Crigler Najjar Syndrome: Understanding a Rare Condition

September 7, 2023

newborn suffering from Crigler Najjar Syndrome receiving treatment — Stockphoto of a newborn girl undergoing phototherapy treatment for hyperbilirubinemia, a very common newborn condition.

Crigler Najjar syndrome is an inherited disorder in which genetic abnormality causes a poor function of enzymes involved in bilirubin processing, and it leads to excessive levels of bilirubin in the body¹. This surplus bilirubin manifests as jaundice in newborns. As these individuals age, the accumulation of this toxic substance begins to interfere with typical developmental and physical processes.
Moreover, the syndrome leads to irreversible harm to brain cells and tissues, resulting in affected children displaying atypical cognitive capacities. Furthermore, they encounter challenges in coordinating their bodies and experience involuntary movements in various body parts.

What Causes Crigler Najjar Syndrome?

Crigler-Najjar syndrome is a rare medical condition in which genetic abnormality with autosomal recessive tendency, a condition in which offspring inherit the abnormal genes from both parents, affects normal ways of processing bilirubin in the body. Bilirubin is a substance that is produced when the central protein of red blood cells named hemoglobin undergoes breakdown².
After being created, the liver processes bilirubin by transforming it from an insoluble form known as unconjugated bilirubin to a water-soluble form referred to as conjugated bilirubin. Subsequently, the body expels this conjugated bilirubin through the excretory system.
In this genetic disorder, the presence of mutated genes(for instance, UGTA1A gene) produces a deficiency of UDP-glucuronosyltransferase, an enzyme that plays a crucial role in the processing of bilirubin. As a result of this deficiency, unconjugated bilirubin³ piles up inside the body and causes a situation called jaundice, a condition in which patients develop pale skin and yellowing of eyes.

Types of Crigler Najjar Syndrome

This disorder is classified into two types based on zero or poor function of the UDP-glucuronosyltransferase enzyme.

Crigler Najjar syndrome type I

In this type of syndrome, there is a complete absence of the UDP-glucuronosyltransferase enzyme. As a result of zero enzyme activity, the accumulation of toxic substances named unconjugated bilirubin reaches a dangerous level. This type is most severe in intensity.
Patients who develop type 1 have a poor prognosis and have a high mortality rate as in childhood there can be high levels(more than 15 mg/dL) of bilirubin ⁴. However, rigorous treatment intervention can help patients survive longer ⁵.

Crigler Najjar syndrome type II

In this type of syndrome, patients have a deficiency of bilirubin processing enzyme. Some percentage of unconjugated bilirubin is still converted to conjugated bilirubin. Hence, the level of bilirubin doesn’t rise to danger. This type is mild in intensity and shows quite a favorable prognosis for the patient if he takes medical intervention properly. In this type, the chances of brain tissue damage are meager. So, there is a greater chance of the patient enjoying a good life for a long time ⁶.

Clinical symptoms of Crigler Najjar syndrome

High levels of bilirubin in the body causes multiple physical and mental disturbance. There are some differences in the clinical picture of type I and type II.

Clinical manifestation for type I

The clinical manifestations of type I are:

Jaundice is the continuous yellowness of skin, eyes, and mucosal membranes. In type 1, this condition becomes evident at birth or three weeks after birth.
Kernicterus is a condition in which excessive bilirubin levels in the blood cause extensive damage to the brain structure and function of the central nervous system. This is a life-threatening condition.
BIND – Bilirubin-induced Neurological Dysfunction is a symptom when too much bilirubin in the body harms the brain, causing problems with thinking and movement, especially in conditions like Crigler-Najjar syndrome.
Lethargy: The patient has a lean body and disturbed gait. He does not have enough energy to carry out daily tasks.
Nausea
Vomiting
Continuous high body temperature
Muscle spasms in this condition, different body muscles show abnormal contraction and relaxation activity. Patients have poor control over their muscle activity.
Abnormal body reflexes

Clinical manifestation of type II

Clinical manifestations of type II Crigler Najjar Syndrome are:

Jaundice: Individuals born with this milder form of syndrome develop jaundice after
Neurological impacts: Most patients also develop kernicterus, but the intensity of brain damage and symptoms appearing due to brain damage, like poor bodily reflexes, are low as compared to type 1.
Episodes of muscle spasticity
Lack of body energy
Time of onset: Most symptoms appear later in life. Unlike type 1, most patients have a healthy childhood while they develop symptoms when they get any illness.

