Abstract

Hypothyroidism results from impaired production and secretion of thyroid hormone. 95% of cases are due to destruction of the thyroid gland itself (and not due to hypothalamic or hypophyseal disease). This is one of the most common canine endocrine diseases. Most cases are not difficult to diagnose, but in some cases interpretation of thyroid hormone assay results can be difficult. Prognosis is good following successful treatment.

Classification

Primary (Thyroidal) Hypothyroidism

Primary destruction of the thyroid gland is the most common cause of this disease. Idiopathic atrophy of the thyroid and lymphocytic thyroiditis are the two most common causes of thyroid gland loss. Congenital or juvenile onset hypothyroidism, neoplastic destruction of the thyroid gland and iatrogenic hypothyroidism can also occur, but are much less common.

Secondary (Pituitary) Hypothyroidism

This denotes an impaired ability of the pituitary gland to secrete TSH, causing secondary thyroid follicular atrophy. This mechanism is responsible for < 5% of cases. Pituitary tumors, pituitary malformation and isolated TSH deficiency are possible causes.

Signalment

This is classically a disease of middle-aged, large breed dogs of either sex. Golden Retrievers and Doberman Pinchers are reported to be at increased risk. Mean age at diagnosis is 7 years, with a range of 0.5–15 years. The disease is rare in small breed dogs.

Clinical Signs

Metabolic Signs

Mental status and physical activity are most affected. Dogs become dull, depressed and lethargic. They show a propensity to gain weight, without an increase in appetite. They tend to be "heat-seekers" and are cold intolerant. These signs develop slowly and are often not noticed by owners or a veterinarian examining the dog for the first time.

Dermatological Signs

Skin disease is the most common sign and the most common reason for seeking veterinary care. The presentation is classically a bilaterally symmetrical, non-pruritic alopecia, mainly affecting the trunk. The coat is dry and lusterless. Seborrhea is common (often greasy, scaly and malodorous). Secondary bacterial infections are common due to immunosuppression. These infections may result in pruritus. Skin may thicken and facial folds may become more prominent (resulting in the well-described "tragic" facial expression). Clipped areas fail to re-grow properly. Poor wound healing and easy bruising are common.

Reproductive Signs

Reproductive failure may be the initial presentation in both male and female patients. Hyperprolactinaemia can cause lactation in intact bitches - elevation in TRH (due to decreased negative feed-back) stimulates prolactin release.

Neuromuscular Signs

Neurologic signs may be the only complaint. Signs referable to central or peripheral nervous disease may be seen. These signs are very rarely seen in isolation. Central disease is associated with demyelination or atherosclerosis of cerebral vasculature, which may cause cerebro-vascular accidents. Peripheral disease is associated with mucopolysaccharide accumulation in the peri- and endoneurium causing pressure on nerves (e.g., vestibular signs or facial nerve paralysis and even limb lameness).

Cardiac Signs

The animals present with bradycardia and this relates to myocardial hypokinesis. Cardiac failure can also cause euthyroid sick syndrome (ESS), thereby creating the false impression that the cardiac failure occurred secondary to hypothyroidism, when it is actually the other way round.

Ocular Signs

Uncommonly corneal lipid deposits will be seen.

Gastrointestinal Signs

Constipation and diarrhoea have been described. Mega-oesophagus and megacolon have also been described, but are rare.

Myxedematous Coma

A rare syndrome associated with profound weakness and diminished consciousness. Mortality rate is high and intravenous hormone replacement is required.

Clinico-Pathologic Abnormalities

There are well-recognized clinical pathological abnormalities, where the degree of abnormality correlates well with the severity and chronicity of the disease.

Haematology

Mild normocytic, normochromic, non-regenerative anaemia. Occasionally, reduced iron absorption from the gut may cause a hypochromic microcytic anaemia. Lipid metabolism abnormalities lead to an increase in the number of leptocytes that occur. No classic white cell abnormalities are seen.

Serum Biochemistry

Fasting hypercholesterolemia is seen in 75% of cases. Occasionally mild elevations in liver enzymes are seen (ALP, ALT). CK may be elevated rarely.

Urinalysis

Usually normal. Sometimes a urinary tract infection may be seen.

Thyroid Function Tests

Thyroid hormone assays are Radio Immuno-Assay (RIA) and ELISA techniques and are actually produced for use in humans. These assays work in dogs because of good cross-reactivity of thyroid hormone between species. Healthy dogs tend to have lower total T4 values (12–45 nmol/l) than healthy humans (40–128 nmol/l). Hence the assay must be sensitive enough to detect values less than 12 nmol/l to differentiate hypothyroid from euthyroid dogs. The diagnosis of this disease depends on finding many features consistent with the disease. One should have worked the case up the point where you are sure that hypothyroidism is high up on the differential list, before running specific hormone assays. The interpretation of thyroid hormone assay results can be difficult. Never base a diagnosis on a single test result. Thyroid hormone is very stable and is resistant to degradation by freezing/thawing, standing at room temperature, haemolysis or contact with cells in blood. Samples can be drawn in serum tubes, heparin or even EDTA. Serum may be stored in plastic tubes for 8 days at room temperature and for 5 days at 37°C without affecting the concentration of T4. Storage in glass at 37°C can cause a significant increase in serum T4 concentrations. So, although T4 is stable, whenever possible, serum samples should rather be stored in plastic tubes, frozen and sent to the laboratory as soon as possible.

