Internal Medicine for Dermatologists Flashcards
1
Q
What is phosphorylation of hormone sensitive lipase (HSL)?
A
involved in steroid genesis
a protein that increases the levels of intracellular cholesterol
2
Q
What is steroidogenic acute regulatory protein (StAR)?
A
involved in steroid genesis
a protein that becomes phosphorylated and promotes the transport of cholesterol into the mitochondria
3
Q
What is side-chain cleavage cytochrome P450 (CYP11A1)?
A
involved in steroid genesis
aka desmolase
an enzyme that converts cholesterol into pregnenolone
*first and rate limiting step
4
Q
What is 3β-hydroxysteroid dehydrogenase?
A
converts pregnenolone to progesterone
*inhibited by trilostane
5
Q
What are circulating glucocorticoids typically bound to?
A
corticosteroid binding globulin
most synthetic glucocorticoids do not bind CBG
6
Q
What is 11β-hydroxysteroid dehydrogenase?
A
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
7
Q
What is ferret adrenal gland disease?
A
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
8
Q
Which internal disease in ferrets can cause face pawing?
A
insulinoma (pancreatic islet cell tumors)
9
Q
What is the functional unit of the thyroid gland?
A
follicle -> sphere of cells with a lumen containing a clear proteinaceous colloid
- colloid contains primarily thyroglobulin
Parafollicular cells between follicles make calcitonin
10
Q
What is thyroglobulin?
A
large glycoprotein dimer that serves as a reservoir for thyroid hormone
11
Q
What mineral is needed for formation of thyroid hormone?
A
iodine
12
Q
What is thyroid-stimulating hormone?
A
increases both synthesis and secretion of T4 and T3 and is the major modulator of thyroid hormone concentration
made by the anterior pituitary
13
Q
What does thyroperoxidase (TPO) do?
A
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)
14
Q
How are T4 and T3 secreted from cells within the tyroid?
A
Tg hydrolyzed by lysosomal proteases –>
T4 and T3 (less so) are freed from Tg –>
pass from phagolysosome into peripheral blood by diffusion
15
Q
What is the major negative feedback signal to TSH?
A
T3 – produced locally by the monodeiodination of T4
16
Q
What is the major modulator of thyroid hormone concentration?
A
TSH = “thyrotropin” – increases secretion of T4 and T3
17
Q
How is thyroid hormone synthesis and secretion regulated?
A
extrathyroidal (thyrotropin)
intrathyroidal (autoregulatory)
- regulate iodine uptake
18
Q
How does the central nervous system increase circulation of thyroid hormones?
A
Hypothalamus releases TRH –>
Pituitary thyrotropes release TSH –>
Thyroid follicular cells release T3, T4
19
Q
What is the major secretory product of the normal thyroid gland?
A
T4
20
Q
What are the thyroid binding proteins?
A
thyroxine-binding globulin (TBG)
- absent in cats
thyroxine-binding prealbumin (TBPA)
albumin
plasma lipoproteins
21
Q
What percent of thyroid hormone is unbound in circulation?
A
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
22
Q
Which thyroid hormone is most active?
A
T3 enters the cells quicker, has a more rapid onset of action, and is 3-5 times more potent than T4
23
Q
What are the physiologic functions of thyroid hormones?
A
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)
24
Q
What are the 3 ways by which a dog can develop hypothyroidism?
A
Decreased stimulation by TSH from the pituitary
Thyroid gland destruction
Failure in the steps of thyroid hormone synthesis
25
What is primary hypothyroidism?
disease at the level of the thyroid gland
>95% of acquired hypothyroidism in adult dogs
- lymphocytic thyroiditis vs idiopathic atrophy
26
What are the major thyroid antigens subject to antibody attack?
Thyroglobulin and TPO
27
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)
28
What is stage 1 lymphocytic thyroiditis?
subclinical thyroiditis: characterized by focal lymphocytic thyroid gland infiltration and positive Tg and thyroid hormone autoantibody tests
29
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
30
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
31
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
32
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
33
What is “polyglandular autoimmune syndrome”?
Multiple immune-mediated diseases
Treating one may lead to resolution/improvement of the other(s)
34
Other than thyroiditis, what are other causes of primary hypothyroidism?
Neoplastic destruction
Iodine deficiency/excess
Sulfonamides
Leishmaniasis
Congenital hypothyroidism
35
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
36
How is a majority of T3 formed in dogs?
derived from outer ring monodeiodination of T4 in peripheral tissues
37
How do you diagnose primary hypothyroidism?
T3/4 low
TSH usually elevated
+/- TGAA
38
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
39
How do you diagnose secondary hypothyroidism?
