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Chemical Pathology

Biochemical Testing for Growth Hormone

Growth hormone deficiency (GHD) has traditionally been investigated and diagnosed in children with short stature or failure to thrive. However, GHD can occur at any age and may affect total body composition and bone density as well. Growth hormone (GH) and related growth factors also regulate a variety of metabolic processes. These include protein synthesis, lipid oxidation and lipolysis. GH also counteracts the effects of insulin action.

Definitive diagnosis of growth hormone deficiency can be challenging, due to the complex nature of GH functions and the interactions between GH and other related growth factors. GH, insulin like growth factor (IGF-1) and IGF binding protein (IGFBP3), are thought to work independently and in concert to regulate body composition and increase linear growth. GH directly stimulates the production of IGF-1 and IGFBP3, which are the mediators of the biological activity of GH in peripheral tissues.

The cause of GHD in paediatrics is often unknown. GHD may occur in isolation or associated with other pituitary hormone deficiencies. Other causes of GHD include head injury, previous cranial surgery, infiltrative pituitary pathology, cranial irradiation or pituitary tumours. Some genetic defects have also been described in a small percentage of patients presenting with GHD.

GROWTH HORMONE EXCESS

Excess growth hormone secretion presents clinically as gigantism in children or acromegaly in adults. In both these situations there is often a strong clinical suspicion for GH excess. Measurement of all three tests (GH, IGF1 and IGFBP3) demonstrates increased levels in such patients. GH suppression tests may be required to demonstrate subtle abnormalities of increased GH secretion.

GH INSENSITIVITY

This is uncommon. The primary cause in children is a genetic defect, usually at GH receptor level. The commonest described in the literature is the Laron Syndrome. Growth hormone secretion is normal but the actions of GH are absent due to receptor or post receptor genetic defects.

GROWTH HORMONE AND RELATED GROWTH FACTORS

GH is produced by the pituitary gland. It is released in a pulsatile fashion and exhibits diurnal variation. Serum levels are also affected by meals and most GH measurements should be done after an overnight eight hour fast or as part of a stimulation test.

GH stimulates growth. Some of the functions of GH involve protein synthesis in muscle and bone. GH is also associated with lipid and carbohydrate metabolism. Growth hormone stimulates IGF1 (insulin like growth factor 1) and IGF binding protein 3 (IGFBP3) production in the liver. Some of the actions of GH are direct actions of peripheral somatic cells, but many are mediated via IGF1.

IGF1, also called somatomedin, is similar in structure and function to insulin. IGF1 production is stimulated by GH and in turn, IGF1 has a negative feedback effect on release of GH from the pituitary gland. IGF1 is produced primarily in the liver (>80%) with some local production in cartilage and skeletal muscle. IGF1 released into the bloodstream from the liver acts as an endocrine hormone in peripheral tissues effecting the actions of GH.

Circulating IGF1 is bound to a carrier protein (IGFBP3). This allows for a more stable measurement of the actions of GH compared to GH itself. IGFBP3 is the most abundant member of the IGF binding protein family. It transports IGF1 and controls the bioavailability of IGF1. The control and secretion of IGFBP3 is similar to that of IGF1.

TESTS RELATING TO GH STATUS

Some of the current literature suggests that the first-line tests in the evaluation of GH status, especially GHD states, should be IGF1 and IGFBP3. This is because GH is secreted in a pulsatile fashion and peak levels occur during sleep. In contrast, IGF1and IGFBP3 levels are stable and display minimal diurnal variation, so random sampling may be more practical and informative.

IGF1 and IGFBP3 are almost always low in children with severe GHD. Low IGF1 and IGFBP3 together with decreased height velocity may be diagnostic for GHD (sensitivity and specificity >90%). In patients with borderline results, GH stimulation tests may be necessary to demonstrate subtle or moderate GHD.

GH insensitivity may also occur as a result of chronic illnesses (malnutrition, chronic kidney disease etc). In patients with GH insensitivity, GH levels are normal or increased, but they have low levels of IGF1 and IGFBP3.

Table 1: Interpretation of results

CLINICAL STATUS GH IGF1 IGFBP3
NORMAL Normal Normal Normal
GH DEFICIENCY (DWARFISM) Low Low Low
GH EXCESS (ACROMEGALY) High High High
GH INSENSITIVITY High Low Low

All three tests (GH, IGF1 and IGFBP3) are available at Lancet Laboratories.
Sample type: Serum (Gold/SST)

Note: For specialised testing (GH stimulation or GH suppression tests) contact one of the chemical pathologist at Lancet Laboratories.

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