Therapeutic management of hypothyrodism with concurrent babesiosis in a non-descript dog

Introduction

Hypothyroidism is one of the most common endocrine diseases in dogs, caused by a decrease in the production of thyroxine (T 4 ) and triiodothyronine (T 3 ) by the thyroid gland (Strey et al., 2021) [62] with an estimated prevalence of 0.174% to 0.23% (Panciera, 1994; Kour et al., 2020 and O'Neill et al., 2022) [49,32,48] . Hypothyroidism in dogs is commonly reported in middle-aged animals, between 4 and 10 years old, castrated and of both sexes (Strey et al., 2021 and O'Neill et al., 2022) [62,48] . A recent study revealed that the most common breeds diagnosed with hypothyroidism were Tibetan Terriers, Standard Doberman Pinschers and Boxers (O'Neill et al., 2022) [48] . The condition is often manifested as weight gain, lethargy, hair loss, intolerance to the cold and a tragic facial expression thereby reducing the quality of life of affected dogs (Bugbee, et al. 2023 and Fleeman and Barret 2023) [10,12] . Measurement of serum total thyroxine (TT4) concentration is most commonly performed for clinical diagnosis and management of the condition is often a lifelong, daily oral thyroid hormone replacement (Suranti et al., 2008; Bugbee, et al. 2023) [63,10] . Canine babesiosis is a common vector-borne disease caused by intraerythrocytic protozoan parasite of the genus Babesia (Irwin 2009) [29] . The disease is endemic to the Indian subcontinent with varying prevalence across different regions depending on vector population, climate and dog demographics. The disease is clinically manifested by anorexia, dehydration, high body temperature, dullness/depression, diarrhoea/constipation, pale mucosa, hepatomegaly, vomiting/nausea, splenomegaly, distended abdomen/ascites, yellow coloured urine, emaciation/weight loss, and ocular discharge (Irwin 2009) [29] .

The diagnosis of babesiosis is based on cytological evidence of Babesia organism in freshly prepared blood smears. The recommended therapeutic drugs for babesiosis are diminazine aceturate and imidocarb dipropionate. This report describes a case of successful management of hypothyroidism with concurrent babesiosis in a nondescript dog.

Case Presentation

A 4 years old nondescript dog was presented to the Veterinary Clinical Complex, College of Veterinary Science, Assam Agricultural University, Khanapara, Guwahati, Assam with the history of fever for the past 3 days, black coloured soft stool, dark yellow urine, loss of hair on the back of the body, lethargy, chronic obesity (previous record of body weight up to 39 kg) and irregular treatment with thyroxine sodium. On physical examination, temperature was found to be 104.6℉, congested visible mucous membrane, with severe alopecia on the back region and hyperpigmentation (Fig. A), dry hair coat, presence of ticks (++), and lethargy. The body weight of the dog was 35.6 kilograms. Approximately 5 ml of whole blood was collected from the affected dog on the day of presentation by using 22-gauge needle attached to a 5 ml syringe through saphenous venipuncture. A fraction of whole blood was transferred into K 3 -EDTA vacutainer and was subjected to haematological analysis. Haematological parameters viz., haemoglobin (g/dl), Packed cell volume (%), Total leucocyte count (×10 3 /µl), Total erythrocyte count (×10 6 /µl), Thrombocyte count (×10 6 /µl) was estimated on zero-day, day 30 and day 60 after treatment by using Automated Hematology Analyzer (MELET SCHLOESING Laboratoires, FLS257). Serum samples were used for determination of TT4 (µg/dl) by using fully automated Chemistry Analyzer (IDEXX's the Catalyst One TM Chemistry Analyzer) based on dry-slide technology. Biochemical analyses of the blood samples were completed on the day of collection. Serum TT4 was estimated on day zero (before treatment with Thyroxine), day 30, day 60 and day 180 after initiating treatment with Thyroxine. Peripheral blood smears (eartip) were obtained and subjected to Giemsa staining technique and microscopy for detection of the haemoprotozoan parasite. Detailed haemato-biochemical examination revealed low haemoglobin, TEC, and total thyroxine (TT4) (Table 1). Blood smear was positive for Babesia gibsoni (Fig. D).

