Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests

Abstract

A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT₄) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully.

A 7-month-old male intact Siamese cross-breed kitten was presented to the Clinic for Small Animal Internal Medicine, University of Zurich with a history of chronic obstipation and retarded growth. The cat had been adopted by the present owner at the age of 4 months. Initially, it had been alert but had developed lethargy a few weeks prior to presentation.

Physical examination revealed a lethargic, dull, small cat with juvenile appearance, a body weight of 1.1 kg and body condition score of 3/9. Body temperature was 38°C, pulse rate 180 beats/min and respiration rate 20 breaths/min. It was a third of the size of its littermates (Fig. 1a and b). The neck was short, the head appeared broad and body proportions were regarded as disproportional. Abdominal palpation revealed distention of the colon due to severe constipation.

Fig 1.

(a) The 7-month-old Siamese mixed breed kitten at the time of presentation. The kitten has infantile appearance, the head appears broad in comparison to the rest of the body. Scanty hair coat with crusts on the ear margins and a ‘rat tail’ are also present. (b) Same kitten with one of his normal-sized littermates. It has about the third of the size of his littermate.

Additional findings were scanty hair coat with crusts on the ear margins and in the area of the shoulders, a scantily haired tail and bilateral cryptorchidism. Palpation of the thyroid showed bilateral enlargement.

Haematology and serum biochemistry revealed some non-specific age-related findings such as slightly low haematocrit (0.29 l/l, reference range (RR) 0.33–0.45 l/l) and erythrocyte count (6.0×10¹²/l; RR 7.0–10.7×10¹²/l), increased mature neutrophils (15.9×10⁹/l; RR 2.3–10.0×10⁹/l), decreased albumin (25 g/l; RR 30–40 g/l), increased alanine aminotransferase (166 U/l; RR 34–98 U/l) and increased phosphate (2.1 mmol/l; RR 0.9–1.8 mmol/l).

Radiographic examination revealed mild scalloping of the vertebral bodies, mildly widened vertebral physes and a prominent concave shape of the vertebral end plates. Additionally, the presence of large amounts of faeces in the colon was confirmed (Fig. 2). At this stage, the main differential diagnoses were congenital hypothyroidism, congenital hyposomatotropism and portosystemic shunt. Liver function was evaluated by measuring post-prandial bile acids and performing an ammonium tolerance test. The latter was performed measuring blood ammonia concentration before and 30 min after administration of NH₄Cl₂, 100 mg/kg of body weight. The results of both tests were abnormal (Table 1). Insulin-like growth factor 1 (IGF-1) was measured to investigate for hyposomatotropism and was found to be decreased (Table 1). The serum total thyroxine (tT₄) concentration was low and did not increase considerably 6 h after the administration of thyroid stimulation hormone (TSH) (75 μg rhTSH IV: Thyrogen; Genzyme). ¹ Endogenous TSH was measured using an assay (DPC radioimmunoassay Coat-A-Count cTSH, Diagnostic Product Corporation, Los Angeles, CA) for canine TSH that has been validated for use in the cat ² and was found to be increased (Table 1). Abdominal ultrasonography was unremarkable, except from the distended colon.

Fig 2.

The laterolateral abdominal radiograph shows mild scalloping of the vertebral bodies, mildly widened vertebral physes and a prominent concave shape of the vertebral end plates. Large amounts of faeces are present in the colon.

Table 1.

Results of liver function tests and hormone measurements.

	Initial presentation	Six weeks after initiating levothyroxine therapy	RR
Baseline ammonia (μmol/l)	50.0	61.2	≤60.0
Ammonia after NH4Cl2 (μmol/l)	133.9	47.7	<Twice baseline
Post-prandial bile acids (μmol/l)	76.3	14.1	≤25
Baseline tT4 (nmol/l)	2.5	14.2	12.87–51.5
tT4 after rhTSH (nmol/l)	5.1	Not done	>25.7
Endogenous TSH (ng/ml)	3.4	Not done	<0.03–0.19
IGF-1 (ng/ml)	104	214	185–525

Trans-splenic portal scintigraphy using 74 MBq Sodium ^99mTc-pertechnetate showed normal distribution of the radionuclide in the liver excluding a portosystemic shunt. At 20 min after the injection, an acquisition of the thyroid gland was performed which revealed a bilateral enlargement with increased uptake (thyroid salivary ratio 4.35:1).

The results of the TSH stimulation test, endogenous TSH concentration and the radiographic and scintigraphic findings were supportive of hypothyroidism and treatment with levothyroxine (Eutirox 25 μg, Bracco SpA), 12.5 μg bid was initiated. To ameliorate the constipation, enemas and oral lactulose were also administered. The overall attitude of the cat improved within a few days. Six weeks later the cat was alert, playful and constipation had improved. It had grown and its body weight had increased to 1.3 kg. Both liver function tests and measurement of IGF-1 were repeated and found to be normal. tT₄ concentration had increased but was still at the lower end of the RR, therefore, the levothyroxine dosage was increased to 25 μg bid. The cat was re-evaluated several times during the following months and levothyroxine dosage was adjusted according to tT₄ concentrations and body weight. One year after initiating therapy the cat was doing well and its body weight had increased to 2.9 kg. At present the cat is 3 years old, in a good general condition, with a body weight of 3.3 kg (Fig. 3).

Fig 3.

Same cat at the age of 3 years.

