Digestive manifestations of parathyroid disorders

Abstract

The parathyroid glands are the main regulator of plasma calcium and have a direct influence on the digestive tract. Parathyroid disturbances often result in unknown long-standing symptoms. The main manifestation of hypoparathyroidism is steatorrhea due to a deficit in exocrine pancreas secretion. The association with celiac sprue may contribute to malabsorption. Hyperparathyroidism causes smooth-muscle atony, with upper and lower gastrointestinal symptoms such as nausea, heartburn and constipation. Hyperparathyroidism and peptic ulcer were strongly linked before the advent of proton pump inhibitors. Nowadays, this association remains likely only in the particular context of multiple endocrine neoplasia type 1/Zollinger-Ellison syndrome. In contrast to chronic pancreatitis, acute pancreatitis due to primary hyperparathyroidism is one of the most studied topics. The causative effect of high calcium level is confirmed and the distinction from secondary hyperparathyroidism is mandatory. The digestive manifestations of parathyroid malfunction are often overlooked and serum calcium level must be included in the routine workup for abdominal symptoms.

INTRODUCTION

The parathyroid glands play a major role in calcium homeostasis, and ultimately have an effect on all organs because of the complexity of intracellular calcium physiology. The gut and accessory organs are not spared. However, digestive manifestations of dysparathyroidism are not well known and typically rely on old articles and theories. This paper summarizes the digestive consequences of parathyroid disorders and highlights recent theories based on older studies.

DIGESTIVE MANIFESTATIONS OF HYPOPARATHYROIDISM

Hypoparathyroidism may be transient, genetically inherited, or acquired due to an autoimmune process. It may also be secondary to surgery or neck irradiation[1]. Digestive manifestations of hypoparathyroidism are few and consist mainly of steatorrhea.

Steatorrhea related to hypoparathyroidism is a consequence of bilio-pancreatic exocrine deficit due to insufficient meal-stimulated cholecystokinin secretion by the duodenal mucosa[2]. The treatment of fat malabsorption in idiopathic hypoparathyroidism comprises: medium-chain triglycerides diet[3], correction of hypoparathyroidism, administration of vitamin D[4], and normalization of hypocalcemia[5]. In contrast, secondary hyperparathyroidism, as a consequence of malabsorption and steatorrhea, is accompanied by normal or sub-normal serum calcium level.

Idiopathic hypoparathyroidism can be associated with other digestive autoimmune diseases that may cause diarrhea. Few reports have been published on the coexistence of primary hypoparathyroidism and celiac disease[6-8]. Kumar et al[9] have explored this association in a cross-reactive immunological pathway. If suspected by resistance to vitamin D supplementation[10], the coexistence of celiac sprue must be ruled out by duodenal biopsy. In such cases, gluten-free diet should be included in the treatment regimen[11,12]. Moreover, in the specific context of celiac sprue, Parathyroid hormone (PTH) level might not be elevated because of parathyroid atrophy, and secondary hyperparathyroidism might not appear[13]. Finally, since its description by Reisner et al[14] more than 50 years ago, the coexistence of idiopathic hypoparathyroidism and pernicious anemia has not been further reported.

DIGESTIVE MANIFESTATIONS OF HYPERPARATHYROIDISM

The gastrointestinal manifestations of primary hyperparathyroidism (PHPT) have been described many decades ago[15]. Truly asymptomatic hyperparathyroidism is rare when thorough anamnesis looks for subtle symptoms. Most frequent digestive manifestations are constipation, heartburn, nausea and appetite loss that occur in 33%, 30%, 24% and 15% of cases, respectively[16]. Significant reduction in symptom rates is found after parathyroidectomy. Vague abdominal pain can be as frequent as 29%[17]. The exact pathophysiological mechanism is not fully understood. Alterations in gene expression secondary to sustained stimulation of PTH receptors may help explain the symptoms[18]. As a result, gut atony occurs and leads to constipation in the colon and dyspepsia in the stomach[17]. Finally, PHPT has been associated with increased incidence of malignancies, especially of the colon[19].

