Internal Medicine for Dermatologists Flashcards
What is phosphorylation of hormone sensitive lipase (HSL)?
involved in steroid genesis
a protein that increases the levels of intracellular cholesterol
What is steroidogenic acute regulatory protein (StAR)?
involved in steroid genesis
a protein that becomes phosphorylated and promotes the transport of cholesterol into the mitochondria
What is side-chain cleavage cytochrome P450 (CYP11A1)?
involved in steroid genesis
aka desmolase
an enzyme that converts cholesterol into pregnenolone
*first and rate limiting step
What is 3β-hydroxysteroid dehydrogenase?
converts pregnenolone to progesterone
*inhibited by trilostane
What are circulating glucocorticoids typically bound to?
corticosteroid binding globulin
most synthetic glucocorticoids do not bind CBG
What is 11β-hydroxysteroid dehydrogenase?
Two forms
11β-HSD1:acts as a predominant 11β-reductase in all the glucocorticoid target tissues such as the liver, adipose tissue, brain and lung, and facilitates the conversion of inactive precursor cortisone to bioactive cortisol
*this enzyme does not appear to be very functional in cat livers
11β-HSD2: converts cortisol to cortisone
What is ferret adrenal gland disease?
Not traditional hyperadrenocorticism
Overproduction of sex steroids by adrenocortical hyperplasia or neoplasia
- unknown exactly why
- related to genetics, early spay/neuter, long (8+hr) photoperiod, group housing
- more common in the US than Europe
Usually ay least 3 yrs old
Alopecia +/- pruritus +/- vulvar enlargement +/- urinary problems +/- sexual behavior +/- lethargy and muscle atrophy +/- other diseases
Usually have increase in sex hormones and cortisol on UT panel
- normal endocrine panel doesn’t rule it out
- ACTH stim/LDDST not useful
Treated with GnRH agonists (deslorelin, leuprolide), androgen receptor blockers, aromatase inhibitors, maybe melatonin
Which internal disease in ferrets can cause face pawing?
insulinoma (pancreatic islet cell tumors)
What is the functional unit of the thyroid gland?
follicle -> sphere of cells with a lumen containing a clear proteinaceous colloid
- colloid contains primarily thyroglobulin
Parafollicular cells between follicles make calcitonin
What is thyroglobulin?
large glycoprotein dimer that serves as a reservoir for thyroid hormone
What mineral is needed for formation of thyroid hormone?
iodine
What is thyroid-stimulating hormone?
increases both synthesis and secretion of T4 and T3 and is the major modulator of thyroid hormone concentration
made by the anterior pituitary
What does thyroperoxidase (TPO) do?
1) catalyzes the oxidation of iodide to iodine
2) binding of iodine to tyrosine residues on thyroglobulin (termed organification)
3) coupling of monoiodotyrosine and diiodotyrosine to produce thyroxine (T4) and 3,5,3′‐triiodothyronine (T3)
How are T4 and T3 secreted from cells within the tyroid?
Tg hydrolyzed by lysosomal proteases –>
T4 and T3 (less so) are freed from Tg –>
pass from phagolysosome into peripheral blood by diffusion
What is the major negative feedback signal to TSH?
T3 – produced locally by the monodeiodination of T4
What is the major modulator of thyroid hormone concentration?
TSH = “thyrotropin” – increases secretion of T4 and T3
How is thyroid hormone synthesis and secretion regulated?
extrathyroidal (thyrotropin)
intrathyroidal (autoregulatory)
- regulate iodine uptake
How does the central nervous system increase circulation of thyroid hormones?
Hypothalamus releases TRH –>
Pituitary thyrotropes release TSH –>
Thyroid follicular cells release T3, T4
What is the major secretory product of the normal thyroid gland?
T4
What are the thyroid binding proteins?
thyroxine-binding globulin (TBG)
- absent in cats
thyroxine-binding prealbumin (TBPA)
albumin
plasma lipoproteins
What percent of thyroid hormone is unbound in circulation?