Low/undetectable TSH
- difficult because current assays are not very sensitive
40
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
41
How do you diagnose tertiary hypothyroidism?
low TSH levels that increase after administration of TRH
42
What stimulates the release of TRH and TSH?
catecholamines and ⍺‐melanocyte‐stimulating hormone
43
What (other than thyroid hormones) inhibit the release of TRH and TSH
TRH
- leptin
- neuropeptide Y
- glucocorticoids
TSH
- glucocorticoids
- somatostatin
- dopamine
44
How is dietary iodide absorbed from the gastrointestinal tract becomes concentrated in the thyroid gland?
sodium iodide symporter located in the basolateral membrane
45
What is the main secretory product of the thyroid gland?
Thyroxine (T4)
46
What converts T4 to T3 in peripheral tissue?
Iodothyronine deiodinase enzymes
47
How do glucocorticoids affect the thyroid?
Decreased TRH and TSH secretion and decreased 5′‐deiodinase activity (decreased T4 to T3)
48
How do sulfonamides affect the thyroid?
Decreased thyroid hormone synthesis and secretion by inhibiting TPO
49
How does phenobarbital affect the thyroid?
Decreased thyroid hormone secretion and increased hepatic metabolism
50
How do NSAIDs alter thyroid function?
displace T4 and T3 from their plasma protein carriers
51
How to TCAs alter thyroid function?
inhibiting thyroid hormone synthesis, enhancing 5′‐deiodinase activity, and interfering with the HPT axis
52
Which method of measuring thyroid hormones in blood avoids effects of T4 autoantibodies?
equilibrium dialysis
53
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
54
Giant Schnauzers are prone to which form of hypothyroidism?
Have an autosomal recessive congenital hypothyroidism
55
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
56
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
57
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
58
Why can central nervous signs occur with hypothyroidism?
hyperlipidemia (Labradors), atherosclerosis, vascular encephalopathy, functional metabolic derangements of neuronal or glial cell population
- myxedema com
59
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
60
Why can ocular changes occur with hypothyroidism?
secondary to hyperlipidemia (corneal lipid deposits)
61
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
62
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
63
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)
64
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
65
What is the "gold standard" test for hypothyroidism?
Thyroid gland provocation (TSH stimulation test)
*rarely performed due to expense
66
Why is TT3 not usually measured?
it has a predominant intracellular location and dogs often have T3AAs which interfere
67
What is the most accurate test of thyroid gland function?
Serum fT4 concentration measured by MED
- equilibrium dialysis
68
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
69
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
70
What happens to serum T4 with age?
decreases
and TSH goes up
71
Since sighthounds tend to have low TT4 and fT4, what may be a better test?
TT3 or fT3
72
What happens to thyroid hormones in athletic dogs?
TT4, fT4, and T3 may be below reference range in conditioned healthy dogs
73
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
74
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
75
What is the most common cause of hypothyroidism in cats?
Iatrogenic secondary to overtreating hyperthyroidism
76
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)
77
What are the causes of congenital hypothyroidism in cats?
Thyroid dyshormonogenesis (expect to see goiter)
TSH resistance
Iodine deficiency in all-meat diet kittens
78
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
79
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)
80
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
81
What are some goitrogens?
Biphenyls
- BisphenolA (BPA)
- Inhibits TPO + inhibits transcription
- found in food can lining
Polybrominated diphenyl ether (PBDE)
- flame retardants
- found in household dust
- Binds with TR
- interacts with binding proteins
- inhibits deiodinases
- increases hepatic clearance
Perfluorinated chemicals
Phthalates
Perchlorate
Dioxins
82
Which breeds of cats have a decreased risk of hyperthyroidism?
purebred cats (Siamese, Himalayan) have decreased risk
83
What are some clinical signs of hyperthyroidism in cats?
Polyphagia and weight loss
PUPD in 30-40%
vomiting, diarrhea, increased defecation
unkempt/matted hair, seborrhea
heat and stress intolerance
Weakness/lethargy
84
What are some signs of thyrotoxicosis?
shallow rapid breathing, enhanced oxygen utilization and CO2 output, low anaerobic threshold
85
What causes weakness/lethargy in hyperthyroid cats?
hypokalemia (cervical ventroflexion)
- from GI loss
cobalamine deficiency
thiamine deficiency
86
Why can hyperthyroidism contribute to HCM in cats?
Tachycardia + increased ejection fraction + increased blood volume (via RAAS) + decreased vascular resistance 🡪 increased cardiac output
87
Thyroid storm has not yet been reported in cats but what are the clinical signs in humans?
Fever
CNS manifestations
GI/hepatic dysfunction
Cardiovascular compromise (tachycardia, Afib, CHF, etc.)
