Rickets

Define: Rickets is a defect in mineralisation of the osteoid matrix that occurs before physical closure.

Features: clinically it is associated with

• Long bones
  • Physical cupping
  • Bowing
• Spine
  • Codfish vertebrae
  • Kyphosis
• Thorax
  • Rachitic rosary

Pathology: Disruption of the normal Ca/Phos metabolism causes poor calcification in the Zone of Provisional Calcification can occur through a number of different mechanisms

• Nutritional deficiencies (Vitamin D common; Calcium and Phosphate rarer)
• Renal tubular defects and osteodystrophy
• GI absorption disorders

Vitamin D deficiency

Rarer now that Vitamin D is added to milk. Risk factors include prematurity, asian immigrants, and malabsorption.

Say

1. Low Ca is sensed by chief cells which release PTH
2. PTH acts to upregulate osteoclasts via OB differentiation, inhibiting OPG and increasing RANKL, but…
3. Deficiency means feedback cannot act to increase 1,25 Vitamin D so strong signal for GI absorption is absent
4. Net effect is that balance between PTH and Vitamin D is lost so that Ca is maintained by PTH (secondary hyperparathyroidism) action on the bone, presenting as rickets

Usually managed with dietary replacement of Vitamin D.

Draw

Low Vitamin D uncouples its effect from PTH which supports Ca at the expense of Phos

Calcium and phosphate deficiencies

Follow a similar pattern but are rarer.

In Ca deficiency, low Ca drives PTH (secondary hyperparathyroidism) and conversion of 25 Vit D to 1,25 Vit D. The biochemical findings are similar, with PTH driving raised Alk Phos, low serum Phos, low urinary Ca, but also depleting 25 Vit D stores.

In Phos deficiency, proximal tubule is stimulated to convert 25 Vit D to 1,25 Vit D and depleting its stores, but there is no PTH stimulus so no secondary hyperparathyroidism.

Hereditary Vitamin D dependent rickets

Similar feaures to Vitamin D deficient rickets, but tends to be more severe and associated with total baldness. There are two types with an analgous aetiology to diabetes type 1 & 2:

1. Type 1 is caused by reduced production of 1,25 Vitamin D due to a defect in 1-alpha hydroxylase.
2. Type 2 is caused by insensitivity to 1,25 Vitamin D due to a receptor mutation.

Say - Type 1

1. Type 1 is an autosomal recessive mutation in the 1 alpha hydroxylase gene
2. 1,25 Vitamin D dependent Ca homeostasis cannot occur
3. This drives a secondary hyperparathyroidism
4. Consequent imbalance in net effects of PTH and Vitamin D, which tends to present more severely than pure dietary Vitamin D deficiency.

Treatment is by oral supplementation of activated 1,25 Vitamin D at physiological doses (1-2 microgram per day)

Draw - Type 1

Say - Type 2

1. Type 2 is also autosomal recessive, but affects the 1,25 Vitamin D receptor, blocking its end organ effects
2. Loss of negative feedback drives significantly raised 1,25 Vit D levels and a fall in precursors
3. These are ineffective at maintaining serum Ca and Phos which stimulates PTH
4. The net effect is very high levels of activated Vitamin D with low serum and urinary Ca

Treatment is high dose Vitamin D with elementary calcium.

Draw - Type 2