Diagnosis – Crigler Najjar syndrome

If your infant displays persistent yellowing of the skin and eyes accompanied by unusual bodily movements and gait, it is crucial to delve into the child’s complete medical history and conduct a thorough medical examination. During the examination, notable signs include pronounced skin yellowness and discoloration of the white part of the eyes. The palm of the hands is utilized to assess the extent of yellowness. Following a comprehensive general examination and preliminary tests, the doctor will pursue a specific diagnostic protocol for Crigler Najjar syndrome. This protocol involves:

Genetic Testing:

This test involves analyzing the individual’s DNA to identify any genetic mutations or abnormalities that may be causing the dysfunctional enzymes responsible for bilirubin processing. It helps pinpoint the underlying genetic cause of Crigler-Najjar syndrome.

Blood Test:

A blood test measures the level of unconjugated bilirubin in the bloodstream. Elevated levels of unconjugated bilirubin indicate the impaired processing of bilirubin by the liver, a hallmark of Crigler-Najjar syndrome. The level of unconjugated bilirubin is high in type I as compared to type II disease. In Crigler-Najjar syndrome type I, the level of unconjugated bilirubin is between 20 to 25 mg/dL, but severe cases can be around 50 mg/dL. In type II, it is usually less than 20 mg/dL.⁷

Stool Test:

Stool testing aims to detect the presence and amount of bilirubin in the stool. High levels of bilirubin in the stool can provide further evidence of the disorder’s impact on bilirubin metabolism.

Liver Function Test:

This test evaluates the liver’s overall function and health. Abnormal liver function may suggest the extent to which the liver’s inability to process bilirubin contributes to the syndrome. Liver function tests usually reveal a normal range of liver enzymes; however, these enzymes may become elevated due to cholestasis.

Bile Analysis:

Bile is collected from the duodenum using an upper gastrointestinal endoscopy or an orally placed duodenal catheter. The collected bile is then analyzed for bilirubin glucuronides using high-performance liquid chromatography (HPLC). This procedure offers definitive insights into the specific bilirubin compounds present. Specific findings help differentiate between Crigler-Najjar syndrome type I and type II. Conjugated bilirubin is either absent or present in trace amounts in Crigler-Najjar syndrome type I, whereas a significant amount of conjugated bilirubin is present in Crigler-Najjar syndrome type II. The HPLC analysis of bile obtained from the duodenum serves as the definitive test, aiding in accurate diagnosis and differentiation between these types of the syndrome.

Treatment – Crigler Najjar syndrome

The primary treatment goal is to lower the concentration of unconjugated bilirubin, achieved through methods like phototherapy and plasmapheresis. Many patients experience survival rates extending beyond puberty with minimal brain damage, although kernicterus may eventually emerge later in life. Currently, the lone curative recourse for Crigler-Najjar type I syndrome is liver transplantation. However, the best line of action is,

Symptomatic treatment

The foremost treatment intervention is taking medicine to treat the symptoms. For instance, if the patient has a fever, he should be given an antipyretic. In case of nausea and vomiting, prescribe medicines to treat the respective condition. However, for neurological symptoms, no medicine works until the level of unconjugated bilirubin drops to the normal level.

Phototherapy

Following symptom management, it’s crucial to assess the patient’s health status to determine the most suitable course of treatment. If the patient is in good health, the option of phototherapy can be considered. During phototherapy, a clinician employs bright light of a specific wavelength to eliminate excess bilirubin through the skin tissue. To ensure safety, the patient is provided with protective goggles and only exposes the necessary area of skin to the bright light.
Intensive phototherapy serves as the cornerstone of treating Crigler-Najjar type I syndrome. This approach is commonly used for neonatal hyperbilirubinemia treatment as well. The effectiveness of intensive phototherapy surpasses conventional methods by yielding more rapid and efficient results. Moreover, it reduces the treatment duration and minimizes the risk of later complications. Notably, phototherapy is less effective in older children and adults due to factors like thicker skin, increased skin pigmentation, and a reduced surface area relative to body mass.⁸. With the help of phototherapy, unconjugated bilirubin will be removed from the body without conversion into conjugated form.

Plasmapheresis

Plasmapheresis is the most effective process to remove the excess unconjugated bilirubin from the blood during a severe hyperbilirubinemia crisis. It is a procedure in which plasma from the body containing a high level of toxic substance is replaced with healthy plasma from the donor. This procedure requires a proper armamentarium to undertake the whole process. The only thing that one must ensure is the correct matching of plasma with the donor before donation.