88
What are the typical abnormalities seen on serum chemistry for cats with hyperthyroidism?
Increased liver enzymes
- usually ALT and ALP
- toxic effects of thyroid on the liver
- normalize with treatment
- increased bone metabolism
Increased phosphate/decreased iCa
- 60-80% have elevated PTH
Elevated fasting serum ammonia
- increased protein catabolism
10% of hyperthyroid cats are azotemic
- can mask CKD due to increased GFR and cachexia
89
What are common CBC findings for cats with hyperthyroidism?
40-50% have elevated PCV
- stimulates secretion of erythropoietin
Macrocytosis and Heinz bodies
- Depletion of antioxidants + protein/fat catabolism 🡪 Heinz body formation
+/- stress leukogram
90
What happens to fructosamine in hyperthyroid cats?
lower due to catabolism of proteins
- increase as the cat is being treated
Don’t use fructosamine to monitor the diabetic state of a hyperthyroid cat
91
How are cats with hyperthyroidism diagnosed?
TT4 (+/- fT4)
T3 are rarely useful
TSH has poor sensitivity in cats
+/- thyroid scintigraphy
+/- cervical ultrasound
+/- methimazole trial
*need to have clinical signs
92
What factors can affect TT4 when trying to diagnose hyperthyroidism in a cat?
Nonthyroidal illness
Thioureylene drugs
Iodinated contrast agents
Glucocorticoids
93
What is thyroid scintigraphy?
provides both anatomic and functional information about the thyroid gland
imaging procedure of choice for the feline thyroid gland
94
What are the treatment options for feline hyperthyroidism?
Thyroid hormone inhibition
- Anti-thyroid drugs
- Iodine restrictive diets – Hill’s y/d
Definitive therapy
- Surgical thyroidectomy
- Radioactive iodine
95
How can hyperthyroidism contribute to progression of renal disease?
Proteinuria
Activation of RAAS
Hypertension
Alterations in serum calcium levels and phosphate homeostasis
96
What are some side effects of methimazole?
Anorexia, vomiting, lethargy
Excoriations of the face/neck (2-3%)
Lymphadenopathy
Blood dyscriasis (rare)
- Mild leukopenia
- Eosinophilia
- Severe thrombocytopenia
- Severe neutropenia
- Bleeding without thrombocytopenia
--> vitamin K coagulation factors?
Hepatotoxicity
Myasthenia gravis
Hypothyroidism
- increased risk of azotemia
- have shorter survival times
97
What are the potential serious side effects of thyroidectomy in cats?
hypothyroidism
- usually other gland will kick in
hypoparathyroidism
- post-operative hypocalcemia
- usually transient and due to edema
- may need dihydrotachysterol/calcitriol
Horner’s syndrome
98
How does I131 work?
Thyroid cells concentrate radioactive iodine
- only in functional tissue, not atrophic
Beta particles lead to follicular cell death
- travel short distances so parathyroid not affected
thyroid hormone concentrations normalize over days to a few weeks
99
Where is somatotropin (GH) produced?
somatotropic cells in the anterior pituitary
100
What are the 5 types of endocrine cells in the anterior pituitary?
Corticotrophs – secrete ACTH
Thyrotrophs – secrete TSH
Gonadotrophs – secrete LH and FSH
Somatotrophs – secrete GH
Lactotrophs – secrete prolactin
101
What are the parts of the adenohypophysis (anterior pituitary)?
Pars distalis
pars intermedia
pars infundibularis
102
How are the hormones of the anterior pituitary secreted over the course of a day?
In a pulsatile fashion
103
How do thyroid hormones affect GH synthesis?
Hypothyroid dogs have increased GH and IGF-1 levels
104
What dogs are predisposed to congenital hyposomatotropism (pituitary dwarfism)?
Autosomal recessive disorder
- GSD, Karelian Bear dog, Wolfdogs
- Genetic defect in the LHX3 gene
- GH, TSH, and prolactin decreased
- ACTH secretion is preserved
Weimaraners, Spitz, Miniature pinscher, Goldens, Labradors also predisposed
105
What are the clinical signs of congenital hyposomatotropism (pituitary dwarfism)?
Mostly due to lack of GH and TSH
Present at 3-5 months
Proportionate growth failure
- Pointed muzzle like a fox
- Delayed closure of growth plates/fontanelles
Soft/wooly coat due to retention of secondary hairs
Primary hairs do not develop or are only present on the face and distal extremities
Hair loss (frictional areas 🡪 whole body)
Hyperpigmentation, scale, atrophy, wrinkling, comedones, papules, and pyoderma
Gonadotropin deficiency
-reproductive abnormalities
Persistent puppy bark
Lively puppy 🡪 dull adult at 2-3 yr old
- From secondary hypothyroidism + progressive enlargement of pituitary cysts + development of renal insufficiency
106
What is the histopathologic findings of a dog with pituitary dwarfism?
