Hyperparathyroidism in celiac disease: A case study from UAE

Celiac disease (CD) is the most common autoimmune disorder induced by gluten ingestion which is found in wheat, oats, rye, barley and other grains. It occurs in subjects with genetic predisposition namely, HLA-DQ2 and HLA-DQ8 haplotypes and characterize by high titers of serum antigliadin and antitransglutaminase antibodies that improves after removal of gluten from the diet [1]. Generally CD occurs between 6 and 18 months of age, after the introduction of gluten containing diet [2], however it can present at any age and the peak of onset of adult CD is during the 4th and 5th decades in females and 5th and 6th decades in males [3].


Introduction
Celiac disease (CD) is the most common autoimmune disorder induced by gluten ingestion which is found in wheat, oats, rye, barley and other grains. It occurs in subjects with genetic predisposition namely, HLA-DQ2 and HLA-DQ8 haplotypes and characterize by high titers of serum antigliadin and antitransglutaminase antibodies that improves after removal of gluten from the diet [1]. Generally CD occurs between 6 and 18 months of age, after the introduction of gluten containing diet [2], however it can present at any age and the peak of onset of adult CD is during the 4th and 5 th decades in females and 5th and 6th decades in males [3].
CD is most missed disease, was once thought to be very rare and affect only European population but current data showed worldwide prevalence of about 1% of the general population [4]. The time taken to make the diagnosis may go to more than 10 years [5]. Studies in UAE showed positive celiac serology in 2.3% of asymptomatic pre marriage individuals [6]. Diagnosis rates are increasing, and this seems to be due to a true rise in incidence rather than increased awareness and detection [5].
CD is characterized by histopathological changes in the small intestine that includes; decreased enterocyte height, crypt hyperplasia, villous atrophy, increased intraepithelial T lymphocytes [7]. These changes in the intestinal mucosa lead to malabsorption and development of a number of nutritional de iciencies such as anemia, hypoproteinemia, and hypocalcemia.
The presentation of CD is greatly heterogeneous, depending on the patient's age, the duration and severity of disease. The classic presentation is growth failure, malnutrition, diarrhea, abdominal pain and distension within the irst 2 years of life. In contrast, many patients with celiac disease present at a later age with subtle symptoms such as diarrhea, unexplained anemia and osteoporosis and the diagnosis may be delayed [8]. Therefore, serological testing should be done in subjects in whom the diagnosis of CD is considered, such as those with vitamin or mineral de iciencies, osteoporosis/osteopenia, infertility or other clinical symptoms.
Endomysial (EMA) and tissue transglutaminase (TG IgA) autoantibodies are the most sensitive and speci ic for the diagnosis of CD [9]. Also, antibodies against deamidated gliadin peptides (DGP) that re lect immunity against the dietary antigen have been identi ied [10]. Diagnosis of CD is usually suggested by the presence of TG autoantibodies, but con irmed by biopsy of the small bowel by upper intestinal endoscopy [11].
Hypocalcemia has been reported in 5.7% of patients with CD as a result of vitamin D malabsorption or calcium loss due to binding to unabsorbed fatty acids [12]. Primary hyperparathyroidism (PHPT), usually owing to parathyroid adenoma, is associated with multiple complications such as osteoporosis, bone fractures and renal stones. Most of cases are asymptomatic and incidental hypercalcemia is the initial inding in the diagnosis [13]. To our knowledge no reported cases in UAE with celiac disease and PHPT.

