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SMALL ANIMALS CASE REPORT AND CLINICAL REVIEW SMALL ANIMALS
Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed T Johnstone,a* E Terzob and CT Mooneyb
Background The aetiology of insulin resistance (IR) in naturally occurring canine hypothyroidism is poorly understood and likely multifactorial. Excess secretion of growth hormone (GH) by transdifferentiated pituitary cells may contribute to IR in some hypothyroid dogs, but although this has been demonstrated in experimental studies, it has not yet been documented in clinical cases. Case report A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics and glucocorticoid therapy. The dog also exhibited exercise intolerance and polydipsia of 12 and 2 months duration, respectively. On physical examination, obesity, poor coat condition, widened interdental spaces and mild respiratory stridor were noted. Initial laboratory test results revealed concurrent hypothyroidism and diabetes mellitus (DM). Further investigations showed IR, GH excess and a paradoxical increase of GH following stimulation with thyrotropin-releasing hormone. Conclusions To the authors’ knowledge, this is the first reported case that suggests that GH alterations may have clinical significance in naturally occurring hypothyroidism. Among other factors, hypothyroidism-induced GH excess should be considered as a possible cause of IR in patients suffering from hypothyroidism and concurrent DM. In such cases, DM may reverse with treatment of hypothyroidism, as was documented in this case. Keywords acromegaly; diabetes mellitus; dogs; hypothyroidism; insulin resistance Abbreviations DM, diabetes mellitus; GH, growth hormone; IGF-1, insulin-like growth factor-1; IR, insulin resistance; P : B, pituitary to brain ratio; PUPD, polyuria/polydipsia; TRH, thyrotropinreleasing hormone; TSH, thyroid-stimulating hormone Aust Vet J 2014;••:••–••
doi: 10.1111/avj.12237
H
ypothyroidism and diabetes mellitus (DM) are common endocrine conditions in dogs, although it is uncommon for both conditions to occur concurrently.1–4 Previous studies have suggested that concurrent hypothyroidism and DM may be the result of simultaneous autoimmune destruction of the endocrine cells of the pancreas and thyroid gland5 and a link to abnormal dog leuco*Corresponding author. a University of Melbourne Veterinary Hospital, Department of Small Animal Medicine, 250 Princes Highway, Werribee, Victoria 3030, Australia; [email protected] b School of Veterinary Medicine, University College Dublin, Belfield, Dublin, Ireland
© 2014 Australian Veterinary Association
cyte antigen genes has been proposed.6 In such cases, insulindependent DM would be expected. Cases of insulin-resistant DM and hypothyroidism have also been described.3 The aetiology of insulin resistance (IR) in these clinical cases has not been completely elucidated. Net effects that have been observed in thyroid hormonedeprived peripheral cells include a reduced ability to transport glucose across cell membranes and a reduction in intracellular glucose metabolism. These effects are thought to be caused by decreased expression of glucose-transporter-47 and downregulation of various proteins involved in intracellular glucose catabolism.8–11 Other factors, such as reduced tissue blood flow and reduced oxidative capacity of cells, are thought to contribute to the abnormal glucose disposal.12,13 The effect of hypothyroidism on insulin receptors is less clear; with previous studies suggesting an increase, a decrease or no change in receptor number or affinity.8,14 Secondary changes associated with hypothyroidism, such as obesity and hypertriglyceridaemia, may also contribute to peripheral IR, and can influence insulin receptor density, insulin binding to receptors and post-receptor glucose catabolism.15–17 Lastly, hypothyroidism has been associated with alterations in hormones that influence glucose metabolism.18,19 In particular, previous studies evaluating hypothyroid dogs have documented excessive production of growth hormone (GH), a known insulin antagonist.19,20 A canine patient with features of naturally occurring hypothyroidism, acromegaly and DM, in which DM was reversed with appropriate treatment of hypothyroidism, is presented. Case report A 4-year-old male entire Samoyed was presented to the University College Dublin Veterinary Hospital with an 8-month history of intermittent shifting lameness, hyperkeratosis of all footpads and interdigital dermatitis. The hyperkeratosis had not responded to zinc supplementation and surgical removal of hyperkeratotic tissue had been performed 7 months before referral. Medical management had included a selective protein diet (Royal Canin Sensitivity, Royal Canin UK, Somerset, UK). Before the surgery, the dog had also received several 10-day courses of cephalexin (Keflex®, Flynn Pharma Ltd, Ireland) and prednisolone (5 mg every 12 h; Prednisolone®, Clonmel Healthcare Ltd, Ireland). The treatment had had limited response. One month prior to referral, mild left forelimb lameness recurred and the dog had received treatment with prednisolone (0.13 mg/kg every 12 h, then 0.13 mg/kg every 24 h, each given for 7 days) and cephalexin (12.5 mg/kg every 12 h for 7 days); both had been discontinued 2 weeks prior to admission. The owner additionally reported exercise intolerance of 12 months’ duration and polyuria/polydipsia (PUPD) over the past month. Although the onset of PUPD coincided with the
Australian Veterinary Journal Volume ••, No ••, •• 2014
1
SMALL ANIMALS
SMALL ANIMALS
Figure 1. Face and mouth of the 4-year-old Samoyed dog at initial presentation, showing marked interdental spacing.
