), and metabolic enzymes. The uptake of bilirubin by brain can be expressed by the equation [49]: D = (F)(B)(t)[1 − fe(−k1T)], where D is amount of bilirubin per weight of brain tissue, F is cerebral blood flow, B is total bilirubin concentration (>99% of which is albumin-bound), e is the dimensionless value 2.718, and t is duration of exposure. The last term expresses the relative quantity of bilirubin extracted by the brain for any given total plasma bilirubin value. It depends on the fraction of bilirubin unbound (f) and the dissociation constant of the bilirubin-albumin complex (k1) relative to the transit time of blood moving through brain capillaries (T). Total bilirubin-binding capacity of blood [58] is a function of albumin concentration, the number of high-affinity sites (n) per albumin molecule, and affinity of those sites for bilirubin (Kab = k2/k1); where Kab = [B]/(b[nA−B]). A variety of drugs, preservatives, and endog- enous anions interact with albumin to either reduce the number of high- affinity binding sites (L1) or increase the dissociation rate of the complex (L2; increase k1, decrease Kab). In experimental animals, fractional extraction and brain uptake of bilirubin is invariably 30–50% lower than predicted by this model [59]. This may reflect both the unmeasured effect of erythrocyte binding and the important role of brain endothelial proteins in bilirubin extrusion (e.g. P-glycoprotein, MDR1). Brain bilirubin extrusion matures postnatally and may increase considerably in chronically jaundiced patients 312 (approximately 13 W-h/nm/day), four albumin infusions (2 g/kg/dose), and enteral ursodiol (30 mg/kg/day) lowered the bilirubin:albumin molar ratio to 0.57. She recovered uneventfully. Case 4. Acute kernicterus during an infectious illness in a patient with CND An Amish boy with CND (not in the 20- patient cohort) had chronic bilirubin levels of 15–25 mg/dl receiving 6–12 h of phototherapy per day. Albumin levels were not monitored. Bilirubin levels periodically increased to 25–35 mg/dl during illnesses. Growth and development were normal. At 7 years of age he developed streptococcal pharyngitis and was prescribed amoxicillin as an outpatient. The following day his speech became slurred and he stopped eating. Four days later he presented to a Midwestern hospital deeply jaundiced, stuporous and mute, unable to swallow or stand, and febrile. Deep tendon reflexes were increased, he had ankle clonus, and Babinski reflexes were plantarflexion. Total bilirubin was 39 mg/dl (667 μmol/l), albumin was 2.9 g/dl (441 μmol/l), and the bilirubin:albumin ratio was 1.51. Serum chemistries were normal, including glucose (97 mg/dl), bicarbonate (26 mEq/l), and blood urea nitrogen (4 mg/dl). An EEG showed diffuse slowing and paroxysms of generalized polyspike activity. A brain MRI was normal. At the Midwestern hospital, he was managed with contin- uous phototherapy, intravenous crystalloid, albumin, and phenobarbital. The bilirubin level decreased to his baseline value, but neurological function did not improve. He died at home a few weeks later. Liver transplantation Case 5. Liver transplant in a 19-year-old Mennonite man with CND and increasing bilirubin levels The first of our patients to undergo a liver transplant had total bilirubin levels that ranged from 23 to 29 mg/dl (molar ratio to albumin: 0.7–0.9) despite rigid compliance with photo- therapy, treatment with ursodiol, and cholecystectomy at age 18 years. Post-transplant, the bilirubin decreased to normal within 48 h, but yellow discoloration of the skin and sclera persisted for 2 weeks. Liver explant showed portal tract fibrosis, inflammation, ductal proliferation, and patchy bridging fibrosis. Crystallized plugs of biliru- bin were seen in small degenerating ductules. Centrolob- ular hepatocytes showed focal hepatocellular giant cell transformation, pseudoacinar formation, leathery degen- eration, and cholestasis. Discussion Diagnosis and management of CND in the newborn period Our data demonstrate that CND patients can be detected by universal screening procedures for neonatal hyperbiliru- binemia [1, 5, 30] (Fig. 1a). Whether or not a jaundiced newborn has CND does not change their basic need for timely detection and effective treatment; in all of our patients