Diagnosis and Management of Feline Hypersomatotropism

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Acromegaly and Hypersomatotropismin cats

DR. ALISON KHOO

11/14/2017CE FALL 2017 | ACROMEGALY & HYPERSOMATOTROPISM IN CATS

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SPEAKER INFORMATION


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Akron= extremity mega=large

‘Acromegaly’ was first described in 1886 and linked to a distinct clinical disease with a characteristic clinical picture.

Pituitary enlargement was noted in almost all patients with acromegaly (eventually linked to pituitary hyperfunction)

20th century: treated with surgery/ radiotherapy

After 1970: treatment with medical therapy introduced

ACROMEGALY IN HUMANS

11/14/2017C FALL 2017 | ACROMEGALY & HYPERSOMATOTROPISM IN CATS

https://en.wikipedia.org/wiki/Acromegaly

WWW.UVSONLINE.COM11/14/2017CE FALL 2017 | ACROMEGALY & HYPERSOMATOTROPISM IN CATS

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Aims to increase FFA in the blood (available for energy)

Decreases rate of glucose utilization

Decreases insulin’s action to stimulate glucose uptake

Leads to increased BG and compensatory increase in insulin secretion

PHYSIOLOGICAL FUNCTIONS OF GROWTH HORMONE:

CATABOLIC




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Anabolic effects exerted through somatomedins/ insulin-like growth factor

Most important: somatomedin C aka insulin-like growth factor (IGF-1)

IGF-1’s actions

Increase lean body mass

Proliferation of bone, cartilage and soft tissue

Organomegaly

Increase glucose uptake by adipocytes (like insulin)

PHYSIOLOGICAL FUNCTIONS OF GROWTH HORMONE:

ANABOLIC


https://www.memorangapp.com/flashcards/123684/9-27+Pituitary+Dsyfunction/

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Acromegaly

A syndrome of bony and soft tissue overgrowth and insulin resistance due to excessive growth hormone secretion

Results from overexposure of tissues to GH and IGF-1

Hypersomatotropism

Refers to the pathologic overproduction and subsequent secretion of growth hormone which leads to the clinical syndrome of acromegaly

Terms often used interchangeably

Excess GH is dx in a large proportion of cats that do not yet show the typical acromegalic phenotype. Therefore, using the term hypersomatotropism instead of acromegaly might be more appropriate

ACROMEGALY VS. HYPERSOMATOTROPISM


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Majority are due to a functional adenoma of the somatotropic cells of the pituitary pars distalis

Minority are due to hyperplasia of the cells of the pituitary pars distalis

Possible explanations:

Interrelationship between these 2 etiologies (hyperplasia transforming to adenoma?)

Suprahypophyseal process (possibly located in the hypothalamus) driving the disease

PATHOGENESIS


http://sites.tufts.edu/progressnotes/category/clinical-case-challenge/

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SIGNALMENT


Hypersomatotropism

Median age in years (range) 11 (4-19)

Gender Male bias

Breed DSH bias (other breeds documented)

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Early + late stages Usually only in late stages

Polyuria/ polydipsia/ polyphagia Prognathia inferior

Weight gain Broad facial features

Enlarged kidneys Respiratory stridor

Enlarged liver

Systolic cardiac murmur

Plantigrade stance

CLINICAL SIGNS


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Insulin-resistant diabetes mellitus

However, there is a net weight gain of lean body mass

MOST COMMON CLINICAL SIGN


http://todaysveterinarypractice.navc.com/consider-case-uncontrolled-diabetic-cat/

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Less pronounced than dogs

Absence of acromegalic appearance should not decrease index of suspicion in an insulin-resistant cat

Polyphagia might be extreme

Snoring/ stridor: increase soft tissue in the oropharynx and soft palatedisturbed airflow

PHYSICAL CHANGES



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http://www.google.ca/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjUnp6qtYLKAhWFVj4KHeQ3ApcQjRwIBw&url=http://old.qi.com/talk/viewtopic.php?t%3D25886%26start%3D63%26sid%3D03a03bdc4ccf6967e35a8f1e34870d18&psig=AFQjCNHbL1vP8-1GLG0tMZHIc0OsU3NuSg&ust=1451524727519804

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Growth of flat bones of skull and mandible prognathia inferior and increased interdental spaces

Approximately 50% have proliferative changes in jointsprogressive arthropathy and lameness

OSSEOUS SIGNS


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Cardiomegaly (radiographic + echocardiographic)

85% mild to moderate in first few months

Worsen in 50%

Systolic murmurs (60% within first few months of diagnosis)

