Nutritional Secondary Hyperparathyroidism Case Challenge Discussion

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Introduction

Husbandry-related conditions are very common in reptiles, and nutritional secondary hyperparathyroidism (NSHPT) is frequently encountered by exotic animal veterinarians. Nutritional secondary hyperparathyroidism is often called metabolic bone disease (MBD), however MBD not only refers to NSHPT but several conditions that affect the integrity and function of bones, including renal secondary hyperparathyroidism, hypertrophic osteopathy, osteomyelitis, osteitis deformans, and diffuse osteomalacia among others.2,7,11 Most affected reptiles present to a veterinarian late in the disease process due to owner inexperience, reptile stoicism, and the slow progression of the disorder.7 Thus, prognosis is often guarded and prevention is key for this condition.

 

Pathogenesis

Metabolic bone disease generally results from abnormal physiological levels and/or function of minerals (calcium, phosphorus, magnesium), or vitamin D and parathyroid hormone (PTH).3  Nutritional secondary hyperparathyroidism occurs following inappropriate dietary or husbandry management, leading to deficits in plasma calcium levels that physiologically stimulate the parathyroid glands to produce PTH. Parathyroid hormone induces bone resorption to correct the plasma calcium concentration, leading to bone demineralization and decreased bone density (Table 1). Eventually, when  bones are depleted of their calcium stores and if the initial causes of calcium depletion are not corrected, clinical hypocalcemia can develop.2,3,7,11

Common causes of NHSPT include inadequate dietary calcium, poor calcium:phosphorus ratio in the diet, inadequate oral cholecalciferol, inadequate exposure to UV light, and inappropriate temperature or humidity. Stress is also mentioned as a potential factor for lizards housed in the same cage or in close proximity.7 In an experimental study of juvenile veiled chameleons (Chamaeleo calyptratus), NSHPT developed in all individuals that did not receive dietary supplementation of calcium, vitamin A, or cholecalciferol, even if UVB where provided. Provision of calcium and vitamin A supplements was sufficient to prevent development of the disorder, suggesting a connection between NSHPT and low dietary vitamin A as previously suspected in growing panther chameleons (Furcifer pardalis).5

Reptiles that are primarily nocturnal and that consume whole vertebrate prey, such as snakes or crocodilians, generally obtain cholecalciferol completely from their diet. However, diurnal and/or herbivorous or insectivorous reptiles need UV light to activate the cholecalciferol pathway. In the skin, provitamin D3 (7-dehydrocholesterol) is converted to previtamin D3 in response to UVB (280-315 nm wavelength) and UVA (315-400 nm wavelength) exposure. Previtamin D3 is then thermochemically isomerized to cholecalciferol in the skin, and this reaction’s rate is dependent on heat. Cholecalciferol is not the biologically active form of vitamin D. Cholecalciferol is hydroxylated in the liver to calcidiol (23-hydroxycholecalciferol), which is then hydroxylated in the kidneys to obtain calcitriol (1,25-dihydroxycholecalciferol, the biologically active form). This last conversion can be affected by calcium and phosphorus levels, and is stimulated by PTH.7

Calcium homeostasis is regulated by three hormones:  calcitriol (vitamin D3), PTH, and calcitonin. The effects and the regulation of these hormones is summarized in Table 1. This table also summarizes the different way these hormones act on bones, kidneys, and the gastrointestinal tract to maintain calcium and phosphorus plasma levels within physiological ranges.

Table 1. Regulation, production and effects of hormones involved in calcium (and phosphorus) homeostasis 3,7
HormonePTHCalcitriol (vitamin D)Calcitonin
Effect on plasma levels↑ Ca ↓ P↑ Ca and P↓ Ca and P
Actions↑ bone release of Ca (demineralization)

↑ renal hydroxylation of vitamin D
↑ bone release of Ca (demineralization)

↑ Ca reabsorption and P secretion in kidneys

↑ intestinal absorption of Ca and P
↓ bone demineralization
↑ osteoblast bone formation

↓ kidney Ca reabsorption
↑ urinary P excretion
Factors stimulating production/release↓ Ca
↑ P
PTH
Heat
↑ Ca
Factors decreasing production/release↑ Ca
Calcitriol
Calcitonin
↑ P
Lack of UV or cholecalciferol intake
Renal failure
Site of productionParathyroid glandsKidneys (but pathway involves liver and skin)Ultimobranchial bodies
(C cells of thyroid gland)
PTH: parathyroid hormone ↑: increase ↓: decrease Ca: calcium P: phosphorus UV: ultraviolet