phototherapy was started well before molecular confirmation of the diagnosis (Case 1). Thus, brain injury in neonates with CND does not result from delayed di- agnosis per se, but from poor recognition and inadequate treatment of “idiopathic” neonatal hyperbilirubinemia (Case 2). CND patients can be managed safely to prevent death and disability Table 3 compares our study to various population measures from five previously published clinical surveys. Crigler and Najjar’s classic description preceded the advent of effective phototherapy, and all of their patients developed brain injury and eventually died [19]. The combined data from four recent surveys [37, 52–54] suggest that 23–42% of CND patients suffer neurological injury ranging from mild to severe, 28–50% of patients will need one or multiple exchange transfusions, and 9–38% die of complications related to the disease. In contrast, we had no brain injuries or deaths extending over 200 patient-years and did not perform a single exchange procedure since we began caring for children with CND in 1989. Long-term biochemical data suggest that liver transplantation or some other curative procedure may ultimately be necessary to manage CND patients safely (Fig. 1b, Case 5). Nevertheless, a systematic Fig. 4 In vitro studies [8] show a progressive rise in free bilirubin when the bilirubin:albumin molar ratio exceeds 0.7 (dotted line) and a sharp rise in free bilirubin when the ratio exceeds 1.0 (i.e., sat- uration, dashed line). Maximum bilirubin:albumin molar ratio was recorded during 19 hospitalizations of our CND patients with transient exacerbation of hyperbilirubinemia (open circles). None of these patients developed kernicterus. From our consultation records and published cases, we found 11 cases of brain injury in patients for whom bilirubin and albumin values were available (solid circles). Maximum recorded bilirubin:albumin molar ratio was significantly higher in patients that developed kernicterus (1.37±0.04 vs. 0.76± 0.07, p<0.0001) 313 approach to neonatal screening, light dosing, and kernicterus prevention can assure that children and adults proceed to transplantation in good neurological health. Providing effective phototherapy Effective phototherapy for any patient requires education of health care providers and parents, phototherapy systems that are in good working order, a supply of fresh BB tubes or an energetic equivalent (e.g., TL52s, LEDs), and the use of calibrated and affordable light meters [56]. Variables that influence light dose can be monitored intermittently by a nurse, physician, or parent, and allow patients to derive adequate phototherapy from a variety of sources in the hospital or at home. To be meaningful in terms of efficacy, a phototherapy order should specify light source and number, distance from the patient’s skin, and nature of surrounding materials (e.g., white sheets and mirrors), with a goal to achieve a measured irradiance over a percentage of skin surface for a specified period of time. A physician’s order for phototherapy in “hours per day” is incomplete, and an order for “double” or “triple” phototherapy is uninformative. One good light is usually sufficient, provided it is used correctly. Surprisingly, many hospital practices use phototherapy systems without regularly monitoring or recording their performance. Data in Fig. 2a was obtained from a 20 W fluorescent BB system in use at the NICU of a local community hospital. It revealed visually imperceptible aging of the tubes. In hospital settings, tubes may only be replaced when they no longer function, such that phototherapy systems operate for long periods emitting well below their energy potential. Furthermore, fluorescent devices are often fitted (1:1) with cool-white bulbs to attenuate the blueness of BB light; this makes the system less effective. Figure 2a also shows that despite measurement within a similar bandwidth and peak sensitivity, irradiance readings from different commercial light meters can vary as much as two- to threefold, while all meters show the decay of energy as a function of distance from the light source. Light power calculations also demonstrate the comparatively low efficacy of fiber-optic blankets and halogen-quartz spotlights, which are inappropriate for