Less than 1% circulate in the unbound state (free state)
Rest is protein bound (T4>T3)
but only free/unbound thyroid hormones enter cells, produce a biologic effect, and have negative feedback on TSH
Which thyroid hormone is most active?
T3 enters the cells quicker, has a more rapid onset of action, and is 3-5 times more potent than T4
What are the physiologic functions of thyroid hormones?
Critical for fetal development, particularly neural and skeletal
Stimulate calorigenesis, protein/enzyme synthesis, and carbohydrate and lipid metabolism
Chronotropic and inotropic effects on the heart
Enhance response to catecholamines
Necessary for normal hypoxic and hypercapnic drive to the respiratory system
Stimulation of erythropoiesis
Stimulation of bone turnover (formation and resorption)
What are the 3 ways by which a dog can develop hypothyroidism?
Decreased stimulation by TSH from the pituitary
Thyroid gland destruction
Failure in the steps of thyroid hormone synthesis
What is primary hypothyroidism?
disease at the level of the thyroid gland
>95% of acquired hypothyroidism in adult dogs
- lymphocytic thyroiditis vs idiopathic atrophy
What are the major thyroid antigens subject to antibody attack?
Thyroglobulin and TPO
When do clinical signs of lymphocytic thyroiditis occur?
Clinical signs do not start until 80% of the gland has been destroyed (takes 1-3 years)
What is stage 1 lymphocytic thyroiditis?
subclinical thyroiditis: characterized by focal lymphocytic thyroid gland infiltration and positive Tg and thyroid hormone autoantibody tests
What is stage 2 lymphocytic thyroiditis?
antibody positive subclinical hypothyroidism: loss of greater than 60% to 70% of thyroid mass results in a compensatory increase in TSH, which stimulates the thyroid gland to maintain normal T4 concentrations
What is stage 3 lymphocytic thyroiditis?
antibody positive overt hypothyroidism: most functional thyroid tissue is destroyed, and decreased serum thyroid hormone concentrations and increased TSH concentration are present
What is stage 4 lymphocytic thyroiditis?
noninflammatory atrophic hypothyroidism: characterized by replacement of thyroid tissue by fibrous and adipose tissue and disappearance of inflammatory cells and circulating antibodies
What is idiopathic thyroid atrophy?
characterized microscopically by progressive reduction in the size of the thyroid follicles, and replacement of the degenerating follicles with adipose tissue
may be either a primary degenerative disorder or an end stage of lymphocytic thyroiditis
What is “polyglandular autoimmune syndrome”?
Multiple immune-mediated diseases
Treating one may lead to resolution/improvement of the other(s)
Other than thyroiditis, what are other causes of primary hypothyroidism?
Neoplastic destruction
Iodine deficiency/excess
Sulfonamides
Leishmaniasis
Congenital hypothyroidism
What is secondary hypothyroidism?
failure of pituitary thyrotrophs to develop due to pituitary malformation or acquired dysfunction of the pituitary thyrotrophs causing impaired secretion of TSH
How is a majority of T3 formed in dogs?
derived from outer ring monodeiodination of T4 in peripheral tissues
How do you diagnose primary hypothyroidism?
T3/4 low
TSH usually elevated
+/- TGAA
What are the causes of secondary hypothyroidism?
Pituitary suppression
- The most common cause
- concurrent illness, drugs, hormones, malnutrition
Congenital malformations of the pituitary gland
Pituitary destruction
- tumors
How do you diagnose secondary hypothyroidism?