The association between PHPT and peptic ulcer disease is a yet-to-be-resolved issue. Most studies about this subject date were performed several decades ago[18,20-23], did not include prospective large-scale studies, and led to controversial results. Compared to 30% in adults with hyperparathyroidism[18], peptic ulcer was found in 5% of autopsies in the general population before the advent of the proton pomp inhibitors[20]. Other studies have reported results between these two extremes[21]. On the other hand, among patients with duodenal ulcer, Frame et al[22] have shown a 10-fold increase in the incidence of PHPT. As reported in old studies, complete correlation between hyperparathyroidism and increased gastric acid secretion could not be found, and normalization of the latter was not systematic after parathyroidectomy[21,23-28]. Again, the correlation between hypergastrinemia and hyperparathyroidism was not constant throughout previous studies[28,29], although Reeder et al[30] have found a direct calcium-to-gastric hypersecretion relationship in hypergastrinemia. The only prospective study conducted by Corleto et al[31] failed to confirm these findings. Zollinger-Ellison syndrome (ZES) may coexist with PHPT in the context of multiple endocrine neoplasia type 1. In a prospective study, Norton et al[32] reported a significant biochemical improvement of ZES in 20% of patients who underwent resection of more than three parathyroid glands. Finally, pancreatic polypeptide was once correlated with hyperparathyroidism[33].

Acute pancreatitis caused by PHPT was first described by Cope et al[34] in 1957. Since that date, the exact relationship between these two entities has been questioned, until PHPT was accepted as an etiology for pancreatitis[35]. Incidence of acute pancreatitis in patients with PHPT has varied from 1%[36] to 12%[37] in retrospective series, with intermediate values[38,39]. Jacob et al[40] have shown a 28-fold increased risk of pancreatitis in hyperparathyroid patients compared to the general population. After eliminating all other causes, mean plasma calcium level seems to be the only predictive factor for pancreatitis development[37,40,41]. Its dosage must be included in the etiological work-up, although hyperparathyroidism is found in < 1% of patients who present with acute pancreatitis[42]. Carnaille et al[37] have shown that most patients had single adenoma, which suggested that pancreatitis was a consequence (and not the cause) of hyperparathyroidism. Additionally, acute pancreatitis may be the presenting form of PHPT[38,43,44], even in its ectopic localization[45,46]. In contrast, Felderbauer et al[39] have stressed that genetic mutations constitute a greater risk factor for pancreatitis than serum calcium.

The pathophysiological mechanism that leads to pancreatitis seems more related to hypercalcemia than to PHPT. It has been shown that hypercalcemia from any cause can lead to pancreatitis[47-49]. As confirmed by experimental studies, calcium ions cause calculus deposition within the pancreatic ductules, with consequent obstruction and inflammation[50]. Moreover, calcium can trigger the pancreatitis cascade by promoting conversion of trypsinogen to trypsin[51,52].

Interrelation between acute pancreatitis and parathyroid function can be summarized as follows: (1) acute pancreatitis results in a tendency to hypocalcemia and secondary hyperparathyroidism[53,54]. Compensation need is correlated to pancreatitis severity as shown by PTH level[55]; (2) severe and/or complicated pancreatitis can lead to overt hypocalcemia through relative deficiency in PTH secretion[54], because exogenous administration of PTH normalizes calcium level[56]; (3) in severe pancreatitis, resistance to PTH action in bones and kidneys may occur because of fluid sequestration and reduction in efficient arterial blood volume[53]; (4) once the diagnosis of PHPT-induced acute pancreatitis is established, parathyroidectomy is mandatory because it prevents recurrence[37,42].

Bhadada et al[57] have studied PHPT-induced chronic pancreatitis and compared it to pancreatitis of other causes. PTH and calcium levels are significantly more elevated in PHPT, while in others, elevated PTH level is secondary to maintain normocalcemia. With regard to complications, it seems that chronic pancreatitis secondary to PHPT does not differ from chronic pancreatitis of other causes. This entity needs to be studied by larger studies for further understanding.

In conclusion, serum calcium level must be considered among the usual tests in patients with rare and/or non-specific abdominal symptoms. Hypoparathyroidism mainly manifests in the gut as malabsorptive diarrhea. Laboratory tests are essential for the diagnosis of secondary hypocalcemia when treatment is medical. PHPT causes non-specific digestive symptoms that are consequent to smooth-muscle atony. Association of peptic ulcer with PHPT is not as clear as described by old literature except for ZES in MEN 1. In contrast, PHPT is a confirmed risk factor for acute pancreatitis that can be its presenting form. Finally, PHPT-induced chronic pancreatitis needs further study for confirmation.