SEQC Spanish Society of Laboratory Medicine

• Congenital hypothyroidism is the most common cause of preventable mental retardation in paediatrics
• Brain damage depends directly on the time elapsed from the onset of hypothyroidism to the time of treatment, so in those newborns that are detected and start treatment in the first days of life, morbidity, mortality, and possible disabilities associated with this condition are reduced
• Optimizing strategies by applying different cut-off points, new markers, and decision algorithms, a challenge for neonatal screening laboratories in detecting this pathology.

Congenital hypothyroidism (CH) is an endocrine disease characterized by a decrease in the biological activity of thyroid hormones at the tissue level and is the most frequent cause of preventable cognitive impairment in paediatrics. Brain damage depends directly on the time elapsed from the onset of hypothyroidism to the time of treatment, so those newborns who are detected and start treatment in the first days of life reach a normal or almost normal IQ, reducing morbidity, mortality and possible disabilities associated with this condition.

With the aim of updating advances in early diagnosis and screening of the disease, the Spanish Society of Laboratory Medicine (SEQC^ML) has organized the course 'Advances in neonatal screening for congenital hypothyroidism: current situation and future perspectives in the new detection strategies', coordinated by the member doctors of the SEQC^ML Perinatal Diagnosis Commission, Rosa Mª López Galera, from the Biochemistry and Molecular Genetics Service of the Barcelona Hospital Clínico and the Neonatal Screening Program of Catalonia; and Hugo Rocha, from the Neonatal Screening, Metabolism and Genetics Unit of the Department of Human Genetics of the Instituto Nacional de Saúde Doutor Ricardo Jorge in Portugal.

"In the last decade -explains Dr López Galera- the incidence of CH has been increasing, due among other factors to the increased risk of suffering from it in premature newborns, those with low birth weight, and identical twins (whose numbers have increased with advances in neonatology), and detection strategies that favour the detection of moderate forms of this pathology”.

This condition has little clinical expression in the neonatal period, and its suspected presence is based on some clinical signs and symptoms such as: respiratory difficulties, bradycardia, cyanosis, persistent jaundice, umbilical hernia, lethargy, drowsiness, lack of interest in feeding, hoarse crying, constipation, or the presence of a large open anterior or posterior fontanelle. As Dr Rocha indicates, "if it is not diagnosed and treated early (by hormone replacement therapy) the sequelae can be permanent with the appearance of a clinical profile consisting of delayed growth and physical and mental development, which can be manifested by short stature and short limbs, persisting infantile proportions, and delayed bone maturation and dentition. Intellectual retardation can be of variable intensity, from profound cognitive deficits to mild learning disorders.

Therefore, as the moderators of the course underline, the early detection of CH is of paramount interest in Public Health and Preventive Medicine, and that is why it is included in neonatal screening programs. In Spain, the CH Early Detection Program was launched in 1978, its implementation being generalized in all the Autonomous Communities between that year and 1982; with a percentage of coverage at present of practically 100%.

Regarding its prevalence in Spain, according to data published in the 2019 Evaluation Report of the Neonatal Screening Programs of the National Health System of the Ministry of Health, the variable detection rate depending on the Autonomous Community ranges from 1 in every 587 newborns in Navarra to 1 in every 4,610 in the Canary Islands.

Advances and challenges in neonatal screening

Congenital hypothyroidism is classified into three large groups: primary (the cause is in the thyroid gland itself), central (the disorder is located in the pituitary gland, producing a deficiency of thyroid-stimulating hormone (TSH) or in the hypothalamus, generating in this case a decrease in the production of thyrotropin-releasing hormone (TRH)), and peripheral (due to a generalized resistance of target tissues to thyroid hormones).

Following the WHO criteria, the main objective of neonatal screening programs would be the detection of primary CH, but currently some of the strategies used are aimed not only at detecting primary CH but also central CH and other moderate or transitory secondary forms that can benefit from early diagnosis and treatment.

Neonatal screening for CH detection consists of measuring TSH or TSH + total thyroxine (T4t) in dried capillary blood specimens on paper. Diagnosis is based on complementary tests in venous blood for TSH and free thyroxine (free T4) as well as tests to confirm the presence or absence and location of the thyroid gland using imaging techniques (ultrasound and thyroid scintigraphy with isotope Tc-99m).

On the other hand, in primary CH there is increasing scientific evidence that approximately 20-40% of diagnosed cases have a genetic cause. "In this sense, the study of the molecular bases of hypothyroidism is a field that is being explored and has a long way to go," says Dr López Galera.

For Dr Rocha, advances in the detection of the disease should be aimed at developing new strategies with more optimized adjustments in the cut-off points, improvement of analytical methods, the inclusion of other markers in the detection, and the application of more specific analytical tools such as second-tier tests and “big data“ bioinformatic tools such as CLIR (Collaborative Laboratory Integrated Reports), which are already being used to detect other diseases, such as metabolic diseases, in neonatal screening programs, and that could be very useful for CH”, he points out.

In summary, for the moderators of the course, the challenge for neonatal screening laboratories in the detection of congenital hypothyroidism lies in optimizing strategies by applying different cut-off points, new markers, and decision algorithms with the aim of reducing the rate of false positives, as well as avoiding as much as possible the cases of false negatives.

Likewise, the collaboration of Laboratory Medicine in the area of ​​biochemistry and in the near future in genetics for the early detection, diagnosis, control and follow-up of these patients is key. Along the same lines, "the participation of Laboratory Medicine professionals in the preparation of guidelines and/or protocols and in scientific societies can further contribute to the efficiency of screening programs for this congenital pathology", they conclude.