Low/undetectable TSH
- difficult because current assays are not very sensitive
What is tertiary hypothyroidism?
deficiency in the secretion of TRH by peptidergic neurons in the supraoptic and paraventricular nuclei of the hypothalamus
Neurologic signs and additional pituitary dysfunction may also be present
How do you diagnose tertiary hypothyroidism?
low TSH levels that increase after administration of TRH
What stimulates the release of TRH and TSH?
catecholamines and ⍺‐melanocyte‐stimulating hormone
What (other than thyroid hormones) inhibit the release of TRH and TSH
TRH
- leptin
- neuropeptide Y
- glucocorticoids
TSH
- glucocorticoids
- somatostatin
- dopamine
How is dietary iodide absorbed from the gastrointestinal tract becomes concentrated in the thyroid gland?
sodium iodide symporter located in the basolateral membrane
What is the main secretory product of the thyroid gland?
Thyroxine (T4)
What converts T4 to T3 in peripheral tissue?
Iodothyronine deiodinase enzymes
How do glucocorticoids affect the thyroid?
Decreased TRH and TSH secretion and decreased 5′‐deiodinase activity (decreased T4 to T3)
How do sulfonamides affect the thyroid?
Decreased thyroid hormone synthesis and secretion by inhibiting TPO
How does phenobarbital affect the thyroid?
Decreased thyroid hormone secretion and increased hepatic metabolism
How do NSAIDs alter thyroid function?
displace T4 and T3 from their plasma protein carriers
How to TCAs alter thyroid function?
inhibiting thyroid hormone synthesis, enhancing 5′‐deiodinase activity, and interfering with the HPT axis
Which method of measuring thyroid hormones in blood avoids effects of T4 autoantibodies?
equilibrium dialysis
German shepherds are prone to which form of hypothyroidism?
Congenital secondary hypothyroidism
pituitary dwarfism
- autosomal recessive mutation in LHX3
- combined pituitary hormone deficiency
- decreased GH, TSH, prolactin, and gonadotrophins
Giant Schnauzers are prone to which form of hypothyroidism?
Have an autosomal recessive congenital hypothyroidism
Why does hypothyroidism cause symmetrical alopecia and scale?
Thyroid hormone is necessary for anagen
- Lack of thyroid hormone = premature telogen
Decreased cutaneous fatty acids and prostaglandin E2 = sebaceous gland atrophy, hyperkeratosis, scaling, seborrhea sicca, dull haircoat
Why does hypothyroidism cause myxedema?
Hyaluronic acid (hygroscopic) accumulates in the dermis and binds water = increased thickness and non-pitting edema of the skin
Can lead to cutaneous mucinous vesiculation
Why do peripheral nervous signs occur with lymphocytic hypothyroidism?
nerve entrapment from mucin deposits, demyelination due to disrupted Schwann cell metabolism, vascular nerve damage due to alteration in blood-nerve barrier, disturbances in axonal cell transport
- may also be an immune attack
Why can central nervous signs occur with hypothyroidism?
hyperlipidemia (Labradors), atherosclerosis, vascular encephalopathy, functional metabolic derangements of neuronal or glial cell population
- myxedema com
Why can laryngeal paralysis, megaesophagus, and myasthenia gravis be seen in association with hypothyroidism?
Not certain
May be a similar autoimmune attack
Do not always improve with treatment of hypothyroidism
Why can ocular changes occur with hypothyroidism?
secondary to hyperlipidemia (corneal lipid deposits)
What are the typical clinical features of congenital hypothyroidism?
Usually develop postnatally between 2-12 weeks of age
Disproportionate dwarfism, enlarge/protruding tongue, mental dullness, inability to feed themselves, stenotic ear canals, inability to open eyes, soft/puppy hair coat persists, alopecia, seborrhea, delayed dental eruption, goiter
Many not viable to adulthood
What are the typical changes on CBC with acquired hypothyroidism?
Normocytic, normochromic, nonregenerative anemia in 30% of dogs
- Likely due to decreased erythropoietin
- RBC survival time is not affected b
Target cells
- cholesterol loading on the RBCs
Thrombocytosis
- normal to decreased platelet size
What are the typical changes on serum chemistry with acquired hypothyroidism?