Liver transplant

In cases of severe Crigler Najjar syndrome, the medical team resorts to a liver transplant as the ultimate solution. This intricate procedure involves the meticulous removal of the diseased liver and its replacement with a healthy liver obtained from a donor. This treatment avenue is primarily reserved for the most critical instances, especially among type 1 patients.
To mitigate potential complications such as brain damage, it is advisable to perform the transplant at an early stage. The transplanted liver possesses a functional UGT1A1 enzyme responsible for bilirubin conjugation, leading to a swift reduction in serum bilirubin levels. To preempt the development of kernicterus, which might be irreversible once it manifests, prophylactic liver transplantation is recommended.⁹.

The life expectancy of a patient with Crigler Najjar syndrome

Most patients of severe type 1 die before the completion of their infancy period. However, in cases of type 2 and cases where proper treatment intervention is given to patients, there are good chances of patients enjoying a normal life expectancy.

Gilbert syndrome vs. Crigler Najjar syndrome

Despite belonging to the category of rare genetic disorder involving autosomal recessive tendency, both Gilbert syndrome and Crigler Najjar syndrome differ in severity (Strassburg et al., 2010). In the case of Gilbert syndrome, there is less than normal activity of the enzyme responsible for bilirubin processing ¹⁰. As a result, the patient develops a mild increase in bilirubin levels in the body. In Crigler Najjar syndrome, there is almost no or zero activity of that enzyme. As a result, a severe rise in bilirubin levels in the body takes place.

To sum it up, Crigler Najjar syndrome is a disorder owing to a high level of toxic substance named bilirubin in the body. Patients should be given immediate medical intervention to enjoy health and life.

Refrences

1
Bhandari, J., Thada, P. K., & Yadav, D. (2022). Crigler-Najjar Syndrome. In StatPearls. StatPearls Publishing.
2
Memon, N., Weinberger, B. I., Hegyi, T., & Aleksunes, L. M. (2016). Inherited disorders of bilirubin clearance. Pediatric Research, 79(3), 378–386. https://doi.org/10.1038/pr.2015.247
3
Singh, A., Koritala, T., & Jialal, I. (2023). Unconjugated Hyperbilirubinemia. In StatPearls. StatPearls Publishing.
4
Cozzi, L., Nuti, F., Degrassi, I., Civeriati, D., Paolella, G., & Nebbia, G. (2022). Gilbert or Crigler-Najjar syndrome? Neonatal severe unconjugated hyperbilirubinemia with P364L UGT1A1 homozygosity. Italian journal of pediatrics, 48(1), 59. https://doi.org/10.1186/s13052-022-01251-4
5
Strauss, K. A., Ahlfors, C. E., Soltys, K., Mazareigos, G. V., Young, M., Bowser, L. E., Fox, M. D., Squires, J. E., McKiernan, P., Brigatti, K. W., Puffenberger, E. G., Carson, V. J., & Vreman, H. J. (2020). Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier. Hepatology (Baltimore, Md.), 71(6), 1923–1939. https://doi.org/10.1002/hep.30959
6
Huang, C. S., Tan, N., Yang, S. S., Sung, Y. C., & Huang, M. J. (2006). Crigler-Najjar syndrome type 2. Journal of the Formosan Medical Association = Taiwan yi zhi, 105(11), 950–953. https://doi.org/10.1016/S0929-6646(09)60182-0
7
Bhandari J, Thada PK, Yadav D. Crigler-Najjar Syndrome. [Updated 2022 Sep 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562171/
8
Torres, M., & Bruguera, M. (2005). Síndrome de Crigler-Najjar [Crigler-Najjar syndrome]. Gastroenterologia y hepatologia, 28(10), 637–640. https://doi.org/10.1016/s0210-5705(05)71530-2
9
Tcaciuc, E., Podurean, M., & Tcaciuc, A. (2021). Management of Crigler-Najjar syndrome. Medicine and pharmacy reports, 94(Suppl No 1), S64–S67. https://doi.org/10.15386/mpr-2234
10
Thoguluva Chandrasekar, V., Faust, T. W., & John, S. (2023). Gilbert Syndrome. In StatPearls. StatPearls Publishing.

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What Causes Crigler Najjar Syndrome?

Types of Crigler Najjar Syndrome

Crigler Najjar syndrome type I

Crigler Najjar syndrome type II

Clinical symptoms of Crigler Najjar syndrome

Clinical manifestation for type I

Clinical manifestation of type II

Diagnosis – Crigler Najjar syndrome

Genetic Testing:

Blood Test:

Stool Test:

Liver Function Test:

Bile Analysis:

Treatment – Crigler Najjar syndrome

Symptomatic treatment

Phototherapy

Plasmapheresis

Liver transplant

The life expectancy of a patient with Crigler Najjar syndrome

Gilbert syndrome vs. Crigler Najjar syndrome

Refrences

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