The principal endocrine dysfunction associated with complex regional pain syndrome (CRPS) evaluated in this 12-year longitudinal observational case study is hyperparathyroidism. The purpose of this study is to increase awareness of CRPS-induced hyperparathyroidism (HPT).
CRPS and Hyperparathyroidism
In general, endocrine dysfunction is not often discussed or evaluated in people with CRPS, and missed diagnoses increase when normocalcemic primary hyperparathyroidism (nPHPT) is present.
The pathophysiology of CRPS is complex and poorly understood. As a systemic disease, CRPS can affect any organ or body system, including endocrine function. The following case demonstrates the need for CRPS patients to be monitored for HPT, even in the presence of normocalcemia.
CRPS and Hyperparathyroidism Case Scenario
Background
This 12-year longitudinal observational case study, which ran from 2009 to 2021, describes the causal relationship between CRPS type 2 (presence of nerve damage), which was diagnosed six months after orthopedic foot surgery in 2016, and hyperparathyroidism, specifically normocalcemic primary hyperparathyroidism (nPHPT), which started 4 weeks post-surgery. (More on CRPS types below.)
The subject was an active 51-year-old white female and healthcare professional with an advanced college degree and no significant comorbidities at the time of the CRPS-inciting event. CRPS did not go into remission during this study. The strength of this case study is normal range parathyroid hormone (PTH) levels (22.1 pg/ml -74 pg/ml) 7 years prior to the CRPS-inciting event (ie, orthopedic foot surgery), elevated PTH levels starting 1 month after the event, and consistently elevated PTH levels for 4 years until the removal of two enlarged hyperplastic parathyroid glands.
Blood Tests and Imaging
In this case, the severity of HPT symptoms occurred when the PTH level was 150 pg/ml, which was one of the deciding factors in proceeding with parathyroid surgery. PTH levels remained elevated until parathyroid surgery in 2020. Calcium levels remained consistent at 9.1-9.9 mg/dl (normal range 8.5-10.7 mg/dl) between 2009 and 2021 with normal vitamin D, phosphorus, and creatinine levels. Ionized calcium level was 1.32 mmol/L (normal range 1.12-1.32 mmol/L) in 2020, which confirmed nPHPT diagnosis.
Sestamibi scans and neck ultrasounds in 2019 and 2020 were negative for parathyroid adenomas, and a 4-D CT scan of the neck in 2020 showed possible parathyroid adenoma versus hyperplasia.
Initial Treatment and Response
Two hyperplastic parathyroid glands were removed utilizing a radio-guided intra-operative gamma probe (IoGP), resulting in a normal PTH level of 15.5 pg/ml (normal range 12 pg/ml -88 pg/ml) in the post anesthesia care unit. Severe HPT symptoms, specifically severe bone pain and nocturnal polyurea, resolved 6 weeks after parathyroid surgery.
One year postoperatively and despite CRPS not in remission, PTH levels remained nominal between 72.3 pg/ml and116 pg/ml (normal range 8.5 pg/ml to 72.5 pg/ml) with no return of severe HPT symptoms. In sum, parathyroid surgery was successful and drastically improved severe HPT symptoms and quality of life.
CRPS Overview
The FDA officially named CRPS a “disease” in 2014.¹ Hooshmand & Phillips, Schwartzman, and others classify CRPS (types 1 and 2) as a systemic “disease” that “can affect any organ or system.”²˒³ Figure 1 illustrates the treating CRPS specialties in this case, and the importance of a multi-disciplinary approach in treating the disease due to its complex, systemic pathophysiological mechanisms.
CRPS Symptoms
CRPS symptoms can occur immediately to several weeks after an injury and can result in various treatment options.⁴⁻⁶ CRPS is predominantly neuropathic and a partly musculoskeletal pain disorder affecting the somatosensory nervous system and is associated with central sensitization, endocrine dysfunction, autonomic disturbances, alterations in bone metabolism and remodeling, and bone pain.¹˒²˒⁵⁻¹¹
CRPS Types
CRPS is classified into two types:¹˒ ¹²⁻¹⁵
CRPS type 1 (absence of nerve injury), which is the more common form (50% to 60%), formerly known as Reflex Sympathetic Dystrophy (RSD)
CRPS type 2 (presence of nerve injury), formerly known as causalgia
CRPS Symptoms and Progression
Variations in CRPS symptoms can occur immediately to several weeks or years after injury. CRPS is potentially a disabling and often chronic condition, and consists of various treatments.⁴˒⁵ Although 90% of CRPS cases have an inciting event, no precipitating factors can be found in 10% to 26% of CRPS cases and 50% have spontaneous recurrence.¹⁴Children are more likely to respond to CRPS treatment and go into remission.