 

History

Signalment

Reptile patients presenting with nutritional secondary hyperparathyroidism are typically juveniles. Calcium is particularly critical for bone development, making young, growing reptiles more susceptible to disease.7 Species that are most commonly affected are herbivorous or insectivorous, diurnal lizards and chelonians, such as green iguanas (Iguana iguana), bearded dragons (Pogona vitticeps), chameleons, such as panther chameleons (Furcifer pardalis) or veiled chameleons (Chamaeleo calyptratus), or Mediterranean tortoises, such as Testudo hermanni, T. graeca, and T. marginata. But some more carnivorous species, such as red-eared sliders (Trachemys scripta) or other semi-aquatic turtles, are also commonly presented with this condition. Species that feed on whole vertebrate preys (i.e. snakes, crocodilians) are rarely affected.

Presenting complaint

Usually, progressive changes have been noted by owners for several weeks, if not months, before presentation. Anorexia, lethargy, lameness or reluctance to move, external deformities, and constipation are commonly reported.2,3,7 In severe cases with clinical hypocalcemia, the chief complaint can be tremors or even seizures.7

Diet

A complete dietary history is essential and there are some common mistakes that can be very suggestive of NSHPT.

  • For herbivorous species, owners may be offering few to none leafy greens (or a very low variety) or might be providing a fruit-based diet.
  • For insectivores, a commonly encountered error is the absence of gut-loading of insects.
  • For both herbivores and insectivores, calcium supplementation in the form of dusting may also be absent or insufficient, as well as multivitamin (and more specifically vitamin D) supplements that may have been discontinued for several months.
  • For carnivores, NSHPT is most commonly observed when feeding exclusively newborn whole prey, such as 1-day old chicks or newborn mice, as these generally contain lower stores of calcium and vitamin D when compared to their adult forms.

Housing

Husbandry must also be thoroughly questioned. Ultraviolet light sources may be absent, inadequately placed (location in the enclosure is an essential information) or too old. The type of UVB lamp may also be inappropriate for the species. Temperature and humidity must also be questioned, as inappropriate levels may contribute to the development of this condition.7

 

Examination findings

Clinical signs of NSHPT are often variable and non-specific, however there are some findings that can be suggestive of the condition.

Hands-off examination

Abnormalities commonly include:2,3,7,9

  • Inability to fully the lift the body of the ground (absence of carpal lift)
  • Reluctance to move
  • Paresis to paralysis of the pelvic limbs or tail
  • Lameness
  • Vertebral column deformity (kyphosis, lordosis, scoliosis)
  • Facial deformities with typically thickening of the mandible
  • Cloacal or rectal prolapse
  • Stunted growth
  • Intention tremors of the extremities or tongue
  • In chameleons, discoloration and casque deformation 5

In cases of clinical hypocalcemia, neurological signs develop, commonly characterized by tremors, seizures, or tetany.7,10 Coma or death are also possible.

Physical examination

Clinical findings may include:2,3,7,9

  • “Rubber jaw” or a soft and swollen mandible due to demineralization of the bones is a typical finding in lizards. Thickening and swelling can also occur in late stages due to fibrous osteodystrophy, which is caused by replacement of resorbed bone by connective tissue. Cheilitis, gingivitis, or stomatitis can also be observed secondary to this deformity.
  • Fractures of long bones (limbs)
  • Bloating
  • Abdominal masses:  Dystocia can occur secondary to malunion of pelvic fractures or  hypocalcemia. Follicular or pre-ovulatory stasis or constipation can also be observed.
  • Inability to retract the tongue in chameleons

In chelonians, deformities of the shell, sometimes with disproportion of the shell and body are common. The shell is typically soft and pliable on palpation, often with secondary areas of abscessation or ‘shell rot’.

 

Diagnosis

History and clinical signs are often very suggestive of the condition, however, other diseases and concurrent issues still need to be ruled out. Besides, secondary opportunistic conditions, such as infections can occur and may be investigated. Plasma biochemistry and radiography are the most useful diagnostic tools.

