Congenital Hypothyroidism and Dysmaturity Syndrome in Foals

Hypothyroidism in Foals
Thyroid Physiology
Clinical Signs
Diagnosis
Risk Factors
Treatment
Prevention

Congenital hypothyroidism and dysmaturity (CHD) syndrome is a manifestation of hypothyroidism in foals, resulting in overdue yet dysmature foals that are born weak with contracted tendons, mandibular prognathism (underbite), poor ossification of the cuboidal bones, and poor muscular development. ^[1]

The basic cause of CHD is hypothyroidism in the foal during late gestation, however the underlying cause of hypothyroidism has not been identified. ^[2]

Currently, the main risk factors identified for development of CHD are low levels of dietary iodine and high dietary nitrates. ^[1] There is also suggestion that low selenium can be a factor ^[#]

Due to these findings, the main prevention measure proposed is careful management of the broodmare’s diet, ensuring adequate iodine intake and that all forages and water sources are tested for nitrates. ^[3] Contamination of forage by plants of the Brassica genus (such as mustard plants and cabbage)
may also interfere with thyroid hormone production. ^[4]

Treatment for CHD is primarily supportive, and aims to correct the musculoskeletal abnormalities and support the foal’s weight until the cuboidal bones can ossify completely. Affected foals have a very poor prognosis for long-term soundness due to their musculoskeletal abnormalities. ^[1]

Hypothyroidism in Foals

Hypothyroidism in foals can refer to several clinical entities, however the most commonly considered is congenital hypothyroidism and dysmaturity (CHD) syndrome.

The first description of CHD was reported in the 1980s in western Canada. More recently, cases of the syndrome have been identified in the United States, Australia, South America, and Europe. ^[5] It is unknown if the condition is newly arising in these areas or is now being identified as CHD when previously was just considered a poor doing foal.

Foals affected with CHD have a poor prognosis for life and survivors have poor prognosis for long-term soundness, making this syndrome a concern for horse breeders as well as veterinary practitioners.

Besides CHD, other causes of hypothyroidism in foals include euthyroid sick syndrome, excess of dietary iodine in the mare, and ingestion of Acremonium coenophilaum-infested fescue grasses by the mare. ^[1]

Brief Review of Thyroid Physiology

The major function of the thyroid gland is production of thyroid hormones, primarily thyroxine (T₄) and triiodothyronine (T₃). Thyroid hormones control metabolism, with functions such as maintaining the basal metabolic rate, stimulating thermogenesis, and regulating blood flow. ^[1]

Thyroid hormone production begins when the hypothalamus produces thyrotropin-releasing hormone (TRH), which acts on the anterior pituitary to stimulate release of thyroid-stimulating hormone (TSH). TSH is the major regulator of thyroid hormone production. Release of TSH results in filling of the thyroid follicles of the storage form of thyroid hormone, thyroglobulin.

TSH stimulation can induce cleavage of thyroglobulin to release T₄ and T₃ hormones. The vast majority of thyroid hormone produced by the thyroid gland is T₄, which is considered the inactive form. In circulation, T₄ can undergo deiodination to form more T₃, which is three to five times more biologically active than T₄. ^[1]

Role of Iodine

Iodine is a critical micronutrient involved in thyroid hormone production, as it forms the basis of both T₄ and T₃’s protein structure. However, both a deficiency and an excess of iodine can negatively impact the thyroid.

With iodine deficiency, there is inadequate iodine stores available for hormone production. Excess iodine also has an inhibitory effect on hormone production and release.

In both cases, goitre (enlarged thyroid gland) can result, as TSH stimulation continuously attempts to resolve the low thyroid hormone production, resulting in hyperplasia of the thyroid gland. ^[6]

Clinical Signs

Symptoms of CHD reflect the immature development of the foal despite a prolonged gestation. Symptoms include:

Prolonged gestation; averaging 360 days
Mandibular prognathism (underbite)
Minimal ossification of the cuboidal carpal and tarsal bones
Contracted tendons with or without rupture of the common digital extensor tendon
Soft, silky hair coat
Floppy ears
Poor muscle development
No palpable enlargement of the thyroid glands, which is unusual for a hypothyroid condition

At birth, CHD foals may be weak and non-responsive, or may be bright and alert with a strong suckling reflex. ^[1]

A recent, unpublished study used radiographs to differentiate and grade the severity of mandibular prognathism using incisor tooth width to measure the protuberance of the mandible. Any more than ½ a tooth width prognathism resulted increased severity of the CHD. ^[18]

Diagnosis

Foals with CHD typically have normal bloodwork that evaluate for signs of inflammation, organ function and some electrolytes and mineral status (CBC and blood chemistry).

