Persistent challenges in the diagnosis of acute pancreatitis due to primary hyperparathyroidism during pregnancy

Abstract

In this manuscript, we provide critical commentary on the systematic review by Augustin et al, which investigated acute pancreatitis induced by primary hyperparathyroidism during pregnancy. Although this is an infrequent complication, it poses severe risks to both maternal and fetal health. Due to its infrequent occurrence in clinical practice, this review is based on an analysis of individual case reports over the past 55 years. While this is not the first study to utilize this sampling method for primary hyperparathyroidism-induced acute pancreatitis, it is unique in that it has a sufficiently large sample size with statistically significant results. Our discussion focuses on the diagnostic challenges associated with this condition, which are grounded in the mechanisms of parathyroid hormone secretion and variations in serum calcium levels. We also address the limitations of the current review and suggest potential strategies to increase diagnostic accuracy and improve health outcomes for both mothers and fetuses during pregnancy.

Key Words: Primary hyperparathyroidism; Acute pancreatitis; Pregnancy; Diagnostic algorithm; Parathyroid hormone; Systematic review

Core Tip: This manuscript focuses on a systematic review of acute pancreatitis triggered by primary hyperparathyroidism during pregnancy, with an emphasis on diagnostic challenges. The study explored the mechanisms of parathyroid hormone secretion and serum calcium variations during pregnancy and analyzed their effects on maternal and fetal health. Additionally, this article highlights current research limitations and offers potential solutions and future research directions to improve diagnostic methods and enhance healthcare outcomes for both mothers and fetuses.

INTRODUCTION

Primary hyperparathyroidism (PHPT) is one of the most common endocrine disorders in the general population and is becoming increasingly prevalent. It is the predominant cause of hypercalcemia, which can affect various organ systems[1,2]. Although PHPT is frequently encountered in the general population, its manifestation during pregnancy, acute pancreatitis (AP), is infrequent and poses severe risks to both maternal and fetal health[3]. The pathophysiology of PHPT during pregnancy is complex and involves fluctuations in parathyroid hormone (PTH) levels and serum calcium, leading to potential complications that require careful management. A systematic review by Augustin et al[4] provides a valuable compilation of 55 years of case reports on PHPT-induced AP during pregnancy, offering a diagnostic-treatment algorithm to improve clinical outcomes. While the study provides important insights, certain limitations, such as small sample size and the challenges of diagnosing PHPT during pregnancy, highlight the need for further research. This article will critically evaluate the systematic review, discuss these challenges, and propose future directions to enhance patient care.

OVERVIEW OF PHPT

PHPT is characterized by hypersecretion of PTH, leading to hypercalcemia and relative hypophosphatemia[5]. A study reported that PHPT is predominantly (> 90%) sporadic and is most often caused by a solitary benign adenoma (85%-90%). Less commonly, it arises from multiglandular involvement, such as multiple adenomas or hyperplasia of all four glands (5%-10%), with parathyroid carcinoma being responsible for less than 1% of cases[6]. PTH is a polypeptide hormone that is pivotal for maintaining serum calcium homeostasis. PTH increases serum calcium through direct actions on bone and kidney and indirect action on the gut[7]. It stimulates bone resorption, causing the release of calcium into the extracellular fluid. Additionally, PTH increases calcium reabsorption and decreases phosphate reabsorption by renal tubules, leading to decreased excretion of calcium and increased phosphate excretion. PTH is also necessary for the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, which, in turn, increases calcium absorption by the intestines[8]. In patients with PHPT, excessive PTH secretion can cause hypercalcemia, which may result in dysfunction across multiple organs. Symptoms include anorexia, nausea, vomiting, polydipsia, polyuria, lethargy, extreme hypercalcemia, coma, and even death[5]. PHPT can cause numerous complications, including loss of bone mineral density, fractures, bone pain, hungry bone syndrome, gastrointestinal disturbances, neuropsychiatric complaints, nephrocalcinosis, AP, and an increased risk of nephrolithiasis[9,10].