Fasting hypercortisolemia in 75% of dogs
Fasting hypertriglyceridemia is also common
- Thyroid hormone stimulates virtually all aspects of lipid metabolism
- Synthesis and degradation is depressed in hypothyroid dogs, but degradation more-so = accumulation of plasma lipids –> atherosclerosis
Mild hypercalcemia (congenital and acquired)
Mild to moderate increase in LDH, AST, ALT, and ALP (maybe from myopathy)
What are the histopathologic findings associated with hypothyroidism?
Increased kenogen, decreased anagen, excessive trichilemmal keratinization, follicular atrophy, follicular dystrophy
May have significantly thicker epidermis and dermis, with fewer atrophic follicles than other endocrinopathies
What is the “gold standard” test for hypothyroidism?
Thyroid gland provocation (TSH stimulation test)
*rarely performed due to expense
Why is TT3 not usually measured?
it has a predominant intracellular location and dogs often have T3AAs which interfere
What is the most accurate test of thyroid gland function?
Serum fT4 concentration measured by MED
- equilibrium dialysis
In dogs with hypothyroidism, are anti-T4 or anti-T3 antibodies more common?
incidence of anti-T3 antibodies is higher than anti-T4 antibodies
- of attached to larger protein molecules
but thyroglobulin (Tg) is the primary target
What typically occurs with TRH stimulation testing for dogs with hypothyroidism?
Dogs with primary hypothyroidism will have less TSH response to TRH administration compared to normal dogs (TRH receptor desensitization at the pituitary)
Substantial overlap in results between hypothyroid dogs and euthyroid dogs
What happens to serum T4 with age?
decreases
and TSH goes up
Since sighthounds tend to have low TT4 and fT4, what may be a better test?
TT3 or fT3
What happens to thyroid hormones in athletic dogs?
TT4, fT4, and T3 may be below reference range in conditioned healthy dogs
Why does euthyroid sick syndrome occur?
The following reasons alone or in conjunction:
- Decreased TSH production
- Decreased synthesis of T4
- Decreased concentration or binding affinity of circulating proteins
- Presence of serum protein binding inhibitors
- Inhibition of de-iodination of T4 🡪 T3
Can get worse with disease severity
What happens when hypothyroidism and diabetes mellitus occur in the same patient?
can lead to insulin resistance
- Increased GH and IGF-1 also play a role in this
- patient may become hypoglycemic when you start levothyroxine
Hypothyroid dogs have increased fructosamine
- difficulty assessing glycemic control in a hypothyroid diabetic dog
What is the most common cause of hypothyroidism in cats?
Iatrogenic secondary to overtreating hyperthyroidism
What are the clinical signs of congenital hypothyroidism in cats?
Disproportionate “dwarfism”
- usually evident by 4-8 weeks of age
- large heads, short/broad necks, and short limbs
Lethargy, dullness, constipation, hypothermia, bradycardia, prolonged retention of deciduous teeth
Hair coat = undercoat with primary guard hairs scattered thinly throughout (fluffy)
What are the causes of congenital hypothyroidism in cats?
Thyroid dyshormonogenesis (expect to see goiter)
TSH resistance
Iodine deficiency in all-meat diet kittens
What is the most common cause of hyperthyroidism in cats?
Adenomatous hyperplasia leading to autonomous thyroid hormone synthesis
- Follicular cell adenoma
- Multinodular adenomatous hyperplasia
Both are benign and can occur at the same time
What are some risk factors for hyperthyroidism in cats?
Consumption of canned food (fish/liver)
Exposure to fertilizers/pesticides
Iodine excess or deficiency
Soy isoflavones
- inhibit conversion of T4 to T3
Goitrogens (thyroid disrupters)
How does selenium affect thyroid function?
Selenium modifies thyroid hormone metabolism through the activity of selenoproteins, such as glutathione peroxidases and thioredoxin reductase, which protect thyrocytes from oxidative damage
