Case 2: Newborn with jaundice and “hyperglycemia”

A nine-day-old boy was admitted to the paediatric ward of a regional hospital after a maternal-newborn clinic appointment, where he was found to be jaundiced with a total serum bilirubin of 400 μmol/L. He had been followed by the public health nurse in the community for poor weight gain in his first week of life. His weight on the day of admission was 2.52 kg, while his birth weight had been 2.81 kg.

The pregnancy and family history were unremarkable, and the boy was born at term with an uncomplicated initial stay in the hospital. Breastfeeding had been established before discharge home on the second day of life and was supplemented with formula by bottle after an appointment on the fifth day at the maternal-newborn clinic, where the boy was found to have lost over 10% of his birth weight. His parents reported that he was becoming less and less interested in eating, and by the day of admission, they needed to wake him for most feeds.

On admission, he was jaundiced and moderately dehydrated but otherwise had a normal physical examination. Other than the hyperbilirubinemia, the remainder of the initial blood work was unremarkable. The direct antiglobulin test was negative. The baby was started on double phototherapy and intravenous rehydration, and within 6 h, he had a repeat total bilirubin of 309 μmol/L, with a direct bilirubin of 34 μmol/L. A glucose meter check also performed at the time showed a reading of 26 mmol/L. A serum sample sent to the laboratory showed the glucose to be 2 mmol/L. Repeat glucose meter checks performed overnight were all greater than 20 mmol/L, while laboratory samples were in the low to normal range. After approximately 24 h of phototherapy, the total bilirubin was 250 μmol/L, with a direct bilirubin of 39 μmol/L. The baby developed a bronzed colour (direct hyperbilirubinemia), and liver function tests showed an alkaline phosphatase of 685 U/L, alanine aminotransferase of 83 U/L and aspartate aminotransferase of 155 U/L. A urine test result was able to quickly point to the likely diagnosis.

CASE 2 DIAGNOSIS: GALACTOSEMIA (GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE DEFICIENCY)

The urine was strongly positive for reducing substances and negative for glucose. Other studies performed as part of the evaluation of the direct hyperbilirubinemia included abdominal ultrasound (to assess liver and biliary anatomy); alpha-1-antitrypsin level; urine for viral culture; thyroid function; metabolic screen; and hepatitis viral serology. A confirmatory red blood cell study of galactose-1-phosphate uridyl transferase (GALT) activity showed markedly reduced quantity. The baby was started on a lactose-free soy formula two days after admission, resulting in a marked improvement in feeding, growth and liver function tests.

The differential diagnosis for a newborn with a direct hyperbilirubinemia (conjugated bilirubin greater than 30 μmol/L or greater than 15% of total bilirubin) is broad. Etiologies can be divided into three general categories (1): obstruction to biliary flow, hepatic cell injury and chronic bilirubin overload. Obstruction to biliary flow can be secondary to anatomic abnormalities (eg, extrahepatic biliary atresia) or from the production of viscous bile (eg, cystic fibrosis). Hepatic injury can be from numerous sources, such as congenital infections, parenteral nutrition or inborn metabolic errors (eg, galactosemia). Chronic bilirubin overload is less commonly a cause of direct hyperbilirubinemia in the newborn period but can be seen with hemolytic anemias, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency or hereditary spherocytosis.

Initial investigations should confirm a cholestatic picture, establish liver function and detect readily treatable disorders. Secondary investigations should identify a specific diagnosis among the more common etiologies. Preliminary investigations include total and direct bilirubin levels, blood and urine cultures, direct antiglobulin test, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, serum glucose, albumin, ammonia, coagulation studies and a complete blood count with differential. To further delineate a diagnosis, more specific testing can be done, such as an abdominal ultrasound, alpha-1-antitrypsin, congenital infection screen, metabolic screen (blood gas, serum amino acids and urine organic acids), sweat chloride, urine for reducing substances (see below), thyroid studies or other tests as indicated.

Galactosemia is an autosomal recessive disorder in which galactose is not properly metabolized. Dietary lactose is broken down by lactase into glucose and galactose and then, in a three-step process, galactose is converted to glucose. This metabolic pathway is particularly important for the newborn, whose main carbohydrate source is lactose. Classic galactosemia, by far the most common variant, involves a deficiency of GALT. This results in a buildup of galactose-1-phosphate and other precursors, causing damage to many organs, including the liver, spleen, kidney, ocular lens, cardiac muscle, brain, gonadal tissue and erythrocytes. The earlier the disorder is diagnosed and a galactose-free diet is implemented, the less damage will ensue. Even with optimal dietary treatment, developmental delays and learning disabilities are common, and affected women almost invariably suffer premature ovarian failure (2).

Galactosemia has an incidence of approximately one in 60,000 in North America (3). Several countries have universal newborn screening for galactosemia, but the practice is not widespread. In Canada, only a minority of provinces have a newborn galactosemia screening program in place. More common symptoms and signs suggestive of galactosemia are as follows (4):

• poor feeding or weight gain

• vomiting

• diarrhea

• jaundice

• cataracts

• lethargy

• hypotonia

• hepatomegaly

• encephalopathy

• full fontanel

• bleeding or easy bruising

There are also several reports of galactosemic infants presenting with Escherichia coli sepsis (5).

The presence of urinary reducing substances in the absence of glucosuria (as detected by a routine dipstick test) supports the diagnosis of galactosemia. False-positive and false-negative results are not uncommon. Urinary reducing substances will not be present if the infant is not receiving any dietary galactose (ie, infants already switched to a soy-based formula). The Beutler enzyme spot test is not widely available outside of academic centres but is a more sensitive, rapid test for galactosemia due to GALT deficiency. A recent blood transfusion can cause a false-negative result, while G6PD deficiency results in false-positive results. The confirmatory test (red blood cell quantitative GALT assay) may take some time, but in the interim, a galactose-free diet should be instituted. Finally, red blood cell galactose-1-phosphate concentrations are elevated in all causes of galactosemia regardless of the specific enzyme defect, but the test is not widely available.

In the above case, the discordant glucose meter and serum sample glucose concentrations also provided an important clue to the diagnosis. The need to confirm glucose meter checks with serum samples should be emphasized. Some glucose meters will overestimate the serum glucose in the setting of hypergalactosemia due to the lack of specificity of the enzyme used by the assay (6). As well, untreated galactosemic infants like the one described above may be hypoglycemic because a major source of their dietary glucose is, in effect, not available.

CLINICAL PEARLS

• Conjugated hyperbilirubinemia in the newborn is always pathological and requires a systematic approach to diagnosis. Common and treatable conditions should be ruled out promptly.

• Galactosemia is a relatively rare disorder, but early recognition is key to improving outcome.

• If galactosemia is suspected, a galactose-free diet should be initiated pending confirmatory test results.

• Those caring for newborns need to be aware that some commercially available glucose meters will overestimate serum glucose levels in the setting of galactosemia.