MECHANISMS OF PHPT-INDUCED AP IN PREGNANCY

PHPT during pregnancy is a rare but serious condition that reportedly occurs in approximately 1% of cases[11]. Among its potential complications, AP stands out as an exceedingly rare yet severe consequence, with no specific prevalence statistics readily available. The challenges of managing PHPT in pregnant women are closely linked to the intricate processes of maternal calcium metabolism (Figure 1). These processes begin as early as the first trimester and continue to evolve throughout pregnancy. Throughout pregnancy, calcium and phosphate metabolism are primarily directed toward the growing fetus[12]. The fetus requires approximately 25-30 g of calcium during pregnancy, which is transported from the mother through the placenta to support fetal development, particularly bone formation[1,13]. During this period, the mechanism of calcium transport across the placenta is influenced primarily by PTH-related peptide (PTHrP), which facilitates “reverse gradient” movement via an energy-dependent calcium-adenosine triphosphatase. Although this process can affect maternal calcium levels, physiological adaptations in absorption, excretion, and metabolism during pregnancy create conditions that allow for efficient calcium transfer across the placenta without significantly impacting maternal calcium levels[13-15].

Figure 1 Key mechanisms of calcium regulation in pregnant individuals with primary hyperparathyroidism. In patients with primary hyperparathyroidism, excessive secretion of parathyroid hormone (PTH) leads to hypercalcemia by impacting bones, kidneys, and intestines. It initiates this process in bones by promoting the secretion of receptor activators of nuclear factor kappa beta ligand, which activates osteoclasts to increase bone resorption, releasing calcium into the bloodstream. Concurrently, in the kidneys, PTH enhances calcium reabsorption by increasing transient receptor potential vanilloid 5 activity and stimulating the enzyme 1α-hydroxylase, which is crucial for converting vitamin D into its active form, 1,25-dihydroxyvitamin D, which is essential for effective calcium metabolism. PTH also indirectly influences intestinal calcium and phosphate absorption by upregulating transport proteins such as transient receptor potential vanilloid 6, calbindin, and adenosine triphosphate-dependent calcium pumps. During pregnancy, the situation is compounded by increased levels of estrogen and PTH-related protein, which activate 1-alpha hydroxylase, facilitating the conversion of 25-hydroxyvitamin D to calcitriol. This increase in calcitriol levels further increases the expression of calcium transport proteins in the intestines, thereby exacerbating hypercalcemia. PTH: Parathyroid hormone; PTHrP: Parathyroid hormone-related protein; 25(OH)D: 25-hydroxyvitamin D; NACX: Sodium-calcium exchanger; PMCA: Plasma membrane calcium adenosine triphosphatase; RANK: Receptor activator of nuclear factor kappa beta; TRPV5: Transient receptor potential vanilloid 5.

One of the most significant physiological changes during pregnancy is the increased reabsorption of calcium in the intestines. During pregnancy, increased levels of estrogen and PTHrP are believed to stimulate the bioactivity of 1α-hydroxylase (cytochrome P450 family 27 subfamily B member 1) in maternal kidneys, placental trophoblasts, and decidua. This enzyme catalyzes the conversion of 25(OH)D (calcidiol) to its active form, 1,25(OH)2D (calcitriol), enhancing intestinal calcium absorption. As calcium absorption increases, the kidneys respond by enhancing calcium filtration and excretion. However, these excretory effects are modest compared with the increase in intestinal absorption, ensuring a positive calcium balance to meet both maternal and fetal needs[16,17].

During pregnancy, PTH levels also undergo significant changes. In the early stages, the increased intestinal absorption of calcium and increased concentrations of calcitriol can trigger a negative feedback loop that suppresses PTH production in the parathyroid glands. This leads to a modest decrease in serum PTH levels during the first half of pregnancy[12]. As pregnancy progresses into the second half, PTH levels may either rise to above-normal levels or remain suppressed, influenced by factors such as dietary deficiencies in vitamin D and calcium[18]. In pregnant women with PHPT, hypercalcemia can worsen due to abnormal PTH secretion. This condition is associated with a series of mechanisms that affect the activity of pancreatic enzymes (Figure 2). First, elevated calcium levels in the blood increase the activation of trypsinogen by trypsin and protect trypsin from autodigestion. Additionally, calcium inhibits the breakdown of trypsinogen into intermediate proteins, thus promoting its conversion to trypsin in pancreatic fluid[19]. Furthermore, high calcium levels lead to calcium deposits in the pancreatic ducts, resulting in obstruction and the formation of pancreatic stones[20].