Congestive heart failure late in the course

CARDIOVASCULAR CHANGES


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Cause not fully understood

Lesions resemble hyperfiltration injury

Hypertension

Reported but…

Large studies have not detected an increased prevalence (based on Doppler measurements and fundic exams)

NEPHROPATHY


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Develops late in course of disease

Blindness, depression, anisocoria, circling

Resolve after radiation therapy

NEUROLOGICAL SIGNS


http://www.pophangover.com/34600/simon-the-depressed-cat-is-my-new-favorite-meme/


Large pituitary tumor in a cat with acromegaly

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DIAGNOSIS


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Does not differentiate from type 2 diabetes

Identifies comorbidities

Ketosis is rare, but can occur

No greater incidence of azotemia among acromegalic vs. nonacromegalic cats

Azotemia and chronic renal failure develop late in the course of the disease in approx. 50% acromegalic cats

Total protein

Significantly higher in acromegalic group

BUT, large amount of overlap between groups

ROUTINE CLINICAL PATHOLOGY


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Only available for research purposes

Sensitivity: 95%; specificity: 84%

If elevated

Acromegalic

Secretory pulse in normal animal

Cats with HCM (mild elevation compared to cats with acromegaly)

If within reference range

Non acromegalic

Mild/ beginning of disease

Should be determined by a species specific radioimmunoassay

BASAL PLASMA GROWTH HORMONE


http://www.thecatclinic.co.uk/pet-health-club/4578080486

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Produced by the liver

Protein bound so much less subject to fluctuation than GH

Assay offered at Michigan State University

Sensitivity:80-100% Specificity 70-92%

Production induced by growth hormone BUT only in the presence of sufficient portal insulin –significance??

INSULIN-LIKE GROWTH FACTOR-1 (IGF-1)



Modified from: http://genf20plus.info/igf1.php

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Duration of exogenous insulin administration plays a crucial role in false negative IGF-1 results

During treatment, hepatic IGF-1 production is stimulated via insulin-dependent hepatic GH receptors

An insulin deficient state can act as an inhibitor of IGF-1 production

Consider repeating IGF-1 concentration 6-8 weeks into treatment OR measure once, 6-8 weeks after institution rather than at the time of diagnosis

IGF-1: WHEN TO MEASURE?


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A mild elevation in the presence of severe insulin resistance could justifiably trigger further diagnostic studies

Liver and kidney disease increases IGF-1 in humans

Short term fasting can decrease IGF-1 concentrations

IGF-1


http://www.funnyordie.com/topic/cute-cat-pictures

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Do Not Use

Gold standard in humans

GLUCOSE SUPPRESSION TEST


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ADVANCED IMAGING


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MRI more sensitive than CT

Can have false negatives

Structural pituitary abnormality strengthens evidence for dx of hypersomatotropism

Can have concurrent increases in frontal bone thickness and/or evidence of soft tissue accumulation in the nasal cavity, sinuses and pharynx

Does not differentiate from non-functional tumor

DIAGNOSTIC IMAGING





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As an attempt to confirm disease

Preradiation planning

Presurgical planning

NOT as a screening test

WHEN SHOULD I CONSIDER MRI OR CT SCAN?


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Thicker skull bones

Thicker skin and subcutis

Narrow nasopharynx (thickening of surrounding tissues)

66% have increased bone measurements

24% had prognathia inferior

CT SCAN FEATURES IN CATS WITH HYPERSOMATOTROPISM


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Spectrum of changes

No structural abnormalities

Diastolic dysfunction most common

Other common changes: left ventricular hypertrophy and left atrial enlargement

ECHOCARDIOGRAPHY


http://www.allevamentosiberiani.it/media/k2/items/cache/9f6d22dec5a20bcdd01cd84e98637764_XL.jpg

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Cats with hyperadrenocorticism can present similarly to cats with hypersomatotropism

UCCR can be elevated in acromegalic cats

LDDST is the preferred test in cats

Pay attention to specific clinical differences

OTHER TESTS TO CONSIDER: UCCR/ LDDST/ACTH

STIMULATION


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0.1mg/kg Dexamethasone

Sample collection at 4 and 8 hours post administration

Cortrosyn: 125ug/cat

Sample collection at 1 hour +/- 30 minutes

LDDST AND ACTH STIMULATION PROTOCOL IN CATS


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Hypersomatotropism (HS) Hyperadrenocorticism (HAC)

