History

Fact Explanation
Yellowish discoloration of skin and sclera. (it is present at birth in type 1 disease, whereas in type 2 disease the infant is healthy at birth and jaundice may present later in life.) It occurs due to deposition of bilirubin in these tissues as a result of high serum levels of unconjugated bilirubin. The disease is caused by an absence (type 1) or strong reduction (type 2) of the activity of the hepatic enzyme bilirubin UDP glucuronosyltransferase. This enzyme is needed for the conjugation of bilirubin in the liver, which is essential for efficient biliary excretion of bilirubin [1].
Consanguinity among parents and/or a family history of severe jaundice. The disease has an autosomal recessive inheritance pattern [2].
Confusion, lethargy and other features of encephalopathy (it occurs in the second week of life in type 1 disease. Although jaundice may not be apparent in type 2 disease, kernicterus may occur.) Free unconjugated bilirubin exhibits toxicity particularly to neuronal cells. All known toxic effects of bilirubin are abrogated by binding to albumin. Cerebral toxicity (kernicterus) from bilirubin occurs when the molar ratio between bilirubin and albumin exceeds 1.0. Bilirubin toxicity is usually seen in patients with Crigler–Najjar syndrome at all ages [3].
References
  1. SEPPEN J, BOSMA P J, GOLDHOORN B G, BAKKER C T, CHOWDHURY J R, CHOWDHURY N R, JANSEN P L, OUDE ELFERINK R P. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase.. J. Clin. Invest. [online] 1994 December, 94(6):2385-2391 [viewed 06 October 2014] Available from: doi:10.1172/JCI117604
  2. RITTER J K, YEATMAN M T, FERREIRA P, OWENS I S. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient.. J. Clin. Invest. [online] 1992 July, 90(1):150-155 [viewed 06 October 2014] Available from: doi:10.1172/JCI115829
  3. WANG XIA, CHOWDHURY JAYANTA ROY, CHOWDHURY NAMITA ROY. Bilirubin metabolism: Applied physiology. Current Paediatrics [online] 2006 February, 16(1):70-74 [viewed 06 October 2014] Available from: doi:10.1016/j.cupe.2005.10.002

Examination

Fact Explanation
Jaundice. It occurs due to deposition of bilirubin in these tissues as a result of high serum levels of unconjugated bilirubin. The disease is caused by an absence or strong reduction of the activity of the hepatic enzyme bilirubin UDP glucuronosyltransferase. This enzyme is needed for the conjugation of bilirubin in the liver, which is essential for efficient biliary excretion of bilirubin [1].
Hypotonia, deafness, oculomotor palsy, etc. Free unconjugated bilirubin exhibits toxicity particularly to neuronal cells. All known toxic effects of bilirubin are abrogated by binding to albumin. Cerebral toxicity (kernicterus) from bilirubin occurs when the molar ratio between bilirubin and albumin exceeds 1.0. Bilirubin toxicity is usually seen in patients with Crigler–Najjar syndrome at all ages [2].
Absence of features of anemia or evidence of splenomegaly. These features may occur in diseases of ineffective erythropoiesis such as thalassemia, where jaundice is an associated feature [3]. Therefore absence of these features would rule out diseases of ineffective erythropoiesis as a cause.
Absence features such as tremor, increased sweating, etc. These features occur in thyrotoxicosis where jaundice is an associated feature [4]. Therefore absence of these features would rule out thyrotoxicosis as a cause.
References
  1. SEPPEN J, BOSMA P J, GOLDHOORN B G, BAKKER C T, CHOWDHURY J R, CHOWDHURY N R, JANSEN P L, OUDE ELFERINK R P. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase.. J. Clin. Invest. [online] 1994 December, 94(6):2385-2391 [viewed 06 October 2014] Available from: doi:10.1172/JCI117604
  2. WANG XIA, CHOWDHURY JAYANTA ROY, CHOWDHURY NAMITA ROY. Bilirubin metabolism: Applied physiology. Current Paediatrics [online] 2006 February, 16(1):70-74 [viewed 06 October 2014] Available from: doi:10.1016/j.cupe.2005.10.002
  3. GHONE RAHUL A., KUMBAR K. M., SURYAKAR A. N., KATKAM R. V., JOSHI N. G.. Oxidative stress and disturbance in antioxidant balance in beta thalassemia major. Indian J Clin Biochem [online] December, 23(4):337-340 [viewed 06 October 2014] Available from: doi:10.1007/s12291-008-0074-7
  4. BAL C, CHAWLA M. Hyperthyroidism and Jaundice Indian J Nucl Med [online] 2010, 25(4):131-134 [viewed 06 October 2014] Available from: doi:10.4103/0972-3919.78244

