Acquired primary hypothyroidism

Hypothyroidism is a clinical condition resulting from a thyroid hormone production deficiency secondary to structural or functional diseases of the thyroid gland. In animals hypothyroidism may occur in a congenital form or, more often, as an acquired form; from an aetiological standpoint it is further classified as primary, if the disease primarily involves the thyroid gland, and as central if it results from a TSH deficiency (secondary/pituitary or tertiary/hypothalamic). A thyroid hormone deficiency may manifest itself with several clinical symptoms that vary above all based on the age of the subject at the time of onset of the disease. In the dog, acquired primary hypothyroidism is an endocrine disorder commonly found in adult subjects and is most often caused by a process of immune-mediated destruction of the thyroid gland. Forms of acquired secondary hypothyroidism (TSH deficiency) are quite rare in dogs and are caused by pituitary gland tumours or malformations. Tertiary forms (TRH deficiency) are extremely rare and to date there is only one documented case in literature. Occasionally, hypothyroidism affects young subjects as a congenital (cretinism) or acquired form.

AETIOLOGY

In adult dogs, over 90% of the acquired forms of hypothyroidism are attributable to a primary thyroid disease, most frequently caused by an immune-mediated process of lymphocytic thyroiditis. Macroscopically, the gland may appear to be of normal or reduced size while the histological picture is characterised by an inflammatory process with the presence of lymphocytes, macrophages and plasma cells. Thyroiditis leads to the progressive and irreversible destruction of the gland with replacement of the follicular parenchyma with connective tissue. The rapidity of progression of the disease varies considerably depending on the breed, thus affecting the age of onset of the clinical symptoms, which become evident when a loss of over 75% of the follicular tissue occurs.

Idiopathic thyroid atrophy, until recently considered the second main cause of the primary acquired forms, is instead characterised by glandular atrophy and by the presence of connective tissue. This latter form is currently considered none other than the final outcome of lymphocytic thyroiditis, mainly because of the peculiar histological features that characterise it.

The molecular and immune pathogenesis of lymphocytic thyroiditis is not definitively clarified, but the higher incidence of the disease in some canine breeds, including Beagles, Golden Retrievers, Dobermann Pinschers, German Shepherds and Cocker Spaniels, confirms the predominant role of the genetic component in the development of hypothyroidism in adult dogs. The loss of immune tolerance by the CD4+ lymphocytes to thyroglobulin is believed to be at the base of the disease.

Other less frequent causes of acquired primary hypothyroidism are: thyroid neoplasms (primary or metastatic) involving the destruction of over 75% of the glandular tissue, iatrogenic forms secondary to treatment with radioactive iodine or to the administration of antithyroid drugs, or transient forms present after a thyroidectomy.

SIGNALMENT

Subjects of any breed may develop hypothyroidism, however, as mentioned previously, in some breeds (Golden Retrievers, Dobermann Pinschers, Beagles, German Shepherds and Cocker Spaniels) the incidence is greater than in others. According to recent studies a gender predisposition does not appear to be present, while previous studies highlighted a greater risk for neutered male dogs and spayed female dogs compared to sexually intact animals. The average age at diagnosis is around 7 years (range 0.5 to 15 years).

CLINICAL SIGNS

In the majority of dogs the clinical manifestations of thyroiditis go unnoticed and all subjects progressively develop the clinical signs of hypothyroidism; occasionally, in the initial phase of destruction of the gland some transitory symptoms of hyperthyroidism (polyuria) linked to the release of thyroid hormones may be present.

The clinical signs of hypothyroidism are generally fairly non-specific and arise gradually and subtly. In the majority of subjects they develop between ages 2 and 6 and manifestations correlated to decreased metabolic activity and to dermatological alterations are observed more frequently.

Common clinical signs correlated to the decrease in metabolic activity are: lethargy, dull mentation, cold and exercise intolerance. Dogs with hypothyroidism generally have an increased body condition score (BCS) even though their appetite is normal or in some cases decreased.

Sixty-eighty (60-80%) percent of dogs with hypothyroidism have dermatological conditions that mainly vary based on the breed, on the severity and on the duration of the state of hypothyroidism. The abnormalities detected most often are poor haircoat condition with changes in colour, delayed or lack of hair regrowth after clipping, localised or widespreadalopecia (Figs. 1a, 1b, 2a, 2b), primarily nonpruritic, and seborrhoea (dry or oily). Dogs with hypothyroidism are also predisposed to the onset of recurrent pyodermatitisand infections from opportunistic pathogens like Demodex and Malassezia. Less common skin manifestations include: hyperkeratosis and cutaneous hyperpigmentation, presence of blackheads, ceruminous otitis and cutaneous myxoedema mainly located in the areas of the head and limbs.

