\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Primary hyperparathyroidism in horses: What can we learn from human
medicine?}



\author[1]{Philip Johnson}%
\author[2]{Kile Townsend}%
\affil[1]{University of Missouri }%
\affil[2]{University of Missouri}%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Equine primary hyperparathyroidism is rare compared with the condition
in human medicine where it is often encountered and represents the most
common explanation for hypercalcemia in the outpatient setting. Primary
hyperparathyroidism results from a hyperfunctioning parathyroid gland
and surgical treatment (parathyroidectomy) is typically curative.
Successful surgical removal of a diseased parathyroid gland can be
challenging in horses as both normal and hyperfunctioning glands are
difficult to localize. Identification of surgical targets using
ultrasonography and/or Technetium-99m sestimibi scintigraphy are useful
for this purpose in both the human and equine contexts. However, these
localization approaches are not aways effective. Moreover, not all
patients are candidates for general anesthesia and surgery and the costs
associated with diagnostic localization and parathyroidectomy may be
prohibitive for some owners. This commentary presents information about
primary hyperparathyroidism in the event that it is not treated and
strives to review aspects of the disease when left untreated from the
human medical context.%
\end{abstract}%



\sloppy


\emph{Clinical Commentary}

\textbf{Primary hyperparathyroidism in horses: What can we learn from
human medicine?}

P. J. Johnson* and K. S. Townsend

Veterinary Health Center, University of Missouri, Columbia, Missouri,
USA

*Corresponding author email: johnsonpj@missouri.edu

The authors of the aforementioned article have described an innovative
and helpful method for the identification and surgical excision of an
abnormal parathyroid gland that was identified at the thoracic inlet
using a combination of pre- and intra-operative Technetium-99m sestimibi
scintigraphy but that could not be visualized with ultrasonography
(Connard et al., 2023). Whereas the clinical diagnosis of primary
hyperparathyroidism (PHPT) in horses is usually straightforward and
based on documentation of hypercalcemia, hypophosphatemia, and normal or
elevated serum PTH concentrations, the positive identification of the
location of an abnormal (hyperfunctioning) parathyroid gland can be very
challenging.

Confounding explanations for hypercalcemia that must be routinely
considered and ruled out in the human, but not equine, medical context
include pseudohypercalcemia and treatment with some pharmaceutical
agents. Fictitious total hypercalcemia (pseudohypercalcemia) may be
present when hyperalbuminemia is identified because approximately 45\%
of the calcium in the serum is bound to protein (usually albumin). If
hyperalbuminemia is present, the `true' calcium concentration is
determined using the following formula: corrected calcium = measured
calcium + (40 -- measured albumin \selectlanguage{ngerman}× 0.02) {[}units for calcium
concentrations: mmol/l; units for measured albumin concentration:
g/l{]}. A similar correction formula for horses has not been reported
and measurement of ionized calcium concentration in serum should allow
the diagnostician to rule out pseudohypercalcemia. Pseudohypercalcemia
may also occur in the presence of calcium-binding paraproteins and,
following blood collection, through release of intracellular calcium by
platelets in thrombocythemic states. Treatment with lithium may elevate
both circulating plasma parathyroid hormone and calcium concentrations.
Hypercalcemia may also result from treatment with thiazide diuretics
(such as hydrochlorothiazide), which enhance renal calcium reabsorption.
When applicable, reassessment of calcium and parathyroid hormone levels
should be undertaken at least three months following discontinuation of
these medications (Al-Azem and Khan 2011; Dandurand et al., 2021).

In human medicine, familial hypocalciuric hypercalcemia (FHH) must also
be considered in the differential diagnosis of hypercalcemia,
particularly in younger patients (\textless{}20 years of age); acquired
PHPT is more common in older human and equine individuals. Although not,
to our knowledge, described in horses, FHH is an inherited condition
(autosomal dominant transmission) in which the calcium-sensing receptor
is inactivated because of a gene mutation. Elevated levels of both serum
calcium and parathyroid hormone (or inappropriately normal parathyroid
hormone levels in the face of hypercalcemia) are also identified in FHH,
thus mimicking PHPT. The FHH mutation also affects the kidneys;
hypocalciuria results from increased renal tubular calcium resorption.
Diagnosis of FHH is additionally based on demonstration of a very low
urinary clearance ratio of calcium to creatinine and genetic studies.
Although it must be considered as an explanation for incidental
hypercalcemia in asymptomatic (human) patients, identified on routine
screening, FHH is an otherwise benign condition that does not require
surgical treatment (parathyroidectomy) (Al-Azem and Khan 2011; Carrala
et al., 2021).