Frequent weight GAIN Frequent weight LOSS

Lack of dermatologic signs apart from unkemptcoat

Frequent dermatologic signs

Lack of muscle wasting Frequent muscle wasting

Severe or extreme insulin resistance Lack of or modest insulin resistance

Infrequent generalized poor condition Frequent generalized poor condition

Absence of diabetes very rare Absence of diabetes possible

IGF-1 elevated IGF-1 usually not elevated

DIFFERENTIATING DIABETIC CATS WITH HS SV. HAC


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Medical treatment

Definitive treatment

Conservative treatment

Radiation therapy

Surgery

TREATMENT


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With ANY definitive treatment, clinicians and owners need to be vigilant for rapid changes in insulin demands if treatment is proven effective

Iatrogenic hypoglycemia is frequently encountered

Consider home blood or urine glucose measurements

Cats with these signs should be immediately evaluated

Negative urine glucose

Dramatic decline/ resolved pu/pd

MONITORING DURING TREATMENT


http://www.peteducation.com/article.cfm?c=1+2130&aid=201

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Aimed at inhibiting pituitary secretions of growth hormone

Somatostatin analogues

Pasireotide shows the most promise

Octreotide and lanreotide: no convincing clinical improvement

Dopamine agonist did not result in clinical improvement

GH-receptor antagonists: requires more research

MEDICAL TREATMENT


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Currently the most widely applied treatment modality

Disadvantages:

Multiple fractions required (frequent anesthesia)

Slow rate of tumor shrinkage (>3 years)

Possibility of relapse and unpredictable clinical response

IGF-1 and GH concentrations decrease but not to normal levels in seemingly successfully treated animals

Negative sequelae of HS might continue to develop (cardiac, joint and renal changes)

Extended hospitalization, depigmentation and radiation injury

Hypopituitarism, optic nerve damage

RADIATION THERAPY


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Transsphenoidal hypophysectomy results in an immediate decrease in GH levels postoperatively and normalization of IGF-1 concentration

Possible resolution of DM within weeks

Perioperatively and postoperatively, desmopressin, thyroxin and GC supplementation req

Iatrogenic diabetes insipidus is transient; hypocortisolism and hypothyroidism is life long

Risk of regrowth of tumor in 30-40% cases

Niessen’s preferred treatment option

Method of choice in humans

SURGICAL TREATMENT


https://www.researchgate.net/profile/Stijn_Niessen

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Ignores the underlying disease mechanism and focuses on gaining maximal control over DM

Will require very high dosages of insulin or combinations of short and long acting insulin types

High doses employed with gradual increases guided by BG curves +/- fructosamine concentrations

Feed a balanced diet that is low in carbs and high in protein (may require 3-4 feedings a day)

Palliate arthropathies with analgesia

Treat CHF with diuretics and ace-inhibitors

CONSERVATIVE TREATMENT


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Short-term

Fair to good

Long-term

Relatively poor

Benefit with any treatment modality compared with tx of DM alone has yet to be documented

1990 study: 11/14 cats were euthanized/ dead 4-42 months after onset of hypersomatotropism because of renal failure, CHF, progressive neurologic signs, persistent anorexia and lethargy and owner’s unwillingness to treat

PROGNOSIS


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CASE EXAMPLE


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Harry

9 yo MC DSH

Presented with a 1 year history of diabetes mellitus

Receiving between 25 and 30 units PZI insulin daily

Eating a low carbohydrate, high protein diet

Spot glucose tests revealed BG between 50 and 250mg/dl

MEET THE PATIENT


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Large cat : 7kg (gained 1kg in the past 5 months)

Snoring occasionally

Before and after photos revealed potential enlargement of paws but owners think he looks unchanged

PHYSICAL EXAMINATION


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Target tissues cannot respond to insulin due to peripheral antagonism

Due to:

Degradation of insulin

Insulin receptor defects

Post-receptor defects

Glucose transport defects

WHAT DOES INSULIN RESISTANCE MEAN TO YOU?


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Persistent hyperglycemia in the face of insulin dosages >2-2.5 units/kg

Note: This may or may not reflect true insulin resistance at the cellular level

Harry was receiving ~4units/kg

WHEN DO WE WORRY ABOUT INSULIN RESISTANCE


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Inappropriate handling and storage of insulin

Improper administration of insulin

Improper care and feeding

Using the wrong type of insulin

Insulin-induced hyperglycemia

WHAT CAN MIMIC INSULIN RESISTANCE?


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INSULIN RESISTANCE- WHO IS AT FAULT?


OWNER?

VETERINARIAN?

CAT?

http://www.petmd.com

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Ensure owners can mix, draw up and administer insulin

Ensure insulin syringe is correct (40-U syringe)

Check expiration date

Ensure owner is varying the injection site

All family members involved in insulin administration should be investigated

OWNER?


