Crigler-Najjar Syndrome

Etiology

Crigler-Najjar syndrome is caused by an absence or decreased level of the UGT enzyme due to a genetic defect in the bilirubin UDP-glucuronosyltransferase family 1, polypeptide A1 (UGT1A1) gene.[1] In CN1, common mutations include deletions, alterations in intron splice donor and receptor sites, missense mutations, exon skipping, insertions, or the formation of a stop codon within the UGT1A1 gene leading to complete deficiency of the UGT enzyme.[2] Conversely, CN2 results from a point mutation in the UGT1A1 gene, resulting in reduced production of the UGT enzyme.[2][3]

Epidemiology

Crigler-Najjar syndrome is an exceptionally rare disease, with an incidence rate of 0.6 to 1 in 1 million newborns worldwide.[4][5] Despite its rarity, Crigler-Najjar syndrome requires careful medical attention and specialized care due to the severe consequences associated with elevated bilirubin levels in affected individuals.

Pathophysiology

Bilirubin is one of the byproducts produced when erythrocytes break down. Newborns are particularly vulnerable to hyperbilirubinemia due to their higher hemoglobin concentration at birth and impaired bilirubin excretion processes.

Typically, when erythrocytes break down, bilirubin is in its unconjugated form. This unconjugated bilirubin circulates in the bloodstream and enters hepatocytes, where the UGT enzyme conjugates the bilirubin, making the substance water soluble. Once conjugated, the bilirubin is excreted into bile (see Image. Metabolic Pathway for Bilirubin in the Hepatocyte). In Crigler-Najjar syndrome, a genetic mutation reduces (in CN2) or eliminates (in CN1) this enzyme, leading to decreased or no conjugation and causing an excess of unconjugated bilirubin. Due to the reduced or absent conjugation and excretion, the level of unconjugated bilirubin overwhelms the body's albumin. This surplus of indirect bilirubin accumulates in body tissues such as the skin, sclera, and brain. About 99% of bilirubin is typically bound to albumin, which cannot cross the blood-brain barrier. In contrast, free (unbound) unconjugated bilirubin easily crosses the blood-brain barrier, interacting with neural tissue.[6] This accumulation can lead to severe complications in individuals with Crigler-Najjar syndrome.

Histopathology

Historically, hepatic histology in Crigler-Najjar syndrome was believed to be normal. However, recent studies have revealed certain pathological changes. Microscopically, bile plugs are occasionally observed within canaliculi due to cholestasis. Additionally, Crigler-Najjar syndrome can cause hepatic parenchymal injury. A small study reported transplant patients displaying significant fibrosis seen in the explants, indicating the presence of structural abnormalities in the liver tissue.[7][8]

History and Physical

In CN1, a newborn may exhibit jaundice, although its absence does not rule out the disease. In infants born healthy, persistent jaundice caused by unconjugated bilirubin typically appears within a few days and rapidly worsens by the second week. Factors such as a family history of consanguinity, severe jaundice without signs of hemolysis, relatives or family members undergoing or having undergone exchange transfusion therapy, or a family history of liver diseases support the diagnosis. Unconjugated hyperbilirubinemia in CN1 usually ranges from 20 to 25 mg/dL. However, cases with significantly elevated unconjugated bilirubin levels, reaching 50 mg/dL, have been reported.

During physical examination, jaundice is apparent, characterized by yellowish skin and sclera. Stool color remains normal; however, there is reduced excretion of fecal urobilinogen due to markedly decreased bilirubin conjugation. Besides jaundice, there are no abnormal findings in both types, and no signs of liver disease are observed. Older children may exhibit scratch marks on the body due to pruritus. In certain instances, progressive liver dysfunction and additional toxicities can cause hepatosplenomegaly.

Neurological symptoms in Crigler-Najjar syndrome arise from the toxic effects of bilirubin on the basal ganglia and brainstem nuclei for oculomotor and auditory functions. Acute bilirubin encephalopathy (ABE) initially manifests as sleepiness, mild to moderate hypotonia, and a high-pitched cry. Persistence of elevated bilirubin levels leads to the progression of ABE with symptoms such as fever, lethargy, poor suck, irritability, and hypertonia resulting in retrocollis and opisthotonus. Advanced ABE can involve seizures, apnea, and a semi-comatose or comatose state. Respiratory failure or seizures can lead to fatal outcomes. Brainstem auditory-evoked responses (BAER) help detect acute neurological dysfunction.[9]

Chronic bilirubin encephalopathy (CBE), also known as kernicterus, becomes apparent within the first year of life. Choreoathetoid cerebral palsy, sensorineural hearing loss, gaze abnormalities, and enamel hypoplasia characterize CBE. Generally, cognitive function remains unaffected. In instances of CBE, magnetic resonance imaging (MRI) of the brain reveals alterations in the cerebellum, hippocampus, and brainstem.[10][11]

CN2 is a milder condition characterized by fewer and less severe clinical symptoms. Patients with this syndrome may require periodic assessments to monitor bilirubin levels and liver function, aiding in the management and early detection of potential complications.

