Jaundice - Case 15-1: 14-Day-Old Boy
Jaundice - Case 15-1: 14-Day-Old Boy: Excerpt from Pediatric Complaints and Diagnostic Dilemmas
I. History of Present Illness
A 14-day-old, full-term male infant was transferred from a local community
hospital for further evaluation and management of sepsis and
hyperbilirubinemia. He had been discharged home from the well-baby nursery on
the fourth day of life with a bilirubin concentration of 16.7 mg/dL. Two days
later, his bilirubin level was 19.4 mg/dL and he was admitted for phototherapy.
Within 48 hours after admission, he developed emesis and temperature
instability. A blood culture and lumbar puncture were performed, and ampicillin
and gentamicin were started. Additional bilirubin measurements revealed the
direct fraction to be 5.2 mg/dL. An ultrasound study, performed to assess
hepatomegaly, revealed a nondilated biliary system, small gall bladder, and
diffuse hepatic enlargement. A nuclear medicine liver scan did not show bile
excretion after 4 hours, prompting initiation of phenobarbital therapy.
The baby continued to receive breast milk feedings (with nasogastric tube
supplementation required because of poor oral intake) until he experienced
blood-tinged emesis. Coagulation studies at that time revealed the prothrombin
time (PT) to be greater than 50 seconds and the partial thromboplastin time
(PTT) to be greater than 200 seconds; for this reason, vitamin K and a dose of
fresh-frozen plasma were given. By report, the baby
's abdomen was soft and his stool quantity and quality were unremarkable.
Transfer to a tertiary care center was arranged.
II. Past Medical History
The baby was born to a 27-year-old gravida 1 parity 0 mother with unremarkable
prenatal laboratory values. Delivery was via cesarean section at 37 weeks
because of breech presentation. The baby
's birth weight was 3.04 kg. He was discharged with his mother on the fourth day
of life and was breast-feeding every 3 hours.
III. Physical Examination
T, 36.4°C; RR, 48/min; HR, 140 bpm; BP, 83/50 mm Hg
Weight, 2.7 kg
Physical examination revealed a 2-week-old term boy who was listless but
arousable. His skin demonstrated a yellow-green jaundice but no petechiae,
rash, or bruising. He was nondysmorphic and normocephalic, with an open, flat
fontanel. His pupils were equal, round, and reactive with red reflexes present
bilaterally. Mucous membranes were yellow-pink and slightly dry. His
respirations were slightly rapid but otherwise unlabored with clear breath
sounds bilaterally. The heart examination was normal. The abdomen was soft and
nondistended, with a smooth, firm liver edge palpable 3 cm below the right
costal margin. Examinations of the genitalia and extremities were normal. His
tone, power, and primitive reflexes all appeared to be within normal limits.
IV. Diagnostic Studies
A complete blood count revealed the following: white blood cells (WBCs),
9,400/mm
3 (1% band forms, 41% segmented neutrophils, and 45% lymphocytes); hemoglobin,
16.0 g/dL; and platelets, 66,000/mm
3. PT and PTT were markedly prolonged at 50 and 112 seconds, respectively.
Fibrinogen was 127 mg/dL, and fibrin split products were negative. Serum
bicarbonate was 17 mEq/L, but the remainder of the serum electrolytes, calcium,
magnesium, and phosphorus were normal. Serum glucose was 52 mg/dL. A hepatic
function panel revealed the following: alanine aminotransferase (ALT), 115 U/L
aspartate aminotransferase (AST), 126 U/L; alkaline phosphatase, 730 U/L;
γ-glutamyl transferase (GGT), 55 U/L; and albumin, 3.5 mg/dL. The unconjugated
bilirubin concentration was 13.1 mg/dL, and the conjugated bilirubin was 5.9
mg/dL.
