Hyperparathyroidism in Humans and Canines

Calcium makes up 1 to 2% of total body weight. Ninety-nine percent of that calcium is stored in the bones, whilst the remainder is found in the blood, muscles and other tissues. Maintenance of homeostatic levels of calcium in the blood is regulated by two counterregulatory hormones. Parathyroid hormone (PTH) and calcatonin which are released from the parathyroid gland and thyroid gland, respectively, maintain a blood calcium level of about 10mg/dL [Blaine, Chonchol et al. 2015]. Deviation from that amount has been noted in humans and canines and may be due to the presence of tumors on the endocrine glands, nutritional deficiencies, or chronic conditions such as kidney disease.

Anatomically and physiologically, humans and dogs have similar thyroid and parathyroid glands. The thyroid gland is a butterfly shaped gland, consisting of two lobes that are connected by an isthumus, found on the anterior surface of the trachea(Figure 1A). The parathyroid glands, are 4 small endocrine glands, that are found on the posterior side of the thyroid gland.

Microscopically, three features of the thyroid gland are visible; follicles, follicular cells, and parafollicular cells. The thyroid follicles consists of a spherical ring of follicular cells with an inner colloid, which contains precursor metabolites of thyroid hormone. The parafollicular cells(Figure 1B), which are located in the spaces between the follicles, secrete calcitonin. Parathyroid glands contains two groups of cells; chief cells and oxyphil cells. Chief cells synthesize and release the hormone calcitonin. There is no known function of oxyphil cells.

Blood calcium is essential for a variety of internal activities such as: nerve conduction, blood clotting, muscle contraction, and heart contraction.

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When deviating levels of calcium are detected in the blood, the thyroid gland and parathyroid gland release their respective hormone, which mitigate the changing levels of calcium via one of three ways; bone remodeling, direct effect on the kidneys or indirect effects in the gastrointestinal tract [Raggatt and Partridge 2010 ]. Bone remodeling is the continuous process in which bone is broken down, stored calcium is recycled, and new bone is formed. There are two types of cells responsible for this process: osteoclasts and osteoblasts . Osteoclasts secrete hydrogen ions which breaks down the matrix and subsequently releases the stored calcium [Raggatt and Partridge 2010]. The calcium is then either reabsorbed into the blood stream if hypocalcaemia is detected, or reabsorbed by osteoblasts [Raggatt and Partridge 2010]. If the latter occurs, then osteoblasts secrete new matrix and store that calcium back into the bone.

Approximately 20% of ingested calcium is exclusively absorbed in the small intestine by the duodenum, jejunum and ileum [Hu, Luo et al. 2013]. Vitamin D is a fat-soluble vitamin that can be synthesized by the skin or consumed in the diet. It is responsible for increasing intestinal absorption of calcium and other minerals, (Figure 2B) [Hu, Luo et al. 2013]. PTH indirectly influences the absorption of calcium into the blood stream by activating vitamin D. Vitamin D is biologically inactive(calcifediol), however it is enzymatically converted into an active form(calcitriol) in the liver, and subsequently released into plasma where it is carried by its respective binding protein [Hu, Luo et al. 2013]. More specifically, PTH increases the activity of the enzyme responsible for that conversion.

In addition to that, PTH is also responsible for the up-regulation of a calcium transporter onto the tubular epithelium of the nephron[Yuen, Ananthakrishan et al. 2016]. The bulk of calcium reabsorption into the bloodstream proceeds through a paracellular pathway [Yuen, Ananthakrishan et al. 2016]. Although much is known about the role of PTH, it’s counterregulatory hormone is often considered a ‘forgotten’ hormone despite being phylogenetically older and having similar functions [Felsenfeld and Levine 2015]. Calcitonin has shown to play an important role in preserving homeostatic calcium levels. Calcitonin lowers calcium levels in one of two ways. Calcitonin binds to its respective receptor and inhibits osteoclasts activity thus preventing the reabsorption of calcium into the bloodstream [Masi and Brandi 2007]. Calcitonin also enhances the excretion of excess calcium by inhibiting reabsorption of the mineral in the nephron [Masi and Brandi 2007]

Maintaining homeostatic levels of calcium in the blood is vital and if the body unable to do so, it may be due to an underlying condition such as hyperparathyroidism. Hyperparathyroidism is categorized as primary, secondary, or tertiary based on the underlying cause and has been found to be similar in humans and dogs [Mackenzie-Feder, Sirrs et al. 2011]. Although rare, the majority of primary hyperthyroidism cases are due the presence of single benign tumor, (parathyroid adenoma), and the remaining of the cases of hyperparathyroidism are due to the presence of multiple benign tumors [Mackenzie-Feder,Sirrs et al. 2011]. Side by side comparison of a healthy parathyroid gland and parathyroid adenoma is show in figures 3A-C.

