[image]Stratum granulosum layer

Yarim et al Vet Dermatol 2015; 26: 421–e99

Keratinocytes in all of the layers of the epidermis, also in histiocytes, fibroblasts and giant cells

Yarim et al Vet Dermatol 2015; 26: 421–e99

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-inhibits iodine conversion, binding to thyroglobulin, and coupling iodotyrosines (inhibits action of thyroid peroxidase)

-Results in true but reversible hypothyroid state

-Phenobarbital increases metabolism---> decrease TT4 and TT3, TSH can be increased in these cases

-Chloramphenicol decreases metabolism---> increases TT4 and TT3

-NSAIDs (esp aspirin) alter protein binding

-17.20 Lyase

-11B hydroxylase

-Genetic and environmental factors likely involved

-Polygenic in beagles

-Autosomal recessive in a family of Borzoi dogs

-Doberman pinchers, English setters, Rhodesian Ridgebacks, Giant Schnauzers- associated with MCH complex DLA class II haplotypes

-Gordon Setter, Hovawart, Rhodesian Ridgeback-genome wide association analysis identified a major hypothyroidism risk locus on chromosome 12, includes 3 genes (LHFPL5, SRPK1 and SLC26A8)

• Inhibit iodine conversion to iodide
• Inhibit binding of iodide to thyroglobulin
• Interfere with the coupling of iodothyrosines
• Decreased TT4, fT4, TT3, fT3, rT3 and increases in TSH may be seen within 2 weeks
• may take >3 weeks to return to normal after treatment is stopped

-Polygenic in beagles

-Autosomal recessive in a family of Borzoi dogs

-Doberman pinchers, English setters, Rhodesian Ridgebacks, Giant Schnauzers- associated with MCH complex DLA class II haplotypes

-Gordon Setter, Hovawart, Rhodesian Ridgeback- genome-wide associated analysis identified major hypothyroidism risk locus on chromosome 12 (includes 3 genes: LHFPL5, SRPK1 and SLC26A8)

1) Subclinical thyroiditis (+autoantibodies to TG and/or T4, T3, focal lymphocytic infiltrates)- usually starts around 2 years of age

2) Antibody positive subclinical hypothyroidism (antibody positive, >60% destruction of thyroid mass, compensatory increases in TSH maintain normal T4 levels)

3) Antibody positive overt hypothyroidism (>80% destruction of thyroid tissue, decreased T4 levels, increased TSH levels, ~4 years old)

4) Non-inflammatory atrophic hypothyroidism (thyroid tissue replaced with fibrous and adipose tissue, few if any lymphocytes, undetectable anti-TG antibodies, dogs 5-8 years old)

*** Humoral and cell-mediated immunity involved

*** Thyroglobulin (TG) is the major antigen

*** Antibody-dependent cytotoxicity involved in destruction of follicular cells

*** CD4+ cells are involved

• 85-90% of dogs with HAC have Pituitary dependent HAC
• Microadenomas <10mm
• Macroadenomas >10mm
• Pars distalis (71-80%)
• Pars intermedia (20-29%)
• Hyperplasia may be secondary to an imbalance of neurotransmitters (increased serotonin levels)

• Dogs- dysfunction/adenomas of pars distalis
• Horses- dysfunction/adenoma of pars intermedia

-Cholesterol sources include LDL and HDL from blood

-Cholesterol can also be synthesized by adrenal glands from acetate (acetyl CoA pathway)

-Movement of cholesterol into the inner membrane of the mitochondrium is regulated by a transport protein= StAR (steroidogenic acute regulatory protein)

-The next step is the conversion of cholesterol to pregnenolone through actions of cholesterol desmolase, also known as side-chain cleavage enzyme, P450scc, CYP11A- this is the rate-limiting step of steroid hormone synthesis

• Decrease ratio CD4:CD8
• Suppressed humoral immunity
• Predisposition to skin and ear infections, demodex
• Increases in acute-phase proteins, circulating immune complexes, alpha-globulins, beta-2-globulins, gamma-globulins (=systemic inflammatory responses)

• 15% decrease metabolic rate: lethargy, mentally dull "lazy", heat-seeking, weight gain
• Premature telogen, decrease anagen hair growth with hair loss of caudal thighs, ventral thorax, bridge of the nose, and tail
• Decrease cutaneous EFAs, decrease cutaneous PGE2
• Increased hyaluronic acid in dermis---> myxedema

• Glucocorticoids (Decrease TT4, fT4, normal TSH)
• Phenobarbital (Decrease TT4, fT4, normal TSH)
• Potentiated sulfonamides (Decrease TT4, fT4, TT3, fT3, increase TSH)
• Clomipramine (Decrease TT4, fT4)
• Aspirin (Decrease TT4, fT4)

• Glucocorticoids: cortisol is major one produced
• Mineralocorticoids: aldosterone is the major one produced
• Sex hormones (Androgens, Estrogens, Progestogens)
• ALL steroid hormones are derived from cholesterol
• Steroids are lipid-soluble and transported in the blood bound to specific plasma proteins

• 10-15% of dogs with HAC
• Atrophy of contralateral gland
• Arise from zona fasciculata or reticularis
• Adrenocortical carcinomas frequently invade surrounding tissues (eg. vena cava)

• Decreased synthesis of collagen 1 and 3
• Epidermal and piloglandular atrophy
• Decreased synthesis of mucopolysaccharides

