Dealing With Yellowing Skin: Understanding Crigler-Najjar Syndrome

Introduction

Crigler-Najjar Syndrome (CNS) is a rare genetic disease that is estimated to affect less than 1 in 1 million newborns in the world. ¹ The two types of CNS are: type I and type 2. In type I CNS, there is complete or near complete absence of an important liver enzyme, which is due to the fact that patients have an autosomal recessive inherited enzyme deficiency. ^{1 ,8} Type II patients have a less severe form of the disease due to an autosomal dominant gene which makes the enzyme partially functional. ⁸ Type II Crigler-Najjar Syndrome is also known as Arias Syndrome. ²

Genetics

Crigler-Najjar Syndrome is an inherited disorder caused by mutations in the UGT1A1 gene. This mutation leads to a non-proper functioning glucuronyl transferase enzyme. ¹ This non-proper functioning enzyme leads to high levels of bilirubin in the blood of patients with CNS. ¹ Bilirubin is a result of the body’s normal process of breaking down old red blood cells and is found in the bile. ³ Low levels of bilirubin are normal in the blood as the liver gets rid of excessive amounts. ³ The normal amount of bilirubin in the blood is 0.1 to 1.2 mg/dL, ¹² while patients with type I CNS have over 20 mg/dl of bilirubin in their blood and patients with type II CNS have below 20 mg/dl. ¹³ This condition is known as hyperbilirubinemia. ¹

Hyperbilirubinemia leads to bilirubin build-up in the liver, a known as unconjugated bilirubin. ¹ Although, those with type II CNS have a limitedly functioning the enzyme, they may still develop hyperbilirubinemia as the glucuronyl transferase does not function at a high enough level to convert and remove bilirubin. ¹

Symptomatic Progression

The baseline of the disease will show yellowing of the skin, a symptom that is known as jaundice. ^{1 2 13} This symptom is seen in newborns. ¹ At the baseline, children may also feel fatigued and have abdominal pain. ⁹ The acute stages of CNS are caused by an increase in the unconjugated bilirubin which may lead to diarrhea, vomiting, fever, confusion, slurred speech, difficulty swallowing, change in gait, staggering, and frequent falling. ⁹

In addition to these symptoms, type I patients are also at risk for some neurologic damage from kernicterus (bilirubin accumulation in the brain). In developing countries, 19 to 26% of CNS patients have developed brain disorders. ⁴ This condition may appear in the form of weak muscle tone, intellectual disability deafness, involuntary writhing, paralysis of the oculomotor nerve ⁹ which is a cranial nerve. ¹⁰Kernicterus, a brain disorder, can develop in type I patients in early infancy or later on in childhood or adulthood. ⁷ Patients that develop kernicterus and other brain injuries usually die early on, by the age of 2. ¹³ Once brain damage occurs, it is difficult to reverse it. ⁷ In contrast, type II patients are less likely to develop kernicterus as the glucuronyl enzyme is functioning limitedly leading to less bilirubin build-up relative to type I patients. ¹¹ Type II patients have a normal or near-normal life expectancy. ¹³

Medication/Therapeutic Treatments

Treatments for type I CNS require regular phototherapy throughout the patient’s life. Phototherapy devices range from $2095 to $4895 CA ¹⁴ and are covered by provincial insurance in Ontario, Canada. ¹⁵ During phototherapy, the patient is exposed to a blue LED light, which breaks down the unconjugated bilirubin so that it can be excreted into bile and eliminated from the intestines. ⁷ Phototherapy is only needed to respond to severe hyperbilirubinemia. However, the constant exposure to light during phototherapy can cause skin damage, and lead to impaired weight gain due to water loss and diarrhea. ⁸ Not all patients with type II CNS require treatment depending on how high their levels of bilirubin, it is recommended that type II patients monitor their symptoms regularly to determine if treatment is required to reduce their symptoms. ¹ Phenobarbital, a drug, is also used to manage milder forms of CNS ¹¹ as it can reduce bilirubin by 30%. ¹³