Congenital primary hypothyroidism is a rare disease in cats and only a few naturally occurring cases have been described. ^3–13 A recessive mode of inheritance of the disease has been reported in Abyssinian and Japanese breeding lines. ^6,11

Thyroid hormones affect the function of all organ systems and are essential for normal growth and skeletal maturation as well as brain development. Cats suffering from congenital hypothyroidism usually appear normal at birth but within the first 1–2 months of life retarded growth becomes obvious. Typically, disproportionate dwarfism develops. This is characterised by an enlarged, broad head, a short neck and short limbs. Additional findings are lethargy, mental dullness, obstipation, hypothermia, bradycardia, prolonged retention of deciduous teeth, cold intolerance and hair consisting primarily of undercoat. ^4,14 All cases of congenital disease in cats described so far have been primary hypothyroidism, that is, the defects have been at the level of the thyroid gland. Neither secondary (pituitary) nor tertiary (hypothalamic) congenital hypothyroidism have been reported.

Congenital primary hypothyroidism may have various causes. The two main broad categories are: thyroid dysgenesis (developmental defects of the thyroid gland and thyroid aplasia due to TSH receptor abnormalities) and thyroid dyshormonogenesis (defect in any step of iodine uptake and thyroid hormone synthesis). In the latter, the low concentration of thyroid hormones induces, as in all forms of primary hypothyroidism, an increase in TSH concentration, which is followed by an increase in thyroid gland size. Therefore, thyroid dyshormonogenesis is associated with goitre, whereas thyroid dysgenesis is non-goitrous. ¹⁴

In the cat reported here, several of the typical clinical signs such as lethargy, dullness, small disproportionate size, severe constipation and hair coat abnormalities were found. Cryptorchidism was present, a finding which has not yet been previously reported in feline congenital hypothyroidism. The skeletal system was less affected than in most cases described by others. ^3,8,10,12 The thyroid gland was enlarged leading to the assumption that thyroid dyshormonogenesis was the underlying defect. Nutritive iodine deficiency as an exogenous reason for goitre was considered unlikely because the cat was fed a commercial kitten diet and its littermate receiving the same diet was clinically normal. In humans with congenital goitre, different groups of defects in the pathway of thyroid hormone synthesis have been identified: iodine transport defect, defects in expression of function of thyroid peroxidase, defects in thyroglobulin synthesis and iodotyrosine dehalogenase defect. Thyroid hormone resistance may also occur. The severity of clinical signs varies greatly depending on the extent and type of defect and the age at which clinical signs become apparent. ^15,16 In cats, only abnormal peroxidase activities have been described as a cause of dyshormonogenesis. ^5,6,13 As in humans, the severity of the disease varies. In one report on inherited congenital hypothyroidism in a family of Abyssinian cats, considerable differences in the degree of abnormal clinical appearance were seen. ⁶ We, therefore, assume that in our cat, the biosynthetic defect was relatively mild preventing major skeletal abnormalities.

The diagnosis was confirmed by decreased tT₄ concentration, which failed to increase adequately after administration of rhTSH, increased concentration of endogenous TSH, and a positive response to levothyroxine therapy. The increased uptake of ^99mTc demonstrated that the iodine transport mechanism was intact. No further characterisation of the defect was pursued, eg, by administering sodium perchlorate after application of radioiodine to evaluate for organification defects. ^5,6

The case is of particular interest because of the abnormal liver function tests and IGF-1 concentration. As the skeletal system was not severely affected, diseases such as portosystemic shunt and congenital hyposomatotropism were initially thought to be at least as likely as congenital hypothyroidism. Post-prandial bile acids and serum ammonia concentration after ammonium chloride administration were found to be abnormal, although ammonia post-NH₄Cl₂ was only mildly increased. A portosystemic shunt was finally excluded by scintigraphy. Both bile acids and ammonium tolerance tests were normal within 6 weeks of levothyroxine treatment. To the authors' knowledge, liver function has not been investigated in cats with congenital hypothyroidism. Whether the abnormal test results can be attributed to the low metabolic rate seen in hypothyroidism or are due to another more specific cause is unknown.

As growth hormone measurement is not readily available, IGF-1 concentration was measured instead and found to be low. Several reasons were postulated: (1) that hyposomatotropism was present with or without concurrent hypothyroidism, similar to a cat reported previously, ¹⁷ (2) that the young age of the cat influenced the IGF-1 concentration: IGF-1 concentration is less in growing kittens than in adult cats, ¹⁸ (3) that the low IGF-1 concentration in this case could be a consequence of a documented reduced liver function, and (4) that hypothyroidism resulted in decreased IGF-1 concentration. The fourth possibility was considered most likely as thyroid status influences the growth hormone axis in humans, dogs and rats and IGF-1 concentration has been shown to increase in hypothyroid humans after thyroxine replacement therapy. ^19,20

After the initial investigation, the results were reviewed and congenital primary hypothyroidism was considered the most likely diagnosis. Six weeks after initiating thyroxine therapy, IGF-1 concentration had returned to normal so it was unlikely that concurrent hyposomatotropism and juvenile age were reasons for the initial low level.

In summary, congenital hypothyroidism is a rare disease with considerable variation in clinical manifestation. In cases in which clinical signs and pathology are ambiguous, other disorders such as portosystemic and hyposomatotropism have to be taken into account as differential diagnoses. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 levels, both of which return to normal during thyroxine therapy, test results have to be interpreted carefully.