Similar to endocrinopathies
Orthokeratotic hyperkeratosis, follicular keratosis/dilation, follicular atrophy, hair follicles in telogen, excessive trichilemmal keratinization, sebaceous gland atrophy, epidermal melanosis, thinning of the dermis
107
Why can dogs with pituitary dwarfism develop azotemia?
abnormal glomerular development from lack of GH/IGF-1+ decreased GFR over time from low TSH/T4
108
What induces the pituitary to release GH?
GHRH from the hypothalamus
109
What is insulin-like growth factor-1 (IGF-1)?
mainly derived from the liver
GHs and IGFs work in concert to stimulate pathways that lead to growth and regulate metabolic pathways
110
What testing can be done to confirm pituitary dwarfism?
Measurement of GH after stimulation with GHRH, ghrelin, clonidine, or xylazine is gold standard after genetic testing
- GH deficiency may be complete or only partial
Can also do combined pituitary function testing
111
What is the treatment and prognosis of pituitary dwarfism?
Porcine GH (can lead to diabetes)
Levothyroxine and progesterone if combined deficiency
Dogs usually die or are euthanized between 3-5 years of age
112
What causes hypersomatotropism (acromegaly) in cats?
Pituitary adenomas secreting GH, high IGF-1 --> insulin resistance --> diabetes
- IGF-1 does not necessarily mean the diabetic has acromegaly
113
What are the clinical signs of hypersomatotropism (acromegaly) in cats?
PUPD, polyphagia (diabetes)
Weakness, ataxia, plantigrade stance
- diabetic neuropathy
Poor, unkempt hair coat
Weight gain
Broadening of the head
- Prognathia inferior
- enlarged tongue
Widening of interdigital spaces
- “clubbed paws”
Difficult to control DM
Cardiomegaly and systolic heart murmur
Organomegaly
- liver, thyroid, kidneys, adrenals, parathyroids, pancreas, etc.
114
How do you treat hypersomatotropism (acromegaly) in cats?
neurosurgery (1st line)
- hypophysectomy
radiation therapy (2nd line)
- good success on any neuro signs
medical management (3rd line)
- Somatostatin receptor ligands
- Dopamine agonists
- GH receptor antagonists
also control diabetes
115
How do you diagnose hypersomatotropism (acromegaly) in cats?
*collect 3-5 samples for GH measurement at 10-minute intervals
Feline GH measured by canine assays
- availability is still tricky
glucose tolerance tests are difficult
- healthy cats do not show GH suppression after glucose like humans
IGF-1 measurement
Imaging of pituitary +/- adrenals
116
What causes hypersomatotropism in dogs?
almost always induced by endogenous or exogenous progestagens giving rise to GH hypersecretion from the mammary gland
117
What are the clinical signs of hypersomatotropism in dogs?
Diestrus-associated hypersecretion of GH
- dogs present 3-5 weeks after estrus
Clinical signs will reflect the anabolic, growth-promoting, anti-insulin effect of GH
- Highly variable if the dog will present with signs secondary to DM or acromegaly
inspiratory stridor +/- dyspnea, panting, and exercise intolerance
- increased oropharyngeal soft tissue
broadening of the head
- Enlarged tongue
- prognathia
widening of interdigital spaces
increased skin thickness
excessive skin folds
weight gain
thickened hair coat with long/curly hair
degenerative arthropathy
mammary tumors
PUPD from secondary DM
118
How do you diagnose hypersomatotropism in dogs?
Measurement of GH in 3-5 samples
- taken in 10-minute intervals
Measurement of GH during somatostatin suppression test
Measurement of GH during IVGTT
- Also measure insulin during this test
Single IGF-1 measurement paired with clinical signs
119
How do you treat dogs with hypersomatotropism in dogs?
Spaying female dogs with diestrus-associated hypersecretion of GH
Stop progestogen medications
Surgical excision of mammary gland tumors
Hypophysectomy or RT for pituitary tumors
Treat diabetes (may go into remission)
120
What is the pathomechanism of proteinuria?
the abnormal transglomerular passage of proteins due to increased permeability of glomerular capillary wall
- glomerular diseases will cause this
Then subsequent impaired reabsorption by the epithelial cells of the proximal tubuli
121
What cells in the pancreas produce insulin?
Beta cells
122
What cells in the pancreas produce glucagon?
Alpha cells
123
What is the relationship between glucagon and insulin?
They work work antagonistically
124
What is type 1 diabetes?