start of previous prednisolone treatment, it had persisted in severity despite prednisolone dose decrements. Physical examination revealed a poor coat condition, with little undercoat, alopecia of the neck and tail area, and matted hair on the ventral abdomen. There was non-fissuring, non-ulcerative hyperkeratosis involving the skin at the elbows, anus and footpads. Mild interdigital erythema was evident. The dog was obese (body condition score 4/5; weight 40 kg). Oral examination revealed marked interdental spacing (Figure 1). A mild pharyngeal or laryngeal inspiratory stridor was heard. The dog had pain on extension of the hips. There was no evidence of forelimb pain or lameness and no evidence of pain or lameness during and immediately after palpation of the footpads. The remainder of the physical examination was unremarkable. Results of haematology, serum biochemistry, bile acid stimulation test, urinalysis and culture, and thyroid function tests are shown in Tables 1–4. Severe hyperglycaemia, fasting hypertriglyceridaemia and hypercholesterolaemia were present. Alkaline phosphatase was elevated moderately and alanine amino transaminase, gamma-glutamyl transpeptidase, protein and creatinine concentrations were mildly increased. The bile acid stimulation test results were within the reference interval, suggesting appropriate liver function. Haematological abnormalities included leucocytosis with mature neutrophilia, thrombocytosis and mild normocytic hyperchromic anaemia. Circulating total thyroxine (T4), free T4 (by equilibrium dialysis) and free triiodothyronine (T3) concentrations were below, and canine thyroidstimulating hormone (cTSH) above the respective reference limits of the diagnostic laboratory (Diagnostic Center of Population and Animal Health, Michigan State University, MI, USA). Urinalysis revealed marked glucosuria, proteinuria and amorphous phosphate crystals. Radiography of the pelvis showed mild incongruence of the coxofemoral joints. Faecal parasitology showed no evidence of Ancylostoma spp. as a potential cause of the interdigital dermatitis. Based on the initial laboratory test results, both DM and hypothyroidism were diagnosed and their combination could explain the exercise intolerance, changes in the hair coat, skin and footpads and the PUPD. Recent steroid administration may have contributed to the PUPD and
2
Australian Veterinary Journal Volume ••, No ••, •• 2014
Table 1. Haematology results for a 4-year-old Samoyed dog with exercise intolerance and polyuria/polydipsia of 12- and 2-months duration, respectively
Parameter Hct Hb RBC MCHC MCV Platelets WBC NeutM Lymphocytes Monocytes Eosinophils Basophils
Day 0
Day 141
Units
Reference range
0.31 154 4.57 490 68.80 788.0 28.31 22.36 2.83 2.26 0 0
0.46 161 7.58 349 60.90 326.0 13.41 9.97 2.3 0.49 0.61 0.02
L/L g/L ×1012/L g/L fL ×109/L ×109/L ×109/L ×109/L ×109/L ×109/L ×109/L
0.37–0.55 120–180 5.5–8.5 310–362 60–77 150–500 6–17 3–11.5 1–3.6 0–1.35 0–1.47 0–0.1
Hct, haematocrit; Hb, haemoglobin; RBC, red blood cells; MCHC, mean corpuscular haemoglobin concentration; MCV, mean cell volume; WBC, white blood cells; NeutM, mature neutrophils. Bold values are abnormal.
