Sep 092012
 

Therapy for patients with diabetic ketoacidosis DKA involves careful replacement of fluid deficits, correction of acidosis and hyperglycemia via insulin administration, correction of electrolyte imbalances and monitoring for complications of treatment.

1. Dehydration

A patient with severe DKA is assumed to be approximately 10% dehydrated. An initial IV fluid bolus of a glucose-free isotonic solution ( normal saline, lactated Ringer’s solution) at 10-20 ml/kg should be given to restore intravascular volume and renal perfusion. The remaining fluid deficit after the initial bolus should be added to maintenance fluid requirements, and the total should be replaced slowly over 36 to 48 hrs. To avoid rapid shifts in serum osmolality, 0.9% sodium chloride can be used as the replacement fluid for the initial 4 to 6 hrs followed by 0.45% sodium chloride.

2. Hyperglycemia

Fast-acting soluble insulin should be administered as a continuous IV infusion (0.1U/kg/hr). Serum glucose concentration should decrease at a rate no faster than 100 mg/dl/hr. When serum glucose concentration decreases to less than 250-300 mg/dl, glucose should be added to IV fluids.

3. Acidosis

Insulin therapy lowers glucagon and diminishes its activity on liver, decreases the production of free fatty acids and protein catabolism, and enhances glucose usage in target tissues. theses processes correct acidosis. Bicarbonate therapy should be avoided unless there is severe acidosis ( pH < 7.0).

4. Electrolyte Imbalances

Regardless of the serum potassium concentration at presentation, total body potassium depletion is likely. When adequate urin output is shown potassium should be added to the IV fluids. Potassium replacement should be given as 50% KCl and 50% KPO4 at a concentration of 20-40 mEq/L.

5. Monitoring

A flow sheet should be used to record and monitor fluid balance and laboratory measurements. Serum glucose measurements should be repeated every hour during therapy and electrolyte concentrations should be repeated every 2 to 3 hours. Calcium, phosphate and magnesium concentrations should be measured initially  and then every 4 to 6 hours during therapy.  Continue reading »

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Feb 152012
 

Background

Insulin-like growth factor I (IGF-I) is the effector of growth induced by growth hormone (GH). IGF-I deficiency can be the result of GH resistance or insensitivity due to genetic disorders of the GH receptor causing GH receptor deficiency (GHRD, Laron syndrome) or postreceptor defects, including the principal transduction agent STAT5b, the IGF-I/IGFBP3 stabilizer acid labile subunit (ALS), the IGF-I gene, or the IGF-I receptor.Acquired forms of GH insensitivity include the rare GH1 mutation (in which GH inhibiting antibodies develop after a few months of replacement therapy with recombinant GH) and, far more commonly, malnutrition, hepatic disease, renal disease, and diabetes.

Pathophysiology

The GH molecule binds to its specific cell surface receptor (GHR), which dimerizes with another GHR molecule so that the single GH molecule is enveloped by 2 GHR molecules. The intact receptor lacks tyrosine kinase activity, but binding of GH and dimerization results in association with JAK2, a member of the Janus kinase family, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins. The most critical of these proteins is the signal transducer and activator of transcription 5b (STAT5b), which couples GH binding to the activation of gene expression that leads to the intracellular effects of GH, including synthesis of IGF-I, insulin-like growth factor binding protein 3 (IGFBP3), and ALS.

Hepatic IGF-I circulates almost entirely bound to IGF binding proteins (IGFBPs), with less than 1% being free. The IGFBPs are a family of 6 structurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP3, binds approximately 90% of circulating IGF-I in a large (150-200 kD) ternary complex consisting of IGFBP3, ALS, and the IGF molecule. The ALS stabilizes the IGF–IGFBP3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life.

IGF binding involves 3 types of receptors: the structurally homologous insulin receptor and type 1 IGF receptor and the distinctive type 2 IGF-II/mannose-6-phosphate receptor. Although the insulin receptor has a low affinity for IGF-I, IGF-I is present in the circulation at molar concentrations that are 1000 times those of insulin. Thus, even a small insulin-like effect of IGF-I could be more important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I. In fact, intravenous infusion of recombinant human IGF-I (rhIGF-I) can induce hypoglycemia, especially in the IGFBP3 deficient state.

Clinical Presentation

The clinical features of GHRD are not different than those of severe GH deficiency. Postreceptor Continue reading »

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Dec 272010
 
  • Disturbances of growth are the most common presenting complaints in the pediatric endocrine clinic.
    • Fetal growth is dependent on maternal factors (placental sufficiency, maternal nutrition, etc.), insulin-like growth factor-2 (IGF-2) and insulin.
    • Growth in late infancy and childhood is dependent on growth hormone/IGF-1 axis and thyroid hormone. Growth is more rapid during infancy—up to 20 cm per year. It is common to see shifts in the growth curve in the first 18 months when children are adjusting to their genetic potential growth isopleth. During childhood, growth rate is fairly constant at approximately 2 inches (approximately 5 cm) per year.
    • Pubertal growth is dependent on sex hormones as well as growth hormone/IGF-1 axis and the thyroid gland. There is a mild deceleration in growth velocity before initiation of pubertal growth spurt.
  • Abnormal growth and stature: criteria
    • Child’s growth curve is crossing percentiles.
    • Child’s growth rate is <2 inches or 5 cm per year.
    • Height is >2 standard deviations (SDs) (4 inches/10 cm) below from midparental height.
  • If poor weight gain and lack of nutrition is the problem without affecting height velocity, it is unlikely to be an endocrine cause and patient may warrant a gastrointestinal evaluation instead.
Etiology
  • Normal growth patterns that can look like a growth disorder
    • Genetic (familial) short stature. Children have normal growth velocity, normal timing of development and puberty, and bones fuse at the appropriate age. Height is short because of a short mother and/or a short father. Bone age (BA) = chronologic age (CA).
    • Constitutional delay of growth and puberty. Children have normal growth velocity, Continue reading »
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