managing patients with CND or severe idiopathic jaundice (Fig. 2b). These observations have several practical implications: (1) light meter(s) in use at any facility should be calibrated at a determined distance against each phototherapy system operating at maximum output; (2) any light source should be placed as close to the skin as possible; (3) phototherapy systems should be accompanied by a tag or logbook that records the date of bulb/tube replacements and peak irradiance measurement with fresh lights at a standardized distance; (4) for an infant who genuinely needs phototherapy, home treatment with a fiberoptic blanket is inappropriate. Other factors reduce the dose of light achieved with a given source, including plexiglass barriers, pigmented (light- absorbing) materials, and objects that shield the skin. We find that isolettes are not necessary for well-hydrated term or near-term infants receiving phototherapy. In neonates, the thorax, outer arms, and head constitute the majority of Table 3 Historical trends in Crigler-Najjar disease (NR not reported, NA not applicable) Reference Year of publication Number of Patients Age in years mean, standard deviation (range) Bilirubin (mg/dl) mean, standard deviation (range) Exchange transfusion (%) Brain damage (%) Mortality (%) Liver transplant (%) Transplant age, mean (range) Crigler and Najjar [19]a 1952 6 (0.05–0.9) 24.5 (12.6–44.8) 0 100 100 0 NA van der Veere et al. [54]b 1996 57 6.9±6.0 (4.2–42.5) NR 26 9 37 9.1 (1–23) Suresh and Lucey [53]c 1997 42 (<1–21) 20.5±5.5 28 23 0 36 (2.5–16) Shevel [52]d 1998 63 NR NR NR 59 NR NR NA Nazer [37]e 1998 12 NR 23.7 (15–37) 50 42 38 17 NR Present studyf 2005 20 1±6 16±5 (7–28) 0 0 0 20 16 (12–19) aCrigler and Najjar’s original report preceded the advent of exchange transfusion and phototherapy bBrain injured patients (n=8) were transplanted later (14.3±5.9 years) than those without brain damage (n=13, 5.9±5.4 years) cInformation is compiled from an international questionaire involving patients from four continents. There is patient overlap with other studies, including our Amish cohort (12 of the 42 patients reported). In the non-Amish subgroup, neurological disability was present in 9 of 30 patients (30%). Mean ± standard deviation bilirubin values (in mg/dl) varied by sub-group: neonatal peak, 26.6±5.8; neonatal typical, 19.8±4.5; postnatal typical, 20.5±5 dThe 59% incidence of neurological injury is based on an extensive review of 37 published articles (1952–1997) by these authors, who further subdivided adverse outcomes into four discrete patterns of disability eInformation from 5 affected siblings, not included in the 12-patient cohort, is included in the paper by Nazer et al. All 5 died with bilirubin- induced brain injury, resulting in a total brain injury rate of 10/17 (59%) and a disease-related mortality of 38%. Four patients required more than one exchange transfusion, for a total of 13 exchange procedures among 6 of the 12 patients reported fPrior to coming under our care, two patients in the cohort required exchange transfusion as neonates, and one patient developed kernicterus. However, the outcomes reported here were observed for patients under our care from 1989 to the present 314 treatable skin surface, these but may be obscured by unnecessary diapers, monitor leads, and IV boards. We place term newborns with CND in an open crib, naked, lying on an open diaper over bright white sheets. With a BB or LED system placed 10–15 cm from the skin, the newborns appear comfortable, feed well, and maintain core body temperatures of 99°–100°F. Anticipating and preventing kernicterus Patients with all variants of CND remain vulnerable to brain injury throughout life, particularly during intercurrent illnesses, after injuries, or during surgery (Case 4). Routine laboratory measurements can only be used to estimate the magnitude of the whole body bilirubin load and its rate of change, but for any individual patient a variety of other clinical and physiological details more fully characterize the potential for brain injury (Figs. 3, 4). These multiple factors vary from one individual to the next and in a single individual depending on age and clinical conditions. It is thus impractical and misleading to assign rigid guidelines for identifying