Neonatal cholestasis, hyperferritinemia, hypoglycemia and deafness: a diagnostic challenge

Abstract

Neonatal conjugated hyperbilirubinemia is a diagnostic challenge. A full term, small for gestational age boy presented with cholestasis, hypoglycemia, hyperferritinemia and severe bilateral deafness. Diagnostic work-up revealed two hereditary diseases: alpha-1-antitrypsin deficiency (PI*ZZ genotype) and autosomal recessive deafness type 3 (compound heterozygous MYO15A gene mutation). In addition, we found late hypoglycemia on full enteral feeding which complicated this case. Hyperferritinemia is an uncommon finding in newborn cholestasis without liver failure.

Background

Neonatal hyperbilirubinemia remains a diagnostic challenge. Clinical features and laboratory findings are used to reach a fast diagnosis. However, unusual clinical presentation may require unexpected intervention and can delay correct diagnosis.

In this manuscript, we describe how the presence of two hereditary diseases in one newborn, alpha-1-antitrypsin (A1AT) deficiency (PI*ZZ genotype) and autosomal recessive deafness type 3 (compound heterozygous MYO15A gene mutation), complicate timely diagnosis. In addition, we describe early hyperferritinemia as underrecognised feature of neonatal A1AT deficiency and associated transient liver disease, and late hypoglycemia as complicating factor. Our findings are therefore important for clinical management of neonatal cholestasis.

Case presentation

A Caucasian newborn boy, born after 39 weeks gestation, was small for gestational age (SGA), birth weight 2462 g (percentile <2.3), with a good start after birth (Apgar score 7 after 1 min and 8 after 5 min) and no active resuscitation required at delivery. He was admitted to our unit because of feeding difficulties, early hypoglycemia and clinical and biochemical sepsis. He developed clinical icterus with an unconjugated hyperbilirubinemia on day 5 for which he received phototherapy for 2 days. Routine blood control at day 7 showed cholestasis with a conjugated hyperbilirubinemia (max. 177.1 µmol/L), elevated transaminases (aspartate aminotransferase (AST) max. 620 U/L and alanine aminotransferase (ALT) max. 171 U/L) and normal gamma GT (max. 57 U/L). The hyperbilirubinemia slowly decreased over time (figure 1). The boy’s stool was light green.

Figure 1.

Levels of total and direct bilirubin.

In addition, he developed repeated hypoglycemia, lowest 1.4 mmol/L (figure 2), from day 16 onwards while already on full enteral feeding. Despite gradual increase of oral carbohydrate intake from 4.9 g/kg/day to eventually 7.7 g/kg/day and caloric intake from 101 kcal/kg/day to 126 kcal/kg/day on day 21, glucose levels only normalised after replacing regular formula with a medium chain fatty acid-based formula, resulting in a caloric intake of 149 kcal/kg/d.

Figure 2.

Minimum glucose level per day of admission.

Investigations

Evaluation of the cholestasis showed a normal abdominal ultrasound, therefore biliary atresia was very unlikely. Metabolic diagnostics including the Dutch newborn screening for inborn errors of metabolism were normal. Microbiological work-up revealed no viral infection, especially repeated PCR on cytomegalovirus (CMV) in urine and CMV PCR on blood from day 4 (from the Dutch newborn screening) was negative. Liver function (ammonium and coagulation) was normal besides a low albumin (lowest 13.9 g/L). Growth hormone deficiency was suspected, but ruled out both by lab value (22.9 mU/L) and by diagnostic growth hormone supplementation not affecting glucose levels. Lab results also showed high ferritin (max. 10 004 µg/L), with a low transferrin (1.13 g/L) and a low C reactive protein (max. 7 mg/L). A1AT was low (0.34 g/L). Hearing tests by both automated auditory brainstem response and brainstem evoked response audiometry showed severe bilateral hearing loss. Ophthalmological examination was normal. The patient has an aunt recently diagnosed with A1AT deficiency. There are no family member with liver disease, kidney disease nor hearing problems. Parents were not consanguineous.

Subsequent genetic diagnostics revealed A1AT deficiency, with PI*ZZ genotype and PI*Z phenotype. Whole exome sequencing, targeted on both neonatal cholestasis and congenital hearing loss, followed by an analysis of all exome data, revealed a compound heterozygous mutation in the MYO15A gene, causing autosomal recessive deafness type 3.

