Endocrine: GH disorders and hypothyroidism Flashcards
What is pituitary dwarfism caused by?
Hyposomatotropism (lack of growth hormone production)
What is thought to cause congenital hyposomatotropism?
Primary failure of complete differentiation of the craniopharyngeal ectoderm of Rathke’s pouch into a functioning anterior pitutary
What are potential causes of acquired hyposomatotropism?
Trauma, iatrogenic removal (hypophysectomy), neoplasia of the pituitary, infection/inflammatory
The initial post-natal growth period (1-2 months) is mostly determined by what?
Mostly genetically determined - so hyposomatotropism often isn’t visible until after 1-2 months of age
If isolated growth hormone deficiency is present (all other pituitary hormones are normal), the patient will have what physical appearance?
Proportionate dwarfism - the short stature is proportional throughout the body
Apart from dwarfism, what are other physical exam findings with hyposomatotropism?
- Prolonged retention of deciduous teeth
- Hair coat is dry and dull with potential retention of secondary hairs and lack of guard hairs
- Bilateral corneal edema from a reduction in corneal endothelial cell density has been described
How is hyposomatotropism typically diagnosed and why?
Measurement of IGF-1
- Hepatic IGF-1 secretion is primarily induced by GH
- Unlike GH, its secretion is not pulsatile and the results reflect GH concentrations over the prior 24 hours
What other systemic diseases may affect IGF-1 levels and should be ruled out before interpretation?
- Liver dysfunction (PSS)
- Renal disease
- DM
How is feline hyposomatotropism treated?
- No feline GH products, can use human or porcine, but there is some concern for antibody production. Also increases risk of DM and is expensive
- Treat other concurrent pituitary hormone deficiencies
It is recommended that all cats with newly diagnosed DM be screened for what disease?
Hypersomatotropism - in a recent study, 25% of diabetics had acromegaly
If serum IGF-1 is not supportive of hypersomatotropism, but the clinical picture suggests it, when should you repeat IGF-1 testing?
In 2 months or if the patient develops insulin resistance over time
What causes feline hypersomatotropism?
Neoplastic transformation of the somatotrophs (acidophils) in the anterior pituitary - most are adenomas with rare carcinomas described
What environmental contaminant has been linked to the development of hypersomatotropism in cats?
Organohalogenated contaminants (OHC) from flame retardant material, PCBs, etc. Increased in cats with HS but it’s unknown if its a cause or consequence of the disease
What are the clinical signs of feline hypersomatotropism?
- DM with insulin resistance
- PU/PD
- Polyphagia
- Weight GAIN despite suboptimal diabetic control
- Upper respiratory stridor (50%) from tissue swelling/narrowed nasopharynx
- Increased width of the head
- Broad facial features
- Prognathia inferior (protrusion of the lower jaw)
- Clubbed paws
- Abdominal enlargement with organomegaly
- Heart murmur and CHF
- CNS signs - circling, blindness, seizures
A serum IGF-1 > 1000mg/dL has a PPV of what for feline hypersomatotropism?
95%
What is a caveat of IGF-1 testing in new diabetics?
Hepatic IGF-1 synthesis is dependent on adequate concentrations of portal insulin - can be deficient in new diabetics, resulting in false negative IGF-1 results in 9% of cats
What surgical approach is used in a hypophysectomy in cats?
Transsphenoidal - through the soft palate and nasopharynx
What percent of cats enter diabetic remission within 2 months of surgery?
85%, remainder have good glycemic control with traditional insulin dosages
What is the peri- and post-operative mortality of hypophysectomy?
~10%
After a hypophysectomy, what medications are needed?
Hydrocortisone and levothyroxine for life, DDAVP can be temporary in most cats
What is the mechanism of action of pasireotide?
Multi-receptor somatostatin analogue
What hormone stimulates GH production? What inhibits it?