patients “at risk” for kernicterus. Rather, we base treatment decisions on general biochemical indices con- sidered together with particulars of time and circumstance. Our treatment protocol in Table 2 is based on the pathophysiologic model illustrated in Fig. 3 [3, 12, 39, 49, 58, 59] and is designed to lower total body exchangeable bilirubin and prevent its movement to extravascular sites. In jaundiced infants and adults, the total body bilirubin pool is very large and almost exclusively bound to proteins and lipid membranes, while the lower unbound bilirubin concentra- tion [2, 3] is characterized by continual flux between two competing reservoirs – a finite number of intravascular binding sites and a much larger number of lower-affinity sites on endothelia of brain and other organs. As bilirubin passes through the circulation, the fraction deposited in the brain and other tissues depends only on its molar relationship with high-affinity albumin binding sites and the dissociation rate of the bilirubin-albumin complex relative to the time it takes blood to transit a tissue capillary bed [49, 58]. According to this model, when high-affinity bilirubin binding sites on albumin approach saturation, or are occupied by competing ligands, bilirubin can shift rapidly from intravascular to tissue binding sites (Fig. 3). In clinical practice, the most important factor affecting bilirubin-albumin binding is the presence of organic anions which either compete directly for the bilirubin binding site or allosterically reduce its affinity for bilirubin [58]. Numerous exogenous and endogenous organic anions interfere with bilirubin-albumin binding, including intravenous and oral medications, drug metabolites pro- duced in vivo, commonly used preservatives, and endog- enous organic acids and free fatty acids. Drugs which generally do not interfere with the binding equilibrium are cationic, glycosylated, or present in blood at protein- bound concentrations of <15 μmol/l [47]. The number and complexity of bilirubin-albumin-drug interactions under- scores the point that all medications and intravenous solutions should be used cautiously in patients with hyperbilirubinemia, and only after a focused review of drug information in the Physicians’ Desk Reference, medical literature, and/or a comprehensive pharmacology text. Based on available resources [3, 4, 7, 9–11, 13, 17, 20, 23, 24, 26–29, 32, 35, 38, 42–47, 57, 58], we compiled a list of commonly used drugs, infusible substances, and endogenous metabolites in the Appendix. Drugs are listed based on probable safety for use in hyperbilirubin- emic patients. However, it is important to recognize that in vitro studies are not a perfect predictor of drug-albu- min-bilirubin in living patients. For example, drugs in the “variable safety” column show weak displacing activity in vitro which may become clinically significant under certain circumstances. For these compounds, lower dosing and slower infusion rates minimize displacing potential. Important clinical drugs for which no data are available are listed to guide further studies in this important area. Caring for the aging CND population Adolescence is a particularly important period of vulner- ability for kernicterus in patients with CND. As patients mature, phototherapy increasingly interferes with lifestyle, social opportunities, and the formation of intimate relation- ships. Baseline total bilirubin increases with age and approaches dangerous levels in young adulthood (Fig. 1b, Case 5). Contrary to other studies [53, 54], we could not identify a relationship between age and compliance with phototherapy as a plausible explanation. The progressive rise in bilirubin is likely influenced by several physiolog- ical variables. First, “treatable” body surface area decreases relative to bilirubin volume of distribution as patients age (i.e., plasma in the cutaneous vascular bed accessible with light represents a progressively smaller proportion of total extracellular volume and distributed blood flow). Second, bilirubin distributes to peripheral extravascular binding sites over time, creating a large tissue “reservoir” in equi- librium with the intravascular pool. Evidence of this was found in all four transplanted patients, in whom cutaneous and