Hyperparathyroidism as a Differential Diagnosis for ME/CFS

The ME Association recommends checking serum calcium before an ME/CFS diagnosis because hyperparathyroidism causes fatigue, cognitive impairment, muscle weakness, thirst/polyuria, depression and other symptoms that overlap ME/CFS and fibromyalgia. The NICE guideline (NG206, recommendation 1.2.3) lists “calcium and phosphate” among the investigations to exclude other diagnoses when ME/CFS is suspected. The papers below document the symptom overlap, the risk of misdiagnosis in fibromyalgia cohorts, the reversibility of fatigue/cognitive symptoms after parathyroidectomy, and the diagnostic workup.

1 Costa et al. 2016 — High Frequency of Asymptomatic Hyperparathyroidism in Fibromyalgia

Full Citation:: Costa JM, Ranzolin A, da Costa Neto CA, Marques CDL, Duarte ALBP. High frequency of asymptomatic hyperparathyroidism in patients with fibromyalgia: random association or misdiagnosis? Revista Brasileira de Reumatologia. 2016;56(5):391–397. (Costa et al. 2016) DOI:: 10.1016/j.rbre.2016.03.008 PMID:: 27692388 Study Design:: Cross-sectional study Sample Size:: 100 women with fibromyalgia, 57 healthy women Key Findings::

- Hypercalcemic hyperparathyroidism diagnosed in 6% of fibromyalgia patients
- 17% showed isolated high PTH (normocalcemic hyperparathyroidism), frequencies higher than expected for age
- PTH significantly higher in FM (57.06 $\pm$ 68.98 pg/mL) vs controls (37.12 $\pm$ 19.02 pg/mL, $p$ = 0.001)
- No association between hyperparathyroidism and FM symptoms except epigastric pain ($p$ = 0.012)

Conclusion:: A high frequency of hyperparathyroidism is present in women with fibromyalgia; some of these may be misdiagnosed cases of hyperparathyroidism rather than fibromyalgia. (Raw certainty: 0.55, from fibromyalgia population → discounted to 0.44.) Limitations:: Small sample; single centre; cross-sectional so causality cannot be established; authors call for larger longitudinal studies.

2 Ferrari et al. 2015 — Prevalence of Primary Hyperparathyroidism in Fibromyalgia (Null Result)

Full Citation:: Ferrari R, Russell AS. Prevalence of primary hyperparathyroidism in a referred sample of fibromyalgia patients. Clinical Rheumatology. 2015;34(7):1279–1283. (Ferrari and Russell 2015) DOI:: 10.1007/s10067-014-2735-7 PMID:: 24985043 Study Design:: Cross-sectional prevalence study Sample Size:: 125 fibromyalgia, 127 widespread-pain, 138 localized-pain patients Key Findings::

- PHPT prevalence was 6.4% (FM), 5.5% (widespread pain), 6.1% (localized pain)
- No significant difference between groups or versus published general-population prevalence

Conclusion:: The prevalence of primary hyperparathyroidism in fibromyalgia is not different from that in the general population. (Raw certainty: 0.60, from fibromyalgia population → discounted to 0.48.) Limitations:: Referred (tertiary) sample; prevalence relative to general population inferred from published figures rather than a matched local control group.

3 Adkisson et al. 2014 — Fibromyalgia Symptoms Respond to Parathyroidectomy

Full Citation:: Adkisson CD, Yip L, Armstrong MJ, Stang MT, Carty SE, McCoy KL. Fibromyalgia symptoms and medication requirements respond to parathyroidectomy. Surgery. 2014;156(6):1614–1620. (Adkisson et al. 2014) DOI:: 10.1016/j.surg.2014.08.063 PMID:: 25456962 Study Design:: Retrospective cohort Sample Size:: 2184 sporadic primary hyperparathyroidism patients; 80 (4%) with prior fibromyalgia diagnosis Key Findings::

- 97.3% achieved cure (normocalcemia at $\geq$ 6 months)
- After parathyroidectomy, 89% had improvement in $\geq$ 1 FM-attributed symptom; improved cognition/memory most common (80%)
- Narcotics down in 77%, anti-inflammatories 74%, FM-specific medications 33%, antidepressants 30%; 21% discontinued all FM medications

Conclusion:: Fibromyalgia is common in patients operated on for sporadic PHPT; after parathyroidectomy most report symptom response. Providers should exclude PHPT before diagnosing FM because it is surgically correctable. (Raw certainty: 0.70, from fibromyalgia-comorbid population → discounted to 0.56.) Limitations:: Retrospective, single institution; FM diagnosis based on prior clinical history; no sham-surgery control for the placebo effect of surgery.

