Causes and diagnosis of biochemical disturbances in the neonate and early childhood
The foetus utilises maternal glucose and any excess is stored as hepatic glycogen. Fat is also stored in foetal adipose tissue during the last trimester. After birth the baby has to maintain its own blood glucose between feeds by fat and glycogen catabolism and gluconeogenesis. In some babies these mechanisms are insufficient to maintain blood [glucose], and hypoglycaemia occurs. In the neonate a blood [glucose] less than 2.5 mmol/L is widely regarded as being an intervention threshold. The principal causes of neonatal hypoglycaemia are as follows
• Transient hypoglycaemia in healthy term infants is most commonly due to a low milk intake during establishment of breastfeeding. Premature infants, and infants that are small for gestational age, are particularly at risk from hypoglycaemia due to their lack of glycogen and fat stores.
• Hypoglycaemia may also become evident if there is an increased demand for glucose such as may occur in the septic, hypoxic, hypothermic or pyrexial infant.
• In rare cases the hypoglycaemia may be due to an inherited metabolic disorder or a deficiency or imbalance in a range of hormones including GH and glucocorticoids.
Hyperinsulinaemia is the most common cause of persistent or recurrent neonatal hypoglycaemia after the first 24 h of life. There are a number of causes including maternal hyperglycaemia due to poor diabetic control during pregnancy. Maternal hyperglycaemia induces hyperplasia of foetal islet cells, resulting in foetal hyperinsulinaemia that cannot be suppressed in the neonate, and hypoglycaemia results. Rare genetic causes of persistent hyperinsulinism have been identified including deficiencies of glucokinase or glutamate dehydrogenase or recessive mutations of the genes for the sulphonylurea receptor (SUR 1) and the ATP- dependent potassium channel (KIR6.2) in the plasma membrane of the pancreatic β cells. The gene defects in SUR 1 and KIR 6.2 give rise to hyperplasia of insulin-producing cells in the pancreas, a condition known as ‘nesidioblastosis’. Sporadic causes (e.g. Beckwith syndrome) have also been identified. Neonates at risk of hypoglycaemia should have their blood glucose monitored regularly by POCT, with low readings (<2.5 mmol/L) being confirmed by blood collection for laboratory measurement before treatment.
Recurrent hypoglycaemia of infancy and childhood may be due to many causes as well as several other inherited metabolic disorders (e.g. fatty acid oxidation disorders and mitochondrial disorders). Although nesidioblastosis usually presents in the first few days of life, symptoms may be delayed for up to 6 months.
Calcium and magnesium
Plasma [calcium] falls, in normal full-term infants, by about 10–20% in the first 2–3 days of life. It then returns to normal (2.0–2.8 mmol/L) over the course of the next 3–4 days.
Neonatal hypocalcaemia within the first 48 h, sufficient to give rise to twitching, irritability and convulsions, occurs particularly in infants who are premature, those of diabetic mothers and those who have experienced birth asphyxia. Maternal vitamin D deficiency may be a factor (e.g. in Asian women). The mechanism is complex, but the hypocalcaemia tendency usually corrects spontaneously, although calcium gluconate may need to be given if convulsions occur, or if plasma [calcium] falls to less than 1.50 mmol/L. Rarely, hypocalcaemic convulsions in the neonate are associated with maternal hyperparathyroidism, which may produce temporary hypoparathyroidism in the neonate due to suppression of the foetal parathyroid glands by maternal hypercalcaemia.
Late neonatal hypocalcaemia, between the fourth and 10th days of life, may occur in full-term as well as in premature infants. Hyperexcitability of muscles is usually also present. This is liable to occur in infants whose mothers had a low intake of vitamin D during pregnancy; these infants may also have low plasma [magnesium]. Rarely, hypocalcaemia may be due to renal failure. Treatment with calcium, and often magnesium, may be required.
Neonatal rickets. Premature infants have increased requirements for calcium, phosphate and vitamin D for bone growth. The most sensitive indicator of inadequate intake is a rising plasma ALP, which precedes abnormalities in plasma calcium or phosphate.