It has been suggested that, when PHPT is identified in horses with
comorbid thyroid gland neoplasia, pheochromocytoma, and
pituitary\emph{pars intermedia} dysfunction, it may be similar to the
situation in human medicine in which PHPT is sometimes identified as a
component of multi-endocrine neoplasia (MEN) syndromes. Multiple
endocrine neoplasia is defined by simultaneous neoplasia and hyperplasia
of multiple endocrine tissues and has an inherited basis in humans (Hoff
et al., 2000; Miedlich et al., 2002; Bringhurst et al., 2008). In one
horse with PHPT the surgical removal of an abnormal parathyroid gland
failed to resolve hypercalcemia and elevated serum PTH levels. In that
case, it was suggested that there might have been other unidentified
parathyroid tumors, or that the horse was affected by a MEN-like
syndrome (Villagrán et al., 2014). A multi-endocrine neoplasia syndrome
has also been reported to (rarely) cause hypercalcemia in horses (De
Cock and MacLachlan 1999; Germann et al., 2006). Both normal and
abnormal parathyroid glands are difficult to locate in horses (including
at postmortem examination). Type 2a MEN (Sipple's syndrome),
characterized by the co-existence of medullary thyroid carcinoma,
hyperparathyroidism, and pheochromocytoma in the same individual, should
be considered with this finding in horses, even if an affected
parathyroid gland cannot be located (Luethy et al., 2016).

Similar to the situation in other domestic animal species, horses are
invested by two pairs of parathyroid glands; the anatomical location of
the caudal pair of glands is especially variable being located anywhere
along the length of the carotid arteries from the cranial cervical
region to the thymus (Wong et al., 2004; Tomlinson et al., 2014).
Technetium-99m sestimibi parathyroid scintigraphy is a nuclear medicine
procedure that is performed to localize parathyroid adenoma
(hyperfunctioning parathyroid glands absorb the radionuclide faster than
normal glands) (Gotway et al., 2002). As with the case described here,
overactive parathyroid glands can sometimes be identified using
sestimibi scanning; radionuclide uptake by abnormal parathyroid gland
cells correlates with the number and activity of their mitochondria.
Normal parathyroid glands in the same patient are not identified by
sestimibi uptake because they are inhibited through normal negative
feedback mechanisms. Sensitivity of sestimibi scanning for the purpose
of abnormal parathyroid gland localization has been improved in human
medicine through the introduction of single-photon emission computed
tomography (SPECT) (Neumann et al., 2008). Obviously, this technology is
not currently available in the equine diagnostic setting. Even using the
sophisticated imaging technology that is available to human medical
diagnosticians, false negative outcomes are reported for between 5-38\%
of human PHPT cases with sestimibi scanning. Numerous different factors
that are related to the absence of uptake in sestimibi scintigraphy in
PHPT patients have included young age, female gender, ectopic or upper
location, high body mass index, low oxyphilic cell content, small
adenoma size (\textless{}500 mg), patient motion, ectopy, number of
adenomata, and co-existence with nodular thyroid gland disease (Nichols
et al., 2008; Greenspan et al., 2012; Carrala et al, 2021).

Although the sensitivity of Tc-99m sestimibi nuclear medicine scans for
detecting parathyroid adenomas in horses is unknown, it has been
reported to be approximately 90\% in humans (Hillyar et al., 2022) and
17\% in dogs (Matwichuk et al., 2000). In addition to the report in this
issue (Connard et al., 2023), Tc-99m sestimibi scintigraphic scanning
has been reported to be effective in 13 of 16 (81\%) previously
published cases (Wong et al., 2004; Tomlinson et al., 2014; Cottle et
al., 2016; Gorenberg et al., 2020; Colmer et al., 2022).

Three quarters of human patients are asymptomatic and do not exhibit
symptoms that are explained by PHPT, the clinical course of which has
been described as being rather benign (Miedlich et al., 2002). In
contrast to the situation in equine medicine in which it is regarded as
rare, primary PHPT is a much more common endocrine condition in people,
affecting approximately 0.86\% of the USA population (Kahn et al., 2017;
Dandurand et al., 2021). It is the most common explanation for
hypercalcemia in the outpatient setting (Dandurand et al., 2021).
Hypercalcemia associated with PHPT results from the influence of
elevated circulating PTH levels causing increased renal tubular calcium
reabsorption, enhanced bone resorption through stimulated osteoclasis,
and increased renal 1,25(OH)\textsubscript{2}D\textsubscript{3}synthesis
(which stimulates both calcium and phosphate absorption in the
intestine) (Dandurand et al., 2021).