Figure 2 Mechanisms of acute pancreatitis due to hyperparathyroidism during pregnancy. This figure outlines the two principal mechanisms contributing to acute pancreatitis: Increased trypsinogen activation due to elevated calcium levels and increased calcium deposition. This finding also highlights the exacerbating role of genetic variants, with serine peptidase inhibitor Kazal type 1 mutations intensifying trypsinogen activation and cystic fibrosis transmembrane conductance regulator mutations promoting calcium deposition. SPINK1: Serine peptidase inhibitor Kazal type 1; CFTR: Cystic fibrosis transmembrane conductance regulator.

Among the factors contributing to these mechanisms, gene mutations play a significant role. Mutations in genes encoding pancreatic secretory trypsin inhibitors, known as serine peptidase inhibitor Kazal type 1 (SPINK1), and cystic fibrosis transmembrane conductance regulator (CFTR) have been associated with an increased risk of AP[21]. A study by Koziel et al[22] revealed that the SPINK1 mutation was more prevalent in patients with AP than in healthy controls, with mutation rates of 0.063 and 0.032, respectively. This difference was statistically significant, with a Z score of 1.777 and a P value of 0.03. Similarly, a study by Noone et al[23] demonstrated that the risk of pancreatitis increased approximately 40-fold in individuals with two CFTR mutations (P < 0.0001). It is evident that hypercalcemia, particularly in the presence of gene mutations related to SPINK1 and CFTR, significantly increases the risk of AP in pregnant women with PHPT. When AP occurs, it can lead to severe complications for both the mother and the fetus. According to the study by Augustin et al[4], the associated risks of pregnancy include miscarriage in 3.7% of cases, complicated deliveries in 13%, and fetal death in 9.3%. Furthermore, the maternal mortality rate is reported to be 9.3%, underscoring the serious outcomes of PHPT during pregnancy.

CHALLENGES IN THE EARLY DIAGNOSIS OF AP DUE TO PHPT DURING PREGNANCY

While AP resulting from PHPT during pregnancy is uncommon, it poses severe risks[24]. Although early surgical intervention remains the optimal treatment, significantly enhancing outcomes for both mothers and fetuses, the key to effective management is prompt and early diagnosis, which is particularly critical in the second trimester for preventing adverse outcomes[24-26]. Therefore, early diagnosis is essential for timely monitoring and treatment. However, in the context of PHPT during pregnancy, early diagnosis faces certain challenges, primarily related to physiological changes during pregnancy and the safety of the fetus. The challenges in the early diagnosis of AP due to PHPT are illustrated in Figure 3.

Figure 3 Challenges in the early diagnosis of acute pancreatitis due to primary hyperthyroidism during pregnancy. The difficulties in diagnosing primary hyperparathyroidism during pregnancy are related primarily to physiological changes, which lead to overlapping clinical symptoms and affect the results of biochemical tests. Additionally, imaging tests are limited in use because of the potential negative impact on the fetus. ⁹⁹mTc: 99m Technetium; CT: Computed tomography; GFR: Glomerular filtration rate; MRI: Magnetic resonance imaging; PTH: Parathyroid hormone; US: Ultrasound.

Atypical clinical symptoms with overlapping physiological manifestations

The studies conducted by authors including Schnatz et al[27] and Kokrdova[28] revealed that up to 80% of patients exhibit no clinical symptoms or present with ambiguous clinical symptoms and, as a result, are predominantly diagnosed incidentally through the review of laboratory data. However, in pregnant women, PHPT may present symptoms associated with elevated serum calcium levels[26]. Specifically, when the serum calcium concentration exceeds 0.12 g/L, patients may experience symptoms such as fatigue, anorexia, nausea, vomiting, constipation, depression, and blurred vision. At levels above 0.13 g/L, more severe symptoms can arise, including altered mental status, arrhythmias, renal failure, kidney stones, osteoporosis, peptic ulcers, pseudogout, and muscle atrophy. Serum calcium levels greater than 0.14 g/L or 0.15 g/L are rare but can lead to life-threatening complications such as coma, cardiac arrest, and ultimately death[27,29]. PHPT is rarely diagnosed during pregnancy because the symptoms of gestational PHPT may be unrecognized or masked by physiological changes in calcium homeostasis associated with pregnancy. If present, the symptoms are often atypical, including nausea, vomiting, constipation, and fatigue, which overlap with common pregnancy reactions and are therefore overlooked[1,14,30].