Differential Diagnoses

Fact Explanation
Gilbert's syndrome. Here, hepatic bilirubin UDP glucuronosyltransferase is decreased to about 30% of normal. Therefore it also presents with jaundice. however, since the bilirubin concentration fluctuates in Gilbert's syndrome, patients often present with intermittent episodes of jaundice, and do not complain of any other symptoms usually [1].
Thalassemia. It is a disease of ineffective erythropoiesis, and patients also present with jaundice, but profound anemia, splenomegaly and expanded bone marrow space also occur [2].
Hyperthyroidism. It also can also present with jaundice, but features of thyrotoxicosis such as tremor, increased sweating and weight loss are more common [3].
References
  1. OWENS D, EVANS J. Population studies on Gilbert's syndrome.. Journal of Medical Genetics [online] 1975 June, 12(2):152-156 [viewed 06 October 2014] Available from: doi:10.1136/jmg.12.2.152
  2. GHONE RAHUL A., KUMBAR K. M., SURYAKAR A. N., KATKAM R. V., JOSHI N. G.. Oxidative stress and disturbance in antioxidant balance in beta thalassemia major. Indian J Clin Biochem [online] December, 23(4):337-340 [viewed 06 October 2014] Available from: doi:10.1007/s12291-008-0074-7
  3. BAL C, CHAWLA M. Hyperthyroidism and Jaundice Indian J Nucl Med [online] 2010, 25(4):131-134 [viewed 06 October 2014] Available from: doi:10.4103/0972-3919.78244

Investigations - for Diagnosis

Fact Explanation
Liver function tests. Except for the defect in UDP glucuronosyltransferase, hepatic architecture and function are normal in these patients [1]. Therefore liver function test findings would be normal.
High-performance liquid chromatography analysis of duodenal bile. This is used to identify the levels of bilirubin glucurononides. Based on this the syndrome could be divided into two types. Type I has negligible bilirubin glucuronides while type II has reduced concentrations of it [2].
Elevated serum unconjugated bilirubin levels. Due to the absence of the enzyme uridine diphosphate glucuronosyltransferase resulting in impaired conjugation and excretion of bilirubin [3].
Tissue enzyme assay. This is used to identify the levels of the enzyme uridine diphosphate glucuronosyltransferase . Based on this the syndrome could be divided into two types. Type I has negligible amounts of the enzyme while type II has reduced levels of it [3].
Liver biopsy . The disease occurs as a result of either absence or reduction of bilirubin UDP-glucuronosyltransferase activity. Therefore it is a problem in a metabolic process in the liver. Hence a biopsy specimen would reveal normal histology of the liver [4].
References
  1. KHAN A.A., PARVEEN N., MAHABOOB V.S., RAJENDRAPRASAD A., RAVINDRAPRAKASH H.R., VENKATESWARLU J., RAO P., PANDE G., LAKSHMI NARUSU M., KHAJA M.N., PRAMILA R., HABEEB A., HABIBULLAH C.M.. Treatment of Crigler-Najjar Syndrome Type 1 by Hepatic Progenitor Cell Transplantation: A Simple Procedure for Management of Hyperbilirubinemia. Transplantation Proceedings [online] 2008 May, 40(4):1148-1150 [viewed 08 October 2014] Available from: doi:10.1016/j.transproceed.2008.03.022
  2. YOHANNAN MD, TERRY HJ, LITTLEWOOD JM. Long term phototherapy in Crigler-Najjar syndrome. Arch Dis Child [online] 1983 Jun, 58(6):460-462 [viewed 06 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1627975
  3. ROBARDS CHRISTOPHER, BRULL SORIN J.. The Anesthetic Implications of Crigler-Najjar Syndrome. Anesthesia & Analgesia [online] 2007 February, 104(2):435-436 [viewed 06 October 2014] Available from: doi:10.1213/01.ane.0000252462.70451.0e
  4. RITTER J K, YEATMAN M T, FERREIRA P, OWENS I S. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient.. J. Clin. Invest. [online] 1992 July, 90(1):150-155 [viewed 08 October 2014] Available from: doi:10.1172/JCI115829