In the past, PHPT was recognized clinically when affected individuals
developed complications of osteopenia and bone fragility or evidence of
renal disease (Minisola et al., 2018). In more recent years, the
inclusion of plasma calcium concentration as a component of routine
health assessments in Western society has led to earlier recognition of
subclinical PHPT. Asymptomatic PHPT is commonly encountered in people
with mild disease and does not necessarily necessitate surgical
treatment. In these cases, the patients are monitored and treated
conservatively. Early clinical signs of PHPT in equine patients are
often very nonspecific and include lethargy, loss of bodily condition,
reduced appetite or anorexia, ill-defined, shifting lameness, and
stiffness (Tomlinson et al., 2014; Villagrán et al., 2014; Schwarz et
al., 2019; Darby et al., 2020; Gorenberg et al., 2020). A number of
considerations from the human medical context that may be relevant to
some of the signs seen in equine PHPT include the fact that bone pain is
described in people with high calcium concentrations (Miedlich et al.,
2002; Khosla 2014). Additionally people affected with hypercalcemia
commonly report depression, headache, fatigue, exhaustion, and cognitive
dysfunction (Miedlich et al., 2002; Shane and Irani 2006). Other
self-reported symptoms in the human context include weakness,
constipation forgetfulness, and lack of interest (Brown and Macleod
2001; Hall 2011).

There has been increasing recognition of the fact that mild/asymptomatic
PHPT in people may be present for many years before specific clinical
problems arise, affecting principally skeletal structures and the
kidneys. Hyperparathyroidism is often discovered incidentally because
most affected equids do not exhibit clinical signs over the course of
several years (Roussel and Thatcher 1987). If surgical treatment
(parathyroidectomy) is not undertaken (or unsuccessful), the clinical
course for (human) patients with mild or asymptomatic PHPT appears to be
quite stable. Circulating plasma calcium and parathyroid hormone levels
and bone density may remain stable for up to 10 years (Bilezikian et
al., 2009), following which time bone density may begin to decrease
(Al-Azem and Khan 2011). This observation is important to consider from
the equine perspective because PHPT may have been present in affected
horses for at least several years with absence of radiographic or
histopathological evidence of osteopenia (stimulated osteoclasis)
(Schwarz et al., 2019; Connard et al., 2023).

Human patients with asymptomatic mild primary hyperparathyroidism that
are not surgical candidates are monitored and treated with calcimimetic
agents when osteoporosis or declining bone mineral density are
identified (Dandurand et al., 2021). Moreover, pharmacological treatment
of PHPT is also advocated for the management of inherited (familial)
forms of hyperparathyroidism, following surgical failure, and for those
patients who refuse surgery.

Although (human) patients with mild asymptomatic PHPT may be medically
managed for some time without resort to parathyroidectomy, the onset of
renal dysfunction (with diminished glomerular filtration rates) and
osteoporosis (based on monitored densitometric criteria) will eventually
warrant consideration of parathyroidectomy because of the increased risk
of pathological (fragility) fracture. Poor bone mineral density (BMD),
as may arise in cases of PHPT is associated with elevated risk of
fracture. Therefore, the assessment of BMD is routinely undertaken for
human patients using, for example, dual energy X-ray absorptiometry
(DEXA). In addition to PHPT, other conditions that warrant DEXA scanning
in people include age (women after 65 years and men after 70 years of
age), eating disorders, employment of androgen deprivation treatments
for management of prostate cancer, long term glucocorticoid treatment,
and other bone conditions. Although assessment of BMD in horses is
somewhat in its infancy, there have been some post-mortem studies
(dissected bones) employing DEXA that have demonstrated correlation
between BMD and the force needed to break the third metacarpal \emph{in
vitro} (Junge et al., 2011; Tóth et al., 2014). Assessment of BMD has
also been reported for living horses using a radiographic bone aluminium
equivalence method (Nielsen et al., 2017; Maher et al., 2020).
Deprivation of osteoid from bones (osteopenia) as a result of
osteoclast-mediated bone resorption leads to bone fragility and
increased risk for fracture.

Historically, diagnosis of late stage PHPT was commonly based on the
identification of characteristic radiographic changes that include
salt-and-pepper skull appearance, distal clavicle tapering,
subperiosteal bone resorption, bone cysts and brown tumors (collectively
referred to as osteitis fibrosa cystica) (Dandurand et al., 2021).
Encounters with pathological fracture and osteitis fibrosa cystica are
now much less commonly reported in developed countries because earlier
diagnosis of PHPT is facilitated through routine blood testing during
annual medical examinations. Whereas clinical evidence of bone fragility
and radiographic osteopenia have been reported in some PHPT-affected
horses, these abnormalities are not evident in all cases. Results from a
15-year observational study that evaluated 57 human patients with
asymptomatic PHPT showed that worsening hypercalcemia did not occur
until year 13 and that other measured outcomes (including serum PTH
levels) were stable throughout (Rubin et al., 2008). Moreover, whereas
vertebral BMD remained unchanged there was significant bone loss in the
distal radius by year 8. These observations point to the fact that, in
many (human) cases, clinically important osteoid depletion occurs over a
long period of time and that progressive loss of BMD differs between
bones at different locations. Using DEXA scanning, it has been shown
that reduction in BMD is most evident in the radius (mostly cortical
bone) and much less evident in lumbar vertebrae (rich in trabecular
bone) (Syed and Khan 2000; Miller and Bilezikian 2002).