Treatment

Based on clinical and haemato-biochemical examination, and microscopy, the dog was diagnosed to be suffering from hypothyroidism (serum TT4 0.5 mcg/dl), with Babesia gibsoni infection. A two-way therapeutic approach was adopted in this case, first was to treat the babesia infection using Diminazine aceturate, doxycycline, clindamycin, metronidazole and other supportive drugs and second was to manage the hypothyroid condition by hormone replacement. Following standard guidelines, specific therapy for babesiosis was initiated with two doses of Diminazine aceturate @ 3.5 mg/kg body weight, deep intramuscular injections, 48 hrs apart, with metronidazole @ 15 mg/kg body weight orally for 3 weeks, doxycycline @ 5 mg/kg body weight orally for 3 weeks and clindamycin @ 25 mg/kg body weight orally for 3 weeks. Supportive therapy like iron supplements, antiemetics, acid blockers, essential fatty acids (Omega 3 and Omega 6), Vitamin A supplement and B-complexes were given for approximately one month. Noticeable clinical improvement was seen along with improved haemato-biochemical parameters by day 30 post treatment. Microscopic examination for babesia organism was found to be negative 30 days after initiation of treatment. The second therapeutic approach was to stabilize and maintain the thyroid hormone imbalance by hormone replacement and monitoring to provide a comfortable life for the dog. Thyroid hormone replacement was initiated by administering Thyroxine sodium @ 250 mcg, orally once daily before food in the morning and a commercial obesity diet was advised. Serum TT4 concentration increased to 1.3 mcg/dl after one month (30 days) of thyroxine treatment. It was still below the normal level, so the owner was advised to continue thyroxine at the same concentration for another one month. Serum TT4 concentration increased to 4.0 mcg/dl after another month (Total 60 days) of thyroxine treatment. Thyroxine treatment was advised to be continued at the same dose rate till the next monitoring of TT4 levels. Serum TT4 was measured after 180 days of continuous thyroxine and it measured 3.9 mcg/dl. The owner was advised to keep the dog under lifelong thyroid medication with regular evaluation at every 3 months interval. Following intensive anti-haemoprotozoan and thyroid replacement therapy, the dog showed a slow and progressive recovery with improvement in the overall health status, regrowth of hair on its back (Fig. B), reduced pigmentation and improvement in its vitality. A complete regrowth of hair on its back and improved body coat condition was observed in 180 days (Fig. C) following treatment. However, the dog failed to lose its body weight (still 37 kg) after 180 days of treatment, which still left some reservation for the clinicians looking after the dog about the standard therapeutic modalities followed for management of hypothyroidism in dogs and its weight management.

