Casos clínicos

Celiac disease and primary hyperparathyroidism: an infrequent association

Enfermedad celíaca e hiperparatiroidismo primario: una asociación infrecuente

Doença celíaca e hiperparatireoidismo primário: uma associação incomum

Luis Agustín Ramírez Stieben^1,2, Estefanía Pustilnik¹, Rodolfo Néstor Feldman¹, Diamela Bolzán¹, Iván Bedini¹.

DATOS DE AUTORES

1. Unidad de Tiroides y Paratiroides del Grupo Gamma (Rosario).
2. E-mail de contacto: lramirez@grupogamma.com. ORCID: http://orcid.org/0000-0002-8212-1257.

CONCEPTOS CLAVE:

Que se sabe sobre el tema.

El hiperparatiroidismo primario y la enfermedad celíaca pueden afectar la salud ósea causando osteoporosis y dificultades en la absorción de calcio y vitamina D.

Que aporta este trabajo.

Nuestro caso reporta una rara coexistencia de hiperparatiroidismo primario y enfermedad celíaca en una paciente con osteoporosis, destacando la importancia de considerar causas secundarias de osteoporosis en pacientes con baja densidad ósea.

Divulgación

El hiperparatiroidismo primario (HPTP) y la enfermedad celíaca (EC) son dos condiciones médicas que pueden afectar la salud ósea de manera diferente. El HPTP se caracteriza por niveles elevados de calcio en el cuerpo y puede causar problemas óseos, como osteoporosis. Por otro lado, la EC es una enfermedad autoinmune que daña el revestimiento del intestino delgado, dificultando absorción de calcio y vitamina y contribuyendo al desarrollo de osteoporosis. Esta asociación poco común destaca la importancia de considerar las causas subyacentes de la osteoporosis en pacientes con baja densidad ósea.

Abstract

Objective: Primary hyperparathyroidism (PHPT) and celiac disease (CD) are two distinct medical conditions that can affect bone health. While PHPT leads to excessive calcium levels and bone abnormalities, CD impairs calcium and vitamin D absorption due to small intestine damage.

Case report: We present a case of a 49-year-old woman diagnosed with osteoporosis who was found to have both PHPT and CD. The patient underwent a successful minimally invasive parathyroidectomy, which resulted in decreased parathyroid hormone levels.

Conclusion: This case highlights the rare coexistence of PHPT and CD and emphasizes the importance of considering secondary causes of osteoporosis in patients with low bone mass. Further studies are needed to explore the underlying mechanisms and potential links between PHPT and CD.

Resumen

Objetivos: El hiperparatiroidismo primario (HPTP) y la enfermedad celíaca (EC) son dos condiciones médicas distintas que pueden afectar la salud ósea. Mientras que el HPTP provoca niveles excesivos de calcio y anomalías óseas, la EC dificulta la absorción de calcio y vitamina D debido al daño en el intestino delgado.

Caso clínico: Presentamos el caso de una mujer de 49 años diagnosticada con osteoporosis que también se le detectó tanto HPTP como EC. La paciente se sometió con éxito a una paratiroidectomía mínimamente invasiva, lo cual resultó en una disminución en los niveles de la hormona paratiroidea.

Conclusión: Este caso resalta la rara coexistencia de HPTP y EC, y enfatiza la importancia de considerar causas secundarias de osteoporosis en pacientes con baja masa ósea. Se necesitan más estudios para explorar los mecanismos subyacentes y posibles vínculos entre HPTP y EC.

Resumo

Objetivos: O hiperparatireoidismo primário (HPTP) e a doença celíaca (DC) são duas condições médicas distintas que podem afetar a saúde óssea. Enquanto o HPTP leva a níveis excessivos de cálcio e anomalias ósseas, a DC prejudica a absorção de cálcio e vitamina D devido a danos no intestino delgado.