The extent to which PTH-induced loss of BMD affects different bones in
the equine condition has not been much explored and might be examined
prospectively when veterinarians encounter new PHPT cases in the future.
Of specific interest and reported more commonly in horses affected with
secondary hyperparathyroidism (SHPT) (from nutritional etiologies),
horses under the influence of elevated PTH may
develop\emph{osteodystrophia fibrosa} of the facial bones in addition to
osteopenia at other skeletal locations. In their recent retrospective
study of 17 PHPT-affected horses, Gorenberg et al (2019) reported that
skull and limb radiography (or both) was undertaken in 8 horses to
screen for bony changes. Abnormalities that were identified in those
cases included osteopenia of the limbs or skull (5 cases), dystrophic
mineralisation (2 cases), laminitic changes of unknown cause (1 case)
and focal loss of the lamina dura of the first molars (1 case).
Radiographic evidence of diminished BMD is insensitive in that it
requires at least 30\% loss (Toribio 2011). When successful, surgical
treatment of people affected with PHPT (parathyroidectomy) provides
skeletal protection and reverses the risk of pathological fractures
associated with increased bone fragility (Dandurand et al., 2021).

In the human condition, PHPT is also associated with the development of
kidney stones, nephrocalcinosis, and renal insufficiency (Dandurand et
al., 2021). Kidney stones are identified more frequently in asymptomatic
PHPT patients than in the unaffected population; stone formers are more
likely to be hypercalciuric than non-stone formers (Lila et al., 2012).
The risk of further stone formation is lowered following
parathyroidectomy but remains higher than that seen in the euparathyroid
population.

Even though PTH stimulates renal calcium resorption, the primary
determinant of the amount of calcium excreted into the urine per day is
the ionized calcium concentration in plasma. In PHPT, the daily quantity
of calcium excreted in the urine is increased in spite of high
circulating PTH levels, because hyperparathyroidism results in
hypercalcemia, thus increasing the urinary calcium concentration
(hypercalciuria). Nephroliths are often one of the first signs of PHPT
in people, especially when it is considered that hypercalciuria is
accompanied by enhanced urinary phosphate excretion (through the action
of increased PTH); calcium and phosphate concentrations in the tubular
fluid may exceed their solubility product and form precipitate as
calcium phosphate stones.

Renal functional impairment is also identified in approximately 17\% of
asymptomatic human PHPT patients and is associated with the severity and
duration of hypercalcemia (Tassone et al., 2015). When identified,
impaired renal function leads to recommendation for surgical
intervention. Parathyroidectomy prevents worsening renal dysfunction in
PHPT cases. Nephrocalcinosis is identified via CT in approximately 10\%
of asymptomatic PHPT patients. Risk factors for nephrocalcinosis have
not been identified in these PHPT cases and it does not respond to
parathyroidectomy.

Clinically evident renal complications of PHPT are not reported
(hitherto) in horses but acute kidney injury may arise following
parathyroidectomy (Gorenberg et al., 2020). The reason for postoperative
azotemia in these circumstances is unknown, but all of those patients
responded favorably to fluid therapy. Histopathological changes are
sometimes reported in the kidneys of PHPT-affected horses post-mortem
and have included deposition of calcium salts in the form of granules in
the lumen and lining of collecting tubules and in adjacent interstitial
tissue (Schwarz et al., 2019). Close attention to the kidneys and renal
function in horses affected with PHPT is clearly warranted.

Unless an abnormal hyperfunctioning parathyroid gland can be identified
and its location defined, surgical removal (parathyroidectomy) or
chemical ablation with ethanol may not be possible (Colmer et al.,
2022). Whereas surgical treatment (parathyroidectomy) is recommended and
curative for patients with both clinical disease and asymptomatic
disease in the absence of comorbidities, medical treatment can be
employed. Medical treatments are used in cases in which PHPT-affected
individuals are not suitable candidates for general anesthesia or
surgery, surgical treatment is declined, or for those cases in which
previous surgical treatment has failed. Medical treatment may be
explored further for equine PHPT patients because pre-operative
localization of an abnormal parathyroid gland (using sestimibi
scintigraphy and ultrasonography) may be unsuccessful, and the costs
associated with scintigraphy and surgical treatment may be prohibitive.

Medical management of PHPT was partially successful in only 2 of 7
equids in which it was attempted. (Gorenberg et al., 2020) Although
dietary restriction of calcium was undertaken in 5/7 cases in that
retrospective study, it should be noted that calcium restriction is not
recommended in human PHPT patients because it may drive further PTH
release and worsen bone resorption (Marcocci et al., 2014; Dandurand et
al., 2021). Whereas surgical treatment for PHPT in dogs is also often
recommended, the short-term management of severe hypercalcemia may
include administration of IV fluids (for diuresis), bisphosphonates and
glucocorticoids, especially if either or both azotemia or a high plasma
calcium-phosphorus product are identified (Schaefer and Goldstein 2009).