Radiography

Radiography is useful to evaluate bone density and the extent of pathological fractures and potential malunion or deformities, especially for the pelvis and vertebra.7,9  Osteopenia (or low bone density) is often generalized and is characterized by an increased radiolucency of bone.  Fibrous osteodystrophy may manifest as soft tissue swellings around the limbs or mandible, associated with lack of cortical bone density.6  It is important to remember that radiography only detects 30% or greater changes in bone density so early disease might not be radiographically detectable.7 Radiography is also a valuable tool to detect constipation or bloating, dystocia, follicular stasis or other disorders occurring secondary to low calcium levels.

Blood tests

Plasma biochemistry is useful to assess calcium and phosphorus levels. The normal plasma calcium level for most reptiles ranges between 8 and 11 mg/dL (2.0-2.7 mmol/L) but this varies with species and physiological status so species-specific reference ranges should be used when available.4

Ideally, ionized calcium should be used, although reference ranges have not been studied in many species so total calcium is most commonly measured.7  Typically, results with NSHPT show low calcium levels, normal to elevated phosphorus levels,  and a calcium:phosphorus ratio less than 1.7  However, total blood calcium levels remain within reported reference ranges in many reptiles with NSHPT.9  Calcium and phosphorus levels may help differentiate NSHPT from renal secondary hyperparathyroidism (RSHPT), since phosphorus is elevated and calcium remains within normal range in most cases of RSHPT.7

Uric acid may be used to evaluate kidney function but this test has a low sensitivity as changes typically occur late in the evolution of kidney diseases. Renal failure can be a primary cause of MBD, but renal failure can also develop secondary to inappropriate husbandry (chronic dehydration) as a concurrent condition of NSHPT.7  Calcidiol levels have been reported for various species, but is rarely used in clinical settings.7

Complete blood count and a larger biochemistry panel might also be advised as a way to further evaluate concurrent issues and secondary conditions. Signs of inflammation or organ failure may be noted, and may guide treatment and help adjusting prognosis.7

Other diagnostic tests

Depending on clinical and diagnostic findings, additional diagnostics tests designed to assess concurrent conditions may be warranted. Diagnostic imaging, such as ultrasonography, tomodensitometry, or MRI, may be helpful for evaluation of kidneys and other viscera.1 Dual energy x-ray absorptiometry has been used by some authors to better quantify bone density but is not widely available and seems technically challenging.7,13

 

Differential diagnoses

The main differential for NSHPT is renal secondary hyperparathyroidism (RSHPT). This condition is observed in older animals, as it is the result of a slow decline in kidney function leading to the inability to selectively secrete excess phosphorus. Elevated plasma phosphorus levels causes a decrease in the conversion of calcidiol to calcitriol. Calcitriol thus does not exert its negative feedback on PTH production, inducing hyperparathyroidism. Other consequences of phosphorus retention include soft tissue calcifications, renal osteodystrophy, and hypocalcemia (usually late in the disease).7

Other diseases affecting the integrity and function of bones that may be included in the differential diagnosis list include:

  • Hypertrophic osteodystrophy has been reported only in lizards.7  Radiography shows extensive periosteal proliferation beginning in the distal long bones and progressing proximally. Pathogenesis is unknown.
  • Osteopetrosis has been seen by one author with radiographic findings of increased density of bones with eventually obliteration of the bone marrow cavity. The cause of this disease in unknown in reptiles (Reese 1986).12
  • Osteitis deformans or Paget’s disease results from repeated cycles of bone resorption and deposition. This condition is thought to be a progression of osteomyelitis to chronic osteoarthritis and spondylosis, and has mainly been described in snakes.7

 

Key points of case management

Correction of husbandry and dietary factors

The critical part of the management of NSHPT in reptiles is the correction of husbandry and dietary factors. Owners must understand this is where they should put the most effort. Client education should include in-depth recommendations regarding appropriate husbandry and diet for their reptile.7 Details regarding these recommendations are explored in the “Prevention” section below.

Management of hypocalcemia

In cases of acute, clinical hypocalcemia, with tremors, seizures, and/or tetany, intravenous (IV) calcium should be administered until signs resolves.7  If IV administration is not possible, some authors recommend up to 100 mg/kg calcium (10% calcium gluconate) by the intramuscular (IM) or intracoelomic (IC) route every 6 hours until signs of tetany cease, and then switching to oral calcium.2 Dilute calcium before injection and avoid repeated parenteral administration due to the risk of metastatic tissue calcification.9

In chronic cases, oral administration is recommended, although IM or subcutaneous (SC) administration might be used in cases where oral administration is not feasible.7 Doses of 20-50 mg/kg once daily are recommended by Mans and Braun.9

