Discussion:
CNS is a rare hereditary disorder characterized by an inborn metabolic
defect 3. There are two types of Crigler
Najjar Syndrome (CNS): type I and type II. The underlying problem in
both forms is the absence or significantly reduced quantity of the
enzyme UDP-glucuronosyltransferase due to mutations in the UGT1A1 gene4 . Type I CNS, the most dangerous kind, is
characterized by a total deficiency of the enzyme UGT1A1 and affects
infants from birth, with only a small percentage of children living
through infancy before dying to bilirubin encephalopathy. Type II CNS,
also known as Arias syndrome, is a less severe form of CNS resulting
from a partial lack of the enzyme, with affected people having a much
longer life expectancy 5 . Individuals with CN
type II have serum bilirubin levels of 10 to 20 mg/dL (175 to 350 mol/l)
and rarely acquire kernicterus. However, neurological impairment can
develop if hyperbilirubinemia is aggravated by fasting, medications, or
viral illnesses [6] . Although there are reported
differences in the inheritance pattern of type II CNS, Crigler Najjar
syndrome is mostly autosomal recessive 4 .
It’s critical to distinguish between Crigler-Najjar syndrome types I and
II. The use of phenobarbital, a barbiturate that lowers blood bilirubin
levels, is indicated for Crigler Najjar syndrome type II. For patients
with syndrome type I, however, this medication is ineffective. As a
result, failure to react to this medicine is a crucial indicator for
accurate diagnosis 7 . Studies worldwide
suggest an estimated prevalence of 1 per million live births for both
forms of CNS and are believed to impact people of all races and genders
similarly8.
Furthermore, we conducted a thorough review and collated all CN types I
and II cases, considering their age, gender, disease onset, type of CN
syndrome, clinical features, laboratory findings, associated diseases,
and treatment/outcomes. In addition, we conducted a thorough literature
search on Pubmed using the terms ’Crigler Najjar syndrome,
‘phenobarbital,’ ‘outcomes.’ The study included all case reports and
case series of age limits (from birth to 18 years of age) from the past
decade (2010 to 2022). Articles that lacked extractable clinical data
and a description of individual data were eliminated. The titles and
abstracts of the retrieved publications were used to determine their
eligibility. The eligibility criteria were met by 12 papers involving 14
patients (Table 3) .
In our case, a 14-year-old boy demonstrated features consistent with
unconjugated hyperbilirubinemia. Later, on adding phenobarbital therapy,
a drastic fall in the bilirubin levels was noted, and he was diagnosed
with Crigler-Najjar syndrome type II (CNS II). Along with CNS II, he had
celiac disease. This rare co-existing condition was associated with a
significant decrease in his Hemoglobin levels, hematocrit, MCV, and
MCHC. In addition, the presence of tear-drop (dacrocytes) cells in his
peripheral smear indicated Severe Iron deficiency.
Unfortunately, due to fewer limitations in Pakistan, the diagnosis was
made by unconjugated hyperbilirubinemia and family history. Clinically
suspected cases of CNS should undergo serum unconjugated bilirubin level
testing. Levels of unconjugated bilirubin vary in both CNS I and II.
Higher levels between 20 to 25 mg/dL were noted in type I, whereas in
CNS type II, bilirubin is usually less than 20 mg/dL4. Diagnosis can be made, using bile analysis
technique revealing no detectable bilirubin glucuronides or urine
analysis may demonstrate a lack of bilirubin. CNS I and II can be
differentiated by bile pigment analysis and by discerning the response
of serum bilirubin levels to phenobarbital therapy9 .
In patients with CNS type II, treatments include phenobarbital therapy,
light therapy, plasmapheresis, enzyme, and liver transplantation. Light
therapy, also known as phototherapy, effectively decreases unconjugated
bilirubin by causing its excretion in bile and converting it to a
water-soluble photo isomer 10 . Patients
seldom require exchange transfusions or long-term phototherapy11 . In our case, the addition of
phenobarbital resulted in a marked improvement of icterus. Furthermore,
a slight decline in his liver enzyme GGT and ALP was noted.
The gene encoding for bilirubin UDP-glucuronosyltransferase in
conditions like Crigler-Najjar syndromes I and II and Gilbert’s syndrome
are affected. The usual investigative measures for these cases include
molecular genetic testing, which reveals the genetic mutation in
patients with these conditions. A better understanding of genetics-based
on molecular diagnosis will improve the diagnostic efficiency and gain
informed genetic counseling for any acquired disorder characterized by
unconjugated hyperbilirubinemia. 12 .