V. Course of Illness
On admission, the infant received intravenous fluids and antibiotics. In
addition, he required a second dose of fresh-frozen plasma for treatment of his
coagulopathy. A repeat liver ultrasound examination was consistent with the
earlier study. An ophthalmology examination was unremarkable. In light of the
illness as described and mild hypoglycemia, the baby ultimately received a full
10 days of antibiotic therapy for presumed sepsis. The blood culture from the
referring hospital remained negative.
Further testing revealed a specific underlying diagnosis. This determination
guided the infant
's subsequent inpatient management.
Discussion: Case 15-1
I. Differential Diagnosis
The differential diagnosis for the systemically ill neonate is quite broad.
Infectious causes are often considered first, especially common bacterial
pathogens (e.g., group B
Streptococcus, staphylococci, Escherichia coli, Listeria monocytogenes) and viruses (e.g., HSV, enterovirus). Less often, fungi (e.g., Candida species) and other classes of organisms (e.g., parasites) are implicated.
Congenital heart disease is another critically important consideration in sick
neonates; ductal-dependent anatomic lesions (e.g., coarctation of the aorta,
hypoplastic left heart syndrome) and tachydysrhythmias may manifest early in
life with profound cardiovascular compromise. Shock can also be seen in
severely anemic infants
—for instance, after a placental catastrophe or even a major intracranial
hemorrhage. Multiorgan dysfunction can also result from perinatal asphyxia,
neonatal surgical emergencies, and a multiplicity of endocrine and metabolic
abnormalities (including congenital adrenal hyperplasia, glucose and
electrolyte derangements, and numerous inborn errors of metabolism).
Conjugated hyperbilirubinemia in the neonate, such as that seen in the patient
described here, also has a multiplicity of causes. Among the possibilities are
idiopathic neonatal hepatitis,
α1-antitrypsin deficiency, hypopituitarism, hypothyroidism, bile acid synthesis
deficiency, exposure to intravenous hyperalimentation, and long lists of
infections and disorders of hepatobiliary anatomy. Similarly, neonatal
hepatomegaly is seen in a wide variety of settings, including infections
—either congenitally acquired (e.g., TORCH) or acute-onset (e.g., sepsis);
neonatal hepatitis; liver or gall bladder disease (e.g.,
α1-antitrypsin deficiency, biliary atresia, choledochal cyst); hydrops or
congestive heart failure; tumors; and metabolic disease (e.g., glycogen storage
diseases, galactosemia, tyrosinemia).
In addition to jaundice and hepatomegaly, the baby in this case study had
elevated liver enzymes and possible liver synthetic dysfunction (as a potential
contributing factor in his coagulopathy). In addition, his hepatobiliary
scintigraphic examination was concerning for its lack of excretion at 4 hours.
II. Diagnosis
Shortly after interhospital transfer, this baby's state newborn screening results revealed him to have galactosemia.
III. Incidence and Pathophysiology
Galactosemia is a rare inborn error of metabolism that occurs in 1 of every
60,000 infants. It is caused by the absence of an enzyme of galactose
metabolism. Presenting signs in the galactose-exposed, affected neonate can
include jaundice, hepatomegaly, seizures, lethargy, vomiting, hypoglycemia,
cataracts, and failure to thrive. In addition, babies with galactosemia exhibit
a heightened susceptibility to bacterial infection, particularly
Escherichia colisepsis. Although galactosemia is widely assessed in state newborn screening
programs, the onset of life-threatening clinical illness may precede the
completion of testing.
The hydrolysis of dietary lactose produces glucose and galactose. Galactose is
subsequently phosphorylated to galactose-1-phosphate. This compound, in turn,
is converted by the galactose-1-phosphate uridyl transferase enzyme to uridine
diphosphate (UDP)-galactose. These conversions enable galactose to enter the
glycolytic pathway of the cell. If the transferase enzyme is missing, as it is
in
“classic” galactosemia, galactose-1-phosphate accumulates in the tissues, and signs and
symptoms of the disease become evident. Classic galactosemia is caused by a
mutation in the
GALT gene, which codes for the galactose-1-phosphate uridyl transferase enzyme. In
addition, there are two other types of
“nonclassic” galactosemia. Galactokinase deficiency, a deficiency of the enzyme necessary
for the phosphorylation of galactose, can cause jaundice, cataracts, and
elevations of plasma galactose levels but does not result in mental deficiency.