Progressive loss of insulin activity with eventual complete insulin insufficiency
aka insulin-dependent DM in humans
more common in dogs than cats
125
What happens to the canine pancreas with diabetes?
decrease in the number and size of pancreatic islets histologically
126
How does obesity contribute to the development of diabetes?
internalization of cellular insulin receptors
- especially in muscle and fat
reduces insulin receptor affinity
produces post-receptor defects
together it causes an initial delay in insulin release, followed by excessive insulin secretion (humans and cats).
- beta cells of a diabetic patient are less able to compensate
127
What is type 2 diabetes?
Characterized by insulin resistance and dysfunctional beta cells
traditionally thought of as non-insulin dependent DM
- but most all animals need insulin
more common in cats than dogs
128
What does adiponectin do?
Adiponectin enhances insulin sensitivity and has anti-inflammatory properties
129
What does leptin do?
involved in appetite suppression and energy expenditure and modulates insulin sensitivity
130
What are the adipose-derived inflammatory cytokines?
TNF-a, IL-6
131
What happens on histopathology of feline pancreases with diabetes?
deposition of amyloid in pancreatic islets
- Islet-amyloid polypeptide aka amylin
- barrier to the diffusion of glucose
amylin complements insulin in post-prandial glucose control
“Cured” cats still show histologic evidence of islet cell pathology
- means they can relapse in the future
132
What is glucose toxicity?
Chronic hyperglycemia impairs insulin secretion by beta cells and induces peripheral insulin resistance by downregulating glucose transport systems and causing a defect in post-transport insulin action
potentially reversible with correction of hyperglycemia
133
What is the renal glucose threshold for dogs and cats?
180-220mg/dl in dogs
200-320mg/dl in cats
134
Why does polyphagia occur with diabetes mellitus?
glucose can’t enter cells of satiety center in the hypothalamus
135
What are insulinomas?
a functional tumor arising from the beta cells of the pancreatic islets which releases insulin independent of the suppressive effects of hypoglycemia
136
What are the layers of the adrenal gland?
Cortex
- Zona glomerulosa -> aldosterone
- Zona fasciculata -> cortisol (and androgens)
- Zona reticularis -> androgens (and cortisol)
Medulla -> catecholamines)
137
What is corticotropin-releasing hormone (CRH)?
produced in the paraventricular nucleus of the hypothalamus -->
secreted into the hypophysial portal system -->
carried to the anterior pituitary gland
Secretion is pulsatile
- diurnal rhythm in people
138
What is secretion of hypothalamic CRH mediated by?
cytokines (interleukins [IL] 1 and 6, TNF-alpha), leptin, dopamine, arginine-vasopressin (AVP) and angiotensin II
139
What is the feedback cycle that decreases the production of CRH and ACTH?
Cortisol exerts negative feedback on both
“fast-feedback”
- detects the rate of increase in cortisol
“slow-feedback”
- detects absolute cortisol concentrations
ACTH also has negative feedback on itself
CRH can be inhibited by somatostatin
140
What is ACTH?
released from the anterior pituitary’s pars distalis in response to ACTH
- also from the pars intermedia
stimulates the adrenals to make glucocorticoids
processed from a larger precursor molecule known as pro-opiomelanocortin (POMC)
141
How does control of the pars distalis and pars intermedia differ?
pars distalis gets portal vessels from the hypothalamus and blood borne hormones
pars intermedia depends on dopaminergic and serotoninergic nerve fibers for stimulation
142
What is pro-opiomelanocortin (POMC)?
Made by several cell types
Can be processed into:
- ACTH
--> B-cells of the pars intermedia
- beta lipotropin (LPH)
- alpha melanocyte stimulating hormone (a-MSH)
--> A-cells of the pars intermedia
- beta-MSH
- corticotropin-like intermediate-lobe peptide (CLIP)
- beta-endorphin
143
What do serotonergic and dopaminergic nerve impulses do to the processing of POMC?
serotonergic = stimulate
dopaminergic = inhibit
144
What does ACTH do when it reaches the adrenal glands?
ACTH activates adenyl cyclase in the adrenocortical cells -->
increasing cAMP -->
activating the enzyme desmolase
145
What happens to the adrenal glands under constant stimulation of ACTH?
secretion of cortisol
hypertrophy and proliferation of adrenocortical cells of the zona fasciculata and reticularis
146
What are the primary cause of pituitary dependent Cushing's disease in dogs?
Pituitary adenoma - >90% of PDH
- Pars distalis - ~85% of the 90%
- Pars intermedia type A cell
- Pars intermedia type B cell
* pituitary hypertrophy - very few (if any)
Functional pituitary carcinoma - very few
Possible, but not likely, that some PDH is due to hypothalamic abnormality
147
What are the primary cause of adrenal dependent Cushing's disease in dogs?
