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Khan, Iqbal, Galal, Malallah, and Zein: Early severe neonatal hyperbilirubinaemia associated with congenital hypothyroidism treated with exchange transfusions

Introduction

Hyperbilirubinaemia is one of the common reasons for admission to neonatal units. The common cause of early neonatal hyperbilirubinaemia is pathological hyperbilirubinaemia due to haemolytic disease. However, unconjugated hyperbilirubinaemia of any aetiology is of concern once the level is high enough. It is not very difficult to diagnose the common causes of early neonatal hyperbilirubinaemia, unless the aetiology is very rare. Congenital hypothyroidism has long been recognized as a cause of prolonged jaundice, but early neonatal severe hyperbilirubinaemia requiring exchange transfusion is rarely considered to be caused by congenital hypothyroidism.

Case history

The patient was a term female infant, delivered by normal vaginal delivery. The infant’s Apgar score was normal, birthweight was recorded as 4.19 kg and she was doing well in the postnatal ward. The infant was exclusively breastfed and a 12-hour review examination by a neonatologist revealed that the infant was well.

The blood group of both the mother and the infant was O positive; therefore, cord blood bilirubin was carried out and recorded as 1.8 mg/dl. There was no known family history of jaundice, anaemia or haematological disorders. Transcutaneous bilirubin, carried out at 31 hours of age, was 8 mg, and the infant was discharged after 2 days with instructions to repeat serum bilirubin after 2 days, and to present for neonatal screening at 5 days of age at a primary health care facility (neonatal screening is now carried out at 3 days of age).

At 4 days old, the infant presented to the emergency department at Dubai Hospital with yellow discoloration of the skin. During the 2 days at home the infant had remained stable and was breastfeeding well, but yellow discoloration of the skin occurred. She was passing urine and stools normally. There was no history of fever.

On examination, the infant was deeply jaundiced but active, and no neurological signs were noted. Systemic examination was unremarkable and vitals were stable.

Serum bilirubin by heel prick method was carried out and reported as 33.9 mg/dl. The infant was immediately admitted to the neonatal intensive care unit for further management. After umbilical catheter insertion, antibiotics (ampicillin and gentamicin) were administered. In addition, intensive phototherapy was started until whole blood was arranged. After phototherapy, double volume exchange transfusion was performed and pre-exchange investigations [full blood count, reticulocyte count, Coombs test, glucose-6-phosphate dehydrogenase (G6PD), liver function tests, thin-film transistor, urea and electrolytes, blood culture] were collected and post-exchange bilirubin monitored (Table 1). The result of immediate post-exchange bilirubin was 14.9 mg/dl, but after 4 hours increased to 27.8 mg/dl; therefore, a second double-volume exchange transfusion was carried out.

TABLE 1

Laboratory reports

Investigation Result
Direct Coombs test Negative
Haemoglobin 13 g/dl
Reticulocyte count 3.9%
C-reactive protein Negative
Blood culture No growth
Urine culture No growth
G6PD Normal
Urea 38 mg/dl
Creatinine 0.7 mg/dl
Sodium 138 mmol/l
Direct bilirubin 2 mg/dl
Total bilirubin 37.4 mg/dl
Albumin 4.1 g/dl
Total protein 5.8 g/dl
Alkaline phosphatase 278 U/l
Serum glutamic-pyruvic transaminase 28 U/l

The results ruled out ABO incompatibility, Rhesus incompatibility, sepsis and G6PD deficiency. The case was labelled as non-haemolytic hyperbilirubinaemia. At this stage, a metabolic cause or Criggler–Najjar syndrome was considered to be the most probable cause of hyperbilirubinaemia, but the results of thyroid function tests were as follows:

  • triiodothyronine (T3): 3.3 pmol/l (4.5–10.5);

  • thyroxine (T4): 6.3 pmol/l (13.9–26);

  • thyroid-stimulating hormone (TSH) > 100 (1.4–8.8).

An endocrinologist was consulted and an urgent thyroid scan was carried out.

The thyroid scan showed normal location of the thyroid, but with increased uptake, which is in favour of thyroid dyshormonogenesis, although the infant exhibited no signs of goitre.

