Physiology of
calcium, PTH and vitamin D metabolism
Serum calcium is tightly regulated and is predominantly under the control of vitamin D and parathyroid hormone (PTH). The normal range is 2.2–2.6 mmol/L. It is important to understand the physiology of calcium metabolism to interpret abnormalities of serum calcium, vitamin D, phosphate and PTH in disease.
Parathyroid hormone
PTH is a peptide hormone secreted
by the four parathyroid glands, situated behind the thyroid. Because of their
embryological origin, the parathyroids may be in an ectopic position such as in
the thymus within the chest. PTH increases calcium absorption from the gut and
kidney, and increases renal phosphate loss (Figure 15.1). High PTH levels are
associated with low phosphate, and vice versa. Calcium-sensing receptors
(Ca-SR) are situated on parathyroid and renal cell membranes. Hypocalcaemia
increases PTH secretion, while hypercalcaemia suppresses PTH secretion via
stimulation and inhibition of the Ca-SR, respectively. PTH increases
osteoclastic bone resorption and synthesis of vitamin D (Figure 15.1).
Vitamin D
Vitamin D is synthesised by the
skin in response to sunlight. Its chemical structure is similar to that of a
steroid hormone, acting on nuclear receptors. Cholecalciferol, the precursor to
vitamin D, undergoes 1-hydroxylation in the liver, and 25-hydroxylation in the
kidney to produce active 1-25 di-hydroxy-cholecalciferol (Figure 15.1). The
native form of vitamin D is vitamin D3. Vitamin D2 is derived synthetically
from fungi and is less potent than D3. The action of vitamin D is to increase
absorption of calcium in the gut and kidney, both directly and in concert with
PTH.
Vitamin D deficiency
Vitamin D deficiency is very common
in clinical practice. Risk factors include lack of sunlight, pigmented skin,
religious covering of skin and dietary deficiency (Figure 15.2a). Elderly and
housebound patients are particularly at risk, as are patients with chronic
kidney disease or malabsorption. In the UK, there is only sufficient sunlight
between May and September to produce adequate vitamin D. Dietary sources
include oily fish, cod liver oil, margarine and egg yolk. Pregnancy is a major
drain on vitamin D so it is important for young women in at risk groups to
replenish vitamin D levels prior to conception.
Vitamin D deficiency causes
de-mineralisation of bone. Unlike osteoporosis, which refers to brittle bones
that fracture easily (Chapter 18), vitamin D deficiency leads to soft malleable
bone.
The clinical manifestations depend
on whether presentation is in childhood or adulthood (Figure 15.2b).
Childhood presentation
The earliest clinical manifestation
of vitamin D deficiency is neonatal hypocalcaemia. This can develop with
neonatal tetany and seizures, and is a paediatric emergency requiring immediate
correction with intravenous calcium. When the child becomes a toddler and
stands up, bowing of the tibia can occur, which is a classic sign of rickets.
Adult presentation
Increasingly, vitamin D
insufficiency is detected during routine investigation of non-specific
symptoms. Vitamin D deficiency causes lethargy, low mood and alopecia, but
these symptoms are also common in the healthy population. Increasingly, vitamin
D deficiency is detected as part of the investigation of a raised PTH level.
Severe vitamin D deficiency leads to osteomalacia. De-mineralised bone can lead
to pseudo-fractures on X-ray (Looser zones). Neuromuscular dysfunction is
common in osteomalacia, particularly in the gluteal muscles, leading to a
waddling gait. Severe osteomalacia can cause hypocalcaemia (Chapter 16).
Investigation
Vitamin D is measured by
immunoassay or mass spectrometry, which measure total vitamin D levels Figure
15.2. Vitamin D levels are classified as deficient (<30 nmol/L),
insufficient (30– 50 nmol/L) or adequate (>50 nmol/L). Bone health is at
risk in patients with persistently low levels. Severe vitamin D deficiency causes
metabolic bone disease, characterised by elevated alkaline phosphatase,
hypocalcaemia and low phosphate due to secondary hyperparathyroidism. Plain
X-ray can reveal Looser zones, and a bone isotope scan can show hotspots in
areas of increased metabolic activity.
Treatment
Management includes reversal of
risk factors, increased dietary intake, correction of hypocalcaemia and vitamin
D replacement Figure 15.2. The treatment aim is to replenish vitamin D to
>50 nmol/L and improve symptoms. The maintenance replacement dose is
1000–2000 IU/day cholecalciferol. In profound vitamin D deficiency, 20 000
IU/week may be given for 7 weeks as a loading dose. Vitamin D toxicity is rare
and it is not necessary to repeat serum vitamin D levels. Calcium should be
re-checked several months after starting treatment as replacement can unmask
primary hyperparathyroidism. There is a key role for healthcare professionals
in educating at risk grups to reverse the increasing prevalence of severe vitamin D deficiency.