Functional adenomas - 50%
Functional carcinomas - 50%
Adrenal nodular hyperplasia
* independent of pituitary control, but they retain ACTH receptors because they respond to exogenous ACTH
148
What, histologically, is a marker of malignancy in canine adrenal tumors?
Ki-67
149
What are some potential causes of ACTH-independent hyperadrenocorticism in dogs?
hyperactive eutopic adrenocortical membrane-bound hormone receptors
- Gastric inhibitory polypeptide (food-dependent)
- catecholamine
- vasopressin
- serotonin
- luteinizing hormone
150
What does excess cortisol do?
secondary hypothyroidism (low TSH)
reproductive changes (low FSH and LH)
low GH levels
Induce and inhibit DNA transcription (many pieces in many cells)
Stimulate gluconeogenesis
Decrease rate of tissue glucose utilization
Reduce protein stores (except in the liver, where they increase)
Decrease protein synthesis and increase protein catabolism
Decrease amino acid transport (except in liver cells)
Promote mobilization of fat and release free fatty acids
Stimulate food intake
Excert anti- ADH effects
Have potent anti-inflammatory actions Immunosuppressive actions
Neurologic signs (if macroadenoma)
151
What are the most common presenting complaints for a dog with Cushing's?
PU/PD - 80-85%
Polyphagia - 80-90%
Abdominal enlargement - 90-95%
Dermatological changes
Panting
Weakness/lethargy - mistaken for aging change
152
What are the most common physical exam findings for a dog with Cushing's?
Pot bellied
Thin skin
Alopecia/pyoderma/seborrhea/hyperpigmentation
Hepatomegaly
Panting
Muscle wasting
153
How long of a washout is needed between exogenous steroids and measuring blood cortisol concentrations?
24 hour wash out (or at least 5 half-lives)
154
How accurate is ACTH testing for canine Cushing's disease?
sensitivity range reported in literature is 57-95%
specificity range reported in the literature is 59-93%
can NOT distinguish between PDH and adrenal disease, even though there are tendencies for different responses
- PDH tend to jump higher while AD tend to be flatter
*more likely to have false negatives
155
What hormones are elevated in canine Cushing's?
androstenedione, estradiol, progesterone, testosterone, and 17-hydroxyprogesterone alone or along with excess cortisol
156
How accurate is LDDST testing for canine Cushing's disease?
Overall sensitivity is 85-100%
Overall specificity is 44-78%
97% sensitivity for PDH
- 20% do not suppress at all (just like adrenal hyperadrenocorticism)
- 20% suppress somewhat (not as well as they should) but go back up before 8 hours
- 30-40% suppress, but never as low as they should
- 25% suppress low enough, but go back up before 8 hours
- <3% suppress and stay suppressed for the full 8 hours
Doesn't suppress with adrenal tumors
*more likely to have false positives
157
Is combination ACTH stim/LDDS recommended?
less reliable than either of the two alone - combines both their shortcomings, and not widely recommended.
158
When is high dose dexamethasone suppression used?
NOT a screening test
only done after making a diagnosis of Cushing’s syndrome to distinguish between PDH and adrenal disease
not necessary if the dog suppressed >50% or suppressed and escaped on the LDDS test
- then you know not adrenal
159
How is eACTH used in diagnosing canine Cushing's disease?
eACTH should be low in adrenal and iatrogenic disease, high in PDH
- measured by using an Immulite 2000
160
What is metyrapone testing?
enzyme blocker that inhibits 11-b-hydroxylase in steroid synthesis
normal dog = cortisol will decrease, ACTH will increase, and 11-desoxycorticosol
animals with PDH = cortisol decreases and 11-desoxycorticosol increases
animal with adrenal tumors, both cortisol and 11-desoxycorticosol decrease, no increase in ACTH because of the previous suppression
161
How is POMC/pro-ACTH concentrations used in diagnosing canine Cushing's?
correlated with pituitary size in humans
best used to rule out a macroadenoma
If the test is positive imaging of the pituitary is indicated
162
What is Sudden Acquired Retinal Degeneration (SARD)?
syndrome is recognized to occur in dogs only
particularly middle-aged to older individuals
predisposition for female and obese animals
Dachshunds are over-represented
rapid onset blindness
- cause of the retinal degeneration is not known
- non-painful
often associated with signs of Cushing’s disease
- The systemic signs are usually transient and resolve without treatment
163
What is Nelson's syndrome?
that all of the standard medical therapies for PDH have the potential to promote pituitary adenoma growth
tumor expansion occurs because of a lack of negative feedback from cortisol
164
What is the signalment of dogs with Cushing's disease?