Bisphosphonates, acting through inhibition of osteoid degradation by
osteoclasts, are the most commonly prescribed group of drugs for the
treatment of osteoporosis in human medicine. These drugs are also used
for the medical management of human PHPT in nonsurgical cases. Modest
increases in BMD have been documented when bisphosphonates are used for
mild PHPT in people (Dandurand et al., 2021). Tiludronate was
administered to one horse with PHPT in which a mild but incomplete
improvement in hypercalcemia status was reported (Gorenberg et al.,
2020). In another report, tiludronate ameliorated clinical signs (but
not laboratory abnormalities) associated with nutritional secondary
hyperparathyroidism (Lacitignola et al., 2018).

The calcimimetic agent, cinacalcet, acts through allosteric activation
of calcium-sensing receptors at the surface of chief cells in the
parathyroid glands where it increases their sensitivity, reducing PTH
secretion and reducing plasma calcium levels (Kahn et al., 2015; Kahn et
al., 2017). Cinacalcet is primarily indicated for the management of SHPT
in people affected with chronic renal disease. It is also approved for
the management of PHPT in people for whom surgery is not indicated or
possible and in whom surgical treatment has not been successful.
Although cinacalcet treatment for PHPT leads to improvements in both PTH
and plasma calcium levels, it does not afford skeletal protection.
However, treatment using a combination of cinacalcet and a
bisphosphonate improves skeletal health. To our knowledge, treatment of
horses affected with hyperparathyroidism using cinacalcet has not been
reported at this time.

The authors noted that the diagnosis of PHPT had been appropriately
based on identification of hypercalcemia and an elevated serum PTH
level. Two other important explanations for hypercalcemia in the equine
species, chronic renal failure and hypercalcemia of malignancy, were
further ruled out based on normal plasma creatinine and thymidine
kinase-1 levels in blood, respectively. Paraneoplastic hypercalcemia has
been previously recognized in horses affected with lymphoma, multiple
myeloma, ameloblastoma, mesenchymal ovarian cancer, squamous cell
carcinoma, gastric carcinoma, and adrenocortical carcinoma (Barton et
al., 2004; Axiak and Johnson 2012). Demonstration of elevated levels of
circulating cancer biomarkers for the purpose of affirming or ruling out
presence of neoplasia would represent a helpful advance in cancer
diagnosis for all species (Tivey et al., 2020). It is unlikely that a
solitary, ideal biomarker will apply in all cases because the importance
of various biomarkers depends on the type of cancer. Moreover, the
extent to which cancer biomarkers have been investigated in horses is
very limited. Elevated levels of PTH-related peptide (PTH-rP) were
reported in one horse affected with multiple myeloma (Barton et al.,
2004). Although elevated serum thymidine kinase-1 (TK1) levels have been
proposed as useful diagnostic indicators of lymphoma in horses
(Larsdotter et al., 2015), later studies yielded conflicting results
(Moore et al., 2021; Wang et al., 2021). Although the authors concluded
that a paraneoplastic explanation for hypercalcemia could be ruled out
based on a normal TK1 level in their patient, caution in that regard is
recommended until better cancer biomarkers with improved positive and
negative predictive values have been evaluated and validated for both
equine and human medicine.

Although this commentary has been centered on the subject of PHPT, the
fact that horses also develop secondary hyperparathyroidism (SHPT)
should not be overlooked. The equine veterinary literature contains many
excellent and well-illustrated references to SHPT resulting from
historical and contemporary nutritional factors. For review of SHPT in
horses, readers are encouraged to review a recent paper in which SHPT
resulted from the ingestion of soursob weeds (Herbert and Dittmer 2017).
Whereas SHPT is most commonly recognized in the context of renal disease
in people, this phenomenon (renal SHPT) does not appear to occur in
horses. In almost all cases, equine SHPT can be traced back to the
ingestion of nutritional factors that interfere with the oral
bioavailability of calcium from the diet (excessive bran, dietary
feeding errors, plants that contain high levels of oxalate, etc).

\textbf{Authors' declaration of interests}

No conflicts of interest have been declared.

\textbf{Ethical animal research}

None.

\textbf{Source of funding}

None

\textbf{References}

Al-Azem, H. and Khan, A. (2011) Primary
hyperparathyroidism.\emph{C.M.A.J.} \textbf{183} , E685-689. doi:
10.1503/cmaj.090675.

Axiak, S. and Johnson, P.J. (2012) Paraneoplastic manifestations of
cancer in horses. \emph{Equine Vet. Educ. J} . \textbf{24} , 367-376.