- Stimulatory: hypothalamic GH-releasing hormone (GHRH) or gherlin produced by the stomach
- Inhibitory: hypothalamic somatostatin
In dogs, what other tissue secretes GH?
Mammary ductular epithelium - GH concentrations in dogs do not decrease after hypophysectomy, likely due to mammary secretion
What reproductive hormone can increase the mammary secretion of GH in dogs?
Progesterone
What are the rapid (catabolic) effects of GH?
Insulin antagonism => lipolysis, gluconeogenesis, restricted glucose transport across cell membranes, hyperglycemia
What are the slow (anabolic) effects of GH?
Mediated by IGF-1 => stimulates protein synthesis, chondrogenesis, and growth
What is a major factor in the final body size of different dog breeds?
IGF-1 single nucleotide polymorphism
How does hypothyroidism affect GH?
Associated with an increased plasma concentration of GH and IGF-1, but typically causes less severe, subtle clinical signs than a pituitary adenoma
How is progesterone induced GH in dogs treated?
- Ovariectomy or removal of a progesterone secreting mammary tumor
- Progesterone receptor blockers
What dog breed is most predisposed to congenital GH deficiency?
German Shepherds - autosomal recessive mutation
In German Shepherds with GH deficiency, what other hormones are typically absent?
TSH, prolactin
Normal ACTH secretion
What is the proposed pathogenesis of pituitary dwarfism in German Shepherds?
- Mutation in LHX3 gene
- Some dogs develop a pituitary cyst formation leads to pressure atrophy of the pituitary gland - not found in all dogs though
Pituitary dwarfism in dogs results in what clinical signs?
- Growth retardation
- Easily epilated hairs, leading to truncal alopecia
- Skin hyperpigmentation, scaling with secondary bacterial infections
- Pointed muzzle (fox like)
- Cryptorchidism or failure to ovulate
- Malformations of the atlanto-axial joint => instability
In dogs, what changes does pituitary dwarfism cause on blood work?
Increased creatinine - GH deficiency +/- TSH deficiency leads to abnormal glomerular development and impaired renal function
How is pituitary dwarfism diagnosed in dogs?
Stimulation testing: administering GHRG or alpha-adrenergic drugs (clonidine, xylazine) IV and measuring GH before and 20-30 minutes after
- Healthy dogs: GH should increase 2-4 fold
- Pituitary dwarfism: no increase
How is canine pituitary dwarfism treated?
Can use porcine GH, as the amino acid sequence of porcine GH is identical to dogs - monitor GH, IGF-1, and glucose
Binding of TSH to the TSH receptor on thyroid follicular cells leads to what?
- Activation of adenyl cyclese and cAMP => increased activity of the sodium-iodide symporter at the basolateral membrane
- Activation of phospholipase C => increased production of thyroid peroxidase
Describe the movement of iodide in the thyroid follicular cell
- Iodide is imported into the cell with 2 Na+ using the sodium-iodide symporter at the basolateral membrane
- Then moves across the cell and is exported across the apical membrane into the colloid space by the pendrin transporter
Describe the formation of thyroid hormones in the colloidal space
- In the colloid space, iodine is oxidized by the enzyme thyroid peroxidase (TPO): I- => I2
- I2 iodinates thyroglobulin into monoiodotyrosine (MIT) or diiodotyrosine (DIT), catalyzed by TPO
- On thyroglobulin, two DIT molecules couple for form T4 (faster reaction) or MIT couples with DIT to form T3
What is thyroglobulin?
Large glycoprotein synthesized in part from tyrosine by the rough endoplasmic reticulum of thyroid follicular cells, then exported into the colloid space
Describe the secretion of thyroid hormones
- Stored in the colloid until stimulated for secretion by TSH
- Iodinated thyroglobulin is endocytosed into the follicular epithelial cell
- Fuses with lysosomes, where thyroglobulin hydrolysis occurs, releasing T4, T3, MIT and DIT
-T4 and T3 are released into the blood - MIT and DIT are hydrolyzed so the iodide can be recycled
Once in circulation, how is T4 transported?