Discussion

In hypothyroid dogs, distinct dermatological peculiarities like including bilaterally symmetric, nonpruritic alopecia over the trunk or areas of wear and tear, dull and lusterless hair coat, scaling, seborrhoea, hyperpigmentation, absence of itching and recurrent infections (pyoderma or otitis externa) are often manifested (Panciera 1994 [49,18,61,27,43] . Hypothyroidism accounted for 32.90 per cent of total dermatopathies (Costa et al., 2016) [13] and has been reported as the most common endocrinopathies (0.2-0.8 %) in dogs (Ferguson, 2007; De Bellis, 2011 and Mooney 2011) [22,17,44] . In the present case, severe alopecia on the back region (truncal alopecia) and hyperpigmentation and dry hair coat was observed which was similar to the dermatological changes as reported by Haritha et al., (2017) [27] who recorded a decreased value of T 3 and T 4 and increased value of TSH in a five years old Labrador dog with alopecia associated with hypothyroidism. Ramesh et al., (2018) [55] also reported the presence of skin lesions like bilateral alopecia and hyperpigmentation with pruritus in a 7 years old female Labrador dog with hypothyroidism. Thyroid hormones play a crucial role in ensuring the normal function of the skin and approximately 60% to 80% of hypothyroid dogs exhibit dermatological problems. The lack of thyroid hormones leads to decreased fibroblast activity and altered collagen metabolism, causing delayed wound healing and potential excessive fibrous tissue deposition after trauma (Credille et al., 2001) [13] , whereas lack of thyroid hormone impairs cell development in the epidermis and alters sebaceous gland secretion which could either lead to dry or oily seborrhoea (Nelson and Couto, 2020) [46] . Thyroid hormone directly influences the mechanism of proteoglycan synthesis in the skin by stimulation of fibroblasts. In addition, they play a role in epidermal differentiation by their effect on keratinocytes, also it is essential in hair formation and sebum production (Doshi et al., 2008) [19] . Dermatological signs appear later, when T 4 secretion is severely affected as was seen in the current case where the T 4 levels dropped to 0.5 mcg/dl. Hair loss is usually the first symptom perceived by owners, it occurs bilaterally and symmetrically in dorsal region of the neck, ventral and lateral of the thorax, abdomen and tail while head and extremities are usually spared (Scott-Moncrieff, 2007) [60] . Very common characteristic change is the "rat's tail" which it is alopecia located in the tail (Scott et al., 2001) [59] . Hyperpigmentation is often observed in dogs with hypothyroidism, but its mechanism is still unknown (Scott-Moncrieff, 2007; Scarampella, 2011) [60,57] . Hyperpigmentation usually begins in areas with alopecia. This alteration, also affects inguinal region and medial sides of the limbs. In dogs with endocrine dermatopathy, hyperpigmented areas may also present hyperkeratosis when they are related to pruritus and chronic inflammation of the skin (Scott et al., 2001 and Scott-Moncrieff, 2007) [59,60] . Lethargy and weight gain/obesity are also common manifestation seen in hypothyroid dogs (Panciera 1994; Dixon et al., 1999; Mohanambal et al., 2023) [49,18,43] . Obesity is observed in more than 40% of dogs with hypothyroidism in several studies (Kaelin et al., 1986; Panciera, 1994; Dixon et al., 1999; Feldman and Nelson 2004) [32,49,18,21] . Obesity, however, is a common nutritionally related problem in dogs and many dogs with obesity are not hypothyroid. It is estimated that in the general population, between 21-30% of dogs seen in practice are obese (Laflamme et al., 1994) [35] . The effect of obesity on canine thyroid function is frequently cited in the literature (Peterson and Ferguson 1989; Scott-Moncrieff and Guptill-Yoran 2000) [52,58] . Canine obesity is a common medical disorder and a recognized risk factor for obesityrelated metabolic dysfunction. It can seriously influence various physiological functions the body, thereby limiting the longevity of the animals (Pereira-Neto et al., 2018) [51] .