Barton, M. H.; Sharma, P.; LeRoy, B. E.; Howerth, E. W. (2004)
Hypercalcemia and high serum parathyroid hormone-related protein
concentration in a horse with multiple myeloma.

Bilezikian, J.P., Khan, A.A. and Potts, J.T. (2009) Third International
Workshop on the management of asymptomatic primary hyperthyroidism:
guidelines for the management of asymptomatic primary
hyperparathyroidism: summary statement from the Third International
Workshop. \emph{Clin. Endocrinol. Metab} . \textbf{94} , 335--339.

Bringhurst, F.R., Demay, M.B. and Kronenberg, H.M. (2008) Hormones and
disorders of mineral metabolism. In: Kronenberg, H.M., Melmed, S.,
Polonsky, K.S. and Larsen, P.R. (eds) \emph{Williams Textbook of
Endocrinology} , 11th edn., Saunders, Philadelphia. pp 1203-1255.

Brown, E.M. and Macleod, R.J. (2001) Extracellular calcium sensing and
extracellular calcium signaling. \emph{Physiol. Rev} . \textbf{81} ,
239--297.

Carrala, F., Jiméneza, A.I., Toméa, M., Álvarezb, J., et al. (2021)
Factors associated with negative 99mTc-MIBI scanning in patients with
primary hyperparathyroidism. \emph{Rev. Esp. Med. Nucl. Imagen. Mol.
(Engl. Edn.)} \textbf{40} , 222-228.

Colmer, S.F., Wulster, K., Johnson, A.L., et al. (2022) Treatment of
primary hyperparathyroidism in a Miniature Horse using chemical ablation
of abnormal parathyroid tissue localized by 3\selectlanguage{english}-phase computed
tomography.\emph{J. Vet. Intern. Med} . \textbf{36} , 798--804.

Connard S., Hodge, E.A., Demchur, J.A., et al. (2023) Successful removal
of a functional parathyroid adenoma using a radioguided
parathyroidectomy technique with a hand-held gamma detector and
technetium Tc 99m sestimibi scintigraphy in a horse. \emph{Equine Vet.
Educ. J} . \textbf{XX} , ABC-XYZ.

Cottle, H.J., Hughes, K.J., Thompson, H., et al. (2016) Primary
hyperparathyroidism in a 17-year-old Arab x Welsh Cob pony mare with a
functional parathyroid adenoma. \emph{Equine Vet. Educ. J} . \textbf{28}
, 477-485.

Dandurand, K., Ali, D.S., and Khan, A.A. (2021) Primary
hyperparathyroidism: A narrative review of diagnosis and medical
management. \emph{J. Clin. Med} . \textbf{10} , 1604.
doi:10.3390/jcm10081604.

Darby, S., Porter, E., Beatty, S.S.K., Dark, M.J., et al. (2020) Primary
hyperparathyroidism in a Quarter Horse mare associated with a chief cell
adenoma. \emph{J. Equine Vet. Sci} . \textbf{95} , 103302. doi:
10.1016/j.jevs.2020.103302.

De Cock, H.E. and MacLachlan, N.J. (1999) Simultaneous occurrence of
multiple neoplasms and hyperplasias in the adrenal and thyroid gland of
the horse resembling multiple endocrine neoplasia syndrome: Case report
and retrospective identification of additional cases. \emph{Vet. Pathol}
. \textbf{36} , 633--636.

Germann, S.E., Rutten, M., Derungs, S.B. and Feige, K. (2006) Multiple
endocrine neoplasia-like syndrome in a horse. \emph{Vet. Rec}
.\textbf{159} , 530--532.

Gorenberg, E.B., Johnson, A.L., Magdesian, K.G., et al. (2020) Diagnosis
and treatment of confirmed and suspected primary hyperparathyroidism in
equids: 17 cases (1999-2016). \emph{Equine Vet. J} . \textbf{52} ,
83-90.

Gotway, M.B., Leung, J.W.T., Gooding, G.A., et al. (2002)
Hyperfunctioning parathyroid tissue: spectrum of appearances on
noninvasive imaging. \emph{A.J.R. Am. J. Roentgenol} . \textbf{179} ,
495--502.

Greenspan, B.S., Dillehay, G., Intenzo, C., et al. (2012) SNM practice
guideline for parathyroid scintigraphy 4.0. \emph{J. Nucl. Med. Technol}
. \textbf{40} , 111-118.

Hall, J.E. (2011) Parathyroid hormone, calcitonin, calcium and phosphate
metabolism, vitamin D, bone and teeth. In: Hall, J.E. (Ed) Guyton and
Hall Textbook of Medical Physiology (12\textsuperscript{th} edn.), W.B.
Saunders, Philadelphia, Pa, USA, pp. 955--972.