CRPS is incurable and chronic. Individuals may experience “remission,” disease spread to other extremities (ie, contiguous, diagonal, ipsilateral, contralateral/mirror, or independent), spread to any organ system with no or minimal inciting event, and/or result in permanent or temporary systemic complications.²˒³˒¹⁴˒¹⁶
CRPS Treatment Approaches
The International Association for the Study of Pain (IASP) developed the Budapest Criteria as a standardized diagnostic tool for CRPS to decrease misdiagnosis and not delay CRPS treatment.¹˒⁵˒¹¹˒¹⁵˒¹⁷˒¹⁸
CRPS may not respond positively to multimodal, multidisciplinary treatments resulting in decreased CRPS remission rates and moderate, long-term, and debilitating consequences.⁵˒¹¹The physiological response mechanisms in CRPS and its systemic complications are consistent in both CRPS types, and both types are treated the same clinically; however, CRPS type 2 has poorer remission rates.
In sum, CRPS is a complex disease that affects visceral and internal organs and any or all body systems, which contributes to the complexities in managing the disease and increases morbidity and mortality.¹⁷
CRPS and Hormone Dysfunction
Hormones play diverse roles in pain syndromes and pain management; thus, endocrine dysfunction is a common component and area of focus in chronic pain syndromes, such as CRPS.¹⁰˒¹⁹˒²⁰ A connection between CRPS and other pain syndromes with PHPT has been established. Russo et al describe the pathophysiological disease processes in CRPS as immediate local tissue damage and inflammation, pain processing dysregulation at two weeks after CRPS-inciting event, autonomic and endocrine dysregulation at four weeks, and immune system dysfunction at six weeks, which all occurred in this case⁶ (see timeline of homeostatic disturbances in CRPS by Giannotti et al).
Russo et al also state, “these four components can vary in degree in terms of homeostatic disturbance and relative time course of activation.”⁶ However, in CRPS type 2, “local tissue damage” remains constant due to the presence of nerve damage, which also presumably lowers remission rates in type 2.
Tennant states, “Chronic pain patients who demonstrate hormone abnormalities tend to be those who have severe, chronic painful, neuropathic pain conditions.”²⁰ Bazika-Gerasch et al. found CRPS patients had the highest PTH levels (up to 166 pg/ml) with normocalcemia in all groups (nPHPT), which supports the finding in this case study.²¹CRPS patients develop a variety of endocrine disorders, which may include:¹⁷˒²²
parathyroid, thyroid, and hypothalamic-pituitary-adrenal-ovarian system disorders
abnormal vitamin D, estradiol, luteinizing hormone, follicle-stimulating hormone, cortisol, testosterone, norepinephrine, and epinephrine levels
Differentiating CRPS and HPT
CRPS and HPT have similar clinical presentation and may be comorbid conditions, which confounds diagnosis and treatment, increases missed diagnoses, and delays treatment resulting in decreased quality of life and increased mortality and morbidity.⁵˒²³˒²⁴
An incidental finding in this case was unexplained “subtherapeutic” estradiol levels after CRPS onset. In 2016, one month prior to the CRPS-inciting event, the estradiol level was 61 pg/ml. Estradiol levels were not monitored after CRPS in 2016 or in 2017 in order to ascertain timing of hypoestrogenism. In 2018 and 2019, estradiol levels were <10 and 22 pg/ml, respectively, despite current hormone replacement therapy (HRT) and did not respond to increased HRT. In 2020 and 2021, the estradiol levels inexplicably returned to “therapeutic levels” of 71 and 77 pg/ml, respectively, despite lower (pre-CRPS) doses of HRT.
These changes shows another potential type of endocrine dysfunction in CRPS, which further illustrates the complex pathophysiology of CRPS.