Neurological manifestations found in association with hypothyroidism most often involve the peripheral nervous system. Common neurological findings are: generalised weakness, ataxia, reduced spinal reflexes, tetraparesis or paralysis initially involving the hind limbs. Cases of megaesophagus, laryngeal paralysis and cervical spondylomyelopathy have often been reported in association with hypothyroidism, however, a true cause-effect connection between these diseases and the state of hypothyroidism has not yet been demonstrated. Evidence of clinical signs correlated to the central nervous system involvement is uncommon and, in the majority of cases, these manifestations are linked to dysfunctions of the central vestibular system. Episodes of epilepsy, circling and ataxia have been reported in just a few cases, also in conjunction with vestibular signs and with facial nerve paralysis. Further studies will be needed, however, to confirm a possible relationship between hypothyroidism and behavioural alterations, which include both states of aggressiveness and of cognitive dysfunction.

For a long time it was thought that in dogs hypothyroidism might also be frequently associated, as in humans, with reproductive alterations both in males and females; however, recent studies carried out in this field have not demonstrated a significant incidence of reproductive diseases in dogs during hypothyroidism. In females, the reproductive system alterations attributed to hypothyroidism are: lengthening of the interoestrous interval, silent heats, alterations of the oestrous cycle, miscarriages, uterine inertia, stillbirths and birth of weak or small puppies. Alterations of normal reproductive functions may also affect male dogs with hypothyroidism; these include: decreased libido, testicular atrophy, oligospermia and azoospermia.

Thyroid hormone deficiency can also affect cardiac activity, altering its conduction, contractility, frequency and diastolic capacity. In subjects with other hypothyroidism symptoms, the presence of bradycardia and a weakening of the apical pulse are noticeable during the clinical examination. It is more common, however, for cardiac alterations to be detected through diagnostic procedures such as echocardiography and electrocardiography. A hypothyroid state can make a pre-existing cardiac pathology worse (e.g. dilated cardiomyopathy), however, occasionally it may be responsible on its own for a clinically appreciable case of cardiac insufficiency.

In addition to other systems, kidney function is also altered during hypothyroidism. Although a relationship between this endocrine disorder and chronic kidney disease has not yet been found, recent studies have confirmed that also in the dog a thyroid hormone deficiency causes a reduction in the glomerular filtration rate (GFR) which is not accompanied by a rise in serum creatinine levels. In these  subjects kidney function should be evaluated carefully, especially in the presence of a renal or heart disease.

Myxoedematous coma. Occasionally, dogs with hypothyroidism are urgently presented in a comatose state. Myxoedematous coma is a rare syndrome characterised by a state of profound weakness, hypothermia, bradycardia, decreased level of consciousness and electrolytic alterations that may rapidly progress to a state of stuporous coma. This emergency often occurs in subjects exposed to low temperatures that  progressively  become hypothermic due to a thermoregulatory dysregulation.

LABORATORY FINDINGS

Complete blood count
The classic alteration found during the complete blood countin approximately 30-40%of dogs with hypothyroidism is the presence of a mild normocytic, normochromic nonregenerative anaemia, sometimes associated with an increase in the number of leptocytes (target cells).No particular alterations are generally found in the white blood cell count; in some cases leukocytosis may be present due to a concomitant bacterial infection (e.g. pyoderma).

Biochemical profile
The most common alteration found during the biochemical profile in dogs suffering from hypothyroidism is fasting hypercholesterolaemia (75% of subjects) and hypertriglyceridaemia (88% of subjects). These findings cannot be considered pathognomonic for hypothyroidism; however, their presence in dogs with other clinical signs attributable to this endocrinopathy are helpful in strengthening the diagnostic suspicion of the disease. Less common alterations are: a mild increase in alkaline phosphatase (SAP), in alanine aminotransferase(ALT) and in creatine kinase (CK).

Urinalysis
The urinalysis of subjects with hypothyroidism does not usually detect particular alterations. In some subjects with lymphocytic thyroiditis the presence of proteinuria secondary to a glomerulonephritis caused by deposition of immune complexes has occasionally been reported.

DIAGNOSTIC IMAGING

Ultrasound scan
Ultrasound examination of the thyroid gland has been used in veterinary medicine for some time now, but the possibility of using it in dogs to characterise and distinguish hypothyroidism from euthyroid sick sindrome (ESS) has been proposed and discussed only recently. In the case of autoimmune thyroiditis and of thyroid atrophy, a reduction in the volume and echogenicity of the glandular lobes can be observed, while in euthyroid subjects or those with ESS, the echotexture of the thyroid parenchyma is homogeneous and hyperechoic when compared to that of the adjacent sternal muscle.

Scintigraphy
In dogs, scintigraphy is mainly used in cases of suspected tumours in the cervical region. Several studies describing the use of scintigraphy to evaluate thyroid function report that in case of primary hypothyroidism, scintigrams typically show the reduction or absence in the concentration of pertechnetatein the gland.In a minority of dogs with hypothyroidism in which pertechnetate is instead concentrated in the thyroid, the gland appears smaller. In the other cases, in which basal thyroid hormone concentrations are decreased after taking drugs or due to nonthyroidal diseases, the accumulation of pertechnetate in the thyroid is instead normal or increased.