Another treatment for CNS is liver transplantation. Liver transplantation is associated with risks such as surgical, infectious, and malignant links. ³ The new functioning liver will be able to convert unconjugated bilirubin into a form that can be excreted from the body. In order to prevent liver rejection, immunosuppressive medication is used for one year after a patient gets a transplant. ⁹ This is a life-saving treatment, although the UGT1A1 gene mutation can still be transmitted to offspring. ⁹ The survival rate after liver transplantation is high, although there are too few cases of this to make a definitive conclusion on the survival rates. ¹³ There is an urgent need for life-saving transplants and alternative therapies to manage symptoms of and treat CNS. ⁷

Jonta Kamara  

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Support Groups

If you are a patient dealing with Crigler-Najjar Syndrome, below is a selection of support groups to help you:
Canadian Liver Foundation: Supports patients with liver diseases such as Gilbert’s syndrome which arises from a mutation in the same gene
American Association for the Study of Liver Diseases American Liver Foundation
Metabolic Support in the UK : Charity that is committed to improving the lives of those with rare diseases and provides tailored support to families
The Crigler Najjar Association USA : Support and Advocacy group
The Crigler Najjar Association France : Support group created by people with CNJ and their families

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Works Cited

1. National Organization for Rare Disorders. Crigler Najjar Syndrome - NORD (National Organization for Rare Disorders). NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/crigler-najjar-syndrome/. Published 2019. Accessed October 9, 2019.

2. University of Rochester Medical Center. Total Bilirubin (Blood) - Health Encyclopedia - University of Rochester Medical Center. Urmc.rochester.edu. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=total_bilirubin_blood. Published 2019. Accessed October 9, 2019.

3. Strauss K, Ahlfors C, Soltys K, et al. Crigler‐Najjar syndrome type 1: pathophysiology, natural history, and therapeutic frontier. Hepatology. 2019:1-31. doi:10.1002/hep.30959

4. American Liver Foundation. Crigler-Najjar Syndrome - American Liver Foundation. American Liver Foundation. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/crigler-najjar-syndrome/#how-is-cns-treated. Published 2017. Accessed October 12, 2019.

5. Shevell M, Bernard B, Adelson J, Doody D, Laberge J, Guttman F. Crigler-Najjar syndrome type I: Treatment by home phototherapy followed by orthotopic hepatic transplantation. J Pediatr. 1987;110(3):429-431. doi:10.1016/s0022-3476(87)80510-3

6. UPMC. Pediatric Crigler-Najjar Syndrome | Children's Pittsburgh. Children's Hospital of Pittsburgh. https://www.chp.edu/our-services/transplant/liver/education/liver-disease-states/crigler-najjar-syndrome. Published 2019. Accessed October 18, 2019.

7. Samarasinghe S, Emanuele M, Mazhari A. Neurology of the pituitary. Neurologic Aspects of Systemic Disease Part II. 2014:685-701. doi:10.1016/b978-0-7020-4087-0.00047-4

8. Nedredal, G, Mao S, Glorioso, J, Nyberg S. Crigler Najjar Syndrome - an overview | ScienceDirect Topics. Sciencedirect.com. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/crigler-najjar-syndrome. Published 2019. Accessed October 18, 2019.

9. U.S. National Library of Medicine. Bilirubin blood test: MedlinePlus Medical Encyclopedia. Medlineplus.gov. https://medlineplus.gov/ency/article/003479.htm. Published 2019. Accessed October 18, 2019.

10. Tidy C, Bonsall A. Crigler-Najjar Syndrome. CNS information. Patient. Patient.info. https://patient.info/doctor/crigler-najjar-syndrome. Published 2019. Accessed October 18, 2019.

11. Solarc Systems Inc. Phototherapy Selection Guide | Solarc Systems Inc. | Canada. Solarc Systems Inc. | Canada. https://solarcsystems.ca/en/products/selection-guide/. Published 2019. Accessed October 18, 2019.

12. Guenther Dermatology Research Centre. Guenther Dermatology Research Centre | OHIP Coverage. The Guenther Dermatology Research Centre | London, Ontario. http://gdrc.ca/services-referrals/ohip-coverage/. Published 2019. Accessed October 18, 2019.

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Cite This Article:

Kamara J. Dealing With Yellowing Skin: Understanding Crigler-Najjar Syndrome. Rare Disease Review. June 2020.