T₃ and T₄ values can be either low or within normal range, but foals will have a diminished response to TSH. ^[1]

However, TSH stimulation tests are not commonly done in practice. Instead, diagnosis most often relies on clinical symptoms of the foal.

Radiographically, there is severe hypo-ossification (inadequate or reduced mineralization) of the cuboidal bones in the carpus and tarsus. Foals suspected to have CHD should have dorsopalmar (front to back) and lateromedial (outside to inside) views of the carpus (front knee) and tarsus (hock) evaluated. ^[7]

A skeletal ossification index (SOI) is used for grading ossification of cuboidal bones, ranging for Grade 1 having no ossification to Grade 4 having ossification similar to a mature horse. ^[7] Ultrasound evaluation can also provide similar information about the ossification of the cuboidal bones. ^[7]

Confirming a diagnosis of CHD requires biopsy of the thyroid gland to demonstrate thyroid hyperplasia. ^[1]

Risk Factors

Normal fetal thyroid hormone is typically low throughout gestation and increases just before birth. ^[8] During late gestation, increased levels of thyroid hormones likely plays a role in rapid growth and final development of organs and the skeleton. ^[8]

Premature and sick foals have lower T₃ and T₄ concentrations than their healthy peers. ^[1]^[8]

In premature foals, the low hormone levels are likely due to inadequate gestational time for thyroid development. In sick foals, the concentrations likely represent euthyroid sick syndrome, where non-thyroidal illness causes reduced thyroid hormone concentrations. ^[1]^[8]

Unlike premature and sick foals, CHD foals may have normal T₃ and T₄ values, despite having histologic evidence of poor thyroid function. ^[1] Partial thyroidectomy of late gestation foals causes lesions consistent with CHD, supporting hypothyroidism as the cause of disease. ^[2]

The underlying causes leading to hypothyroidism are currently unknown. ^[1]^[9] Suspected causes include dietary deficiency of iodine in the mare, excess dietary nitrates, high glucosinolates intake, toxin exposure, or infectious agents. ^[9]

Case-controlled studies have identified low dietary iodine and high dietary nitrates as two major risk factors for development of CHD in foals. ^[1]

It has also been suggested that affected foals are often deficient in copper, zinc and selenium although there is limited research in this area. ^[17]

It is known that selenium is an essential component of the deionidase enzyme that is responsible for deiodinating T4, providing T3 into circulation and acting as a scavenger enzyme for iodide in the body tissues. ^[16]

Low Dietary Iodine

Iodine is a critical component of thyroid hormone production, and dietary deficiency is well-established as a cause of hypothyroidism in many species. In horses, the association between low iodine levels in the pregnant mare and lesions similar to CHD has been reported as early as the 1920s. ^[10]

Investigation into the link between iodine deficiency and CHD has been minimal, however one study has identified an increased risk of CHD with the absence of a supplemental salt or mineral source in areas with naturally low levels of soil iodine. ^[3]

Areas with iodine-deficient soil include the Great Lakes area and prairie regions of North America, including Western Canada where CHD was first identified. ^[4] Foals born in these areas may have a higher risk of CHD.

Testing can help support more targeted iodine supplementation of mares. Although blood iodine levels can be measured, urine iodine levels are more specific for indicating that iodine is sufficient. ^[15]

High Dietary Nitrates

Nitrate in the feed or drinking water can compete with iodine uptake within the thyroid gland, resulting in altered thyroid activity. ^[11] In other species, such as goats and cattle, high nitrate levels have been associated with enlarged thyroid glands and congenital arthrogryposis. ^[3]^[11]

Studies show an association between development of CHD and feeding diets high in nitrate, with the odds of CHD in foals being eight times greater on farms feeding diets containing at least trace levels of nitrates. ^[3]

Factors including plant species, maturity, nitrogen content of the soil and water, and environmental conditions can influence the nitrate levels in forages. Some plants commonly used for hay or pasture, including alfalfa, timothy, ryegrass, and sweet clover, naturally accumulate high levels of nitrates given the right conditions. ^[3]

In particular, greenfeed forage (cutting immature plants for feed) contains higher nitrates than traditionally grown hay, and is associated with an increased risk of CHD. ^[3]^[11]

Grain crops such as oats, barley, corn, and flax, which may be used in equine diet formulations, can also accumulate nitrates at low levels. ^[3] Fertilization of pastures, droughts, cold stress, and use of herbicides are also known to increase nitrate levels in plants. ^[11]

Nitrates are water soluble and can be present in drinking water at high levels. Typically, nitrates enter water sources through runoff from fertilized pastures, feedlots, dairies, and landfills. ^[3] Nitrate levels in the water and diet are additive, so both sources must be analyzed when assessing a horse’s diet. ^[3]

Glucosinolates

Mustard plants (Brassicaceae family) are a common weed found in pastures and forage production. These plants are high in glucosinolates, which have been reported to inhibit T₄ synthesis and interfere with iodine uptake. ^[4] Contamination of feed sources by these species has been proposed as a potential cause of CHD. ^[1]^[4]

A recent study has shown that increased exposure to sinigrin, one of the main glucosinolates in Brassica species, is associated with decreased iodide levels and T₄ responsiveness in non-pregnant mares, providing some support for this postulate. ^[4]

Multifactorial

A recent (soon to be published) study, suggests that for CHD to be induced by nutritional factors several of the aforementioned factors must be present. ^[18]

Throughout gestation, pregnant mares in the study were fed either:

Low iodine (only that that is supplied by the feed)
Moderate iodine (supplemented with salt blocks)
High iodine (added salt daily and salt blocks)

None of these mares had CHD foals.

However, in a small pilot study CHD was inducible by adding glucosinolate to low iodine ration.

These researchers are postulating that the combination of glucosinolates, high nitrates, or possibly ergot with low iodine will induce CHD. It was suggested that feeding 2 tablespoons of sodium iodized salt daily throughout gestation will help protect the fetus from CHD despite ingestion of these common teratogenic substances. ^[18]

Treatment

Treatment for CHD is primarily supportive. Foals with CHD have inadequate ossification of the cuboidal bones, which predisposes them to angular limb deformities and osteochondrosis. ^[1]^[7]

Angular limb deformities (ALD) typically result from collapse of the cuboidal bones on one aspect of the joint. In the carpus, the lateral cuboidal bones are the last to ossify. In the tarsus, the dorsal cuboidal bones ossify last, predisposing to tarsal valgus and tarsal flexural deformities. ^[7]

Carpal valgus and tarsal valgus refer a condition in which the limbs below the carpus or tarsus grow in a plane that is outside the centre of the carpus or tarsus, respectively.

Osteochondritis dissecans (OCD) arises from shear stress affecting the cuboidal bones, leading to the separation of the cartilage from the underlying bone. ^[7]

Both OCD and ALD increase the likelihood of lameness and early onset osteoarthritis.

Preventing collapse of the cuboidal bones is key to long-term soundness in the foal. Management and prevention of these issues may include treatments such as:

Splints or tube casts to reduce compression of the cuboidal bones
Reducing weight bearing through slings
Stall rest with restriction of activity
Correction of angular limb deformities through surgical intervention or trimming and shoeing management. Results are better with earlier vet and farrier intervention.
Oxytetracycline can help relax contracted tendons
NSAIDs or other pain management
Physical therapy
Supportive care to prevent decubitus ulcers ^[7]

Supplemental levothyroxine has been suggested as a possible treatment for the hypothyroidism associated with CHD, however it has not been experimentally investigated. ^[1] There is some data to suggest that surviving foals may become responsive to TSH over time, resolving their hypothyroidism, so supplemental levothyroxine may be unnecessary. ^[1]^[9]

Prognosis

The prognosis for long-term soundness in CHD foals is poor, unless the foal’s musculoskeletal deformities are mild. Many foals diagnosed with CHD are euthanized due to prognosis and cost concerns. ^[1]

Prevention

As the exact cause of CHD is currently unknown, prevention measures are largely speculative and based on proposed risk factors. According to current theories, prevention should aim at reducing dietary nitrates and ensuring adequate dietary iodine.