scleral icterus took up to 2 weeks to dissipate following liver transplantation, despite normal bilirubin levels within 24–48 post-operative hours. Finally, hepatobiliary clear- ance of lumirubin may become rate-limiting in some patients, as evidenced by cholestatic changes in two of four liver explants. Whatever the causes of rising bilirubin with age, it is apparent that most of our CND patients will face liver transplantation over the next 5–10 years. Liver transplanta- tion is currently the only clinically robust way to replace UGT1A1 and hepatic transferase activity [51]. Viral and non- viral gene transfection techniques are far from human trials, and when these methods reach clinical maturity they may not be safer, cheaper, or even more effective than liver trans- plantation. Fortunately, there is now considerable experience with liver transplantation for primary metabolic disorders as well as reductions in peri-operative mortality and medica- tion-related morbidity over recent years [33, 41, 51]. How- 315 ever, Patient 7 from our cohort suffered life-threatening post- transplant complications. Thus, despite its metabolic ef- ficacy, liver transplantation is not an easy solution for patients with CND. Conclusion: lessons learned from CND Timely recognition of hyperbilirubinemia followed by effective phototherapy makes exchange transfusions and prolonged hospitalizations unnecessary. The core principles of management for neonates with idiopathic hyperbilirubin- emia should be the same as those for CND: pre-symptomatic detection, timely risk assessment, scheduled follow-up monitoring, phototherapy guided by measurements of light power, treatment of maximum body surface, and the use of emergency protocols that emphasize bilirubin biodistribu- tion (Table 2, Figs. 1a, 2a, 3, 4) [1]. A precise formulation of kernicterus mechanisms remains obscure, but a great deal is known about bilirubin, its distribution in the body, and interaction with the brain. We believe this knowledge is sufficient to prevent brain injury in most, if not all, jaundiced patients. The most significant obstacle to the prevention of kernicterus is not scientific ignorance, but inadequate education of parents and health care providers, and a failure to translate established concepts into practice [5, 16, 25, 36, 48]. Acknowledgements We extend thanks to CND patients and their parents from our local community for their support of this work and their hopes for future progress. We thank the outstanding nursing, pharmacology, and biomedical engineering staffs at Lancaster General Hospital for providing patients exceptional clinical care. Floyd and Katie Martin were instrumental in gathering light measurements in the field and Tim Weaver, M.D., helped gather data for Fig. 2. Special thanks to Charles E. Ahlfors, M.D., for a technical review and helpful comments. Finally, thank you to the Dutch Crigler-Najjar Association (Huizen, The Netherlands), for funding development of the PortaBed LED system. Appendix Potential bilirubin-albumin displacing interactions (see text for references) SAFETY CLASS (see Note) 1 2 3 4 ANTI-INFLAMMATORY/ANTIPYRETIC Acetaminophen • Aspirin • Dexamethasone • Ibuprofen • Indomethacin • Ketorolac • Naproxen • Phenacetin • Prednisolone • SAFETY CLASS (see Note) 1 2 3 4 Salicylate, sodium • ANTIMICROBIAL Acyclovir • Amoxicillin • Amoxicillin-Clavulanate • Amphotericin B • Amphotericin, liposomal Ampicillin • Ampicillin-Sulbactam • Azithromycin Azlocillin • Aztreonam • Carbenicillin • Cefazolin • Cefalothin • Cefepime • Cefixime • Cefmetazole • Cefonicid • Cefoperazone • Ceforanide • Cefotaxime • Cefotetan • Cefoxitin • Cefpodoxime proxetil • Ceftazidime • Ceftizoxime • Ceftriaxone • Cefuroxime • Cefuroxime axetil • Cephalexin • Cephapirin • Cephradine • Ciprofloxacin • Clarithromycin • Clindamycin • Dicloxacillin • Doxycycline • Erythromycin • Erythromycin ES-sulfisoxazole • Fusidic acid • Gangcyclovir • Gentamicin • Imipenem • Imipenem-cilastatin • Isoniazid • Levofloxacin • Lincomycin • Linezolid • Meropenem • Methicillin • Metronidazole • Minocycline • 316 SAFETY CLASS (see Note) 1 2 3 4 Nafcillin • Nitrofurantoin • Oxacillin • Penicillin G • Penicillin V • Piperacillin • Piperacillin-Tazobactam • Rifampin • Streptomycin • Sulfisoxazole • Sulphamethoxazole • Sulphasalazine • Tobramycin • Trimethoprim • Trimethoprim-Sulfa (Bactrim) • Vancomycin • CARDIOVASCULAR DRUGS Atropine • Bretylium tosylate • Digoxin • Disopyramide • Dobutamine • Dopamine • Edrophonium chloride • Enalapril • Epinephrine • Hydralazine • Isoproterenol • Lidocaine • Nitroprusside • Procainamide • Propanalol • Verapamil • CONTRAST AGENTS Diatrizoate sodium • Iodate sodium • Iodipamide sodium • Iopanoic acid • Meglumin ioglycamate • Metrizamide • Metrizoate sodium • DIURETICS Acetazolamide • Bumetanide • Chlorothiazide • Ethacrynic acid • Furosemide • Hydrochlorothiazide • Mannitol • Spironolactone • NEUROACTIVE DRUGS Aminophylline • Amitryptyline HCl • SAFETY CLASS (see Note) 1 2 3 4 Atomoxetine • Bupropion • Carbamazepine • Chloral hydrate • Clonazepam • Codeine • Desipramine HCl • Diazepam • Ethosuximide • Etomidate • Fentanyl • Fluoxetine/Norfluoxetine • Inhaled anesthetics • Imipramine HCl • Ketamine • Lorazepam • Meperidine • Methylphenidate • Midazolam • Morphine • Naloxone • Nortryptyline • Olanzapine • Oxazepam • Paroxetine • Phenobarbital • Phenytoin • Primidone • Propofol • Risperidone • Theophylline • Thiopental • Valproic acid • Venlafaxine • NEUROMUSCULAR BLOCKING AGENTS Neostigmine • Pancuronium • Rocuronium • Succinylcholine • Vecuronium • PRESERVATIVES/METABOLITES [a] N-acetyl-DL-tryptophan • N-acetyltyrosine • Benzoic acid (benzoate sodium) • Caprylic acid • Hippurate (from benzoic acid) 2-Hyroxybenzoylglycine • MISCELLANEOUS Bicarbonate • Calcium chloride • Calcium gluconate • Carnitine • Clofibrate • 317 SAFETY CLASS (see Note) 1 2 3 4 Heparin • Intralipid/free fatty acids [b] • Magnesium sulfate • Prostaglandin E1 • Tin mesoporphyrin • 1 Probably SAFE for clinical use 2 Considered UNSAFE 3 Safety variable: eg. drug dosing and combinations 4 Insufficient data a) acetyltryptophan (stabiliser in HSA I), acetyltyrosine (component of some TPN amino acid mixtures), caprylic acid, hexanoic acid (stabiliser in HSA I and II) b) plasma free fatty acids are increased by fasting and infusions of intralipid, epinephrine, or heparin References 1. American Academy of Pediatrics, Subcommittee on Hyper- bilirubinemia (2004) Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114:297–316 2. Ahlfors CE, Herbsman O (2003) Unbound bilirubin in a term newborn with kernicterus. Pediatrics 111:1110–1112 3. Ahlfors CE, Wennberg RP (2004) Bilirubin-albumin binding and neonatal jaundice. Semin Perinatol 28:334–339 4. Andersen DH, Blanc WA, Crozier DN, Silverman WA (1956) A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibac- terial regimens. Pediatrics 18:614–625 5. Bhutani VK, Donn SM, Johnson LH (2005) Risk management of severe neonatal hyperbilirubinemia to prevent kernicterus. Clin Perinatol 32:125–139 6. Bhutani VK, Johnson L, Sivieri EM (1999) Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 103:6–14 7. Brodersen R (1978) Determination of the vacant amount of high-affinity bilirubin binding site on serum albumin. Acta Pharmacol Toxicol 42:153–158 8. Brodersen R (1979) Bilirubin. Solubility and interaction with albumin and phospholipid. J Biol Chem 254:2364–2369 9. Brodersen R, Ebbesen F (1983) Bilirubin-displacing effect of ampicillin, indomethacin, chlorpromazine, gentamicin, and parabens in vitro and in newborn infants. J Pharm Sci 72: 248–253 10. Brodersen R, Funding L (1977) Binding of bilirubin and long- chain fatty acids to human serum albumin with general remarks on displacement of firmly bound ligands. Scand J Clin Lab Invest 37:257–266 11. Brodersen R, Friis-Hansen B, Stern L (1983) Drug-induced displacement of bilirubin from albumin in the newborn. Dev Pharmacol Ther 6:217–229 12. Cashore WJ (1998) Bilirubin metabolism and toxicity in the newborn. In: Polin RA, Fox WW (eds) Fetal and neonatal physiology. W.B. Saunders, Philadelphia, pp 1493–1498 13. Cashore WJ, Oh W, Brodersen R (1983) Bilirubin-displacing effect of furosemide and sulfisoxazole. An in vitro and in vivo study in neonatal serum. Dev Pharmacol Ther 6:230–238 14. Chalasani N, Chowdhury NR, Chowdhury JR, Boyer TD (1997) Kernicterus in an adult who is heterozygous for Crigler- Najjar syndrome and homozygous for Gilbert-type genetic defect. Gastroenterology 112:2099–2103 15. Chowdhury JR, Wolkoff AW, Chowdhury NR, Arias IM (2001) Hereditary jaundice and disorders of bilirubin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3063–3101 16. Christakis DA, Rivara FP (1998) Pediatricians’ awareness of and attitudes about four clinical practice guidelines. Pediatrics 101:825–830 17. Cooper-Peel C, Brodersen R, Robertson A (1996) Does ibuprofen affect bilirubin-albumin binding in newborn infant serum? Pharmacol Toxicol 79:297–299 18. Cremer RJ, Perryman PW, Richards DH (1958) Influence of light on the hyperbilirubinaemia of infants. Lancet 1:1094– 1097 19. Crigler JF Jr, Najjar VA (1952) Congenital familial nonhemo- lytic jaundice with kernicterus. Pediatri 10:169–180 20. Ebbesen F, Brodersen R (1982) Comparison between two preparations of human serum albumin in treatment of neonatal hyperbilirubinaemia. Acta Paediatr Scand 71:85–90 21. Ennever JF (1998) Phototherapy for neonatal jaundice. In: Polin RA, Fox WW (eds) Fetal and neonatal physiology. W.B. Saunders, Philadelphia, pp 1505–1520 22. Farnsworth D (1943) The Farnsworth-Munsell 100 hue dichotomous tests for colour vision. J Opt Soc Amer 33:1–586 23. Fink S, Karp W, Robertson A (1987) Ceftriaxone effect on bilirubin-albumin binding. Pediatrics 80:873–875 24. Fink S, Karp W, Robertson A (1988) Effect of penicillins on bilirubin-albumin binding. J Pediatr 113:566–568 25. Gartner LM, Herrarias CT, Sebring RH (1998) Practice patterns in neonatal hyperbilirubinemia. Pediatrics 101:25–31 26. Guentert TW, Frey BM, Luedin E, Heinzl S, Brodersen R (1990) Increase of plasma nonesterified fatty acid concentration and decrease of albumin binding affinity after intravenous injection of glycocholate-lecithin mixed micelles. J Lab Clin Med 116:66–75 27. Honore B, Brodersen R (1984) Albumin binding of anti- inflammatory drugs. Utility of a site-oriented versus a stoi- chiometric analysis. Mol Pharmacol 25:137–150 28. Ivarsen R, Brodersen R (1989) Displacement of bilirubin from adult and newborn serum albumin by a drug and fatty acid. Dev Pharmacol Ther 12:19–29 29. Jarnerot G, Andersen S, Esbjorner E, Sandstrom B, Brodersen R (1981) Albumin reserve for binding of bilirubin in maternal and cord serum under treatment with sulphasalazine. Scand J Gastroenterol 16:1049–1055 30. Johnson LM, Bhutani VK, Brown AK (2002) System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 140:396–403 31. Kinney HC, Armstrong DD (2002) Perinatal neuropathology. In: Graham DI, Lantos PL (eds) Greenfield’s neuropathology. Arnold, London, p 519–606 32. Krukow N, Brodersen R (1972) Toxic effects in the Gunn rat of combined treatment with bilirubin and orotic acid. Acta Paediatr Scand 61:697–703 33. Kuang AA, Rosenthal P, Roberts JP, Renz JF, Stock P, Ascher NL, Emond JC (1996) Decreased mortality from technical failure improves results in pediatric liver transplantation. Arch Surg 131:887–892; discussion 892–883 34. Lucey JF (1968) The future demise of exchange transfusions for neonatal hyperbilirubinemia. Dev Med Child Neurol 10:521–522 35. Martin E, Fanconi S, Kalin P, Zwingelstein C, Crevoisier C, Ruch W, Brodersen R (1993) Ceftriaxone-bilirubin-albumin interactions in the neonate: an in vivo study. Eur J Pediatr 152:530–534 36. Meropol SB, Luberti AA, De Jong AR, Weiss JC (1993) Home phototherapy: use and attitudes among community pediatri- cians. Pediatrics 91:97–100 37. Nazer H, Al-Mehaidib A, Shabib S, Ali MA (1998) Crigler- Najjar syndrome in Saudi Arabia. Am J Med Genet 79:12–15 318 38. Ostrea EM, Jr., Bassel M, Fleury CA, Bartos A, Jesurun CA (1983) Influence of free fatty acids and glucose infusion on serum bilirubin and bilirubin binding to albumin: clinical implications. J Pediatr 102:426–432 39. Park WS, Chang YS, Chung SH, Seo DW, Hong SH, Lee M (2001) Effect of hypothermia on bilirubin-induced alterations in brain cell membrane function and energy metabolism in newborn piglets. Brain Res 922:276–281 40. Puffenberger EG, Hu-Lince D, Parod JM, Craig DW, Dobrin SE, Conway AR, Donarum EA, Strauss KA, Dunckley T, Cardenas JF, Melmed KR, Wright CA, Liang W, Stafford P, Flynn CR, Morton DH, Stephan DA (2004) Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function. Proc Natl Acad Sci USA 101:11689–11694 41. Rand EB, Olthoff KM (2003) Overview of pediatric liver transplantation. Gastroenterol Clin North Am 32:913–929 