Herbert, E.W. and Dittmer, K.E. (2017) Acute and chronic oxalate
toxicity in miniature horses associated with soursob (\emph{Oxalis
pes-caprae} ) ingestion. \emph{Eq. Vet. Educ. J} . \textbf{29} ,
549-557.

Hillyar, C.R., Rizki, H., Begum, R., et al. (2022) A retrospective
cohort study of the utility of ultrasound, 99mTc-sestamibi scintigraphy,
and four-dimensional computed tomography for pre-operative localization
of parathyroid disease to facilitate minimally invasive
parathyroidectomy. \emph{Cureus} . \textbf{14} , e21177.

Hoff, A.O., Cote, G.J. and Gagel, R.F. (2000) Multiple endocrine
neoplasias. \emph{Annu. Rev. Physiol} . \textbf{62} , 377--411. \emph{J.
Am. Vet. Med. Assoc} . \textbf{225} , 409-413.

Junge, J., Martin-Rosset, W., Coenen, M., Vervuert, I. (2011) Assessment
of cannon bone mineral density by dual X-ray absorptiometry (DXA) in
horses? \emph{Pferdeheilkunde} 27, 642-647.

Khan, A., Bilezikian, J., Bone, H., Gurevich, A., et al. (2015)
Cinacalcet normalizes serum calcium in a double-blind randomized,
placebo-controlled study in patients with primary hyperparathyroidism
with contraindications to surgery. \emph{Eur. J. Endocrinol}
.\textbf{172} , 527-553.

Khan, A.A., Hanley, D.A., Rizzoli, R., Bollerslev, J., Young, J.,
Rejnmark, L., et al. (2017) Primary hyperparathyroidism: Review and
recommendations on evaluation, diagnosis, and management. A Canadian and
international consensus. \emph{Osteoporos. Int} . \textbf{28} , 1--19.
doi:10.1007/s00198-016-3716-2.

Khosla, S. (2014). Hypercalcemia and hypocalcemia. In: Kasper, D.,
Fauci, A., Hauser, S., Longo, D., Jameson, J.L. and Loscalzo, J. (Eds.)
Harrison's Principles of Internal Medicine, 19e. McGraw-Hill Education.

Lacitignola, L., De Luca, P., Santovito, R., di Comite, M.S. and
Crovace, A. (2018) Nutritional secondary hyperparathyroidism in two
ponies. \emph{Open Vet. J} . \textbf{8} , 149-153.

Larsdotter, S., Nostell, K., von Euler, H. (2015) Serum thymidine kinase
activity in clinically healthy and diseased horses: a potential marker
for lymphoma. \emph{Vet. J} . \textbf{205} , 313-316.

Lila, A.R., Sarathi, V., Jagtap, V., Bandgar, T., et al. (2012) Renal
manifestations of primary hyperparathyroidism. \emph{Indian J.
Endocrinol. Metab} . 16\textbf{,} 258--262.

Luethy, D., Habecker, P., Murphy, B. and Nolen\selectlanguage{english}-Walston, R. (2016)
Clinical and pathological features of pheochromocytoma in the horse: a
multi\selectlanguage{english}-center retrospective study of 37 cases (2007--2014) \emph{J. Vet.
Intern. Med} . \textbf{30} , 309--313.

Maher, K., Spooner, H., Hoffman, R., Haffner, J. (2020) The influence of
whole-body vibration on heart rate, stride length, and bone mineral
content in the mature exercising horse. \emph{Comparative Exercise
Physiology} \textbf{16} , 403-408.

Marcocci, C., Bollerslev, J., Khan, A.A. and Shoback, D.M. (2014)
Medical management of primary hyperparathyroidism: Proceedings of the
Fourth International Workshop on the Management of Asymptomatic Primary
Hyperparathyroidism. J\emph{. Clin. Endocrinol. Metabol} . \textbf{99} ,
3607-3618.

Matwichuk, C.L., Taylor, S.M., Daniel, G.B., et al. (2000) Double-phase
parathyroid scintigraphy in dogs using
technetium-99M-sestamibi.\emph{Vet. Radiol. Ultrasound} . \textbf{41} ,
461--469.

Miedlich, S., Koch, C.A. and Paschke, R. (2002) Primarer
Hyperparathyreoidismus Heute ein meist asymptomatisches
Krankheitsbild.\emph{Deutsches Arzteblatt-Koln} \textbf{99} , 2620-2624.

Miller, P.D. and Bilezikian, J.P. (2002) Bone densitometry in
asymptomatic primary hyperparathyroidism. \emph{J. Bone Miner. Res}
.\textbf{17} , 98--102.

Minisola, S., Gianotti, L., Bhadada, S. and Silverberg, S.J. (2018)
Classical complications of primary hyperparathyroidism. \emph{Best
Pract. Res} . \emph{Clin. Endocrinol. Metab} . \textbf{32} , 791--803.