Mostly bound to thyroxine binding protein, small amount bound to albumin and other proteins
How is T4 used by the target tissues?
5’-deiodinase removes one atom of I2, thus converting T4 to T3
How is T4 used by the target tissues?
5’-deiodinase removes one atom of I2, thus converting T4 to T3
How does T3 increase the basal metabolic rate?
Increases NaK-ATPase synthesis => increased oxygen consumption by cells => increased metabolic rate
What effect do thyroid hormones have on the heart?
Increased inotropic and chronotropic effects
Acquired primary hypothyroidism results from what two processes?
Lymphocytic thyroiditis
Thyroid atrophy
What is lymphocytic thyroiditis?
A destructive autoimmune process characterized by multifocal or diffuse infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, leading to replacement by fibrous connective tissue
What is idiopathic thyroid atrophy?
A degenerative process with minimal inflammatory change and gradual replacement of thyroid tissue by adipose and connective tissue. Might be end stage lymphocytic thyroiditis??
How is lymphocytic thyroiditis diagnosed?
- Biopsy required for definitive diagnosis
- Circulating autoantibodies to thyroid antigens, most commonly thyroglobulin autoantibodies, can be measured. High sensitivity and specificity
What percent of the thyroid gland must be destroyed for clinical signs to result?
75%
Describe the “endocrine alopecia” that occurs in hypothyroid dogs
Non-pruritic, bilaterally symmetrical, often noted in areas of friction (the “rat tail” or nasal planum)
What causes myxedema in hypothyroid dogs?
Accumulation of hyaluronic acid in the dermis
What is the appearance of dogs/cats with congenital hypothyroidism?
Disproportionate dwarfism - wide skulls, macroglossia, delayed dental eruption, square trunk, short limbs
Why does hypothyroidism lead to hypercholesterolemia and hypertriglyceridemia?
Thyroid hormones are important in the degradation of lipids => lipid accumulation
LDL, HDL, and VLDL all higher in hypothyroid dogs
Why does a mild ALP/GGT concentration occur in 30% of hypothyroid dogs?
Mild hepatic lipid deposition can occur
How can the measurement of total T4 be affected by the presence of autoantibodies?
Assays that measure TT4 by using antibody bound hormones may be falsely increased (into the normal range or even high)
Assays that measure TT4 by unbound hormone fraction may be decreased as autoantibodies bind some of the normally free TT4
What breeds have low TT4 and sometimes low FT4 concentrations?
Sighthounds
In patients with non-thyroidal illness, TT3, TT4 are low. What is the concentration of TSH?
Normal to low (differentiates it from true hypothyroidism, where TSH is normal to high)
Exception is during the recovery period, where TSH may increase
How can sulfonamides cause hypothyroidism?
Reversibly inhibit TPO
Does free T4 decrease with non-thyroidal illness?
Only in very severe illnesses
What is the single most accurate test for diagnosing hypothyroidism?
Free T4
How can glucocorticoids affect thyroid testing?
Can cause a decrease in TT4, FT4, and TSH
What is goiter and why does it form?
Forms from dyshormonogenesis, or a congenital dysfunction in the synthesis of thyroid hormone => increased TSH secretion => thyroid gland hyperplasia and enlargement (goiter)
What causes dyshormonogenesis?
Defective thyroid peroxidase activity
Impaired iodine organification
What sign of hypothyroidism is common in cats, but rare in dogs?
Constipation
After therapy with I131, marked, transient hypothyroidism can occur. Most cats return to euthyroidism within what time frame?
3-6 months
Do cats that develop transient hypothyroidism post I131 need to be treated?
Usually no treatment is needed if renal function is normal and no clinical signs are noted
If azotemic though, treat immediately - hypothyroidism worsens GFR