A second and still rarer type of galactosemia is caused by uridyl
diphosphogalactose 4-epimerase deficiency. This condition behaves very much
like classic galactosemia.
IV. Clinical Presentation
Classic galactosemia is an autosomal recessive disease. If not recognized and
treated, it can be fatal in the neonatal period. Some of the more common
presenting clinical signs have already been discussed (jaundice, hepatomegaly,
vomiting, and encephalopathy); more fulminant clinical courses may represent
superimposed bacterial sepsis. Among the laboratory findings seen with classic
galactosemia are conjugated (or combined) hyperbilirubinemia, liver function
test and coagulation study abnormalities, elevations of serum and urine amino
acids, and a renal tubulopathy with galactosuria, glycosuria, proteinuria, and
metabolic acidosis. Not surprisingly, plasma galactose and erythrocyte
galactose-1-phosphate levels are also elevated.
Disappointingly, even galactosemic children whose diets were restricted very
early are at increased risk for developmental delays and learning disabilities,
compared with their healthy counterparts. Although many children have IQs in
the normal range, cognitive, speech, and motor impairments are, nevertheless,
more common. Longer delays before initial diagnosis and treatment of
galactosemia correlate with worse neurodevelopmental sequelae.
Hypergonadotropic hypogonadism is often observed in girls with galactosemia, and
most are infertile as adults. Galactosemic males demonstrate normal puberty and
fertility.
The gene for the galactose-1-phosphate uridyl transferase enzyme has been
localized to chromosome 9, and multiple variations at that locus have been
described. Some African-Americans with galactosemia have a milder clinical
course because of a different transferase variant. Still another variant, known
as the Duarte variant, is usually clinically insignificant. Prenatal diagnosis
of galactosemia is available.
V. Diagnosis
Definitive diagnosis of galactosemia is established by laboratory assay of the
glucose-1-phosphate uridyl transferase enzyme in erythrocytes. If clinical
suspicion for galactosemia exists, preliminary evidence for that diagnosis can
be obtained by testing the infant
's urine for nonglucose reducing substances (provided that the infant had
recently been exposed to lactose). Caution must be taken to employ the
appropriate urine tests, because glucose-oxidase strips (e.g., Clinistix) are
sensitive only to glucose, whereas Clinitest tablets detect all reducing
substances, including glucose, galactose, and fructose. An ill-appearing,
jaundiced neonate with nonglucose reducing substances present in the urine
should be presumed to have galactosemia until definitive testing is available.
VI. Treatment
The removal of galactose from the diet remains the first principle of therapy
for galactosemia. The exclusion of milk (including breast milk) and dairy
products is necessary for the patient
's lifetime.
Depending on the degree of illness at the time of presentation, galactosemic
neonates often require supportive care measures such as intravenous fluids and
antibiotics. Liver synthetic function may be compromised, and the sick infant
may require supplemental vitamin K or even transfusion of fresh-frozen plasma.
VII. References
1. Chen YT. Defects in metabolism of carbohydrates. In: Behrman RE, Kleigman RM,
Jenson HB, eds.
Nelson textbook of pediatrics, 16th ed. Philadelphia: WB Saunders, 2000:405–420.
2. D'Agata ID, Balistreri WF. Evaluation of liver disease in the pediatric patient. Pediatr Rev 1999;20:376–389.
3. Gotoff SP. Infections of the neonatal infant. In: Behrman RE, Kleigman RM,
Jenson HB, eds.
Nelson textbook of pediatrics, 16th ed. Philadelphia: WB Saunders, 2000:538–552.
4. Walter JH, Collins JE, Leonard JV. Recommendations for the management of
galactosaemia.
Arch Dis Child 1999;80:93–96.
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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