Symptoms associated with this condition in canines include lack of appetite, vomiting, polyuria, polydipsia, and urinary incontinence [Schaefer., Goldstein 2009]. Physical examination of dogs with suspected hyperparathyroidism, show a small frame, bone deformities involving the mandible or maxilla, and generalized muscle atrophy [Verbruggh, Paepe., et all 2011]. Three treatment modalities are currently available for dogs; surgery, percutaneous ultrasonography-guided ethanol ablation(PUEA) and percutaneous ultrasonography-guided radiofrequency heat ablation (PURHA) [ Schaefer., Goldstein 2009]. If possible, only the abnormal parathyroid tissue is excised, but it is frequently necessary to remove all of the thyroid lobe. If all four parathyroid glands appear abnormal, one gland is often in left in situ to prevent hypocalcaemia and to maintain calcium homeostasis.

In the majority of patients, primary hyperparathyroidism results in the manifestation of symptoms such as a kidney stones, frequent urination, impaired memory, or abdominal pain. Other patients show no physical symptoms except for the presence of high levels of calcium in the blood. Diagnosis of primary hyperparathyroidism is based primarily upon blood and urine tests [Mackenzie-Feder, Sirrs et al. 2011]. A thorough evaluation and a variety of specialized tests are also performed to determine the cause of the condition [Mackenzie-Feder, Sirrs et al. 2011]. The preferred method of treatment for this condition is a parathyroidectomy, which is necessary to prevent the formation of kidney stones, maintenance of cardiovascular health and to decrease the risk of death. Surgical removal of a solitary adenoma has a 97% success rate.

Secondary hyperparathyroidism is due to events that indirectly increases the production of PTH by the parathyroid glands, such as chronic kidney disease or vitamin D deficiency. The kidneys are responsible for osmoregulation and excretion of wastes [Blantz,Deng et al. 2007]. A single kidney contains approximately 1 million nephrons, which are the basic structural and function unit of the kidney [Blantz, Deng et al. 2007]. At any given time, the glomerulus, a network of capillaries, filters out 20% of the plasma volume [Blantz, Deng et al. 2007]. The filtrate is composed of important molecules such as glucose, amino acids, and ions as well as wastes, such as urea and creatine [Blantz, Deng et al. 2007]. Ninety percent of that filtrate is subsequently reabsorbed along different sections of the Loop of Henle [Blantz, Deng et al. 2007 ]. The gradual loss of kidney function due to inability of the nephron to reabsorb vital substances is defined as chronic kidney disease(CDK) [Matovinović 2009]. Excess excretion of calcium due to CDK results in secondary hyperparathyroidism, and has been observed in canines and humans. Clinical signs of secondary hyperparathyroidism in canines is detected when radiographs are performed [Verbruggh, Paepe., et all 2011]. Bone demineralization occurs with progressive renal disease, in attempt to compensate for decreasing calcium serum [Raggatt and Partridge 2010]. Secondary hyperparathyroidism can also be a result of vitamin D deficiency due to an unbalanced diet [Verbruggh, Paepe., et all 2011]. A study from 2011, observed the physical and serum changes in an 8-year-old Briard canine following dietary changes. Within four months, the dog should clinical improvement and normalization of the parathyroid hormone concentration [Verbruggh, Paepe., et all 2011].

Due to the common occurrence of secondary hyperparathyroidism following kidney disease diagnosis, secondary hyperparathyroidism is frequently referred to as renal HPT [Pitt, Sippel et al. 2009 ]. Tertiary hyperparathyroidism is present in patients with prolonged secondary hyperparathyroidism, which eventually results in hyperplasia of the parathyroid gland [Kebebew., Duh, et al 2004]. The parathyroid glands progressively increases as the CKD worsens in humans. Tertiary hyperparathyroidism is not a diagnosis in canines. In humans, tertiary hyperparathyroidism is extremely uncommon, occurring in less than 80% of patients with secondary hyperparathyroidism, following a kidney transplantation [Kebebew., Duh, et al 2004].

Hyperparathyroidism is a relatively common endocrine disorder with a prevalence of one to seven cases per 1000 adults [Elaraj and Clark 2008 ]. It predominantly affects older adults, and prevalence of the condition increases with age [Elaraj and Clark 2008]. Like humans, hyperparathyroidism is usually diagnosed in older generations of canines [Elaraj and Clark 2008]. In both species, the condition may be due to the presence of a benign tumor, chronic kidney disease or nutritional deficiency. Canines serve as a model organism for future research due to the anatomical and physiological similarities between the two species [Kohart, et al 2017]. The parathyroid glands were the last structure to be discovered so little is known of the exact cause of the condition [Elaraj and Clark 2008]. Hyperparathyroidism occurs in females more often than males, so there may be an underlying genetic predisposition to the condition. However, it is unsure of because 80 to 85% if the cases of the condition are sporadic [Elaraj and Clark 2008 ].