2023.01.10 | Questions 19-20
A newborn with elevated bilirubin
Hello,
Please find this week’s questions below. At the end of this email, there’s a video to help remember the clinical features of the disorder in question.
I hope you have a great week!
- Daniel
Questions
Question 19
A 1-week-old girl is being evaluated because of direct (conjugated) hyperbilirubinemia. An echocardiogram shows pulmonic stenosis. Labs are notable for a normal urine succinylacetone. Ophthalmologic exam shows a right-sided posterior embryotoxon. Which of the following is the most likely diagnosis?
Question 20
A liver biopsy is performed on the neonate in question 19. Which of the following is most likely to be seen on histology?
Explanations
The patient in this vignette is a 1-week-old with direct (conjugated) hyperbilirubinemia. This finding, in combination with a right-sided posterior embryotoxon on ophthalmologic exam and pulmonic stenosis, suggest a diagnosis of Alagille syndrome (Question 19). The major clinical manifestations of Alagille syndrome include intrahepatic bile duct paucity (Question 20), cholestasis, congenital cardiac defects (e.g. pulmonic stenosis), butterfly vertebrae, and ophthalmologic abnormalities (most commonly posterior embryotoxon). Over time, cholestasis may be progressive, necessitating liver transplant. Facial features such as a broad forehead, deeply set eyes, hypertelorism, and a pointed chin (giving the appearance of an inverted triangle) can also be seen. Growth failure due to malabsorption or cholestasis can also be seen in patients with Alagille.
Almost all cases of Alagille syndrome are caused by autosomal dominant mutations in the JAG1 gene, which encodes the jagged-1 protein, a transmembrane cell surface protein that serves as a ligand in the Notch signaling pathway (see figure below). A small subset of Alagille syndrome (<5%) is due to mutations in NOTCH2 gene, which encodes a receptor for the jagged and delta-like ligands. Aberrant NOTCH signaling, in turn, leads to organ malformation (e.g. heart and liver). About 60% of patients with Alagille have de novo pathogenic variants, while 40% inherited a pathogenic variant from a parent. Alagille syndrome is characterized by highly variable expressivity (e.g. from subclinical to severe), even between patients with the same molecular variant.
Bilirubin is a breakdown product of heme, a key component of hemoglobin. Bilirubin is conjugated to glucuronic acid prior to excretion in bile, which make the bilirubin more water-soluble (and thus easier to excrete). Issues with the enzyme that catalyzes this conjugation reaction (UGT1A1) cause an unconjugated hyperbilirubinemia (see below). Disorders that disrupt the outflow of conjugated bilirubin (eg issues with formation of bile ducts or with transport of conjugated bilirubin out of hepatocytes) cause a conjugated hyperbilirubinemia.
Incorrect answers
Dubin-Johnson syndrome is due to a defect in bilirubin excretion from liver into bile ducts. This disorder causes a conjugated hyperbilirubinemia, similar to Alagille syndrome, but is typically benign and not associated with multisystemic involvement, as seen in Alagille.
Crigler-Najjar type I (along with milder versions Crigler-Najjar type II and Gilbert syndrome) are due to defects in UDP-glucuronosyltransferase (UGT1A1), an enzyme that conjugates bilirubin with glucuronic acid. Patients therefore present with an unconjugated hyperbilirubinemia, as compared to the conjugated hyperbilirubinemia seen in Alagille.
Tyrosinemia type I is due to mutations in the gene fumarylacetoacetate hydrolase (FAH) and can present with liver failure and elevated succinylacetone. The patient in Q19 has a normal succinylacetone, pointing against this diagnosis.
Paucity of intrahepatic bile ducts is the classic description of the microscopic features found in Alagille syndrome. Large intracellular fat globules are seen in non-alcoholic fatty liver disease (NAFLD). Lymphocytes within hepatic portal tracts can be seen in viral hepatitis, which causes liver inflammation. Widespread hepatocellular necrosis would be found with acetaminophen (Tylenol) toxicity.
Learning objective
Alagille syndrome is a multi-systemic disorder that may present as a neonate with conjugated hyperbilirubinemia due to a fewer-than-usual number of bile ducts. Determining the type of bilirubin (conjugated vs unconjugated) in a patient with hyperbilirubinemia helps narrow the differential diagnosis.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders → x. Other (page 3)
P.S. Here is a short video (with no sound) to help remember the features of Alagille.
And here is a way to remember some of the monogenic causes of hyperbilirubinemia:
