Although hyperthyroidism condition has been increasingly reported in guinea pigs, it remains underdiagnosed because of the lack of publications on its causes, diagnostic methodologies and treatment options (Gibbons et al, 2013; Pignon and Mayer, 2013; Girod-Rüffer et al, 2019). Diagnostic assays have also not been validated and the effects of therapeutic modalities have not been studied sufficiently (Brandão et al, 2013).
Hyperthyroidism or thyrotoxicosis has been documented in several species and it is the most common endocrinopathy in cats (Brandão et al, 2013). While in humans it is most commonly caused by the autoimmune condition Graves' disease (Brandão et al, 2013), in guinea pigs the reported causes are functional unilateral or bilateral thyroid neoplasia (Edis and Pellett, 2019) and excess secretion from ectopic thyroid tissue (Kondo et al, 2018). In a study by Gibbons et al (2013) thyroid tumours were among the most common neoplasias found in laboratory guinea pigs, although it was not established whether the affected animals actually had hyperthyroidism. While in feline medicine hyperthyroidism secondary to a primary thyroid stimulating hormone (TSH)-secreting pituitary tumour has been described (Gordon et al, 2003), to the author ‘s knowledge no documentation on its occurrence in guinea pigs currently exists.
Prevalence
It is widely agreed that hyperthyroidism in guinea pigs is relatively rare and clinically underdiagnosed (Brandão et al, 2013; Künzel and Mayer, 2015; Di Geronimo and Brandão, 2020). In a study by Künzel et al, 2013, of 309 guinea pigs presented to a veterinary university in Vienna, only 4 were diagnosed with hyperthyroidism. In contrast to German literature, English publications on hyperthyroidism in guinea pigs are scarce (Di Geronimo and Brandão, 2020). This is mainly because of the lack of reliable information on diagnostic procedures used to achieve a definitive diagnosis (Künzel and Mayer, 2015). Unlike in cats, the current literature is based on reviews (Thorson, 2014; Di Geronimo and Brandão, 2020), a few case reports (Mayer et al, 2010; Künzel et al, 2013) and only two retrospective studies (Gibbons et al, 2013; Girod-Rüffer et al, 2019).
Signalment
While no scientific data on age predisposition exist (Brandão et al, 2013), affected animals are usually presented when over the age 3 years (Thorson, 2014), with a median age of 5 years found in the study by Girod-Rüffer et al (2019). Females appear to be overrepresented (Di Geronimo and Brandão, 2020), with two retrospective studies showing that the majority of affected animals were female (Gibbons et al, 2013; Girod-Rüffer et al, 2019). Breed or genetic predispositions have not yet been documented.
Clinical signs and physical examination
There is a lack of systematic data on the clinical signs of hyperthyroidism in guinea pigs (Girod-Rüffer et al, 2019), but reported symptoms appear similar to other species (Brandão et al, 2013). Weight loss and a palpable mass or goitre in the ventral cervical region were the most common findings in two retrospective studies performed in guinea pigs (Gibbons et al, 2013; Girod-Rüffer et al, 2019). However, these signs are non-specific and may also occur with diseases such as renal disease and cervical lymphadenopathy, respectively (Brandão et al, 2013). In contrary, the absence of a goitre does not rule out hyperthyroidism (Di Geronimo and Brandão, 2020). A study by Girod-Rüffer et al (2019) demonstrated that 55% of the hyperthyroidism cases did not display a palpable goitre. One limitation of this study was that researchers relied on veterinary practitioners' clinical judgment and could not establish whether the palpated masses were indeed the thyroid gland. This means that misdiagnosis of thyroid hyperplasia could not be ruled out. The aforementioned information highlights the need for improved laboratory and imaging modalities in order to achieve a more reliable diagnosis. Other signs suggested in the literature may include hyperactivity, polyuria or polydipsia, progressive alopecia and hyperaesthesia (Edis and Pellett, 2019). A heart murmur, tachycardia or arrythmia may also be found on cardiac auscultation (Edis and Pellett, 2019).
Diagnosis
Diagnostic approaches in guinea pigs appear to be very similar to those documented for felines (Künzel and Mayer, 2015), which consist of laboratory analysis, imaging techniques and fine needle aspirates or biopsies of the goitre (Thorson, 2014).
Laboratory testing
A complete blood count, serum biochemistry analysis, T4 (total and free) measurement and TSH testing may be performed (Edis and Pellett, 2019).
A full thyroid panel has not yet been validated for use in guinea pigs (Brandão et al, 2013). A total T4 (TT4) test is the initial screening method of choice for detecting hyperthyroidism in this species (Edis and Pellett, 2019). However, in practice, the difficulty lies with interpretation of the results, because a variety of reference intervals have been published and are based on the use of different methodologies (Girod-Rüffer et al, 2019). While radioimmunoassay (Castro et al, 1986), chemiluminescence assay (Müller et al, 2009) and point-of-care T4 enzyme immunoassay (Fredholm et al, 2012) have been proposed, nonee of these methods are validated for use in guinea pigs (Girod-Rüffer et al, 2019). There is also no sufficient knowledge on the TT4 concentration above which an animal is considered to have hyperthyroidism (Girod-Rüffer et al, 2019). Although radioimmunoassay is currently the gold standard for measurement of basal total thyroxine levels in horses (Tangyuenyong et al, 2017), further research to validate its use in guinea pigs is necessary (Pignon and Mayer, 2013). A study carried out by Fredholm et al (2012) demonstrated repeatability of results obtained with enzyme immunoassay, so this method may be useful for the initial screening of the thyroid function in pet guinea pigs (Brandão et al, 2013). There are no papers discussing the differences between the methodologies (Girod-Rüffer et al, 2019). In a study of dogs, cats and horses, chemiluminescence assay greatly underestimated thyroxine values compared to radioimmunoassay (Singh et al, 1997). Fredholm et al (2012) found that pet guinea pigs had a TT4 range of 1.54–6.22 μg/dL using enzyme immunoassay. In contrast, Müller et al (2009) established a TT4 interval of 1.1–5.2 mg/dl using chemiluminescence assay. This suggests that different methods are not directly comparable (Girod-Rüffer et al, 2019), so reference intervals to compare the clinical results against should be chosen based on the diagnostic technique (Di Geronimo and Brandão, 2020). The values determined by Müller et al (2009) were found to be significantly higher than values obtained from a different study where the same method was used (Ewringmann and Glöckner, 2005). The lack of information on the number, age, origin and health status of the individuals, however, made this study invalid. One limitation of the study performed by Müller et al (2009) was the sample size being lower than the recommended size for the determination of reference values in human medicine. This means that possible bias from overrepresentation of small subgroups may influence the outcome (Müller et al, 2009). Further evaluation of all methods is necessary to determine their validity (Thorson, 2014).
Some affected animals may have a normal thyroid hormone level because the influence of nonthyroidal factors such as stress (Brand.o et al, 2013) or concurrent illness (euthyroid sick syndrome) (Gibbons et al, 2013). Free T4 measurements are less influenced by these factors and so may reflect the thyroid function better (Fredholm et al, 2012). While principally it can be used to confirm hyperthyroidism (Brand.o et al, 2013) reference intervals are still incomplete (Thorson, 2014). To the author's knowledge, apart from the report described by Castro et al (1986) there are no scientific papers on free T4 reference ranges in guinea pigs. As a result, accurate interpretation of the results may be impossible. Furthermore, some conditions may result in elevated thyroxine levels (Brand.o et al, 2013; Girod-Ruüffer et al, 2019) so it is important to recognise that a single elevated T4 value does not provide a definitive diagnosis (Edis and Pellett, 2019). Beaton et al (1960) demonstrated a correlation between low vitamin C concentrations and increased uptake of radioiodine-131 (I-131) being suggestive of thyroid hyperactivity.
Measurement of the endogenous TSH concentration can be useful to differentiate pituitary tumours (elevated TSH levels) from primary hyperthyroidism (normal or decreased TSH levels) (Brand.o et al, 2013). However, there are currently no reports detailing antemortem or post-mortem diagnosis of pituitary tumours in guinea pigs, and reference ranges for TSH concentrations in guinea pigs have not yet been established (Brand.o et al, 2013). A TSH response test has proven successful in laboratory guinea pigs (Mayer et al, 2013) and could potentially be used in pet guinea pigs but, to date, the absence of an accurate validated dose makes its application difficult in practice (Thorson, 2014).
While it does not evaluate the thyroid function directly (Thorson, 2014), a full blood panel is essential to assess the patient's health status and identify concurrent illness. In cats, a number of conditions, such as cardiomyopathies, nephropathies and hepatopathies, are linked to hyperthyroidism and in one study of 19 guinea pigs with confirmed thyroid neoplasia, more than half suffered from nephropathies, hepatopathies and cardiomyopathies (Gibbons et al, 2013). Other reported comorbidities were dental disease, ovarian cysts and ocular disease (Girod-Ruüffer et al, 2019). While not yet proven in scientific literature, it is assumed that appropriate treatment of hyperthyroidism in guinea pigs may unmask renal disease (Gibbons et al, 2013). Currently, it is still unclear whether thyroid gland neoplasms play a role in the development of chronic degenerative disease in these animals so further research to investigate their correlation is needed. Biochemistry analysis may also reveal elevated liver enzymes (Edis and Pellett, 2019) which is almost always the case in hyperthyroid humans and cats (Shiel and Mooney, 2007; Kubota et al, 2008). In research performed by Kuünzel et al (2013), all hyperthyroid guinea pigs had increased alanine transferase (ALT) levels.
Imaging
Imaging modalities used in endocrine disease can include thoracic radiography, ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI). It is important to note that these techniques do not provide a definitive diagnosis of hyperthyroidism because they are unable to predict the functionality of the detected tumour (Thorson, 2014), thus they should be used in conjunction with laboratory testing to support the diagnosis of a functional thyroid neoplasia. Thoracic radiography not only may detect differential diseases such as dental disease, it also may demonstrate pulmonary metastasis in case of thyroid carcinoma or osseous metaplasia of thyroid tissue which increases the likelihood for thyroid neoplasia (Thorson, 2014). Ultrasonography may show morphologic changes, vascular involvement and can assist fine needle aspirate (FNA) sampling (Thorson, 2014). CT and MRI may be useful to assess the structure and local infiltration of the mass, respectively (Thorson, 2014).
Nuclear scintigraphy
Nuclear scintigraphy is a useful method for definitive diagnosis in guinea pigs where blood T4 levels cannot be established, or where a normal total T4 and mildly elevated free T4 are found (Mayer et al, 2010). Another benefit is that it can detect metastasis and ectopic thyroid tissue (Thorson, 2014). In dogs and cats, it is considered the preferred imaging method for diagnosing hyperthyroidism (Pignon and Mayer, 2013). While its use has been described in guinea pigs (Mayer et al, 2009), it is still invasive and expensive with limited availability so it is less practical than laboratory thyroxine measurement in first opinion exotic veterinary practice (Fredholm et al, 2012).
Cytology and histopathology
Although cytology on a fine needle aspirate or histopathology on a tissue biopsy may detect thyroid neoplasia, it cannot provide any information on whether it is functional or not (Thorson, 2014).
Methimazole trial
When it is impossible to perform diagnostics (for example when insufficient blood volume is collected to allow for diagnostic interpretation), a methimazole trial could show rapid improvement of clinical signs (Thorson, 2014). However, the lack of safe and effective doses for these animals may make this difficult.
Treatment
As with any other endocrinopathy, the main goal of treatment is normalisation of the circulating hormones, in this case thyroxine (T4) and/or triiodothyronine (T3) (Brand.o et al, 2013). In veterinary medicine, treatment modalities include transdermal or oral thyreostatics, surgical thyroidectomy and radioactive iodine (Di Geronimo and Brand.o, 2020). For guinea pigs, there have not been any recent publications contesting previously held beliefs regarding the benefits and disadvantages of the various treatment options (Di Geronimo and Brand.o, 2020).
There are still substantial gaps in research into treatment in guinea pigs and the absence of controlled clinical trials urges the veterinary practitioner to judge which treatment modality is most appropriate for each individual on a case-by-case basis (Di Geronimo and Brand.o, 2020). These judgements may be based on factors such as owner compliance (Pignon and Mayer, 2013), presence of comorbidities, anaesthetic or surgical risk, relative cost of treatment or, in the case of a surgical approach, inadequate response to conservative treatment (Di Geronimo and Brand.o, 2020).
Medical treatment
Primary evidence on the effects of thyreostatic drugs in guinea pigs is currently unavailable and the medication and dosages for treatment in guinea pigs have been extrapolated from those for cats (Girod-Ruüffer et al, 2019). Oral methimazole and carbimazole are currently the therapeutic drugs of choice because of their success in the management of feline hyperthyroidism where they directly suppress thyroid hormone production (Mayer et al, 2010). The main disadvantage of this modality is that the underlying cause of overproduction is not addressed, so lifelong treatment is necessary and is thus reliant on owner compliance (Thorson, 2014). The successful anecdotal use of methimazole in guinea pigs has been described in one case report (Pignon and Mayer, 2013) and one case series (Kuünzel et al, 2013). Dosages ranged from 0.5–2 mg/kg 1–2 times daily (Mayer et al, 2010) and 1–1.4mg/kg/day (Kuünzel et al, 2013). In the study performed by Kuünzel et al (2013), three out of four animals showed clinical response to treatment, but all four died within 18–28 months following diagnosis of hyperthyroidism. However, the exact cause of death was unknown. Oral thyreostatics may have the advantage of identifying underlying renal disease once the hyperthyroidism is stabilised (Gibbons et al, 2013). Additionally, it may be useful to achieve stabilisation before thyroidectomy in order to minimise the anaesthetic risk. Clinical success of transdermal methimazole has been anecdotally reported (Mayer et al, 2010), although, in light of investigating human hyperpigmentation, the study performed by Kasraee (2002) demonstrated that this resulted in depigmentation of the brown skin of guinea pigs (Thorson, 2014). One retrospective study by Girod-Ruüffer et al (2019) showed that thiamazole also appeared effective in reducing blood TT4 in guinea pigs. Improvement of the clinical signs was achieved in 48% of the guinea pigs receiving conservative treatment, but the exact number of animals treated with thiamazole was not specified.