clinicopathological abnormalities such as the increased alkaline phosphatase concentration, thrombocytosis, neutrophilia and proteinuria. Superficial necrolytic dermatitis, zinc-responsive dermatitis and systemic lupus erythematosus could not be completely excluded as potential causes of the pedal hyperkeratosis and other dermatological changes. It was decided to postpone tests to investigate these disorders21–23 until stabilisation of the DM and hypothyroidism could be achieved. Progression of dermatological changes was monitored during that time. Before treatment for DM and hypothyroidism was initiated, further tests were performed to detect potential causes of the increased interdental spacing and inspiratory stridor, and to investigate a potential link between hypothyroidism and DM. These tests included upper airway examination, assessment of pretreatment serum insulin concentration and measurement of insulin-like growth factor-1 (IGF-1)
© 2014 Australian Veterinary Association
Table 2. Serum biochemistry results for a 4-year-old Samoyed dog with exercise intolerance and polyuria/polydipsia of 12- and 2-months duration, respectively
Table 3. Urinalysis results for a 4-year-old Samoyed dog with exercise intolerance and polyuria/polydipsia of 12- and 2-months duration, respectively
Parameter
Parameter
Day 0
Day 141
Units
Reference range
Protein 79.0 Albumin 36.1 Urea 6.9 Creatinine 123 ALT 106 GLDH 13 ALP 971 GGT 8 CK 28 Lipase 57 Amylase 382 Glucose 26.9 Cholesterol 25.4 Bilirubin 6.5 iPhosphorus 1.51 Calcium 2.83 Sodium 144.2 Potassium 4.5 Chloride 101.1 Triglycerides 25 Preprandial bile acids 2.6 Postprandial bile acids 27.1
70.9 35.3 4.8 122 59 1 254 2 25 14 849 3.9 4.5 5.0 1.08 2.62 151.6 3.86 115.4 1.34 NP NP
g/L g/L mmol/L μmol/L IU/L IU/L IU/L IU/L IU/L IU/L IU/L mmol/L mmol/L μmol/L mmol/L mmol/L mmol/L mmol/L mmol/L nmol/L μmol/L μmol/L
54–71 31–40 3.6–8.6 20–120 0–20 0–10 0–50 0–40 0–50 0–130 0–730 3–6.5 3.2–6.5 0.9–10 0.8–1.8 2.3–3 137–151 3.7–5.8 99–110 0.11–1.69
SMALL ANIMALS CASE REPORT AND CLINICAL REVIEW SMALL ANIMALS
Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed T Johnstone,a* E Terzob and CT Mooneyb
Background The aetiology of insulin resistance (IR) in naturally occurring canine hypothyroidism is poorly understood and likely multifactorial. Excess secretion of growth hormone (GH) by transdifferentiated pituitary cells may contribute to IR in some hypothyroid dogs, but although this has been demonstrated in experimental studies, it has not yet been documented in clinical cases. Case report A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics and glucocorticoid therapy. The dog also exhibited exercise intolerance and polydipsia of 12 and 2 months duration, respectively. On physical examination, obesity, poor coat condition, widened interdental spaces and mild respiratory stridor were noted. Initial laboratory test results revealed concurrent hypothyroidism and diabetes mellitus (DM). Further investigations showed IR, GH excess and a paradoxical increase of GH following stimulation with thyrotropin-releasing hormone. Conclusions To the authors’ knowledge, this is the first reported case that suggests that GH alterations may have clinical significance in naturally occurring hypothyroidism. Among other factors, hypothyroidism-induced GH excess should be considered as a possible cause of IR in patients suffering from hypothyroidism and concurrent DM. In such cases, DM may reverse with treatment of hypothyroidism, as was documented in this case. Keywords acromegaly; diabetes mellitus; dogs; hypothyroidism; insulin resistance Abbreviations DM, diabetes mellitus; GH, growth hormone; IGF-1, insulin-like growth factor-1; IR, insulin resistance; P : B, pituitary to brain ratio; PUPD, polyuria/polydipsia; TRH, thyrotropinreleasing hormone; TSH, thyroid-stimulating hormone Aust Vet J 2014;••:••–••