Treatment

The boy was discharged after 4 weeks, with vitamin A, D, E and K supplementation and medium chain fatty acid-based formula.

Outcome and follow-up

Follow-up at the age of 6 weeks showed a slow decrease in direct and total bilirubin levels, 81.7 µmol/L and 117.1 µmol/L, respectively, for which ursodeoxycholic acid was started. At age 5 months there was a normal direct bilirubin.

At age 22 months cochlear implants were placed.

Discussion

Conjugated hyperbilirubinemia in the neonatal period is always abnormal and subsequent diagnostic should be initiated. Early diagnostics to specify the underlying condition can be of uttermost importance.^1–3

A1AT deficiency is an autosomal recessive disorder, affecting approximately 1 in 2000 live births in northern Europe. It is the most common genetic cause of liver disease and has different phenotypes and genotypes affecting clinical presentation and course. The most common presentation of A1AT in newborns is icterus or cholestasis, hepatomegaly and growth delay.¹ However, our patient presented with unusual diagnostic findings not typically associated with A1AT deficiency. An uncommon finding was transient hyperferritinemia, which normalised after 5 months. Ferritin is an acute phase protein. A1AT deficiency has been associated with systemic disruption in iron homeostasis in adults. This is proposed to be due to an unrestricted activity of specific proteases which would increase iron availability, thereby increased iron storage in the liver and spleen and thus increased blood ferritin.⁴ Also in newborn infants with liver failure serum ferritin levels are raised, irrespective of the cause.⁵ Our patient had cholestasis without severe liver failure. Association of neonatal A1AT deficiency with high ferritin levels has to our knowledge so far not been described, and can be misleading, pointing to other differential diagnosis such as neonatal hemochromatosis or hemophagocytic lymphohistiocytosis.

The second uncommon finding in our case was severe bilateral hearing loss. The most common cause of neonatal cholestasis in combination with congenital hearing loss is congenital CMV infection, which was ruled out in our patient.⁶ Hearing loss is not associated with A1AT deficiency. Further evaluation showed a second genetic defect in this patient, namely a compound heterozygous mutation in the MYO15A gene. This gene is located on chromosome 17p11.2 and causes autosomal recessive deafness type 3 and is the third most common cause of autosomal recessive, non-syndromic deafness. Myosin 15 is expressed in the inner ear and is necessary for both development and long-term maintenance of stereocilia, hair cells of the cochlea. If impaired, sound transduction will be distorted.⁷ Presentation with symptoms associated with two different hereditary diseases made diagnosis even more challenging.

Finally, diagnosis and clinical management was complicated by hypoglycemia detected on day 16. Hypoglycemia associated with neonatal A1AT deficiency has, to our knowledge, so far only been described in an Indian boy who was large for gestational age⁸ and is not a characteristic feature of the disease. Our patient had hypoglycemia in the first 2 days after birth which was most likely due to his low birth weight. The aetiology of the later period of hypoglycemia, while on normal caloric intake, is unclear. In neonatal hypoglycemia, inborn errors of metabolism and endocrine disorders (eg, cortisol deficiency, growth hormone deficiency, transient diabetes mellitus, hyperinsulinism⁹) need to be ruled out. However, we restricted diagnostic work-up due to the fact that hypoglycemia could be managed by adjusting caloric intake. If hypoglycemia from day 16 onwards was caused by SGA status of the baby or if impaired gluconeogenesis and glycogenolysis associated with liver disease caused by A1AT deficiency contributed to the clinical course, remains speculative. Therefore we advise close monitoring of caloric intake and hypoglycemia in cases of neonatal liver disease.

To conclude, diagnostic work-up of neonatal cholestasis stays challenging. Symptoms like hyperferritinemia can be associated with neonatal A1AT deficiency, even if severe liver failure is absent, and hypoglycemia can complicate clinical management. These findings can be misleading during the diagnostic work-up.

Learning points.

• Alpha-1-antitryspin (A1AT) deficiency is the most common genetic cause of liver disease. Neonatal A1AT deficiency can be associated with high ferritin levels without liver failure.

• The unusual presence of two genetic disorders can delay diagnosis.

• Glucose levels and caloric intake should be monitored carefully in all newborn infants with liver disease even if the underlying cause is not yet determined.