Caso clínico: Apresentamos um caso de uma mulher de 49 anos diagnosticada com osteoporose que foi diagnosticada simultaneamente com HPTP e DC. A paciente foi submetida com sucesso a uma paratiroidectomia minimamente invasiva, o que resultou em redução nos níveis de hormônio paratireoidiano.

Conclusão: Esse caso destaca a rara coexistência de HPTP e DC e enfatiza a importância de considerar causas secundárias de osteoporose em pacientes com baixa densidade óssea. Estudos adicionais são necessários para explorar os mecanismos subjacentes e possíveis conexões entre HPTP e DC.

Introduction

Primary hyperparathyroidism (PHPT) represents the most prevalent cause of hypercalcemia. PTHPT is diagnosed in the presence of hypercalcemia and an elevated or inappropriately normal parathormone (PTH) level. Skeletal symptoms can manifest as a combination of fragility fractures, skeletal deformities, and bone pain⁽¹⁾. Celiac disease (CD) is an autoimmune disorder that primarily affects the small intestine and is triggered by the ingestion of gluten⁽²⁾. The classic symptoms of CD include malabsorption, chronic diarrhea, weight loss, and abdominal pain. CD can also manifest in various extra-intestinal complications, including osteoporosis, vitamin D deficiency, secondary hyperparathyroidism, and, less commonly, osteomalacia^(3,4). The association between CD and PHPT is not fully defined⁽⁵⁾.

In this case, we present a patient who presents with osteoporosis and is diagnosed simultaneously with PHPT and CD.

Case Report

A case is presented of a 49-year-old woman who presents for evaluation of osteoporosis. She had a personal history of migraines and had previously undergone surgeries, including cesarean sections and tonsillectomy. She denied tobacco and alcohol consumption and had no history of fractures. Her menarche occurred at the age of thirteen, and she had a hormonal intrauterine device in place. Her father had died from colorectal cancer, and she had second-degree relatives with inflammatory bowel disease and rheumatoid arthritis. Additionally, she reported occasional use of nonsteroidal analgesics and isotretinoin for acne treatment.

During the physical examination, it was noted that the patient had a weight of 54 kg and a height of 1.60 m. A regular heart rhythm was auscultated, and the abdomen appeared flat, soft, and depressible, with present bowel sounds and no evidence of organ enlargement. No palpable lesions were detected in the thyroid area. There were no peripheral edemas, melanotic skin hyperpigmentation, or jaundice observed in the conjunctiva or sclera.

The lumbar spine bone densitometry showed a T score of -1.8 and a Z score of -1.1, while the hip showed a T score of -3.0 and a Z score -2.5, and femoral neck bone showed a T score of -3.3 and Z score -2.6. Consequently, a laboratory evaluation was conducted, revealing a calcium level of 12.2 mg/dl, a phosphate level of 1.79 mg/d, a PTH level of 131 pg/ml, and positive autoimmunity for CD (Table 1).

Table 1

The ultrasound of the parathyroid glands revealed a solid nodule measuring 24 x 13 mm, hypoechoic, and located adjacent to the lower pole of the right lobe (Figure 1A and Figure 1B). 99mTc-sestamibi scintigraphy with SPECT showed a focal area of intense radiotracer uptake, below the right thyroid lobe, posterior to the trachea, and anterior to the vertebral column (Figure 1C and Figure 1D).

Figure N° 1. Preoperative parathyroid localization studies. A and B. Parathyroid ultrasound (sagittal orientation). Adjacent to the lower pole of the right lobe, a mixed, solid formation of approximately 24 x 13 mm is observed, which shows central flow on color Doppler. C and D. 99mTc-sestamibi scintigraphy with SPECT [coronal (C) and axial orientation (D)]. Focus of intense tracer-uptake, located below the right thyroid lobe, behind the trachea, and in front of the spine.

An upper gastrointestinal endoscopy was performed, which revealed low-height, comb-like Kerckring folds in the duodenum. The histopathological examination showed moderate to severe chronic duodenitis associated with marked and diffuse villous flattening and crypt hyperplasia. The estimated count of intraepithelial lymphocytes was forty elements per 100 enterocytes, consistent with a type IIIC lesion of the Marsh classification. These findings indicated severe damage to the small intestinal mucosa, suggestive of CD.