Overlapping Symptoms of CRPS and HPT
Symptoms and systemic complications of CRPS and HPT highlight the importance of early diagnosis and treatment of both diseases. Receptors for PTH are found in the bone, kidney, brain, heart, cartilages, and adrenal glands, which accounts for systemic, multi-organ complications. PTH is a neurotoxin, which also explains why neurocognitive and neuropsychiatric symptoms occur in HPT.²⁵ PTH and calcium levels do not necessarily correlate with the severity of symptoms or complications, including renal calculi, stroke, cancer, renal failure, and osteoporosis.²³˒²⁶
Systemic Complications
Systemic complications of CRPS, which greatly mimic HPT, include the following:
bone metabolism and microstructure, immune, and psychological/limbic system dysfunction; gastrointestinal, neurological, renal/urological, cardiac, and visual and hearing complications, including hormonal disorders (11%), hypothyroidism (33%), low serum cortisol levels (38%), fatigue (69%), and secondary hypoadrenalism, to name a few.²˒³˒⁵˒⁶˒⁸˒⁹˒¹¹˒¹⁵˒²⁷
Systemic complications from HPT range from bone metabolism, immune and psychological/limbic system dysfunction, and GI, neurological, renal/urological, cardiac, and visual and hearing complications, among others.¹⁹˒²³˒²⁷⁻³⁴
Discussion: Identifying Hyperparathyroidism in CRPS
In the presented case study, parathyroid hormone levels ranged from 22.1 to 74 pg/mlbetween 2009 and 2016, 7 years prior to the CRPS-inciting event, were elevated starting 1 month later, peaked at 150 pg/ml (normal range 8.5-72.5 pg/ml), and remained elevated until parathyroid surgery in 2020. Calcium levels remained consistent at 9.1 to 9.9 mg/dl (normal range is 8.5 to 10.7 mg/dl) between 2009 and 2021 with normal range vitamin D, phosphorus, and creatinine levels; and ionized calcium level was 1.32 mmol/L (normal range is 1.12 to 1.32 mmol/L) in 2020, which confirmed nPHPT diagnosis.
In sum, laboratory results from 2009 to 2020 show a distinct and significant increase in PTH levels after the CRPS-inciting event in 2016, with no correlation between calcium and vitamin D levels (see Figure 2).In addition, normal range N-teleopeptide and osteocalcin levels ruled out adynamic bone disease, and no correlation between laboratory levels (calcium, vitamin D, phosphorus, creatinine, and ionized calcium levels) from 2009 to 2021 and elevated PTH levels supported nPHPT diagnosis.²⁹˒³⁰˒³³˒³⁴˒³⁵˒³⁶
Secondary and tertiary HPT can be the result of vitamin D deficiency of <20 ng/ml (hypovitaminosis), chronic kidney disease stage 4 or higher, end stage renal disease (ESRD) on dialysis, medication use (e.g., Lithium), radiation to the neck, radiation exposure, or Familial HypocalciuricHypercalcemia (FHH), which were also ruled out in this case prior to nPHPT diagnosis and subsequent surgical treatment.²⁷˒²⁸˒²⁹˒³⁰˒³³
Sestamibi scans are often utilized as diagnostic tools and to determine surgical intervention in parathyroid and thyroid disease. In this case, Sestamibi scans in 2019 and 2020 were negative for parathyroid adenomas but showed a 2.5 cm left thyroid nodule; neck ultrasounds in 2019 and 2020 were also negative, but also showed a 2.5 cm left thyroid nodule; and a 4-D CT scan in 2020 revealed possible parathyroid adenoma versus hypertrophy.