Case presentation
A 40 year old Iraqi female diagnosed as celiac disease since 1997 and was on gluten free diet that was stopped in 2008, presented in 2019 with severe acid re lux, gaseous distention, polyuria, bone pain and sever osteopenia as detected by DEXA scan. Her laboratory tests at that time showed iron de iciency anemia, strongly positive celiac serology, and slightly elevated calcium (Table 1).
Gastroscopy Augest 2019 showed small hiatus hernia with lax cardia erythema stomach and thin serrated duodenal folds ( Figure 1A). Duodenal biopsy showed CD, Type IIIB (modi ied marsh classi ication) (Figure 2A). Patient came back for a follow up after six months of gluten free diet, when her symptoms were signi icantly improved with weight gain and rise in Hb (Table 1). Gastroscopy was repeated that showed hiatus hernia with erosion and mild serration of duodenal folds with marked improvement in duodenal biopsy compared to the last one ( Figure 1B  Ultrasound of neck in February 2020 showed hypo echoic lesion in the mid and lower left thyroid lobe measuring 12 x 27 mm in diameters suggestive of parathyroid adenoma ( Figure 3). The patient received one injection of Denosumab 60 mg, and the calcium level decreased to 9.4 mg/dl. The patient has been scheduled to have parathyroidectomy.

Discussion
In our experience in Iraq and UAE we came across a variety of presentations of CD ranging from re lux disease, irritable bowel syndrome, anemia, recurrent stomatitis,     [18,19], and in our patient there was large adenoma rather than hyperplasia.

Summary and conclusion
• Celiac disease and hyperparathyroism can be associated • Awareness is needed as both celiac disease and hyperparathyroidism are under recognized • More studies are required to clarify the relationship between coeliac disease and hyperparathyroidism infertility, elevated liver enzymes, short stature, obesity, association with in lammatory bowel diseases and they missed because of lack of awareness by the health care workers. Hypocalcemia is more common than hypercalcemia in patients with untreated celiac disease. A normal or near normal calcium level is a more common inding then either hypo or hypercalcemia. The effect of gluten free diet on ionized calcium has been documented [12].
CD is typically accompanied by vitamin D de iciency and calcium malabsorption, both of them cause secondary hyperparathyroidism [13]. Although the assemblage of CD and elevated PTH levels is anticipated, the association of CD with hypercalcemia and subsequent diagnosis of PHPT is not. After prior scarce reports of the coexistence of these conditions, one study reported the prevalence of primary hyperparathyroidism could reach up to 2.3% in patients with CD [14]. The abnormal absorption of calcium and Vitamin D from intestine due to CD may spuriously lower the Calcium, masking the effect of Primary Hyperparathyroidism, hence delaying the diagnosis. Gluten free diet correcting the intestinal abnormalities leading to normalization of the calcium absorption may then unmask the hypercalcemia caused by the primary hyperparathyroidism.
Our case is the irst reported case in UAE with celiac disease and primary hyperparathyroidism. It is also the irst reported case showing the effect of CD on calcium levels, affecting the diagnosis of primary hyperparathyroidism. The diagnosis of PHPT in patient with celiac disease could be challenging as CD and PHPT share many overlapping, non-speci ic symptoms such as fatigue, depression, bone pain and abdominal pain that may delay the clinical diagnosis [15]. Usually there is 1-4 years delay in diagnosis of hyperparathyroidism in patients with CD as elevated PTH usually justi ied by the low vitamin D levels in patients with CD [16]. In our case the patient had bone pain and osteopenia that was initially linked to malabsorption and vitamin D de iciency. Furthermore, when the patient was not compliant on gluten free diet her calcium level was 10.4 mg/dl, however her calcium level markedly raised up to 14.2 mg/dl after 6 months of gluten free diet and this was corresponding to improvement of intestinal mucosa leading to increased absorption of calcium and unmasking of hyperparathyroidism.This emphasizes the need to look for hyperparathyroidism in patients with CD and normal calcium level and persistent symptoms despite adherence to gluten free diet.
Tertiary hyperparathyroidism may develop in patients with longstanding hypocalcemia as in undiagnosed cases of CD and when they start treatment the hypercalcemia becomes apparent [17]. In our case tertiary hyperparathyroidism is a remote possibility as the patient initially has no hypocalcaemia. Furthermore, hyperplasia of the parathyroid glands is the common morphological feature and the development of adenoma in tertiary hyperparathyroidism