Oral vitamin D supplementation is generally recommended in the form of cholecalciferol, although gastrointestinal absorption capacity is unknown in most reptile species.7 Parenteral calcitriol administration is controversial and generally not recommended as toxicosis and metastatic calcifications have been reported.3,7

Stabilization and supportive care

Nutritional secondary hyperparathyroid patients often suffer from malnutrition and dehydration. It is very important to implement fluid therapy (IV, SC or IC) and/or regular bathing. Nutritional support is essential, and progressive re-feeding must be adapted to the patient’s specific diet (such as possible with EmerAid Critical Care diets) and to the duration of the anorexia. Pain management is also advised as MBD is very painful in mammalians, but specific recommendations have not been reported.7

Management and prevention of secondary conditions

Owing to demineralization, diseased reptiles have very fragile bones and careful handling is essential. Patients should be maintained in cage rest, and branches and other climbing structures should be removed. For arboreal species, such as chameleons, low branches with padding underneath can be used.

Pathological fractures heal quickly in general, but often with malunion. For limb fractures, splinting or cage rest are the best options. Surgical repair is generally not advised owing the anesthetic risks and the potential of iatrogenic fractures.7  For vertebral or pelvic fractures, cage rest and patience are required.

Other secondary conditions requiring specific management include constipation or gastrointestinal stasis, and secondary infections. For constipation, oral laxatives associated with enemas may be implemented. Prokinetics can be attempted if obstruction has been ruled out and the patient’s hydration status allows this. Antibiotic treatment is indicated if secondary infection is suspected.

 

Prognosis and long-term management

Prognosis is often guarded to poor. Owners must be aware of the difficulties associated with the management of NSHPT, including the frustration and emotional exhaustion as well as the significant financial costs of the long-term treatment required for this disease. Their reptile’s quality of life and the ethical aspects of pursuing treatment must be discussed with them prior to beginning.7

Euthanasia is common owing the poor prognosis and financial limitations, and should be offered if the reptile’s quality of life is not acceptable. Owners must also be aware that chronic sequelae may persist despite recovery of NSHPT, depending on the initial extent of fractures or fibrous osteodystrophy. Sequelae are extremely variable and include external deformities, mandibular malocclusion with secondary chronic gingivitis and ptyalism, chronic lameness, hindlimb paresis or paralysis, and pelvic deformities predisposing to dystocia.

Recovery generally takes 4 to 6 months with treatment. During this period, regular follow-ups are advised to ensure observance of proper treatment, to assess the patient’s recovery, and to adapt treatment as necessary. Monthly follow-ups may be a good starting point.

In cases refractory to initial treatment, administration of synthetic salmon calcitonin (SCT) can be considered. In chronic NSHPT, the parathyroid gland becomes hypertrophic and insensitive to the negative feedback exerted by increased plasma calcium level, leading to a continuous production of PTH despite normalization of plasma calcium level. Administration of calcitonin will decrease PTH production (negative feedback, see Table 1) and so accelerate significantly recovery. Synthetic salmon calcitonin has been used in green iguanas at 50 IU/kg IM once a week for 2 weeks (sometimes a third administration is needed).2,8  Lizards treated with SCT recovered in 4 to 6 weeks instead of 5 to 6 months without3, however SCT must be used with caution as it can cause life-threatening hypocalcemic tetany. Thus, plasma calcium level must be evaluated before implementing this treatment.2

 

Prevention

Given the pathogenesis of disease, adequate husbandry and diet are the best prevention of NSHPT and they are also key to its management. Providing adequate husbandry to reptiles requires knowledge of the specific needs of the species. Ultraviolet (UVB) exposure and temperature are the essential points of concern for NSHPT, however, humidity may also require attention. Chronic dehydration is common and so may act as a comorbidity and impair recovery, or even lead to chronic renal failure.

Ultraviolet light

As stated previously, UVB is needed for cholecalciferol production in the skin. Two mains sources of UVB light can be used: natural unfiltered sunlight and artificial lamps. Natural unfiltered sunlight remains the best source but exposure of reptiles to direct sun is not always possible, especially when local climates are significantly different from the natural climates of the reptile species and do not allow outdoor housing or even temporary exposure to sunlight. Besides, direct sunlight exposure carries some risks: overheating, UV burns and aggressive or evasive actions of the reptile.7 Owners should be aware of these risks and adapt the conditions of outdoor exposure (enclosure, shades, hides).