Potential Causes of PHPT
The most common causes of PHPT are the following ²⁷⁻³³˒³⁷˒³⁸
single adenomas (80% to 90%), which has the highest cure rate;
double adenomas (2% to 5%)
solitary hyperplasia (15%)
multiple gland hyperplasia (6% to 43%)
hyperplasia on all four glands (4% to 15%)
parathyroid carcinoma (<1% to 5%)
Parathyroid hyperplasia in secondary HPT usually affects all four parathyroid glands and treatment is focused on the underlying cause. Hyperplasia in PHPT usually affects multiple (1-3) parathyroid glands and usually requires surgery depending on the severity of symptoms and the patient’s ability and willingness to have surgery.³⁰˒³⁸
Osteoporotic changes can occur in CRPS cases, as early as weeks to months, and in HPT patients. Dual-Energy X-ray Absorptiometry (DEXA) scans, the “gold standard” in assessing bone mineral density (BMD), are often utilized to support a CRPS diagnosis (performed in 2016) and to assess bone loss in HPT patients (performed in 2019).¹⁵˒²¹˒³⁵Systemic complications of HPT, including bone loss and cardiovascular disease, may be reversible when treated early, but may also progress when treated late or in cases of delayed surgery.²⁵ BMD improves in approximately half of nPHPT cases after successful, “curative” surgery; however this requires further study in cases of ongoing CRPS.³²
Case Treatment and Outcomes
Parathryroid Surgery
Parathyroid surgery, which has a cure rate of 93% to 100%, is indicated for the following PHPT cases:⁸˒²⁷⁻³¹
those who are asymptomatic (which is up to 80% of HPT patients)
have a reduction of > 30% in the glomerular filtration rate (GFR)
have severe bone demineralization
have calcium levels > 1 dl/ml above the upper limit of normal range
The four parathyroid glands are usually located behind the upper and lower poles of the thyroid gland and are responsible for maintaining calcium homeostasis via the release of PTH, a polypeptide hormone.³⁰˒³⁷ However, ectopic and supernumerary parathyroid glands can be found anywhere from the neck to the intrathoracic cavity, which contributes to the incidence of “unpredictable” surgical outcomes, and failed and/or repeat parathyroid surgeries.²⁷ Locations of missed parathyroid glands include the following areas: carotid sheath (4%), intrathyroidal (10%), paraesophageal (60%), and the thymus (25%).³⁹
In this case, minimally invasive parathyroidectomy utilizing a radio-guided intraoperative gamma probe (IoGP) found the right upper gland producing 96 pg/ml and the left upper gland producing 130 pg/ml of PTH (normal range 30 to 80 pg/ml). These enlarged hyperplastic glands were removed and an “incidental” removal of a 2.5 cm thyroid nodule was also performed. Utilizing a radio-guided IoGP versus “standard 3 ½ gland” parathyroid surgery decreases the risk of removing normal parathyroid glands and/or leaving abnormal glands, decreases the risk of missed ectopic glands, and thus increases surgical success rates and decreases failed or repeat surgeries, which have additional risks.
“Successful” parathyroid surgery is defined as achieving normal range PTH levels postoperatively. Parathyroid surgery in this case was successful with a normal PTH level of 15.5 pg/ml in the Post Anesthesia Care Unit (normal range 12 to 60 pg/ml). Surgical intervention improved severe HPT-related symptoms, specifically severe bone pain and nocturnal polyurea, within six weeks and continued to improve up to five months postoperatively. One year postoperatively and despite CRPS not in remission, PTH levels remain nominal between 72.3-116.1 pg/ml (normal range 8.5-72.5 pg/ml) with no return of severe HPT symptoms.
In sum, parathyroid surgery drastically improved severe HPT symptoms and quality of life. Parathyroid hormone levels remained elevated for four years after the CRPS-inciting event, returned to normal range after the removal of two hyperplastic parathyroid glands, and remained stable one year later.
Study Conclusion
The strength of this longitudinal observational case study from 2009 to 2021 is the normal range PTH levels 7 years prior to the CRPS-inciting event and elevated PTH levels one month later, which is supported by literature. In this case study, CRPS type 2 did not go into remission and PTH levels remained elevated for four years, until the removal of two hyperplastic parathyroid glands. Surgical intervention improved the severity and disability of HPT-related symptoms within six weeks and PTH levels remained stable one year later.
The purpose of this study is to increase awareness of CRPS-induced HPT, specifically nPHPT, since endocrine dysfunction is not often evaluated in CRPS patients. A limitation of CRPS-induced HPT studies is not only the lack of monitoring, but also reporting.
This limitation increases when nPHPT is present. The incidence of CRPS-induced endocrine dysfunction may be more prevalent than thought, which should lead to immediate changes in clinical practice. The connection between CRPS and endocrine dysfunction warrants further study to improve quality of life and decrease morbidity and mortality. Future studies are warranted to determine the incidence of CRPS-induced endocrine dysfunction, whether it is primary or secondary disease, whether it is an anomaly or a common comorbid condition, whether it resolves if CRPS goes into remission, and whether there is a difference between CRPS types.
Patient information and figures printed with permission; identifying details have been altered.