Radiology
Conventional radiographic studies of the cervical region is not routinely performed to diagnose the acquired forms of hypothyroidism since they do not allow to evaluate the condition of the thyroid gland. This diagnostic tool may instead be especially useful in cases of congenital hypothyroidism (cretinism) and thyroid neoplasm.

SPECIFIC DIAGNOSTIC TESTS

Canine hypothyroidism is currently the most over-diagnosed of the endocrinopathies found in dogs. Careful patient evaluation and correct candidate selection based on the clinical history, on the physical examination and on other laboratory findings are an essential requirement to increase the positive prognostic value of the tests and thus reduce the incidence of false positive results.

The specific basic diagnostic tests for evaluating thyroid function include the measurement of the circulating basal levels of T4, fT4, e TSH. Nevertheless, the basal thyroid hormone concentration is affected by several factors that can falsely induce a reduction in the value; for this reason the method considered as the gold standard for diagnosing canine hypothyroidism to date is the TSH stimulation test.   

Interpretation of the basal thyroid hormone concentration (T₄, fT₄, TSH)

From: Bonagura JD and Twedt DC. Current Veterinary Therapy XIV, Saunders Elsevier, 2005.

DIAGNOSIS OF THYROIDITIS

Antithyroglobulin and antithyroid hormone antibodies
The presence of antithyroglobulin antibodies (ATA) has been demonstrated in over 50% of dogs with hypothyroidism. Some laboratories offer the possibility of measuring the presence of antithyroid hormone antibodies through an ELISA method as part of the thyroid profile, especially in those cases in which unexpected T₄ and T₃ values are present. Nevertheless, it should be underlined that the presence of antibodies is not necessarily accompanied by a hypothyroid state. In some subjects a lot of time may pass between the detection of ATA, and hence of a subclinical thyroiditis, and the onset of this endocrine disorder. In addition, thyroiditis is not the only condition in which antibody positivity may be present; occasionally a temporary increase in antibodies may be found even in recently vaccinated dogs.

The presence of antithyroid hormone antibodies in the serum in subjects with lymphocytic thyroiditis can potentially interfere with the RIA methods for measuring T₄ and T₃, creating confusion in the interpretation of results. In these cases (<1%) the antithyroid hormone antibodies can falsely induce an increase in the concentrations of T₄ and T₃ such as to occasionally mimic a state of hyperthyroidism.

TREATMENT

Levothyroxine is the thyroid hormone of choice for treating hypothyroidism. The molecule has a plasma half-life of 12-16 hours and the peak concentration is reached between 4 and 12 hours. A liquid formulation for oral administration registered for veterinary use is now available on the market. The initial recommended dosage for the formulation is approximately 20 μg/Kg per os s.i.d.; it should be administered 2-3 hours before the meal as this reduces its gastrointestinal absorption. In the majority of dogs this dosage has proven optimal to adequately control the disease; only in a few cases is it necessary to increase the initial dosage after clinical and hormonal evaluation. Should the owner have to administer the drug with food, the reduced gastrointestinal absorption of levothyroxine should be accounted for. For the formulation in tablet form, the initial recommended dosage of levothyroxine is instead of 15 μg/Kg per os b.i.d.

Therapeutic monitoring
The first clinical and hormonal follow-up should be carried out 4 weeks after the beginning of treatment. Monitoring is carried out through measurement of the TT₄ concentration 4-6 hours after administration of the drug and possibly of also the endogenous TSH for those subjects that had an increase in this parameter before diagnosis. The T₄ concentration should be within the upper half of the range and the TSH within the reference limit. Further evaluations and corrections of the dose may be made based on the hormonal parameters and on the clinical response every 4 weeks until the optimal dose is reached. The maintenance phase begins once the optimal dose has been established; in this phase it is advisable to monitor hormone concentrations every 6 months since the necessary daily dose is susceptible to variations in the individual patient and can vary over time.

In the majority of dogs the metabolic clinical signs generally improve within the first 4 weeks after treatment begins; the improvement and resolution of the dermatological signs instead require a longer period of time: generally from 3 to 6 months, and the same is true also for the haematobiochemical alterations (anaemia, hypercholesterolaemia).

Dogs with concomitant nonthyroidal diseases
Cardiomyopathy: hormone supplementation in dogs with a concomitant cardiomyopathy should be carried out with great care and only after having confirmed the diagnosis of hypothyroidism since thyroid hormones, by increasing myocardial activity and O₂ consumption, could be the cause of a heart failure. The initial dosage in heart patients should be reduced by 25-50%; subsequent changes are to be made based on hormone monitoring and on cardiac function reassessments.

Diabetes mellitus: hypothyroidism is a strong cause of insulin resistance in diabetic patients; before supplementation with levothyroxine, these dogs frequently do not have a good glycaemic control and require high doses of insulin. After an accurate diagnosis of hypothyroidism, at the time of beginning supplementation with thyroid hormones it will be necessary to consider a concomitant reduction in the insulin dose and to frequently monitor the blood glucose of the patient in order to reduce the risk of hypoglycaemia, until optimal control is attained for both diseases.

Suggested readings

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