Kriegler-Nayyar syndrome: causes, symptoms, diagnosis, treatment

The basis of Crigler-Najjar syndrome (non-hemolytic kernicterus) is the complete absence of the enzyme glucuronyl transferase in hepatocytes and the absolute inability of the liver to conjugate bilirubin (microsomal jaundice). In this regard, the content of unconjugated bilirubin in the blood increases sharply and it has a toxic effect on the central nervous system, affecting the subcortical nodes (kernicterus). Significant dystrophic changes in the myocardium, skeletal muscles and other organs are also detected, as a manifestation of the toxic effect of bilirubin. When examining liver biopsies, as a rule, morphological changes are not detected, sometimes there is a slight fatty hepatosis, insignificant periportal fibrosis.

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Symptoms of Crigler-Najjar syndrome

There are two types of Crigler-Najjar syndrome:

Type I Crigler-Najjar syndrome is characterized by the following features:

• transmitted in an autosomal recessive manner;
• severe jaundice develops during the first days after birth and continues throughout life;
• CNS damage appears already in infancy and is manifested by tonic or juvenile seizures, opisthotonus, athetosis, nystagmus, muscle hypertension, and delayed physical and mental development;
• there is pronounced hyperbilirubinemia (the level of unconjugated bilirubin is increased by 10-50 times compared to the norm);
• only traces of bilirubin are found in bile;
• bilirubinuria is absent, the amount of urobilin bodies in urine and feces is small; acholic feces are possible;
• Phenobarbital does not reduce the level of unconjugated bilirubin in the blood;
• a slight increase in the activity of enzymes in the blood that reflect liver function (alanine aminotransferase, fructose-1-phosphate aldolase) is possible;
• Most patients die in the first year of life.

Type II Crigler-Najjar syndrome has the following characteristic manifestations:

• transmitted in an autosomal dominant manner;
• the course of the disease is more benign;
• jaundice is less intense;
• the content of unconjugated bilirubin in the blood serum is increased by 5-20 times compared to the norm;
• neurological disorders are rare and mild, and may be absent altogether;
• bile is colored, a significant amount of urobilinogen is detected in the feces;
• bilirubinuria is absent;
• The use of phenobarbital leads to a decrease in the bilirubin content in the blood serum.

Distinguishing between types 1 and 2 of Crigler-Najjar syndrome is not always easy. They can be differentiated by assessing the effectiveness of phenobarbital treatment by measuring bilirubin fractions using high-performance liquid chromatography. In addition, the types can be distinguished by measuring the content of bile pigments in bile after phenobarbital administration. In type 2, the serum bilirubin level and the proportion of unconjugated bilirubin decrease, and the content of mono- and diconjugates in bile increases. In type 1, the serum bilirubin level does not decrease, and unconjugated bilirubin is predominantly detected in bile. Apparently, in the future, diagnosis will be based on in vitro expression of mutant DNA of patients.

Crigler-Najjar syndrome must be differentiated from physiological jaundice of newborns, which is caused by insufficient maturity of the conjugation system of the liver at the time of birth. This jaundice has the following characteristic features that distinguish it from Crigler-Najjar syndrome:

• jaundice appears on the second or third day of life, reaches its maximum by the fifth day and goes away without treatment within 7-10 days in full-term babies and 10-14 days in premature babies;
• the content of unconjugated bilirubin in the blood serum does not exceed 170 μmol/l in full-term infants and 250 μmol/l in premature infants;
• no damage to the central nervous system is observed.