Paediatric endocrinologists started the infant on l-thyroxine. Afterwards, the infant remained stable and breastfeeding well, and bilirubin gradually dropped to normal levels. The infant was discharged, subsequent to a check-up in a paediatric endocrinology clinic. The infant exhibited no neurological signs characteristic of neurological deficit. The follow-up in that clinic showed that the infant was growing normally with normal milestones.

Discussion

The association of jaundice with congenital hypothyroidism in the neonatal period has been recognized for decades.1 In cases of congenital hypothyroidism, bilirubin clearance is decreased and bilirubin conjugation is impaired because of immaturity of the uridine diphosphate glucuronyltransferase activity.2 However, prolonged neonatal jaundice is commonly considered one of the manifestations of congenital hypothyroidism. Although rare, it is possible that severe rapidly rising early neonatal hyperbilirubinaemia may also be considered as a manifestation of congenital hypothyroidism when the indirect reacting bilirubin level is raised without an adequate cause.

Weldon et al.3 reported a total of 12 cases in which congenital hypothyroidism was associated with significant neonatal jaundice. Out of these 12 cases, three neonates presented with excessively severe jaundice in the early neonatal period, within the first week of life, and maximum bilirubin level was 22 mg/dl.

Tiker et al.4 reported five cases of congenital hypothyroidism with severe early neonatal hyperbilirubinaemia within 5 days of age and maximum bilirubin was 25.8 mg/dl. All of them had no features of congenital hypothyroidism.

Kortuglu et al.5 reported a case in which the infant presented with jaundice on the third day of life. Serum bilirubin was 27.2 mg/dl. All other results from laboratory investigations were normal, except levels for TSH (49.9 mIU/ml) and T4 (9.6 pg/ml). The infant received intensive phototherapy and thyroxine, after which bilirubin and TSH decreased to normal levels. In addition, results from hepatobiliary ultrasonography showed sludge in the gallbladder that disappeared after treatment with thyroxine.

It is unusual to have such severe early neonatal hyperbilirubinaemia requiring exchange transfusion caused by congenital hypothyroidism.

Because the features of congenital hypothyroidism are usually minimal at this early neonatal age, it would be ideal to perform thyroid function tests in all infants with unexplained hyperbilirubinaemia, especially in those countries where neonatal screening is not included in the national screening programme. If screening of newborns for hypothyroidism is not routine, serum thyroxine and thyrotropin should be measured in any infant who presents with unexplained unconjugated hyperbilirubinaemia. This is of profound importance because congenital hypothyroidism is one of the preventable causes of mental retardation if treated early, preferably within 2 weeks of life. In addition, a neonatal screening programme can be very helpful in the early detection of congenital hypothyroidism.

References

1. 

Akerren Y. Prolonged jaundice in newborn associated with congenital myxedema. Acta Pediatr 1954; 43:411–25. http://dx.doi.org/10.1111/j.1651-2227.1954.tb04049.x

2. 

Labrune P, Myara A, Huguet P, et al. Bilirubin uridine diphosphate glucuronosyltransferase hepatic activity in jaundice associated with congenital hypothyroidism. J Pediatr Gastroenterol Nutr 1992; 14:79–82. http://dx.doi.org/10.1097/00005176-199201000-00014

3. 

Weldon AP, Danks DM. Congenital hyperthyroidism and neonatal jaundice. Arch Dis Child 1972; 47: 469–71. http://dx.doi.org/10.1136/adc.47.253.469

4. 

Tiker F, Gurakan B, Tarcan A, Kinik S. Congenital hypothyroidism and early neonatal severe hyperbilirubinemia. Clin Pediatr 2003; 42:365–6. http://dx.doi.org/10.1177/000992280304200411

5. 

Kortuglu S, Çoban D, Ali Aikin M, Akin L, Yikilmaz A. Neonatal Sludge: a finding of congenital hypothyroidism. J Clin Res Pediatr Endocrinol 2009; 1:197–200. http://dx.doi.org/10.4008/jcrpe.v1i4.54




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