Even when PHPT in pregnant women leads to complications such as AP, early and typical symptoms include nausea and vomiting. These symptoms are relatively common in the early stages of the first trimester. However, they are not specific to AP caused by PHPT during pregnancy. This nonspecific nature could stem from overlapping physiological changes during pregnancy or other concurrent conditions that present similar symptoms. Moreover, delayed or insufficient clinical monitoring further complicates the early diagnosis of this condition[25,31]. Should these symptoms manifest later in pregnancy or persist, accompanied by abdominal pain, they signal an unusual condition that warrants further investigation. Possible differential diagnoses include gastritis, appendicitis, cholecystitis, peptic ulcer disease, bowel obstruction, urinary tract infections, gestational trophoblastic disease, or anomalies related to the fetus and its attachments[25].

Differences in biochemical test results

Incorporating biochemical tests into the diagnostic process is essential for addressing the difficulties of relying solely on clinical observations. Serum calcium levels are pivotal for identifying PHPT and determining suitable treatment strategies. Consistently elevated or improperly high calcium levels should raise suspicions of PHPT. Additionally, when evaluated alongside serum calcium, PTH measurements are instrumental in confirming a PHPT diagnosis[24].

Physiological changes during pregnancy can alter regular biochemical markers in the maternal body, including serum calcium levels[32]. Persistent hypercalcemia or inappropriate hypercalcemia should prompt the consideration of PHPT[24]. However, during pregnancy, physiological processes can lead to reduced serum calcium and calcium adjusted for albumin levels[33,34]. During pregnancy, there is an increase in extracellular volume and a decrease in albumin levels, which can lead to pseudohypocalcemia. This refers to a falsely low total serum calcium level due to the reduced binding of calcium to albumin, as albumin binds to approximately 50% of calcium during pregnancy. In reality, however, ionized calcium levels remain unchanged compared with those in nonpregnant women or may only slightly decrease[29,34-36]. Additionally, hypocalcemia can be attributed to an increased glomerular filtration rate, calcium transport across the placenta, and estrogen-mediated inhibition of PTH-induced bone resorption[11]. Changes in plasma calcium levels are related to clinical manifestations, predict complications, and influence maternal mortality and fetal outcomes such as stillbirth or miscarriage. This information also guides the selection of appropriate treatment methods for patients[29]. In addition to changes in PTH, there are also changes in PTHrP levels during pregnancy. PTHrP begins to rise as early as 3 weeks to 13 weeks of gestation and peaks in the third trimester. Simultaneously, PTH levels may be suppressed, so an increase in serum calcium in the context of nonsuppressed PTH should raise suspicion of PHPT[33].

Difficulties in applying imaging tests

Imaging tests play a critical role in the precise diagnosis of conditions such as PHPT, providing essential insights that can guide effective treatment strategies. Neck ultrasound is considered the first-line examination for diagnosing PHPT in pregnant women and has significantly high detection capabilities[24,31]. However, in patients with multiglandular parathyroid disease, the sensitivity can decrease to 15%-35%[37,38].

Magnetic resonance imaging (MRI), while a valuable diagnostic tool, should not be relied upon exclusively because of its high cost and limited availability in many healthcare facilities, particularly in low-income countries, which restricts its accessibility. MRI with gadolinium contrast agent is not recommended, as gadolinium is water soluble and may cross the placenta[29]. Computed tomography (CT) scans and 99mTc-sestamibi scintigraphy are not recommended during pregnancy because of the risk of fetal radiation exposure, which can lead to congenital abnormalities, cancer, or even death[31,33]. However, for CT scans, this is only a relative contraindication. Imaging of areas that do not involve the lower abdomen or pelvis is considered safe for the fetus. Additionally, initial CT scans performed within permissible limits with low radiation doses have shown minimal effects on the fetus, with a very low incidence of malformations in the second trimester[39]. Similarly, low-dose technetium-99m radionuclide scanning of the neck region, with radiation exposure below 0.05 Gy, is also considered safe for the fetus[39,40]. It is clear that diagnostic imaging plays a crucial role in diagnosing AP due to PHPT. However, the critical question is when and how to use these imaging methods in the safest manner for the patient. Therefore, a consensus between the physician and the patient is necessary when making clinical decisions, not only regarding treatment but also concerning the indications for diagnostic tests.