Serum Total T4 (TT4) Levels

A good screening test. TT4 will be low in most hypothyroid dogs,. i.e., the test has high sensitivity. The overlap between euthyroid and hypothyroid dogs can however be substantial - especially in the presence of concurrent disease i.e., low specificity. TT4 may be spuriously elevated in true hypothyroidism, if there are high circulating levels of anti-T4 antibody that cross-react with the T4 assay, but this is rare. The normal range of the hormone should be established for each laboratory, but is around 12–45 nmol/L. The specificity of this test increases markedly if used in conjunction with endogenous TSH analysis.

Serum Free T4 (fT4) Levels

Measures the unbound fraction of T4. Can be measured by one of two methods - RIA or a modified equilibrium dialysis method (MED). MED is technically more demanding, but is the preferred technique to utilize the superior specificity and thus accuracy of this test over total T4. Accuracy of free T4 by MED is > 90% vs. 75–85% accuracy for total T4. There may be some advantage to using free T4 (MED) over total T4 in discriminating between ESS and hypothyroidism, because free T4 is influenced less by ESS. This advantage is, however, negated if the RIA method is used.

Canine Serum TSH (Thyroid Stimulating Hormone) Levels

This is a recent (past 10 years) addition to the diagnostic testing armoury and has quickly found a place in assisting to differentiate true hypothyroidism from ESS. The theory behind the test is as follows: as thyroid hormone production drops due to destruction of the thyroid gland, the negative feedback of thyroid hormone on the release of TSH decreases and thus ever increasing levels of TSH are secreted in response. Hence, true primary hypothyroidism will classically have a low T4 and a high TSH. ESS will have a low T4 and a normal to low TSH. Unfortunately, the current assays for canine TSH have poor sensitivity and between 13 and 38 % of hypothyroid dogs have TSH concentrations within the reference range. The specificity of TSH for the diagnosis of hypothyroidism in combination with a low fT4 or TT4 however approaches 100%.

Establishing a Diagnosis

A low serum total T4 concentration (< 6 nmol/l), hypercholesterolaemia and clinical signs strongly suggestive of hypothyroidism support the diagnosis, especially in the absence of systemic disease. In the absence of performing a TSH assay, the definitive diagnosis must then rely on trial therapy with sodium levothyroxine. Additional tests (i.e., fT4 by MED or TSH) are warranted in the following scenarios:

 If serum T4 is < 12 nmol/l, but hypercholesterolaemia and clinical signs are absent.

 If severe systemic illness is present and the potential for ESS is high.

 If drugs known to decrease serum T4 concentration are being administered (prednisolone, phenobarbitone, etc).

Euthyroid Sick Syndrome (ESS)

The presence of concurrent disease can have a profound effect on baseline T4 levels. It becomes difficult to judge what effect concurrent illness is having on a T4 level in a particular patient. Correction of the ESS with thyroid hormone is contraindicated and may in fact do harm - i.e., the problem is not with the thyroid gland function, but rather the fact that the thyroid gland is secondarily affected by disease in some other organ system. ESS is a serious confounder in the interpretation of T4 results. This is probably the most important reason why the diagnosis of hypothyroidism should never be based on a hormone assay alone, but depends on a large range of findings. Conditions commonly associated with the ESS include:

Dermatologic disorders: because of the frequency of skin involvement in hypothyroidism this may be especially confusing. It is however not a common cause of ESS. Widespread deep pyoderma or generalized demodicosis are possible causes.

Systemic disease: Other endocrine diseases (especially hyperadrenocorticism and Diabetes mellitus) are important causes. Liver, cardiac, renal, pancreatic, lung etc. may all cause ESS. Virtually all ICU cases will have ESS.

Treatment

Thyroid hormone replacement will need to be administered lifelong (this is one reason why every attempt should be made to ensure a correct diagnosis, before commencing treatment). Should all attempts to make a definitive diagnosis fail and you still feel that hypothyroidism may be the primary problem, a trial of replacement therapy may be applied and the response evaluated. This is an unusual set of circumstances, but is nevertheless a recognised approach. Synthetic sodium levothyroxine (T4, Eltroxin®) is the drug of choice. A starting dose of 20 µg/kg twice daily is usually used. The maximum dose is 800 µg twice daily. This is a much higher dose than is necessary in man, because the oral absorption of levothyroxine is lower in dogs. Once the dog has shown adequate response to treatment, this dose may be dropped to once daily (usually after around 8 weeks of treatment). Some dogs will however always require twice daily treatment. Drug dose may need to be gradually stepped up from 10 µg/kg once daily to 20 µg/kg twice daily over 3–4 weeks in patients with concurrent illness e.g., cardiomyopathy. The patient's general sense of well being will improve within a few weeks, but improvement in dermatological signs, myocardial function and weight loss may take 2–3 months. Response to treatment is often the only form of therapeutic monitoring required. However, post pill testing may be necessary in some cases (for e.g., poor responders). T4 levels can be measure 6–8 weeks after initiating treatment. Samples should be drawn just before tablet administration (trough) and 4–6 hours after administration (peak). Ideally levels of both peak and trough samples should be within the high and low normal range, respectively. Another way in which to monitor the success of your therapy is to monitor the TSH levels. It should lower and return to the normal range (< 0.6 ng/ml) as the negative feedback of the supplemented T4 takes effect. Serum T4 concentrations should be monitored every 8 weeks for the first year (because the metabolism of T4 changes as the metabolic rate normalizes) and twice yearly thereafter.

Prognosis

Prognosis for return to normal function following adequate treatment is excellent in most adult hypothyroid dogs. Prognosis in myxoedema coma is dependent on early diagnosis and puppies with congenital hypothyroidism have variable resolution of clinical signs, being more complete if treatment was started early.

References

1.  Feldman and Nelson's Canine and Feline Endocrinology and Reproduction. 3rd ed, 2004, Elsevier Science, USA.