4 Borgia et al. 2012 — Hyperparathyroidism, a Forgotten Cause of Musculoskeletal Pain

Full Citation:: Borgia AR, Cavallasca JA, Costa CA, Musuruana JL. Hyperparathyroidism, a forgotten cause of musculoskeletal pain. Reumatologia Clinica. 2012;8(5):299–301. (Borgia et al. 2012) DOI:: 10.1016/j.reumae.2012.06.019 PMID:: 22658789 Study Design:: Case series / perspective Key Findings::

- Documents hyperparathyroidism as a frequently overlooked cause of musculoskeletal pain that can be mistaken for fibromyalgia or other rheumatic syndromes

Conclusion:: Hyperparathyroidism should be considered in the differential diagnosis of musculoskeletal pain and fatigue syndromes. (Raw certainty: 0.30, from fibromyalgia/musculoskeletal population → discounted to 0.24.) Limitations:: Case series; no abstract available on PubMed; limited generalizability; illustrative rather than systematic.

5 Mairinger et al. 2026 — Neuropsychiatric Manifestations of Primary Hyperparathyroidism

Full Citation:: Mairinger M, Godbersen GM, Kasper S. Neuropsychiatric manifestations of primary hyperparathyroidism. Wiener klinische Wochenschrift. 2026;138(7-8):232–240. (Mairinger, Godbersen, and Kasper 2026) DOI:: 10.1007/s00508-025-02688-3 PMID:: 41504896 Study Design:: Narrative review Key Findings::

- Neuropsychiatric manifestations occur in ~25% of patients with primary hyperparathyroidism
- Symptoms range from depression, anxiety, fatigue and cognitive dysfunction (common) to mania, delirium, psychosis (rare)
- Proposed multifactorial pathophysiology: elevated PTH and hypercalcemia affecting monoamine neurotransmission and neuroinflammation

Conclusion:: Fatigue and cognitive symptoms of PHPT overlap those of ME/CFS, supporting hyperparathyroidism as a differential to exclude in the pre-ME/CFS-diagnosis workup. (Raw certainty: 0.50, from general population → discounted to 0.38.) Limitations:: Narrative review; no systematic meta-analysis; pathophysiologic mechanisms partly speculative.

6 Koman et al. 2022 — Neuropsychiatric Comorbidity in Primary Hyperparathyroidism: Population Study

Full Citation:: Koman A, Bränström R, Pernow Y, Bränström R, Nilsson IL, Granath F. Neuropsychiatric comorbidity in primary hyperparathyroidism before and after parathyroidectomy: a population study. World Journal of Surgery. 2022;46(6):1420–1430. (Koman et al. 2022) DOI:: 10.1007/s00268-022-06485-1 PMID:: 35246714 Study Design:: Population case-control + prospective cohort Sample Size:: 8279 PHPT patients treated with parathyroidectomy vs 82,790 matched controls Key Findings::

- Pre-operatively, PHPT patients used significantly more antidepressants, anxiolytics and sleep medication (benzodiazepines OR 1.40, 95% CI 1.31--1.50; SSRIs OR 1.38, 95% CI 1.30--1.47)
- Postoperatively the excess anxiolytic benzodiazepine use fell (30% to 19%) and sleep benzodiazepines (31% to 14%); no decrease for SSRIs

Conclusion:: PHPT is associated with increased neuropsychiatric medication use; some psychiatric symptoms improve after parathyroidectomy. (Raw certainty: 0.70, from general population → discounted to 0.53.) Limitations:: Medication use as proxy for psychiatric comorbidity; register-based; does not directly assess fatigue or cognitive symptoms.

7 Oberger Marques & Moreira 2020 — Primary Hyperparathyroidism (Rheumatology Review)

Full Citation:: Oberger Marques JV, Moreira CA. Primary hyperparathyroidism. Best Practice & Research Clinical Rheumatology. 2020;34(3):101514. (Oberger Marques and Moreira 2020) DOI:: 10.1016/j.berh.2020.101514 PMID:: 32336576 Study Design:: Narrative review (rheumatology) Key Findings::

- PHPT causes hypercalcemia from PTH hypersecretion; mostly asymptomatic now (80--90%)
- Symptoms include bone pain, nephrolithiasis, muscle weakness; atypical manifestations are neuropsychiatric/cognitive, neuromuscular, rheumatological, gastrointestinal
- Diagnosis usually from routine calcium measurement showing high total calcium with high or inappropriately normal PTH

Conclusion:: PHPT causes fatigue, muscle weakness and rheumatological symptoms that overlap ME/CFS; diagnosis is typically from a routine serum calcium measurement. (Raw certainty: 0.50, from general population → discounted to 0.38.) Limitations:: Narrative review; no primary data; rheumatology-focused scope.

8 Wootton et al. 2026 — Primary Hyperparathyroidism in Adults: Diagnosis and Management

Full Citation:: Wootton E, De Sousa SMC, Prince RL, McLeod DSA, Pattison DA, Grossmann M. Primary hyperparathyroidism in adults: recent developments in diagnosis and management. Medical Journal of Australia. 2026;224(5):e70194. (Wootton et al. 2026) DOI:: 10.5694/mja2.70194 PMID:: 42132449 Study Design:: Narrative review Key Findings::

- PHPT prevalence ~1% in the general population
- Diagnosis requires biochemical testing of serum calcium and PTH plus urine calcium, and screening for complications including neuropsychiatric disturbance
- Up to 10% have hereditary PHPT; surgery is curative

Conclusion:: Provides the diagnostic workup basis for excluding hyperparathyroidism (serum calcium + PTH) in the pre-ME/CFS-diagnosis evaluation. (Raw certainty: 0.50, from general population → discounted to 0.38.) Limitations:: Narrative review; recent (2026) without long-term outcome data.

