Jaundice - Case 15-6: 5-Week-Old Girl
Jaundice - Case 15-6: 5-Week-Old Girl: Excerpt from Pediatric Complaints and Diagnostic Dilemmas
I. History of Present Illness
A 5-week-old girl was referred to the hospital for evaluation of her jaundice
and poor weight gain. Her father stated that she had been
“yellow her whole life,” starting before she left the newborn nursery. Except for some nasal congestion,
the baby seemed to be acting and sleeping normally. She had been feeding on cow
's milk formula, taking 2 to 3 ounces every 3 hours, and made five to six wet
diapers per day. The father described the baby
's stool output as two to four “loose” and “pasty” bowel movements per day. There was no history of fever, emesis, diarrhea,
travel, or unusual exposures.
II. Past Medical History
The baby weighed 3.25 kg at birth; she was the product of a full-term gestation,
delivered via cesarean section to a mother with a history of osteoporosis and
back pain. The mother took no medications and denied use of drugs or alcohol.
The baby was discharged home with her mother on the second day of life. She
lived at home with both parents. There was no family history of cystic
fibrosis, cardiac or gastrointestinal disease, or other pediatric illnesses.
III. Physical Examination
T, 37.2°C; RR, 28/min; HR, 120 bpm; BP, 80/56 mm Hg
Weight, 3.35 kg (5th percentile); length, 51 cm; head circumference, 36 cm
The infant appeared small but comfortable in her father's lap. She had an open, flat fontanel and a broad forehead; equal and round
pupils; and scleral icterus. The oropharynx was clear with moist mucous
membranes. Respirations were clear and unlabored. Cardiac examination revealed
a II/VI systolic murmur that was loudest at the left sternal border; the rate,
rhythm, and distal pulses were all normal. Her abdomen was soft and
nondistended, with a smooth liver edge palpable 3 cm below the right costal
margin; no spleen or other masses were appreciated. The genitourinary,
extremity, and neurologic examinations were all normal.
IV. Initial Diagnostic Studies
A complete blood count revealed the following: 16,700 WBCs/mm3 (31% segmented neutrophils and 61% lymphocytes); hemoglobin, 9.6 g/dL; and
625,000 platelets/mm
3. The BUN and creatinine concentrations were 26 and 1.1 mg/dL, respectively.
Serum electrolytes were normal. The total bilirubin concentration was 11.0
mg/dL; unconjugated and conjugated bilirubin were 8.0 and 3.1 mg/dL,
respectively. The remainder of the hepatic function panel was as follows: ALT,
190 U/L; AST, 94 U/L; albumin, 3.0 mg/dL; and alkaline phosphatase, 450 U/L.
Blood and urine cultures were obtained and were negative. Evaluations for
toxoplasmosis, rubella, cytomegalovirus, and HIV were also negative.
V. Course of Illness
The baby was admitted to the hospital for further evaluation. A renal ultrasound
study showed two somewhat small but otherwise unremarkable kidneys, and
biochemical measurements of her renal function (e.g., BUN, creatinine, non
–anion gap metabolic acidosis) trended toward normal during the hospitalization
without specific therapy. Echocardiography revealed a structurally normal
heart. An extensive investigation of her cholestatic jaundice culminated in a
liver biopsy and intraoperative cholangiogram. The biopsy showed prominent
cholestasis, occasional giant hepatocytes, and a ratio of bile ducts to portal
tracts of about 0.5 (normal, 0.9 to 1.8); the cholangiogram was normal.
Discussion: Case 15-6
I. Differential Diagnosis
This infant presented with the following signs: a nonobstructive conjugated
hyperbilirubinemia; renal insufficiency with a mild, non
–anion gap metabolic acidosis; poor weight gain; and a heart murmur. Her liver
biopsy revealed cholestasis and bile duct paucity.
Interlobular bile duct paucity is the characteristic, but not unvarying,
pathologic finding in Alagille syndrome; biopsies performed early in the
disease
's course might simply reveal findings of cholestasis, inflammation, or even
ductal proliferation. In addition, bile duct paucity is sometimes seen in
diseases other than Alagille syndrome. So-called nonsyndromic bile duct paucity
can be a feature of congenital infections (e.g., CMV, rubella, syphilis),
metabolic disorders (e.g.,
α 1-antitrypsin deficiency, defects of bile acid synthesis), sclerosing
cholangitis, and idiopathic cholestasis.
II. Diagnosis
As part of an extensive evaluation, the baby was seen by a geneticist, who noted
hypertelorism and a pointed mandible in addition to the broad forehead noted on
initial examination. The recommended ophthalmology examination revealed the
baby to have posterior embryotoxon, and a review of her admission chest
radiograph detected butterfly vertebrae. The baby
's constellation of clinical and pathologic findings led to a diagnosis of Alagille syndrome.