doi: 10.1111/avj.12237
H
ypothyroidism and diabetes mellitus (DM) are common endocrine conditions in dogs, although it is uncommon for both conditions to occur concurrently.1–4 Previous studies have suggested that concurrent hypothyroidism and DM may be the result of simultaneous autoimmune destruction of the endocrine cells of the pancreas and thyroid gland5 and a link to abnormal dog leuco*Corresponding author. a University of Melbourne Veterinary Hospital, Department of Small Animal Medicine, 250 Princes Highway, Werribee, Victoria 3030, Australia; [email protected] b School of Veterinary Medicine, University College Dublin, Belfield, Dublin, Ireland
© 2014 Australian Veterinary Association
cyte antigen genes has been proposed.6 In such cases, insulindependent DM would be expected. Cases of insulin-resistant DM and hypothyroidism have also been described.3 The aetiology of insulin resistance (IR) in these clinical cases has not been completely elucidated. Net effects that have been observed in thyroid hormonedeprived peripheral cells include a reduced ability to transport glucose across cell membranes and a reduction in intracellular glucose metabolism. These effects are thought to be caused by decreased expression of glucose-transporter-47 and downregulation of various proteins involved in intracellular glucose catabolism.8–11 Other factors, such as reduced tissue blood flow and reduced oxidative capacity of cells, are thought to contribute to the abnormal glucose disposal.12,13 The effect of hypothyroidism on insulin receptors is less clear; with previous studies suggesting an increase, a decrease or no change in receptor number or affinity.8,14 Secondary changes associated with hypothyroidism, such as obesity and hypertriglyceridaemia, may also contribute to peripheral IR, and can influence insulin receptor density, insulin binding to receptors and post-receptor glucose catabolism.15–17 Lastly, hypothyroidism has been associated with alterations in hormones that influence glucose metabolism.18,19 In particular, previous studies evaluating hypothyroid dogs have documented excessive production of growth hormone (GH), a known insulin antagonist.19,20 A canine patient with features of naturally occurring hypothyroidism, acromegaly and DM, in which DM was reversed with appropriate treatment of hypothyroidism, is presented. Case report A 4-year-old male entire Samoyed was presented to the University College Dublin Veterinary Hospital with an 8-month history of intermittent shifting lameness, hyperkeratosis of all footpads and interdigital dermatitis. The hyperkeratosis had not responded to zinc supplementation and surgical removal of hyperkeratotic tissue had been performed 7 months before referral. Medical management had included a selective protein diet (Royal Canin Sensitivity, Royal Canin UK, Somerset, UK). Before the surgery, the dog had also received several 10-day courses of cephalexin (Keflex®, Flynn Pharma Ltd, Ireland) and prednisolone (5 mg every 12 h; Prednisolone®, Clonmel Healthcare Ltd, Ireland). The treatment had had limited response. One month prior to referral, mild left forelimb lameness recurred and the dog had received treatment with prednisolone (0.13 mg/kg every 12 h, then 0.13 mg/kg every 24 h, each given for 7 days) and cephalexin (12.5 mg/kg every 12 h for 7 days); both had been discontinued 2 weeks prior to admission. The owner additionally reported exercise intolerance of 12 months’ duration and polyuria/polydipsia (PUPD) over the past month. Although the onset of PUPD coincided with the
Australian Veterinary Journal Volume ••, No ••, •• 2014
1
SMALL ANIMALS
SMALL ANIMALS
Figure 1. Face and mouth of the 4-year-old Samoyed dog at initial presentation, showing marked interdental spacing.