• Antifungal dose: inhibits the conversion of lanosterol to ergosterol
• High doses for HAC: inhibit 17-20 desmolase and 11-hydroxylase
• decreases serum levels of cortisol and testosterone when given at 10-15 mg/kg PO q 12 hours
• For treatment of HAC
• Side effects include anorexia, vomiting, hepatotoxicity

• Spontaneous hypercortisolism is rare in cats (80% PDH and 20% adrenal tumors)
• Clinical signs: PU/PD, polyphagia, weight loss, lethargy, weakness, alopecia, reduced grooming, coarse hair coat, curled ear tips, decreased appetite, thin skin, fragile skin, pot-bellied appearance, vomiting, diarrhea
• 90% pre-diabetic or diabetic
• Laboratory findings may be normal for non-diabetics (do not have increased ALP)

• Increased alpha-MSH
• Increased # of melanocytes
• Increased production of melanin

• Evaluation of hypothalamic-pituitary-adrenal axis sensitivity to glucocorticoid negative feedback
• Administer 0.01mg/kg dexamethasone IV and collect Pre, 4-hour post, and 8-hour post
• Normal dogs suppress >50% of baseline and/or to <1.4ug/dL lasting 24-48 hours
• Lack of suppression at 8 hours has 85-100% sensitivity for HAC
• Lack of suppression at 8 hours has 44-73% specificity for HAC
• Suppression only at 4 hours seen in 4-60% of dogs with PDH

****Drug interference: phenobarbital, phenytoin, rifampin, carbamazepine, barbituates (activate P450 3A4 and accelerate DXMS clearance)

• Synthetic steroid analogue
• Inhibits adrenal 3-B-hydroxysteroid dehydrogenase (3 B-HSD) +/- 11-B-hydroxylase and 11-B-hydroxysteroid dehydrogenase
• Better absorption with food
• Peak concentration 1.7-3.8 hours
• Cortisol levels back to baseline within 12 hours
• Metabolite ketotrilostane has increased potency

• Trilostane- has been reported as effective
• Lysodren- not effective
• Metyrapone (blocks adrenal conversion of 11-doxycortisol to cortisol- reported effective with PDH
• Adrenalectomy

• Decreased pars intermedia dopamine levels (some are 88% below normal)
• degeneration of dopamine secreting neurons
• Loss of dopaminergic regulation
• Hyperplasia of pars intermedia
• Excess ACTH production leads to adrenocortical hyperplasia, increased cortisol and androgens
• Poorly responsive to negative feedback from corticosteroids

• 2nd most common tumor- adrenocortical zona reticularis adenoma
• Excess secretion of estradiol, 17-hydroxyprogesterone, androsteindione
• Tumors may invade vena cava

• Clinical signs: hair loss, stranguria (from prostamegaly), enlarged vulva, pancytopenia possible (estradiol--> BM suppression)
• Diagnosis is via abdominal US which reveals enlarged adrenals
• Ferret Hormal panel (UT) will show increases in estrodiol, 17-hydroxyprogesterone and/or androsteindione

• Chromophobe adenoma of the pars distalis (~70% cases)

• Sulphonamides interfere with thyroid hormone synthesis
• The exact mechanism is unknown but may reduce the conversion of iodine into organic form and inhibit peroxidase
• It is will also bind directly to thyroglobulin so it affects action of hormone (but does not inhibit formation of hormone)

The production of ACTH by the pituitary has three negative feedback mechanisms. The first is via the concentration of ACTH itself within the blood. What are the other two mechanisms?

• Levels of dopamine and serotonin may affect the production of ACTH
• ACTH acts on the adrenal cortex to release cortisol and androgens
• An increase in cortisol provides a negative feedback system to decrease the amount of CRH released from the hypothalamus
• ACTH plays a role in glucose metabolism and immune function

• Autosomal recessive condition located at chromosome 9
• The pituitary is a hormone produced by the endocrine gland at the base of the brain
• The anterior pituitary produces GH, TSH, prolactin, FSH, LH, ACTH, endorphins, ADH, and oxytocin

• Acromegaly in adult humans is a disorder in which the pituitary gland produces too much growth hormone
• usually caused by noncancerous tumor, middle-aged adults are most commonly affected
• Diagnose via history and clinical signs
  • Lab findings: increased PCV, hyperglycemia, increased liver enzymes, increased BUN, increased TP
  • Radiographs/US reveal organomegaly
  • increased levels of GH and insulin like growth factor-1
  • CT/MRI reveal pituitary tumor
• Treatment is to discontinue progesterones, OHE
• Control diabetes if present
• Hypophysectomy
• pituitary radiation therapy
• somatostatin analogs (have not worked well in dogs/cats)

• Prolonged telogen
• Atrophy of hair follicles and adnexa

• Increased hyaluronic acid in dermis---> myxedema
• Decreased cutaneous EFAs, decrease cutaneous PGE2
• Premature telogen, decrease anagen hair growth 

• Inhibit iodine conversion to iodide and inhibit binding of iodide to thyroglobulin
• Interfere with coupling of iodothyrosines
• Decreased TT4, fT4, TT3, fT3 and rT3 and increase in TSH may be seen within 2 weeks, may take > 3 weeks to return to normal after treatment is stopped

• insulin
• IL-GF
• TGF-B1
• TNF-α
• IFN-G
• IL-1
• IL-6

• cholesterol

• Accelerate follicular activity
  • general metabolic stimulus
  • directly affects hair growth
    • T4 increases hair matrix keratinocytes
    • T3 and T4 down regulate apoptosis and prevent catagen
    • T3 and T4 prolong anagen in vitro via decreased regulation of TGF-Β (key anagen inhibitory growth factor)