Pathlet 003
Jeff Schlaack KCUMB '15

All the jagged parts of my life have come together to form a complete and mystical whole. An epiphany. My life is over.

      -- "Hook" (1991)

These pathlets are edutainment. This site collects no information about visitors, and cannot substitute for your own doctor's care. It has some questions without clear right-or-wrong answers. Scripting by Ed Friedlander MD.

Picasso, detail
Las Vegas, 1987, Fall

A young couple came to the hospital because they were concerned about their first-born child. This wasnít the first time this couple had made a trip to the hospital because something seemed wrong with their baby boy. When they first brought home their boy, he had turned blue. At the hospital the doctor said it was a patent ductus arteriosus (PDA) that caused the cyanotic episode. Indomethacin was given and the baby went back home a couple days later. That was 6 months ago.

Now the parents came to the doctor because the boy was showing some irregular problems with his stool. The stool was a clay/white color and the baby seemed to not being gaining any weight. Also they notice the baby has been looking yellow and keeps scratching his butt.

The father told the doctor that his own younger brother died during infancy following a failed liver transplantation. He still has the autopsy report and says that what ended up killing his younger brother was a cardiac malformation that wasnít noticed/treated at the hospital. The fatherís own past medical history is unremarkable, but he has two relatives with "progressive familial intrahepatic cholestasis."

Physical exam revealed a malnourished baby with severe growth retardation, obvious jaundice, and a palpably enlarged liver. There was something strange about the eyes as well, and the clinicians decided to phone the ophthalmologist. The baby had a broad, prominent forehead; deep-set eyes; and a small, pointed chin.

Temperature is 98.5, pulse 90, RR 16. Physical exam is remarkable upon auscultation of the heart. A loud systolic murmur was evident. At this time, the baby was not cyanotic. Lab workup was remarkable for markedly increased conjugated bilirubin, moderately increased unconjugated bilirubin, slightly increased transaminases, and bilirubin in the urine. A quick stain for fecal fat confirmed steatorrhea.

Based on the history and physical exam, what likelihood would you assign each of the following?

ALAGILLE SYNDROME Very Unlikely                   Very Likely
ANTITRYPSIN DEFICIENCY Very Unlikely                   Very Likely
BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS Very Unlikely                   Very Likely
BILIARY ATRESIA Very Unlikely                   Very Likely
BYLER SYNDROME Very Unlikely                   Very Likely
CAROLI SYNDROME Very Unlikely                   Very Likely
CYSTIC FIBROSIS Very Unlikely                   Very Likely
CRIGLER-NAJJAR Very Unlikely                   Very Likely
DUBIN-JOHNSON SYNDROME Very Unlikely                   Very Likely
LUCEY-DRISCOLL SYNDROME Very Unlikely                   Very Likely
NEONATAL HEPATITIS Very Unlikely                   Very Likely
TYROSINEMIA Very Unlikely                   Very Likely
VON GIERKE'S GLYCOGEN STORAGE DISEASE Very Unlikely                   Very Likely
WILSON'S DISEASE Very Unlikely                   Very Likely

We thought all of the above are worth considering. The child is too sick to have Dubin-Johnson or Lucey-Driscoll. This would be early but not unheard-of for Wilson's, and "eye findings" not-otherwise-specified would make any physician think of Wilson's, which is good because it's treatable. Some cystic fibrosis children have early liver damage, and this fits with the steatorrhea. Alagille's also has eye findings and the history of liver / heart disease of varying severity on Dad's side is a good match.

Here's the biopsy of the liver. We took photos of two portal areas. What's your diagnosis now?

Alagille's -- no bile ducts or ductules
Antitrypsin deficiency -- intracellular globules
Biliary atresia -- intense reactive ductular proliferation
Byler's -- chief finding is bile in the hepatocytes
Caroli's's -- the bile ducts are dilated
Neonatal hepatitis -- hepatocyte-derived giant cells
Von Gierke's -- liver cells distended with glycogen
Wilson's -- chief finding is copper in hepatocytes

The clinicopathologic diagnosis is Alagille's. The bile ducts are absent both portal areas, and there is no proliferation of the bile ductules as would be seen in other causes of biliary obstruction.
Here is another photo showing cholestasis away from the portal areas. If you have a good eye, you can spot bile in distended canaliculi.

Which of the following would you consider doing now?

Call the genetics lab and ask about JAG-1 (jagged)
Call the cardiology team to study the heart and pulmonary arteries
Call the ophthalmology team to examine the eyes
Call the liver transplant team
Offer hydroxyzine for symptomatic relief of itching
Offer ursodeoxycholic acid to reduce the levels of bile salts in the blood
Offer cholestyramine to reduce the levels of bile salts in the blood
Offer rifampin to reduce the levels of bile salts in the blood
Supplement the fat-soluble vitamins A, D, E and K.

These all sound like good ideas to us. Talk with other people who know about liver disease and general pediatrics and see what they think.

Perhaps one person in 100,000 has clinical Alagille's disease. It is inherited as an autosomal dominant with tremendously variable expressivity. The gene JAG1 ("jagged") is part of the NOTCH signalling pathway.

Among Alagille's patients...

Click here for the original paper's abstract.


Jeff Schlaack KCUMB '15

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