Moore, C., Stefanovski, D. and Luethy, D. (2021) Clinical performance of
a commercially available thymidine kinase 1 assay for diagnosis of
lymphoma in 42 hospitalized horses (2017-2020). \emph{J. Vet. Intern.
Med} . \textbf{35} , 2495-2499.

Neumann, D.R., Obuchowski, N.A. and Difilippo, F.P. (2008) Preoperative
123I/99mTc-sestamibi subtraction SPECT and SPECT/CT in primary
hyperparathyroidism. \emph{J. Nucl. Med} . \textbf{49} , 2012-2017.

Nichols, K.J., Tomas, M.B., Tronco, G.G., et al. (2008) Optimizing the
accuracy of preoperative parathyroid lesion localization. \emph{Radiol}
.\textbf{248} , 221--232.

Nielsen, B. D., Eckert, S. M., Robison, C. I., Mills, J., et al. (2017)
Omeprazole and its impact on mineral absorption in horses. \emph{Animal
Production Science} \textbf{57} , 2263-2269.

Roussel, A.J. and Thatcher, C.D. (1987) Primary hyperparathyroidism in a
pony mare. \emph{Compend. Contin. Educ. Pract. Vet} . \textbf{9} ,
781--783.

Rubin, M.R., Bilezikian, J.P., McMahon, D.J., Jacobs, T., et al. (2008)
The natural history of primary hyperparathyroidism with or without
parathyroid surgery after 15 years. \emph{J. Clin. Endocrinol. Metab}
.\textbf{93} , 3462--3470.

Schaefer, C. and Goldstein, R.E. (2009) Canine primary
hyperparathyroidism. \emph{Compend. Contin. Educ. Vet} . \textbf{31} ,
382-389.

Schwarz, B., Klang, A. and Schwendenwein, I. (2019) Primary
hyperparathyroidism associated with atypical headshaking behavior in a
Warmblood gelding. \emph{J. Equine Vet. Sci} . \textbf{88} , 102840.
doi.org/10.1016/j.jevs.2019.102840.

Shane, E. and Irani, D. (2006) Hypercalcaemia: pathogenesis, clinical
manifestations, differential diagnosis and management. In: Favus, M.J.
(Ed.) \emph{Primer on the metabolic bone diseases and disorders of
mineral metabolism} . American Society for Bone and Mineral Research,
U.S.A., pp. 176-180.

Syed, Z. and Khan, A. (2000) Skeletal effects of primary
hyperparathyroidism. \emph{Endocr. Pract} . \textbf{6} , 385--388.

Tassone, F., Gianotti, L., Baffoni, C., Pellegrino, M., et al.
K.D.I.G.O. categories of glomerular filtration rate and parathyroid
hormone secretion in primary hyperparathyroidism. \emph{Endocr. Pract}
.\textbf{21} , 629--633.

Tivey, A., Church, M., Rothwell, D., Dive, C., Cook, N. (2022)
Circulating tumour DNA - looking beyond the blood. \emph{Nat. Rev. Clin.
Oncol} . \textbf{19} , 600-612.

Tomlinson, J.E., Johnson, A.L., Ross, M.W., et al. (2014) Successful
detection and removal of a functional parathyroid adenoma in a pony
using technetium Tc 99m sestamibi scintigraphy. \emph{J. Vet. Intern.
Med} . \textbf{28} , 687-692.

Toribio, R.E. (2011) Disorders of calcium and phosphate metabolism in
horses. \emph{Vet. Clin. N. Am. Equine Pract} . \textbf{27} , 129-147.

Toth, P., Hinton, G., Horvath, C., Ferencz, V., et al. (2014) Bone
mineral density and computer tomographic measurements in correlation
with failure strength of equine metacarpal bones. \emph{Acta Veterinaria
Brno} . \textbf{83} , 45-50.

Villagran, C.C., Frank, N., Schumacher, J. and Reel, D. (2014)
Persistent hypercalcemia and hyperparathyroidism in a horse. \emph{Case
Rep. Vet. Med} . \textbf{2014} , doi.org/10.1155/2014/465425.

Wang, L., Unger, L., Sharif, H., Eriksson, S., et al. (2021) Molecular
characterization of equine thymidine kinase 1 and preliminary evaluation
of its suitability as a serum biomarker for equine lymphoma. \emph{BMC
Mol. And Cell Biol} . \textbf{22} , 59
doi.org/10.1186/s12860-021-00399-x.

Wong, D., Sponseller, B., Miles, K., et al. (2004) Failure of technetium
Tc 99m sestamibi scanning to detect abnormal parathyroid tissue in a
horse and a mule with primary hyperparathyroidism. \emph{J. Vet. Intern.
Med} . \textbf{18} , 589--593.

\selectlanguage{english}
\FloatBarrier
\end{document}