Evaluation

Patients suspected of having Crigler-Najjar syndrome should undergo serum unconjugated bilirubin level testing, with significantly higher levels seen in CN1 than CN2. In CN1, the unconjugated bilirubin is between 2 and 25 mg/dL, but severe cases can reach 50 mg/dL. CN2 cases typically exhibit levels below 20 mg/dL.

Historically, collection for bile analysis involved procedures like upper gastrointestinal endoscopy or duodenal catheterization, followed by high-performance liquid chromatography (HPLC). However, modern diagnoses primarily rely on genetic testing methods.[12]

The administration of phenobarbital for 2 weeks has decreased serum bilirubin concentration in most patients with CN2.[13] Notably, CN1 does not respond to phenobarbital treatment. 

Genetic analysis can be performed on DNA extracted from peripheral blood leukocytes, buccal scrapings, and other tissues, enabling the identification of mutations in the gene encoding the UGT enzyme. Prenatal diagnosis is possible with genetic analysis of chorionic villus samples or amniotic cells aspirated from amniotic fluid aspirates. Additionally, diffusion tensor brain imaging may help detect microstructural gray and white matter changes in CN1 syndrome.[14] Liver biopsy and histopathologic analysis can help to evaluate liver cirrhosis in established cases of hepatosplenomegaly.

Treatment / Management

The primary treatment goal focuses on lowering unconjugated bilirubin levels through phototherapy and plasmapheresis. Although most patients survive beyond puberty without significant brain damage, they are at risk of developing kernicterus later in life. Presently, liver transplantation stands as the sole curative option for CN1.[15] 

Phototherapy

The primary treatment approach for CN1 involves intensive, often daily, phototherapy. Phototherapy is often part of the treatment of neonatal hyperbilirubinemia.[16] Intensive phototherapy proves more effective than conventional approaches as it leads to a quicker response, shortens the treatment duration, and minimizes late complications.[17] Phototherapy is less effective in older children and adults due to thicker skin, increased skin pigmentation, and smaller body surface area in proportion to body mass.[15]

Plasmapheresis

Plasmapheresis is the most effective method for removing excess unconjugated bilirubin from the blood during severe hyperbilirubinemia crisis. This process involves extracting blood from the patient, separating blood cells from plasma, and replacing the plasma with donor plasma. The patient's blood is then transfused back after this exchange. Bilirubin tightly binds to albumin; therefore, removing albumin during plasmapheresis effectively reduces bilirubin levels in the bloodstream. Plasmapheresis serves as a targeted approach to eliminating unwanted substances from the blood.  

Orlistat

Orlistat, a lipase inhibitor, demonstrates enhanced efficiency when used alongside calcium phosphate. The theory behind its mechanism suggests that it captures unconjugated intestinal bilirubin and aids in its excretion, correlating with the amount of fat expelled in stools.[18](B3)

Calcium Phosphate Supplementation

A randomized controlled study of patients with CN1, who have undergone phototherapy and were supplemented with calcium phosphate, demonstrated an 18% reduction in serum bilirubin levels. This indicates that calcium phosphate may trap photoproducts excreted in the bile.[19] Supporting this, animal studies with rats have shown decreased serum bilirubin concentrations following oral calcium phosphate supplementation, likely due to the trapping of unconjugated bilirubin in the gut.[20](A1)

Liver Transplantation

Liver transplantation stands as the sole therapeutic and definitive treatment method for CN1. The transplanted liver possesses a healthy UGT enzyme, enabling effective bilirubin conjugation and rapidly lowering serum bilirubin levels. Prophylactic liver transplantation is highly recommended to prevent kernicterus, as once this condition develops, it may not be reversible.[21]

Hepatocyte Transplantation

Hepatocyte transplantation is a promising alternative to liver transplantation. During this procedure, healthy hepatocytes are infused into the portal vein or the peritoneal space. This method offers a temporary reduction of serum bilirubin levels, with published reports showing a 50% reduction in bilirubin levels.[22][23](B3)

Gene Therapy

The potential cure for the genetic defect lies in introducing a normal UGT1A1 gene, achieved through ex vivo gene transduction, where the gene is introduced into cultured hepatocytes or vector-mediated gene delivery methods. Adenovirus is the most effective vector for transferring genes to liver cells.[4] Currently, plans for conducting clinical trials in humans are underway, marking significant progress in pursuing a cure.