42. Rasmussen LF, Ahlfors CE, Wennberg RP (1978) Displace- ment of bilirubin from albumin by indomethacin. J Clin Pharmacol 18:477–481 43. Rasmussen LF, Ahlfors CE, Wennberg RP (1976) The effect of paraben preservatives on albumin binding of bilirubin. J Pediatr 89:475–478 44. Robertson A, Brodersen R (1983) Effect of lactate, pyruvate, acetone, acetoacetate, and beta-hydroxybutyrate on albumin binding of bilirubin. J Pediatr 102:433–438 45. Robertson A, Brodersen R (1991) Effect of drug combinations on bilirubin-albumin binding. Dev Pharmacol Ther 17:95–99 46. Robertson A, Fink S, Karp W (1988) Effect of cephalosporins on bilirubin-albumin binding. J Pediatr 112:291–294 47. Robertson A, Karp W, Brodersen R (1991) Bilirubin displacing effect of drugs used in neonatology. Acta Paediatr Scand 80:1119–1127 48. Robertson AF, Baker JP (2005) Lessons from the past. Semin Fetal Neonatal Med 10:23–30 49. Robinson PJ, Rapoport SI (1987) Binding effect of albumin on uptake of bilirubin by brain. Pediatrics 79:553–558 50. Roger C, Koziel V, Vert P, Nehlig A (1995) Mapping of the consequences of bilirubin exposure in the immature rat: local cerebral metabolic rates for glucose during moderate and severe hyperbilirubinemia. Early Hum Dev 43:133–144 51. Schauer R, Stangl M, Lang T, Zimmermann A, Chouker A, Gerbes AL, Schildberg FW, Rau HG (2003) Treatment of Crigler-Najjar type 1 disease: relevance of early liver trans- plantation. J Pediatr Surg 38:1227–1231 52. Shevell MI, Majnemer A, Schiff D (1998) Neurologic perspectives of Crigler-Najjar syndrome type I. J Child Neurol 13:265–269 53. Suresh G, Lucey JF (1997) Lack of deafness in Crigler-Najjar syndrome type 1: a patient survey. Pediatrics 100:E9 54. van der Veere CN, Sinaasappel M, McDonagh AF, Rosenthal P, Labrune P, Odievre M, Fevery J, Otte JB, McClean P, Burk G, Masakowski V, Sperl W, Mowat AP, Vergani GM, Heller K, Wilson JP, Shepherd R, Jansen PL (1996) Current therapy for Crigler-Najjar syndrome type 1: report of a world registry. Hepatology 24:311–315 55. Vreman HJ, Wong RJ, Murdock JR, Stevenson DK (2003) In vitro efficacy of an LED–based phototherapy device (Neo- BLUE™) compared to traditional light sources. Pediatr Res 53:400A 56. Vreman HJ, Wong RJ, Stevenson DK (2004) Phototherapy: current methods and future directions. Semin Perinatol 28:326– 333 57. Wadsworth SJ, Suh B (1988) In vitro displacement of bilirubin by antibiotics and 2-hydroxybenzoylglycine in newborns. Antimicrob Agents Chemother 32:1571–1575 58. Walker PC (1987) Neonatal bilirubin toxicity. A review of kernicterus and the implications of drug-induced bilirubin displacement. Clin Pharmacokinet 13:26–50 59. Wennberg RP (2000) The blood-brain barrier and bilirubin encephalopathy. Cell Mol Neurobiol 20:97–109 319 Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease Abstract Introduction Patients and methods Patients Clinical management Vision testing Results Diagnosis Phototherapy Hospitalizations Neurological outcome Liver transplantation Case summaries Type I Crigler-Najjar disease in the newborn period Case 1. Prospective management of CND Case 2. Poor neonatal risk assessment, inadequate therapy, and kernicterus Hospital management Case 3. Prevention of kernicterus in a CND patient during an infectious illness Case 4. Acute kernicterus during an infectious illness in a patient with CND Liver transplantation Case 5. Liver transplant in a 19-year-old Mennonite man with CND and increasing bilirubin levels Discussion Diagnosis and management of CND in the newborn period CND patients can be managed safely to prevent death and disability Providing effective phototherapy Anticipating and preventing kernicterus Caring for the aging CND population Conclusion: lessons learned from CND Appendix Potential bilirubin-albumin displacing interactions (see text for references) References << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (None) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (ISO Coated) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.3 /CompressObjects /Off /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJDFFile false /CreateJobTicket false /DefaultRenderingIntent /Perceptual /DetectBlends true /ColorConversionStrategy /sRGB /DoThumbnails 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