III. Pathology
Alagille syndrome (also known as arteriohepatic dysplasia) is an uncommon
disorder of intrahepatic bile duct paucity associated with well-defined
anomalies of the heart, eyes, kidneys, and skeleton. The inheritance is
autosomal dominant with variability in expression, although many cases appear
to arise from new mutations. The disease has been mapped to chromosome 20,
specifically to mutations in
JAGGED1, which is part of a cell signaling pathway important in embryogenesis.
IV. Clinical Presentation
Alagille syndrome typically manifests as cholestasis in the first months of
life. Clinical and laboratory findings of the liver disease include jaundice,
acholic stools, pruritus, growth failure, conjugated hyperbilirubinemia, and
elevations of hepatic enzymes. Most patients with Alagille syndrome also have
heart murmurs, and the underlying heart conditions range in severity from
benign (e.g., mild peripheral pulmonary stenosis) to complex disease requiring
surgery (e.g. tetralogy of Fallot). The most common ocular finding in Alagille
syndrome is posterior embryotoxon, a dysgenesis of the anterior chamber of the
eye (best seen on slit-lamp examination) in which there is prominence of
Schwalbe
's ring, a ridge of collagenous fibers surrounding the periphery of Descemet's membrane.
Patients with Alagille syndrome often have a distinctive facies that may be
detectable as early as infancy. Features can include a triangular face with a
broad forehead and pointed chin, deeply set eyes, and a long nose with a
bulbous tip. Xanthomas are another physical finding common to patients with
Alagille syndrome.
Other problems associated with Alagille syndrome include renal anomalies (both
structural and functional), pancreatic insufficiency, intracranial hemorrhage,
and cognitive impairments. Assessments of renal function and anatomy (i.e.,
ultrasonography) should be performed. The patient presented in this case, for
example, demonstrated slow but spontaneous improvement in her renal function
and never required alkali supplementation.
V. Diagnostic Approach
Patients with known or suspected Alagille syndrome require a multidisciplinary
initial assessment. The diagnosis is based on the histopathologic demonstration
of bile duct paucity in the setting of well-recognized clinical associations as
described later. Early evaluation and follow-up by specialists in
gastroenterology and nutrition is critical. In addition, cardiology and
ophthalmology evaluations should be performed as early as possible.
Chest radiography. Radiographs of the chest are necessary to assess for vertebral anomalies
(butterfly vertebrae and hemivertebrae).
Ophthalmologic evaluation. Ophthalmologic evaluation detects posterior embryotoxon.
Echocardiography. Recognized cardiac involvement includes peripheral pulmonary artery stenosis and
tetralogy of Fallot.
Genetic consultation. As previously noted, most patients with Alagille syndrome have a characteristic
facial appearance. Early evaluation by a geneticist can help guide diagnosis
and provide appropriate genetic counseling. In addition, genetic testing is now
available for
JAGGED1 mutations. The testing is far from perfect, however, and a significant
percentage of patients with Alagille syndrome have no demonstrable mutation.
VI. Treatment
Treatment of Alagille syndrome focuses on the medical management of cholestasis,
promotion of growth and development, and treatment of any comorbidities (e.g.,
congenital heart disease). Children with Alagille syndrome suffer from
malabsorption and require supplementation of fat-soluble vitamins and provision
of sufficient calories for growth, which may necessitate tube feeding. Infants
should receive formulas containing medium-chain triglycerides, which are
absorbable without bile salts. Medications that may benefit Alagille patients
(for example, by promoting bile flow or reducing pruritus) include
phenobarbital, cholestyramine, ursodeoxycholic acid, and antihistamines.
Long-term follow-up of patients with Alagille syndrome includes monitoring for
the development of cirrhosis, portal hypertension, ascites, and liver failure.
The 20-year life expectancy for patients with Alagille syndrome is about 75%
overall, although rates are lower for those patients who require liver
transplantation and for those with severe associated abnormalities (e.g.,
congenital heart disease).
VII. References
1. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92
patients: frequency and relation to prognosis.
Hepatology 1999;29:822–829.
2. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997;34:152–157.
3. Piccoli DA. Alagille syndrome. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver disease in children, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2001:327–342.
4. Piccoli DA, Witzleben CL. Intrahepatic bile ducts. In: Walker WA, Durie PR,
Hamilton JR, et al., eds.
Pediatric gastrointestinal disease, 3rd ed. Hamilton, Ontario: BC Decker, 2000:895–914.
5. Suchy FJ. Anatomy, histology, embryology, developmental anomalies, and
pediatric disorders of the biliary tract. In: Feldman M, ed.
Sleisenger and Fordtran's gastrointestinal and liver disease, 7th ed. Philadelphia: WB Saunders, 2002:1019–1042.
Book Source Details
- Book Title: Pediatric Complaints and Diagnostic Dilemmas
- Author(s): Samir S Shah MD; Stephen Ludwig MD
- Year of Publication: 2003
- Copyright Details: Pediatric Complaints and Diagnostic Dilemmas, Copyright © 2003 Lippincott Williams & Wilkins.
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