Canine hypothyroidism is diagnosed based on history and clinical findings that are suggestive of the disease along with supporting laboratory findings and responsive hormonal therapy (Ferguson, 1994) [22] . Approximately 80% of the secreted thyroid hormone is T 4 and 20% is T 3 . A failing thyroid gland preferentially makes T 3 , so in developing hypothyroidism, T 4 is expected to decrease earlier than T 3 . Serum T 4 , levels are considered more useful in the diagnosis of hypothyroidism than are triiodothyronine (T 3 ) level (Nelson et al., 1991) [46] . In the present case only T 4 was estimated (0.50 mcg/dl) which confirmed the hypothyroidism, similar to that reported by Daminet and Paradis (2000) [14] . Estimation of free thyroxine (fT 4 ) was reported to be better assessment for hypothyroidism evaluation in dogs since it was less commonly affected by drugs and concurrent illness (Celeska and Atanaskova, 2020 and Bennaim et al., 2022) [11,5] . In the current case, the dog was diagnosed to be suffering from concurrent babesia infection as confirmed by clinical signs, serum biochemistry and microscopic detection of babesia organism in blood smear. A confirmation of canine babesiosis is often based on history (particularly the presence of ticks on the body) and clinical signs along with the identification of Babesia organism within infected erythrocytes, positive serologic results, and molecular detection of amplified nucleic acid extracted from blood or tissues ( [7,36,34,50] . A number of drugs have been used in the management of canine babesiosis, including antiprotozoal agent like diminazene aceturate/diaceturate, imidocarb diproprionate, atovaquone (Farwell et al., 1982; Fowler et al., 1972; Baggish and Hill, 2002) [20,25,4] , and antibiotics like azithromycin, clindamycin, doxycycline and metronidazole (Birkenheuer et al., 2004; Wulansari et al., 2003; Vercammen et al., 1996; and Almendros et al., 2020) [6,68,66,2] . However, no single drug has been reported to successfully eliminated B. gibsoni from infected dogs (Vercammen et al., 1996; Wulansari et al., 2003; Vial and Gorenflot 2006; and Lin and Huang 2010) [66,68,67,38] . In the present case, we have also selected a combination of three drugs ie., metronidazole, clindamycin and doxycycline with a standard dosing of diminazine aceturate to manage the babesia infection. Diminazine aceturate is an antiprotozoal agent widely used to treat babesiosis in (Lee et al., 2009; Hwang et al., 2010) [37,28] . The exact mechanism of action is still poorly understood but it appears to interfere with aerobic glycolysis and synthesis of deoxyribonucleic acid in the parasite (Matsuu et al., 2008; Plumb, 2011) [40,53] . However, treatment with diminazine often fails to eliminate the parasite from the affected dog and high incidences of relapses or recurrences are often observed even after a temporary improvement is obtained by the administration of diminazine (Adachi et al., 1993; Boozer and Douglass, 2003; and Suzuki et al., 2007) [1,9,65] . Moreover, diminazine in dogs have a narrow margin of safety and often induces many adverse effects like tachycardia and CNS signs such as ataxia, nystagmus, and opisthotonos, haemorrhages in the cerebellum, hepatotoxicity and necrosis at the site of injection (Wulansari et al., 2003 [68,39,41,26,64,16] . Because of the above-mentioned reasons, in the present case, we have used a combination of metronidazole, clindamycin and doxycycline (MCD) as an additional treatment protocol for B. gibsoni infection and could eliminate the babesia organism as the blood smear examination was found to be negative after a month and the dog did not show any signs of relapse or recurrence even after 180 days of treatment. This combined MCD therapeutic protocol was first reported in 2007 by Suzuki et al. [65] where they could successfully eliminate B gibsoni from peripheral blood in 3 out of 4 dogs. Since then, many reports have been documented on the successful management of babesiosis caused by B gibsoni in dogs (Nandini et [45,3,54,2,42] .

Hypothyroidism, in the present case was managed using oral levothyroxine hormone replacement as per standard dosing with treatment monitoring at 4 weeks interval for two consecutive months. To keep the obesity in control, a dietary limitation of calorie intake and gradual addition of commercially available obesity diet was advised. An increase in physical activity was noticed within two weeks after initiation of treatment, but significant improvement in skin condition required more than four weeks treatment, however negligible weight loss was observed even after 6 months of therapy and the dog remained obese with a body weight of 37kg. Levothyroxine has been extensively used as the standard treatment for hypothyroidism in humans as well as canines. Treatment with levothyroxine sodium, a synthetic form of the thyroid hormone (T 4 ), plays a crucial role in maintaining normal thyroid hormone levels in the body (Jaiswal et al., 2018) [30] . When taken orally, it is effective, has a prolonged serum half-life that allows for once-daily dosing, and typically leads to the resolution of hypothyroidism symptoms in most patients (Jonklaas et al., 2014) [31] . Clinical improvement was mostly observed after 6-8 months from the levothyroxine administration (Das et al., 2021 and Ryad et al., 2020) [15,56] .

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