Management - General Measures

Fact Explanation
Avoidance of drugs such as sulfonamides, ceftriaxone, ampicillin, salicylates, and furosemide. These drugs displace bilirubin from albumin [1].
Avoid certain conditions such as fasting, infections, trauma, etc. Serum bilirubin concentration fluctuates during fasting stressful conditions [2]. Elevated levels could lead to bilirubin encephalopathy.
Parent education. Certain drugs (as above) [1], as well as certain conditions (as above) [2] can increase free serum bilirubin levels and cause further complications. Therefore parents should be educated on protecting their affected children from these aggravating factors.
Counselling. Consanguinity among parents is a risk factor since this is an autosomal recessive condition [3]. Therefore counselling couples at risk is vital.
Family support. Kernicterus is a complication of the disease [4]. Since this can lead to conditions such as deafness, nerve palsies and other permanent neurological complications, family support is needed.
References
  1. ROBARDS CHRISTOPHER, BRULL SORIN J.. The Anesthetic Implications of Crigler-Najjar Syndrome. Anesthesia & Analgesia [online] 2007 February, 104(2):435-436 [viewed 07 October 2014] Available from: doi:10.1213/01.ane.0000252462.70451.0e
  2. COSTA ELíSIO, VIEIRA EMíLIA, MARTINS MARCIA, SARAIVA JORGE, CANCELA EUGéNIA, COSTA MIGUEL, BAUERLE ROSWITHA, FREITAS TERESA, CARVALHO JOãO R., SANTOS-SILVA ERMELINDA, BARBOT JOSé, DOS SANTOS ROSáRIO. Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler–Najjar syndromes. Blood Cells, Molecules, and Diseases [online] 2006 January, 36(1):91-97 [viewed 07 October 2014] Available from: doi:10.1016/j.bcmd.2005.09.002
  3. RITTER J K, YEATMAN M T, FERREIRA P, OWENS I S. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient.. J. Clin. Invest. [online] 1992 July, 90(1):150-155 [viewed 06 October 2014] Available from: doi:10.1172/JCI115829
  4. WANG XIA, CHOWDHURY JAYANTA ROY, CHOWDHURY NAMITA ROY. Bilirubin metabolism: Applied physiology. Current Paediatrics [online] 2006 February, 16(1):70-74 [viewed 06 October 2014] Available from: doi:10.1016/j.cupe.2005.10.002

Management - Specific Treatments

Fact Explanation
Phenobarbital It is given 60-180 mg per day. It has the ability to induce the activity of the enzyme UDP- glucuronosyltransferase [1].
Plasma exchange transfusion. This removes the unconjugated bilirubin from the plasma [2].
Phototherapy. Intensity of light should be at a level of at least 4-10 µW/cm2/nm. The appropriate wave length is at 425-475 nm in the blue-green spectrum . Phototherapy induces photoisomerization of unconjugated bilirubin, which increases its hydrophilicity and biliary secretion [3].
Oral calcium phosphate. patients with Crigler–Najjar disease excrete normal amounts of bilirubin and bilirubin breakdown products in the feces despite extremely low excretion of bilirubin in bile. Thus, intestinal excretion of bilirubin has been postulated as an alternative pathway for disposal of bilirubin during unconjugated hyperbilirubinemia. Unconjugated bilirubin binds to amorphous calcium phosphate, leading to intestinal trapping of bilirubin which would ultimately lead to reduced reabsorption and increased excretion of unconjugated bilirubin [4].
Liver cell transplantation. Cells can be infused safely in the diseased liver, and are expected to bring sufficient enzyme activity to restore bilirubin metabolism [5].
References
  1. COSTA ELíSIO. Hematologically important mutations: Bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler–Najjar syndromes. Blood Cells, Molecules, and Diseases [online] 2006 January, 36(1):77-80 [viewed 06 October 2014] Available from: doi:10.1016/j.bcmd.2005.10.006
  2. NISHIOKA TOMOJI, HAFKAMP ANJA M., HAVINGA RICK, VAN LIEROP PIETER P.E., VELVIS HERMAN, VERKADE HENKJAN J.. Orlistat treatment increases fecal bilirubin excretion and decreases plasma bilirubin concentrations in hyperbilirubinemic Gunn rats. The Journal of Pediatrics [online] 2003 September, 143(3):327-334 [viewed 06 October 2014] Available from: doi:10.1067/S0022-3476(03)00298-1
  3. HAFKAMP ANJA M, NELISSE-HAAK RINEKE, SINAASAPPEL MAARTEN, OUDE ELFERINK RONALD P J, VERKADE HENKJAN J. Orlistat Treatment of Unconjugated Hyperbilirubinemia in Crigler-Najjar Disease: A Randomized Controlled Trial. Pediatr Res [online] 2007 December, 62(6):725-730 [viewed 06 October 2014] Available from: doi:10.1203/PDR.0b013e3181598cc5
  4. VAN DER VEERE CN, JANSEN PL, SINAASAPPEL M, VAN DER MEER R, VAN DER SIJS H, RAMMELOO JA, GOYENS P, VAN NIEUWKERK CM, OUDE ELFERINK RP. Oral calcium phosphate: A new therapy for Crigler-Najjar disease?. Gastroenterology [online] 1997 February, 112(2):455-462 [viewed 07 October 2014] Available from: doi:10.1053/gast.1997.v112.pm9024299
  5. LYSY PHILIPPE-A. Liver cell transplantation for Crigler-Najjar syndrome type Ⅰ: Update and perspectives. WJG [online] 2008 December [viewed 07 October 2014] Available from: doi:10.3748/wjg.14.3464