Clearly, combining clinical symptoms, biochemical tests, and imaging diagnostics plays a crucial role in diagnosing AP due to PHPT in pregnant women. Therefore, a structured approach to diagnosis is essential, as it helps guide physicians in providing appropriate care tailored to the patient. In their study, Augustin et al[4] proposed a detailed flowchart for the diagnosis and treatment approach. However, this flowchart does not provide a clear explanation of the diagnostic steps, and the use of imaging tests should be carefully weighed in terms of their benefits and risks, as well as the priority in their application. Therefore, building on this flowchart, we have developed a more comprehensive and user-friendly diagnostic and treatment approach (Figure 4).

Figure 4 Algorithm for primary hyperparathyroidism-induced acute pancreatitis during pregnancy. Pregnant patients presenting with symptoms such as anorexia, abdominal pain, nausea, vomiting, and constipation from the 20^th week of pregnancy should undergo careful clinical evaluation. If acute pancreatitis is suspected, tests including amylase, lipase, and imaging studies should be performed, with abdominal ultrasound being the first-line test because of its low cost and lack of fetal impact. After acute pancreatitis is diagnosed, biochemical and imaging tests should be conducted to confirm the presence of primary hyperparathyroidism. In patients with symptoms of hypercalcemia due to primary hyperparathyroidism, parathyroidectomy should be considered. Additionally, the fetal condition should be assessed. If fetal distress is present, treatment with tocolytic drugs should be initiated, and an emergency cesarean section should be considered if initial medical management is ineffective. ¹Consider using a low radiation dose with patient consent when an magnetic resonance imaging cannot be performed; ²When the patient has a family history, it is young and is able to undergo the procedure; ³Perform when MRI cannot be detected/used, with patient consent, and using a low radiation dose. ⁹⁹mTc: 99m Technetium; CT: Computed tomography; MRI: Magnetic resonance imaging; US: Ultrasound.

CURRENT LIMITATIONS AND DIRECTIONS FOR FUTURE RESEARCH

The systematic review by Augustin et al[4] on PHPT-induced AP during pregnancy provides valuable insights on the basis of an extensive sample collected over 55 years, leading to the development of diagnostic guidelines. Despite its strengths, limitations remain, particularly the relatively small sample size, owing to the rarity of this condition. A multicenter study spanning multiple regions is recommended to improve reliability and build a more extensive data repository. While this presents particular challenges, time, along with case studies or smaller-scale research, is essential to provide healthcare professionals with an initial understanding and highlight the significance of this rare yet potentially dangerous clinical condition. Early diagnosis and prompt, appropriate treatment are crucial, as they greatly enhance the survival prognosis for both the mother and the fetus.

A more specific symptom profile could be developed through symptom grouping and correlation analysis with the occurrence of acute AP due to PHPT, improving both sensitivity and specificity. Identifying positive and negative predictive values would help support clinical diagnosis and guide appropriate paraclinical investigations to confirm the diagnosis. Paraclinical tests, including biochemical markers, imaging, and genetic biomarkers, play crucial roles in the accurate and early diagnosis of AP due to PHPT. Improving the accuracy of these tests is therefore essential. Future research should focus on refining diagnostic tests and gaining a deeper understanding of the pathophysiology, particularly parathyroid adenoma, the most common cause of PHPT, which may explain the occurrence of severe hypercalcemia, especially during the second trimester.

CONCLUSION

A positive aspect of PHPT-induced AP is the potential for complete resolution after parathyroid surgery if it is the sole cause. However, from the perspective of the pathophysiological mechanisms and physiology during pregnancy, the overlap of clinical and paraclinical symptoms makes the early diagnosis of PHPT challenging. This study offers personalized diagnostic guidelines and identifies maternal and fetal mortality factors. Using individual samples from existing studies on this rare condition is innovative and effective. While this is the fifth study using this approach and has shown the best results to date, data synchronization may be imperfect due to various factors, a common issue in studies spanning over five decades.