start of previous prednisolone treatment, it had persisted in severity despite prednisolone dose decrements. Physical examination revealed a poor coat condition, with little undercoat, alopecia of the neck and tail area, and matted hair on the ventral abdomen. There was non-fissuring, non-ulcerative hyperkeratosis involving the skin at the elbows, anus and footpads. Mild interdigital erythema was evident. The dog was obese (body condition score 4/5; weight 40 kg). Oral examination revealed marked interdental spacing (Figure 1). A mild pharyngeal or laryngeal inspiratory stridor was heard. The dog had pain on extension of the hips. There was no evidence of forelimb pain or lameness and no evidence of pain or lameness during and immediately after palpation of the footpads. The remainder of the physical examination was unremarkable. Results of haematology, serum biochemistry, bile acid stimulation test, urinalysis and culture, and thyroid function tests are shown in Tables 1–4. Severe hyperglycaemia, fasting hypertriglyceridaemia and hypercholesterolaemia were present. Alkaline phosphatase was elevated moderately and alanine amino transaminase, gamma-glutamyl transpeptidase, protein and creatinine concentrations were mildly increased. The bile acid stimulation test results were within the reference interval, suggesting appropriate liver function. Haematological abnormalities included leucocytosis with mature neutrophilia, thrombocytosis and mild normocytic hyperchromic anaemia. Circulating total thyroxine (T4), free T4 (by equilibrium dialysis) and free triiodothyronine (T3) concentrations were below, and canine thyroidstimulating hormone (cTSH) above the respective reference limits of the diagnostic laboratory (Diagnostic Center of Population and Animal Health, Michigan State University, MI, USA). Urinalysis revealed marked glucosuria, proteinuria and amorphous phosphate crystals. Radiography of the pelvis showed mild incongruence of the coxofemoral joints. Faecal parasitology showed no evidence of Ancylostoma spp. as a potential cause of the interdigital dermatitis. Based on the initial laboratory test results, both DM and hypothyroidism were diagnosed and their combination could explain the exercise intolerance, changes in the hair coat, skin and footpads and the PUPD. Recent steroid administration may have contributed to the PUPD and
2
Australian Veterinary Journal Volume ••, No ••, •• 2014
Table 1. Haematology results for a 4-year-old Samoyed dog with exercise intolerance and polyuria/polydipsia of 12- and 2-months duration, respectively
Parameter Hct Hb RBC MCHC MCV Platelets WBC NeutM Lymphocytes Monocytes Eosinophils Basophils
Day 0
Day 141
Units
Reference range
0.31 154 4.57 490 68.80 788.0 28.31 22.36 2.83 2.26 0 0
0.46 161 7.58 349 60.90 326.0 13.41 9.97 2.3 0.49 0.61 0.02
L/L g/L ×1012/L g/L fL ×109/L ×109/L ×109/L ×109/L ×109/L ×109/L ×109/L
0.37–0.55 120–180 5.5–8.5 310–362 60–77 150–500 6–17 3–11.5 1–3.6 0–1.35 0–1.47 0–0.1
Hct, haematocrit; Hb, haemoglobin; RBC, red blood cells; MCHC, mean corpuscular haemoglobin concentration; MCV, mean cell volume; WBC, white blood cells; NeutM, mature neutrophils. Bold values are abnormal.
clinicopathological abnormalities such as the increased alkaline phosphatase concentration, thrombocytosis, neutrophilia and proteinuria. Superficial necrolytic dermatitis, zinc-responsive dermatitis and systemic lupus erythematosus could not be completely excluded as potential causes of the pedal hyperkeratosis and other dermatological changes. It was decided to postpone tests to investigate these disorders21–23 until stabilisation of the DM and hypothyroidism could be achieved. Progression of dermatological changes was monitored during that time. Before treatment for DM and hypothyroidism was initiated, further tests were performed to detect potential causes of the increased interdental spacing and inspiratory stridor, and to investigate a potential link between hypothyroidism and DM. These tests included upper airway examination, assessment of pretreatment serum insulin concentration and measurement of insulin-like growth factor-1 (IGF-1)
© 2014 Australian Veterinary Association
Table 2. Serum biochemistry results for a 4-year-old Samoyed dog with exercise intolerance and polyuria/polydipsia of 12- and 2-months duration, respectively
Table 3. Urinalysis results for a 4-year-old Samoyed dog with exercise intolerance and polyuria/polydipsia of 12- and 2-months duration, respectively
Parameter
Parameter
Day 0
Day 141
Units
Reference range
Protein 79.0 Albumin 36.1 Urea 6.9 Creatinine 123 ALT 106 GLDH 13 ALP 971 GGT 8 CK 28 Lipase 57 Amylase 382 Glucose 26.9 Cholesterol 25.4 Bilirubin 6.5 iPhosphorus 1.51 Calcium 2.83 Sodium 144.2 Potassium 4.5 Chloride 101.1 Triglycerides 25 Preprandial bile acids 2.6 Postprandial bile acids 27.1
70.9 35.3 4.8 122 59 1 254 2 25 14 849 3.9 4.5 5.0 1.08 2.62 151.6 3.86 115.4 1.34 NP NP
g/L g/L mmol/L μmol/L IU/L IU/L IU/L IU/L IU/L IU/L IU/L mmol/L mmol/L μmol/L mmol/L mmol/L mmol/L mmol/L mmol/L nmol/L μmol/L μmol/L
54–71 31–40 3.6–8.6 20–120 0–20 0–10 0–50 0–40 0–50 0–130 0–730 3–6.5 3.2–6.5 0.9–10 0.8–1.8 2.3–3 137–151 3.7–5.8 99–110 0.11–1.69