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Interpret the following data before arriving at a diagnosis of true insulin resistance

CLINICAL SIGNS!!

Blood glucose curves

+/- Fructosamine

Underdosing?

Overdosing? Somogyi??

Concurrent administration of diabetogenic drugs

VETERINARIAN?


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Determine the lowest blood glucose concentration (nadir)

Range of blood glucose concentration (ideal for cat: 90-350mg/dL)

Duration of insulin effect (only assess if nadir is >90mg/dL and BG has not decreased rapidly)

BLOOD GLUCOSE CURVES


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8am: fed and insulin administered: 350mg/dl

9am: 70mg/dl

10am:60mg/dl

11am: 60mg/dl

12pm: 50mg/dl cat was offered food and BG curve aborted

BLOOD GLUCOSE CURVE PERFORMED IN CLINIC


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Concurrent endocrinopathy

Hyperadrenocorticism

Hyperthyroidism

Acromegaly

Glucagonoma

Phaechromocytoma

Anti-insulin antibodies (very rare)

Severe obesity

Concurrent disease

Liver, renal, cardiac insufficiency

Neoplasia

Infection

Especially skin, oral cavity and urinary tract

CAT?


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CBC, chemistry, urinalysis

URINE CULTURE!!

T4

Blood pressure

Abdominal ultrasound

INITIAL WORKUP


www.dreamstime.comhttp://www.ironmagazine.com

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T4 and BP: WNL

CBC, CHEMISTRY, UA AND CULTURE


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URINALYSIS AND CULTURE


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IGF-1 level was elevated: 578nM/L (range 12-92nM/L)

MRI

Pituitary is enlarged

FURTHER DIAGNOSTICS


http://sites.tufts.edu/progressnotes/category/clinical-case-challenge/

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Why was Harry hypoglycemic when in hospital?

HYPOGLYCEMIA?


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Due to the pulsatile nature of GH secretion, cats may present with exogenous insulin induced hypoglycemia


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Owner did not want to pursue radiation therapy or surgery

What are our options?

TREATMENT


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Insulin type Concentration Brand name (s) To shake or not to shake

Duration of action

Insulin zinc suspension (lente)

40U/ml Vetsulin/ Caninsulin Shake vigorously Intermediate

PZI 40U/ml Prozinc NO, roll between palms

Long (~8h)

Glargine 100U/ml Lantus NO Long

Detemir 100U/ml Levemir NO Long

INSULIN CHOICES FOR HARRY


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Reduce PZI dose and owner to measure glucose at home and give regular insulin if BG is >270mg/dl

MEDICAL MANAGEMENT



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Niessen et al. Hypersomatotropism, Acromegaly and Hyperadrenocorticism and Feline Diabetes Mellitus. 2013. Vet Clinics Small Anim. 43:319-350

Niessen et al. Feline acromegaly: an underdiagnosed endocrinopathy? Journal of Veterinary Internal Medicine. 2007. 21 (5): 899-905

Elliot et al. Prevalence of pituitary tumors among diabetic cats with insulin resistance. J Am Vet Med Assoc. 2000. 216 (11): 1765-8

Berg et al. Serum insulin-like growth factor-1 concentration in cats with diabetes mellitus and acromegaly. Journal of Veterinary Internal Medicine. 2007. 21(5): 892-898

Niessen et al. Routine screening of diabetic cats for acromegaly: overdue or overkill? Journal of Veterinary Internal Medicine. 2011. 25: 1489-90

Guyton and Hall. 2011. Textbook of Medical Physiology. Pituitary hormones and their control by the hypothalamus. 895-896. Canada: Elsevier

Myers J et al. Echocardiographic Findings in 11 cats with Acromegaly. Journal of Veterinary Internal Medicine. 2014. 28: 1235-1238

Greco, D. Feline Acromegaly. Topics in Copan An Med. 2012. 31-35

Meij et al. Transsphenoidal hypophysectomy for treatment of pituitary dependent hyperadrenocorticism in 7 cats. Vet Surg. 2001. 30:72-86

Blois SL et al. Cryophypophysectomy used in the treatment of a case of feline acromegaly. J Small Anim Pract. 2008. 49:596-600

Lamb et al. Computed tomographic signs of acromegaly in 68 diabetic cats with hypersomatotropism. 2014. Journal of feline medicine and surgery. 16 (2): 99-108

Niessen S. Feline acromegaly: An essential differential diagnosis for the difficult diabetic. 2010. Journal of feline medicine and surgery.12: 15-23

REFERENCES


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QUESTIONS?


Diagnosis and Management of Feline Hypersomatotropism

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