9 Liu et al. 2021 — Neuropsychologic Changes After Parathyroidectomy

Full Citation:: Liu JY, Peine BS, Mlaver E, Patel SG, Weber CJ, Saunders ND, Pofahl WE, Sharma J. Neuropsychologic changes in primary hyperparathyroidism after parathyroidectomy from a dual-institution prospective study. Surgery. 2021;169(1):114–119. (Liu et al. 2021) DOI:: 10.1016/j.surg.2020.06.006 PMID:: 32718801 Study Design:: Dual-institution prospective study Sample Size:: 244 parathyroidectomy patients vs 161 thyroidectomy controls Key Findings::

- Neuropsychiatric symptoms improved after parathyroidectomy (6.2 [5.0--7.4], $p < 0.01$)
- Moderate-severe depression fell from 27.5% to 8.2% and anxiety from 18.0% to 5.3% after surgery (both $p < 0.01$)
- Postoperatively no difference in neuropsychiatric symptoms between groups ($p$ = 0.59)

Conclusion:: Neuropsychiatric symptoms (including fatigue-related) improve after parathyroidectomy, supporting the argument that reversible PHPT symptoms can mimic ME/CFS. (Raw certainty: 0.70, from general population → discounted to 0.53.) Limitations:: No sham-surgery control; neuropsychiatric symptoms assessed by questionnaire; general surgical population not ME/CFS-specific.

References

Adkisson, Cameron D, Linwah Yip, Michaele J Armstrong, Michael T Stang, Sally E Carty, and Kelly L McCoy. 2014. “Fibromyalgia Symptoms and Medication Requirements Respond to Parathyroidectomy.” Surgery 156 (6): 1614–20. https://doi.org/10.1016/j.surg.2014.08.063.

Borgia, Ariel R, Javier A Cavallasca, Cecilia A Costa, and Jorge L Musuruana. 2012. “Hyperparathyroidism, a Forgotten Cause of Musculoskeletal Pain.” Reumatologia Clinica 8 (5): 299–301. https://doi.org/10.1016/j.reumae.2012.06.019.

Costa, Jose Mauricio, Aline Ranzolin, Carlos Alberto da Costa Neto, Claudia Diniz Lopes Marques, and Angela Luzia Branco Pinto Duarte. 2016. “High Frequency of Asymptomatic Hyperparathyroidism in Patients with Fibromyalgia: Random Association or Misdiagnosis?” Revista Brasileira de Reumatologia 56 (5): 391–97. https://doi.org/10.1016/j.rbre.2016.03.008.

Ferrari, Robert, and Anthony S Russell. 2015. “Prevalence of Primary Hyperparathyroidism in a Referred Sample of Fibromyalgia Patients.” Clinical Rheumatology 34 (7): 1279–83. https://doi.org/10.1007/s10067-014-2735-7.

Koman, A, R Bräström, Y Pernow, R Bräström, IL Nilsson, and F Granath. 2022. “Neuropsychiatric Comorbidity in Primary Hyperparathyroidism Before and After Parathyroidectomy: A Population Study.” World Journal of Surgery 46 (6): 1420–30. https://doi.org/10.1007/s00268-022-06485-1.

Liu, Jessica Y, Brandon S Peine, Eli Mlaver, Snehal G Patel, Collin J Weber, Neil D Saunders, Walter E Pofahl, and Jyotirmay Sharma. 2021. “Neuropsychologic Changes in Primary Hyperparathyroidism After Parathyroidectomy from a Dual-Institution Prospective Study.” Surgery 169 (1): 114–19. https://doi.org/10.1016/j.surg.2020.06.006.

Mairinger, M, GM Godbersen, and S Kasper. 2026. “Neuropsychiatric Manifestations of Primary Hyperparathyroidism.” Wiener Klinische Wochenschrift 138 (7-8): 232–40. https://doi.org/10.1007/s00508-025-02688-3.

Oberger Marques, Joao Vitor, and Carolina Aguiar Moreira. 2020. “Primary Hyperparathyroidism.” Best Practice & Research Clinical Rheumatology 34 (3): 101514. https://doi.org/10.1016/j.berh.2020.101514.

Wootton, E, SMC De Sousa, RL Prince, DSA McLeod, DA Pattison, and M Grossmann. 2026. “Primary Hyperparathyroidism in Adults: Recent Developments in Diagnosis and Management.” Medical Journal of Australia 224 (5): e70194. https://doi.org/10.5694/mja2.70194.