A minimally invasive parathyroidectomy (PTX) was performed. The lower right parathyroid gland was located and successfully removed. Intraoperative PTH levels significantly decreased following the resection of the lesion. The histopathological examination revealed a 35 mm nodular lesion without signs of atypia, capsular invasion, lymphovascular invasion, or perineural involvement, consistent with a parathyroid adenoma.

Discussion

Osteoporosis is a prevalent condition characterized by reduced bone strength, leading to an increased risk of fractures⁽⁶⁾. Managing patients with confirmed osteoporosis or low bone mass (osteopenia) involves assessing fracture risk, investigating potential secondary causes of skeletal fragility, deciding on treatment initiation, and considering relevant clinical factors that may impact patient management. Secondary osteoporosis refers to osteoporosis caused by factors other than estrogen deficiency or aging. It has been suggested by some experts that a Z-score below the expected range for age and sex (e.g., below -2.0) may indicate a higher likelihood of secondary osteoporosis⁽⁷⁾. However, since secondary osteoporosis is common, it is more effective to screen all patients with osteoporosis for potential underlying causes⁽⁸⁾. In our case, the presence of a Z-score of -2.6 in the femoral neck and a Z-score of -2.5 in total hip raised suspicions about the presence of secondary osteoporosis. After further evaluation, the patient was diagnosed with PTHP and CD.

PHPT is the most common cause of hypercalcemia in the outpatient setting¹. Epidemiological studies and prospective cohort data have provided evidence of an increased risk of both vertebral and non-vertebral fractures⁽⁹⁾. Post PTX, improvements in the microarchitecture, geometry, cortical thickness, and estimated bone strength translate into a significant decrease in the incidence of fractures⁽¹⁰⁾. On the other hand, CD can lead to malabsorption of calcium and vitamin D due to villous atrophy and inflammation in the small intestine, impairing their absorption. Approximately 25% of patients may develop secondary hyperparathyroidism, which is characterized by elevated PTH levels and serum calcium levels in the normal to low range, along with increased bone turnover ⁽¹¹⁾. A study of 103 patients found that 21% had low vitamin D levels, and alkaline phosphatase, an indicator of osteomalacia, was elevated in approximately 10% of patients⁽¹²⁾. In our patient, we did not demonstrate vitamin D deficiency or biochemical findings consistent with osteomalacia.

Although secondary hyperparathyroidism is common in patients with CD⁽¹¹⁾ , the association between HPTP and CD appears to be coincidental, as only a limited number of case reports have been published on this topic^(5,13,14). In a single-center observational study, Maida et al. reported a prevalence of 2.3% for HPTP in patients with CD⁽⁵⁾. This is significantly higher than the reported prevalence of 2-3 in 1000 in the general population cited in most studies¹. A large population-based study found a 2-fold increased risk of PHPT (42/100000 person-years) in patients with CD respect to nonceliac control group (22/100000 person-years)⁽¹⁵⁾. However, the authors do not rule out the possibility that part of the increased risk of PHPT may be due to biases, as the highest risk estimates were found in the first year after diagnosis when surveillance of patients with CD is more intense. However, an alternative explanation is that treatment for CD may have "unmasked" PHPT, and that the treatment of CD allows for improved absorption of calcium and vitamin D, resulting in the emergence of hypercalcemia and subsequent diagnosis of PHPT. Finally, long-standing undiagnosed CD could lead to parathyroid hyperplasia and tertiary hyperparathyroidism. Although the Ludvigsson cohort did not specifically report the frequency of four-gland hyperplasia⁽¹⁵⁾, the small case series by Maida et al.⁽⁵⁾ reported that parathyroid adenoma, rather than hyperplasia, was the cause of the disease in all of their patients, as was the case with our patient.