Hypomagnesaemia is an occasional cause of neonatal convulsions. It can lead to hypocalcaemia by reducing PTH secretion. Plasma [magnesium] should be measured in all cases of hypocalcaemia.
Hypercalcaemia in the neonatal period is less common than hypocalcaemia. Inadequate phosphate supplements in rapidly growing pre-term infants can lead to hypophosphataemia, bone resorption and thus hypercalcaemia. Oversupplementation may also lead to hypercalcaemia. Much rarer causes include immobilisation, malignancy, hyperparathyroidism, familial hypocalciuric hypercalcaemia and William’s syndrome.
Inherited metabolic disorders
Inborn errors of metabolism usually present in infancy or childhood. They result from alteration in a single gene, leading to a protein product that has suboptimal function. Most of these rare conditions show autonomic recessive inheritance: heterozygotes do not manifest the disorder. The affected protein may be an enzyme, a structural or transport protein or an enzyme cofactor affecting the activity of several enzymes.
The consequences of an inherited defect affecting a metabolic pathway include:
• Accumulation of potentially toxic metabolites that occur in the pathway before the defect.
• Deficiency of essential metabolites produced by the pathway after the defect.
• I ncreased flux of potentially toxic metabolites through alternative metabolic pathways.
• Storage of macromolecules in organs such as liver and spleen if the defect is in their breakdown pathway.
• Negative feedback inhibition of the pathway activity may fail because production of the end-product is decreased.
BIOCHEMISTRY OF GERIATRICS
Scientifically, aging is an extremely complex, multifactorial process, and numerous aging theories have been proposed; the most important of these are probably the genomic and free radical theories. Although it is abundantly clear that our genes influence aging and longevity, exactly how this takes place on a chemical level is only partially understood. For example, what kinds of genes are these, and what proteins do they control? Certainly they include, among others, those that regulate the processes of somatic maintenance and repair, such as the stress-response systems.
The accelerated aging syndromes (i.e., Hutchinson-Gilford, Werner's, and Down's syndromes) are genetically controlled, and studies of them have decidedly increased the understanding of aging. In addition, C. elegans and D. melanogaster are important systems for studying aging. This is especially true for the former, in which the age-1 mutant has been shown to greatly increase the life span over the wild-type strain. This genetic mutation results in increased activities of the antioxidative enzymes, Cu-Zn superoxide dismutase and catalase. Thus, the genomic and free radical theories are closely linked. In addition, trisomy 21 (Down's syndrome) is characterized by a significantly shortened life span; it is also plagued by increased oxidative stress which results in various free radical-related disturbances. Exactly how this extra chromosome results in an increased production of reactive oxygen species is, however, only partially understood. There is considerable additional indirect evidence supporting the free radical theory of aging. Not only are several major age-associated diseases clearly affected by increased oxidative stress (atherosclerosis, cancer, etc.), but the fact that there are numerous natural protective mechanisms to prevent oxyradical-induced cellular damage speaks loudly that this theory has a key role in aging [the presence of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, among others; various important intrinsic (uric acid, bilirubin, -SH proteins, glutathione, etc.) and extrinsic (vitamins C, E, carotenoids, flavonoids, etc.) antioxidants; and metal chelating proteins to prevent Fenton and Haber-Weiss chemistry]. In addition, a major part of the free radical theory involves the damaging role of reactive oxygen species and various toxins on mitochondria. These lead to numerous mitochondrial DNA mutations which result in a progressive reduction in energy output, significantly below that needed in body tissues. This can result in various signs of aging, such as loss of memory, hearing, vision, and stamina. Oxidative stress also inactivates critical enzymes and other proteins. In addition to these factors, caloric restriction is the only known method that increases the life span of rodents; studies currently underway suggest that this also applies to primates, and presumably to humans. Certainly, oxidative stress plays an important role here, although other, as yet unknown, factors are also presumably involved. Exactly how the other major theories (i.e., immune, neuroendocrine, somatic mutation, error catastrophe) control aging is more difficult to define. The immune and neuroendocrine systems clearly deteriorate with age.