Forage Analysis

Because forage makes up the majority of the equine diet, it is prudent to measure forage iodine and nitrate levels in suspected cases of CHD or in regions with high incidence. This will help guide appropriate feeding strategies to help prevent cases of CHD.

Iodine is not typically included in forage trace mineral analysis packages. Iodine levels can be determined for an additional fee if the laboratory has the required equipment.

Nitrate analysis can also be added to your forage analysis for a small fee. If forage nitrate levels are an ongoing concern, it may be more economical to purchase nitrate test strips or test kits to have on hand. In comparison to lab testing, the test strips are more accurate than the test kits and are more cost-effective. ^[12]

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Iodine Supplementation

Iodine levels in hay sampled from across Canada had an average iodine content of 137 ug per kg (0.137 ppm). However, the values ranged from 29 – 517 ug per kg which highlights the significant regional differences in iodine content of forages. ^[13]

Given this range, a horse consuming 10 kg (22 lb) of hay per day could be getting between 0.3 to 5.2 mg of iodine from hay.

The recommended daily intake for iodine in pregnant mares is: ^[6]

Up to 9 months gestation: 0.35 mg / kg of dry matter (roughly 3.5 mg per day)

10 months and beyond: 0.4 mg / kg of dry matter (roughly 4 mg per day)

Considering the average level of iodine in hay, forage alone is unlikely to meet the pregnant mare’s iodine requirement and supplementation may be needed to avoid deficiency and decrease the risk of CHD.

Horses will voluntarily consume salt. Providing free-choice, loose iodized salt is one way to promote iodine intake but doesn’t guarantee it will be consumed.

Instead, adding salt directly to their feed ensures consumption. Two tablespoons (30 grams) of iodized salt adds roughly 1.35 mg of iodine to the diet. ^[14]

Other supplemental sources of iodine include:

Kelp meal
Ration balancers and complete feeds
Vitamin and mineral supplements, such as Omneity or AminoTrace+

Kelp meal is very high in iodine and not recommended as an iodine source for gestating mares. Although ration balancers and complete feeds can provide sufficient iodine they are often fed below recommended levels resulting in mineral deficiencies in the diet.

Careful consideration of all components the diet is required when adding additional iodine to the diet, as excess iodine can also lead to thyroid dysfunction. ^[6]

Reducing Nitrate Intake

Reducing dietary nitrate levels begins during forage production or pasture management, as stressed plants are more likely to accumulate nitrates. ^[11] Anecdotal reports have indicated that reducing application of nitrogenous fertilizers and herbicides can minimize reproductive losses related to nitrate toxicosis. ^[11]

Soil and water nitrate levels can also influence forage nitrates, and should be monitored closely if producing forage for broodmares. ^[11] With current research suggesting mustard plant glucosinolates inhibit thyroid function in mares, ensuring pastures or growing areas are free of Brassica species may also be beneficial. ^[4]

For horse owners, testing hay for nitrate levels prior to feeding is prudent. In years with significant environmental stress to forage crops, seeking hay from distant sources may be required to find adequately low nitrate forage.

Testing the horses’ major drinking water sources is also crucial. These sources may include well water, dugouts, or natural water bodies that the horses have access to.

Other Potential Dietary Factors

Several other minerals are known to antagonize iodine levels in other species, and may play a role in the development of CHD in horses.

Although these dietary factors have not been specifically investigated in horses, careful consideration of the following is recommended when formulating a diet for broodmares:

Calcium: High calcium intake can lead to goitre through decreased iodide clearance by the thyroid ^[15]
Cobalt: Elevated cobalt can inhibit iodine binding by the thyroid, resulting in decreased thyroid hormone production ^[15]
Selenium: Selenium deficiency may impair conversion of T₄ to T₃ ^[6]^[15]
Sodium: Anecdotal reports suggest that adequate sodium in the diet may have a protective effect against high nitrates ^[11]