Naturally occurring HAC is most commonly diagnosed in middle-aged to older dogs. The age at diagnosis ranges from 6 months to 20 years with a mean age of 11 years.
Almost all dogs with HAC are older than 6 years at diagnosis.
Sex predilection in dogs with HAC is possible, with 60 to 65% being female.
165
Why does PU/PD occur in dogs with Cushing's disease?
increased glomerular filtration rates and inhibition of antidiuretic hormone (ADH) action at the renal tubular level
- leads to a decrease in renal tubular water reabsorption
Exogenous ADH causes dramatic reduction in PU/PD
- suggests that cortisol interference with ADH release is responsible
166
Why does calcinosis cutis happen in dogs with Cushing's disease?
Characterized by irregular plaques in or under the skin caused by dystrophic calcium deposition and located on the temporal areas of the head, dorsal midline, neck, ventral abdomen, or inguinal areas
Rearrangement of molecular protein structures leads to formation of an organic matrix that attracts and binds calcium, forming apatite crystals
167
What happens on the CBC of dogs with Cushing's disease?
"stress leukogram"
- Lymphopenia due to steroid lympholysis
- eosinopenia caused by bone marrow sequestration
- neutrophilia and monocytosis due to steroid-enhanced capillary demargination
mild erythrocytosis (direct bone marrow stimulation or ventilatory issues)
thrombocytosis
168
What are the changes seen on serum chemistry of dogs with Cushing's disease?
Increased alkaline phosphatase
Increased alanine aminotransferase
Hypercholesterolemia
Hypertriglyceridemia
Hyperglycemia (mild and not associated with diabetes mellitus)
- Glucocorticoids increase hepatic gluconeogenesis and decrease peripheral utilization of glucose by interfering with insulin action at the cellular level (receptor and post-receptor defects)
- Gene expression of insulin signal molecules (post-receptor) is suppressed in dogs with HAC
169
What is “atypical” or “occult” HAC?
refers to a dog with clinical signs, physical examination and clinicopathologic findings compatible with HAC but with results of LDDST, UCCR, and ACTHST within reference ranges
- secretion of androgens
170
What are common findings on histopathology of skin for dogs with Cushing's disease?
Orthokeratotic hyperkeratosis, epidermal atrophy, epidermal melanosis, follicular keratosis, follicular dilatation, follicular atrophy, telogenization of hair follicles, excessive trichilemmal keratinization, sebaceous gland atrophy
171
What happens to the skin of dogs with Cushing's disease?
Thinned and hyperkeratotic epidermis
- Secondary to suppression of DNA synthesis, decreased mitoses, and keratinization abnormalities
BMZ becomes thinned and disrupted
Pronounced pilosebaceous atrophy
Thinning of the dermis and fragility of the dermal vasculature
Inhibition of fibroblast proliferation, collagen, and ground substance production
Delayed wound healing
Collagen and elastin fibers become attractive sites for mineralization
172
What is the main cause of endogenous Cushing's disease in cats?
Approximately 80% of cats with HAC have pituitary dependent (PDH) disease
173
What are the typical presenting compaints of Cushing's disease in cats?
majority (80%) of cats with HAC present for diabetes mellitus and therefore, polydipsia, polyuria, polyphagia and weigh loss are common clinical signs
174
What are the most common laboratory abnormalities of Cushing's disease in cats?
Hyperglycemia and hypercholesterolemia
Elevated ALP is rare
175
What are the diagnostic tests for Cushing's disease in cats?
LDDS test has excellent sensitivity for HAC in cats, but false positives are possible
- preferred
ACTH stimulation test has a low sensitivity for HAC in cats, with up to 50% of cats with HAC having a normal result and therefore, is not recommended
potentially endogenous POMC/pro-ACTH concentrations
176
What is the treatment of Cushing's disease in cats?
Tilostane
Cats are resistant to mitotane
Ketoconazole is a poor choice
surgery
177
What is aldosterone?
the major mineralocorticoid secreted by the adrenal cortex
- in response to the renin-angiotensin-aldosterone system and serum potassium concentrations
exerts its primary effects on the distal renal tubules, colon and salivary glands
- causes sodium reabsorption, and potassium and hydrogen excretion
- Sodium retention results in volume expansion
178
What does Cushing's disease do to the cutaneous immune system?
Decreased macrophage production of inflammatory cytokines
Upregulation of anti-inflammatory cytokines
Decreased function and maturation of dendritic cells
Decreased T cell activation and proliferation in response to mitogens
Decreased cell-mediated lysis of target cells
Decreased mitogen-induced B cell proliferation
Decreased antibody production
179
How does Cushing's disease cause an increase in cholesterol and triglycerides?