While 41% of the animals in this study were reported to have died, there was no information on their clinical response to treatment before death (Di Geronimo and Brand.o, 2020). From the 40 questionnaires included in this study, only 25 clearly provided dosages. In the guinea pigs treated with carbimazole, dosages ranged from 1–2.5 mg/day, whereas thiamazole dosages varied between 0.1–5mg/day. Variable responses were noted and included reduction of the TT4 levels to within the reference ranges, levels below the reference range and levels higher than the baseline values.
However, retrospective studies are not ideal to evaluate the efficacy of an intervention. This is because they face numerous threats to validity which limit the interpretation of the results (Tofthagen, 2012). For example, the absence of a control group made it impossible to determine a cause and effect relationship between the treatment modality (such as thiamazole) and the outcome (clinical changes) (Tofthagen, 2012). However, it can still be useful in the future for the design of a more reliable prospective study.
Radioiodine therapy
According to the author, the successful anecdotal use of I-131 in guinea pigs has been described in three publications (Mayer et al, 2010; Pignon and Mayer, 2013; Edis and Pellett, 2019). It has got the potential to be curative (Pignon and Mayer, 2013), is less invasive than surgical thyroidectomy and may also target ectopic thyroid tissue (Edis and Pellett, 2019). However, its main disadvantages are its cost, the need to isolate the affected animal, the risk of recurrence (Thorson, 2014) and particularly the lack of primary evidence on accurate dosages and the efficacy of this treatment modality in guinea pigs (Edis and Pellett, 2019). As for antithyroid drugs, the lack of scientific data on radioiodine treatment indicates the need for pharmacokinetic studies to establish a safe and effective dose.
Surgical thyroidectomy
Multiple surgical techniques for thyroidectomy in hyperthyroid cats have been reported (Birchard, 2006) and some reports are available in laboratory and pet guinea pigs (Gibbons et al, 2013; Girod-Ruüffer et al, 2019). While, in theory, surgical thyroidectomy could provide full resolution of the clinical signs, it is technically difficult (Thorson, 2014) and a high incidence of postoperative death in some reports could suggest it carries a poor prognosis (Kuünzel et al, 2013). In addition, a high risk of recurrence has been proposed where a study revealed regrowth of thyroid tissue in 42% of thyroidectomised guinea pigs (Kromka and Hoar, 1975). Although three out of seven thyroidectomised guinea pigs died postoperatively, there was no information on the investigation on potential comorbidities, which may have increased the anaesthetic risk. According to one retrospective study, complete resolution of the clinical signs was achieved in one guinea pig with hyperthyroidism and a moderate improvement was seen in three others with no postoperative complications reported (Girod-Ruüffer et al, 2019). Anecdotally, laryngeal nerve damage, haemorrhage and accidental parathyroid organ removal have been suggested as complications (Edis and Pellett, 2019).
Radiation therapy
The benefit of radiation therapy is that it can provide additional therapy when full thyroidectomy is unsuccessful or in cases where surgery is not ideal (Thorson, 2014). However, to date, there are no publications on the use of radiation therapy in guinea pigs.
Conclusions
While increasing numbers of documented cases indicate that guinea pigs develop hyperthyroidism, most papers still rely on anecdotal recommendations and extrapolation of information obtained from feline medicine. More work is needed to evaluate the validity of the diagnostic modalities and to determine the best treatment methods for these animals.
KEY POINTS
- Guinea pigs increasingly present with signs suggestive of hyperthyroidism.
- Diagnostic and therapeutic modalities are often extrapolated from feline medicine.
- A total T4 test is the preferred method to diagnose hyperthyroidism in this species, but work is needed to establish reference ranges.
- Treatment may consist of thyreostatics, radioiodine treatment or surgical thyroidectomy.