Conclusion

This case highlights the uncommon association between PHPT and CD. The coexistence of both conditions has diagnostic and therapeutic implications as they affect bone health. It is important to consider secondary causes of osteoporosis in patients with low bone density. Further research is needed to understand the underlying mechanisms and potential links between PHPT and CD.

References

1. Bilezikian JP. Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2018 Nov 1;103(11):3993-4004. doi: 10.1210/jc.2018-01225.
2. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018 Jan 6;391(10115):70-81. doi: 10.1016/S0140-6736(17)31796-8.
3. Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol. 2015 Oct;12(10):561-71. doi: 10.1038/nrgastro.2015.131.
4. Zanchetta MB, Longobardi V, Bai JC. Bone and Celiac Disease. Curr Osteoporos Rep. 2016 Apr;14(2):43-8. doi: 10.1007/s11914-016-0304-5.
5. Maida MJ, Praveen E, Crimmins SR, Swift GL. Coeliac disease and primary hyperparathyroidism: an association? Postgrad Med J. 2006 Dec;82(974):833-5. doi: 10.1136/pgmj.2006.045500.
6. Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, Harris ST, Hurley DL, Kelly J, Lewiecki EM, Pessah-Pollack R, McClung M, Wimalawansa SJ, Watts NB. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis- 2020 Update Executive Summary. Endocr Pract. 2020 May;26(5):564-570. doi: 10.4158/GL-2020-0524.
7. Harper KD, Weber TJ. Secondary osteoporosis. Diagnostic considerations. Endocrinol Metab Clin North Am. 1998 Jun;27(2):325-48. doi: 10.1016/s0889-8529(05)70008-6.
8. Favus MJ. Postmenopausal osteoporosis and the detection of so-called secondary causes of low bone density. J Clin Endocrinol Metab. 2005 Jun;90(6):3800-1. doi: 10.1210/jc.2005-0784.
9. Vestergaard P, Mosekilde L. Fractures in patients with primary hyperparathyroidism: nationwide follow-up study of 1201 patients. World J Surg. 2003 Mar;27(3):343-9. doi: 10.1007/s00268-002-6589-9.
10. Hansen S, Hauge EM, Rasmussen L, Jensen JE, Brixen K. Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: a one-year prospective controlled study using high-resolution peripheral quantitative computed tomography. J Bone Miner Res. 2012 May;27(5):1150-8. doi: 10.1002/jbmr.1540.
11. Valdimarsson T, Toss G, Löfman O, Ström M. Three years' follow-up of bone density in adult coeliac disease: significance of secondary hyperparathyroidism. Scand J Gastroenterol. 2000 Mar;35(3):274-80. doi: 10.1080/003655200750024146.
12. Zylberberg HM, Lebwohl B, RoyChoudhury A, Walker MD, Green PHR. Predictors of improvement in bone mineral density after celiac disease diagnosis. 2018 Feb;59(2):311-318. doi: 10.1007/s12020-017-1488-x.
13. Alzahrani AS, Al Sheef M. Severe primary hyperparathyroidism masked by asymptomatic celiac disease. Endocr Pract. 2008 Apr;14(3):347-50. doi: 10.4158/EP.14.3.347.
14. Fanciulli G, Delitala AP, Usai CA, Delitala G. Primary hyperparathyroidism revealed by gluten-free diet in a woman with celiac disease. Intern Emerg Med. 2012 May;7 Suppl 1:S37-8. doi: 10.1007/s11739-011-0604-9.
15. Ludvigsson JF, Kämpe O, Lebwohl B, Green PH, Silverberg SJ, Ekbom A. Primary hyperparathyroidism and celiac disease: a population-based cohort study. J Clin Endocrinol Metab. 2012 Mar;97(3):897-904. doi: 10.1210/jc.2011-2639.

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Recibido: 2023-08-04 Aceptado: 2023-10-23

DOI: http://dx.doi.org/10.31053/1853.0605.v80.n4.42137     

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