Glucocorticoids inhibit lipoprotein lipase activity + increase hormone-sensitive lipase 🡪 increase in serum cholesterol and triglycerides
can also cause secondary hypothyroidism which drives hypercholesterolemia
180
What is the renin-angiotensin-aldosterone system (RAS) system?
activated by activity of the juxtaglomerular apparatus
- senses a decrease in stretch on the renal afferent arterioles
--> rennin is released
--> converts angiotensinogen produced in the liver to angiotensin I
--> Angiotensin I is converted in the lung by ACE to angiotensin II
--> aldosterone secretion
181
What is the most common cause of primary hyperaldosteronism in cats?
bilateral adrenal cortical hyperplasia
or unilateral/bilateral adenoma or carcinoma of the adrenal cortex
182
What are the typical presenting complaints of cats with primary hyperaldosteronism?
Sudden blindness and hypokalemic polymyopathy
183
What is the most common endocrinopathy in horses?
Pituitary pars intermedia dysfunction (PPID, Cushing disease, Cushing syndrome, hirsutism)
estimated to affect 15-30%
of aged horses
184
What is thought to be the primary cause of PPID in horses?
dopaminergic neurodegenerative disease
- dopamine neurons are particularly sensitive to oxidative stress
leads to loss of normal dopaminergic inhibitory control --> classic endocrine processes of hypertrophy, hyperplasia, and, rarely, adenoma formation
- 9x less dopamine in pars intermedia of horses with PPID
185
Which cytokine s increased in horses with PPID?
IL-8
perhaps indicating an inflammatory dysregulation
186
How does dopamine normally influence the function of melanotrophs in the pars intermedia?
release of dopamine normally inhibits function
187
What is proopiomelanocortin (POMC) processed into in the equine pars distalis?
adrenocorticotropin (ACTH)
b-lipotropin (bLPH)
a-lipotropin (aLPH)
188
What is proopiomelanocortin (POMC) processed into in the equine pars intermedia?
a-melanocyte stimulating hormone
(a-MSH)
b-melanocyte-stimulating hormone (b-MSH)
corticotropin-like intermediate lobe peptide (CL1P)
b-endorphin (b-END)
*about 2% of ACTH
189
What is the mechanism by which horses with PPID are predisposed to dyslipidemia and laminitis?
Increased cortisol secretion results in insulin resistance
190
Why does hypertrichosis happen in horses with PPID?
postulated to be due to:
(1) increased adrenocortical production of androgens
(2) increased secretion of a-MSH
(3) pressure of the pituitary lesion on thermoregulatory areas of the hypothalamus
191
What is the difference between hypertrichosis and hirsutism?
Hirsutism = inappropriate hair growth in women under androgen control
Hypertrichosis = hair density or length beyond the accepted limits of normal
for a particular age, race, or sex
192
What breed of horse has spontaneous hypertrichosis?
Bashkir curly breed
193
What breeds of horses are at increased risk for PPID?
ponies and Morgans
194
What is the typical presenting complaints of horses with PPID?
Hypertrichosis (main and tail typically unaffected)
- delayed/incomplete spring shed
develop longer hairs on the legs,
ventrum, and under the chin before generalized hypertrichosis
+/- Hyperhidrosis (60%)
Weight loss, muscular weakness, and muscular atrophy (88%)
Polydipsia and polyuria (39-76%)
- associated with diabetes mellitus
and/or diabetes insipidus
Laminitis (24-82%)
195
Other than PPID, what can cause retention of winter coat in horses?
chronic illnesses and nutritional deficiencies
196
What laboratory abnormalities do you typically see in horses with PPID?
insulin-resistant hyperglycemia;
glucosuria
stress leukogram
elevated plasma insulin concentrations
low serum T4 and T3
Mild anemia
elevated serum liver enzymes hypercholesterolemia/triglyceridemia
197
When in the year do equine concentrations of endogenous hormones such as ACTH and a-MSH increase?
fall in the northern hemisphere
198
When in the year are equine dexamethasone suppression tests less reliable?
fall in the northern hemisphere
199
When is it best to test for PPID in horses in the northern hemisphere?
before June or after October
200
What is the current recommendation for the diagnosis of PPID in horses?
baseline endogenous ACTH
- not fasted but no carbohydrate meals within 12 hr
- not in fall
but are not elevated in all patients
201
Why is basal insulin levels not reliable for the diagnosis of PPID in equines?
ponies are inherently insulin resistant, and so levels are naturally raised
202
What are T4 levels in birds versus mammals?
lower in birds