In most cases, artificial UVB lamps will be used in indoor enclosures. UV lamps must be placed 15 to 60 cm from the animal for maximum effect and need to be replaced every 6 to 12 months depending on the brand used.3 UVB emissions should ideally be measured using a UV meter to ensure adequate exposure.9 No glass nor plastic should stand between the lamps and the animal.3 For optimal exposure, varying UV exposure opportunities should be offered such as recommended for heat, as well as hiding places for the reptile to abstract from UV radiations or expose only certain parts of body.7 The type of artificial lamp and duration of exposure must also be adapted to the species. For instance, for diurnal arboreal lizards such as veiled chameleons (Chamaeleo calyptratus), moderate levels of UVB (5% UVB or 3-120 µW/cm²) are advised for 10-12 hours of daily exposure.5,7

Temperature

Although often overlooked, temperature plays a significant role in the cholecalciferol pathways (see Pathogenesis). The reptile requires a temperature gradient within a range of temperatures adapted to the species. For example, the temperature gradient recommended for veiled chameleons is 20-35°C (68-95°F). Heating lamps and mats are the most commonly used, and thermometers must be placed strategically in the enclosure to ensure temperatures remain within the adequate gradient. This is particularly important as house temperature changes occur due to seasonal variations: settings may need significant changes with seasons.7

Calcium supplementation

Supplementation of the diet with calcium of some sort is generally recommended, except for reptiles eating whole vertebrate prey. Calcium is most commonly offered in the form of calcium carbonate (e.g. Tums®, coral calcium, cuttlebone) dusted on preys or vegetables, but other forms may be used.7  Select supplements containing only calcium, and particularly avoid supplements with vitamin D or high phosphorus content (Ca:P ratio should be at least 2:1). Depending on the species and physiological state, dusting frequency is variable. In veiled chameleons, it is commonly recommended to dust calcium on prey once to twice weekly during adulthood, and once daily in juveniles. Preys should be dusted just before being fed to the reptile as insects will dust off most calcium powder within approximately 30 minutes.

Calcium:phosphorus ratio

In most species, the recommended Ca:P ratio is 2:1, however, invertebrates are naturally poor in calcium, and most have a Ca:P ratio around 1:6. Exceptions include snails, silkworms, pinhead-sized crickets, earthworms (Lumbricus terrestris) fed calcium-rich soils (Ca:P ratio above 1:1), and phoenix worms (although the latter has a low digestibility).7,9  Gut loading the invertebrate with diets enriched in calcium and/or dusting them with a calcium supplement before feeding, is required to increase their Ca:P ratio.7  In a study with juvenile veiled chameleons, gut-loading locust nymphs (Locusta migratoria) with a 12%-calcium diet was sufficient to prevent NSHPT, and the authors even suggested a lower dietary calcium could be advised (8-10%).5

Vertebrate prey have an adequate Ca:P ratio except for 1-day-old chickens and pinkie mice, which must not be considered adequate food for long-term feeding.7

For herbivores, the best Ca:P ratio is found in dark, leafy greens. Non-iceberg lettuces have a great Ca:P ratio, whereas most other vegetables have at best a 1:1 ratio (and many are inverted). Fruits have mostly inverted ratios except for berries that have a 1:1 ratio. Vegetables containing calcium oxalate, such as spinach, rhubarb, cabbage, peas, potatoes and beet greens,  should be avoided due to the capacity of oxalates to bind calcium and reduce its availability.7

Cholecalciferol

Cholecalciferol supplementation, usually in the form of a multivitamin supplement, is commonly advised once to twice a month in adult reptiles. In growing veiled chameleons, daily cholecalciferol supplementation dusted on insects was recommended by Hoby et al (2010) at a dose of 25,000 IU/kg.5

 

Summary

Nutritional secondary hyperparathyroidism can be caused by various factors related to inappropriate husbandry and/or diet. Clinical signs and history are in many cases enough to suspect the disease and implement treatment. Radiography and plasma calcium and phosphorus levels can be useful especially is assessing complications and differentiating from renal secondary hyperparathyroidism. Treatment mostly relies on correction of husbandry and dietary factors, associated with supportive care, management of secondary and concurrent conditions and calcium supplementation. Prognosis is generally guarded to poor and management often requires long-term financial and emotional investment. The welfare of the patient should be considered and euthanasia is recommended in some cases.

 

References