Inhibition of Bilirubin Production

A single dose of heme oxygenase inhibitors, like tin-protoporphyrin or tin-mesoporphyrin, administered to neonates has demonstrated a 76% decrease in bilirubin levels, eliminating the necessity for phototherapy.[24][25] However, in adults, this effect is short-lived and therefore reserved for acute emergencies.(A1)

Phenobarbitol

Patients with Crigler-Najjar syndrome usually do not require treatment with phenobarbital. However, patients experiencing jaundice that impacts their quality of life may receive phenobarbital therapy, which works by inducing the remaining UGT activity. Notably, phenobarbitol has no role in CN1, but it can reduce the serum bilirubin level by 25% in patients with CN2.[13] There have been documented cases where pregnant women with CN2 were successfully treated with phenobarbital during pregnancy.[26][27](B3)

Differential Diagnosis

Distinguishing Crigler-Najjar syndrome from other causes of unconjugated hyperbilirubinemia relies on evaluating the bilirubin levels and the duration of hyperbilirubinemia. Additionally, classification is based on underlying causes and specific conditions.

Increased Production

• Hemolysis: Conditions like sickle cell disease, hereditary spherocytosis, and Rh isoimmunization can lead to hemolysis, where the bilirubin level typically remains below 6 to 8 mg/dL in exclusive hemolysis cases in newborns. Rh isoimmunization,  incompatible fetal and maternal red cells, can cause pronounced jaundice but is always associated with signs of active hemolysis.

• Ineffective erythropoiesis: Diseases related to ineffective erythropoiesis, such as thalassemia, pernicious anemia, iron deficiency anemia, and lead poisoning, can result in a marked increase in bilirubin levels.

• Gastrointestinal (GI) bleeding and hematoma: GI bleeding and hematomas contribute to hyperbilirubinemia. One case report with hematochezia and jaundice reported polyp formation was responsible for rectal bleeding related to biliary abnormalities.[28] Conditions like hemobilia, where GI bleeding leads to resorption of blood and an increase in unconjugated bilirubin concentration, can cause jaundice.[29] 

Decreased Clearance

• Liver diseases: Any liver disease affecting the conjugation and efficient excretion of bilirubin can lead to jaundice. 

• Drug-induced: Liver injury caused by drugs such as amoxicillin, cefazolin, nitrofurantoin, chloramphenicol, and isoniazid can impair the liver's conjugating capacity, resulting in hyperbilirubinemia.[30][31]

Genetic Conditions

• Gilbert syndrome: This common inherited hyperbilirubinemia affects the UGT1A1 gene's promoter region, reducing normal protein production. As the UGT enzyme deficiency is not severe, Gilbert syndrome has benign manifestations, distinguishing it from CN1.

• Lucey-Driscoll syndrome: Also known as transient familial hyperbilirubinemia, it is caused by compounds in the mother's and baby's blood that block the bilirubin breakdown.

• Neonatal jaundice and prematurity: Physiologic jaundice in newborns can result from various factors like liver dysfunction, infection, hypothyroidism, and metabolic disorders. Premature infants often have higher bilirubin levels due to immaturity. Physiologic jaundice usually resolves within the first 10 days of life.

Special Cases

• Breast milk jaundice: Some breastfeeding neonates experience elevated bilirubin within 2 weeks of birth, lasting 3 to 12 weeks, often longer than physiologic jaundice.

• Rotor syndrome and Dubin-Johnson syndrome: Rare inherited disorders causing jaundice with high levels of conjugated bilirubin. Rotor syndrome results from alterations in 2 genes, SLCO1B1 and SLCO1B3, while Dubin-Johnson syndrome results from ABCC2 gene mutations.

Prognosis

CN1 has a poor prognosis, often necessitating emergent intervention during hyperbilirubinemia crises. Once kernicterus develops, this syndrome tends to be irreversible. In contrast, CN2, due to residual UGT enzyme activity, presents with mild symptoms or can even be asymptomatic. Studies report varying incidences of permanent neurological impairment in patients with CN1, ranging up to 30% of cases.[15][32][33]

Complications

An outline of potential complications for Crigler-Najjar syndrome are as follows:

• Kernicterus: Unconjugated bilirubin, being fat-soluble, can penetrate cell membranes. At high serum levels, typically above 25 mg/dL, unconjugated bilirubin can cross the blood-brain barrier, causing neurotoxicity. While more commonly seen in patients with CN1, patients with CN2 are also at risk, especially in cases where serum bilirubin levels may rise to 40 mg/dL. Commonly affected areas of the brain include the hippocampus, geniculate bodies, basal ganglia, and nerve nuclei.[34] Early diagnosis and treatment are crucial to prevent kernicterus. 

• Chronic jaundice: Persistent disease and delayed diagnosis lead to chronic jaundice. Bilirubin levels progressively increase due to limited excretion, leading to widespread deposition throughout the body at later stages.

• Cholelithiasis: Increased unconjugated bilirubin concentration can lead to gallstone formation, usually appearing later in life due to the gradual accumulation of bilirubin.

• Liver cirrhosis: Liver cirrhosis develops over a prolonged period. Most children born with Crigler-Najjar syndrome have healthy livers initially. The exact mechanism of liver cirrhosis remains unknown. However, it may result from chronic biliary obstruction secondary to cholelithiasis, toxicity from drugs primarily metabolized in the liver, toxicity from phototherapy, and heme degradation products.[35]