Importance of understanding a diagnostic-treatment algorithm for primary hyperparathyroidism-induced acute pancreatitis during pregnancy

Abstract

In this article, we have commented on the article by Augustin et al. The authors presented a systematic review of the diagnosis, treatment, and outcomes of primary hyperparathyroidism-induced acute pancreatitis in pregnant women. Since acute pancreatitis during pregnancy could cause maternal as well as fetal adverse outcomes, understanding this pathology is essential. Although there are various etiologies of acute pancreatitis during pregnancy, primary hyperparathyroidism is one of the causes that complicate hypercalcemia. Along with conventional treatment for acute pancreatitis, parathyroidectomy can effectively normalize calcium levels and improve acute pancreatitis. Augustin et al have provided vital information that can enable physicians to understand and treat hyperparathyroidism-induced acute pancreatitis in pregnant women, which could contribute to better maternal and fetal outcomes. In addition, since primary hyperparathyroidism is associated with multiple endocrine neoplasia, further consideration regarding screening for multiple endocrine neoplasia might lead to better prognoses.

Key Words: Primary hyperparathyroidism; Acute pancreatitis; Pregnancy; Multiple endocrine neoplasia; Hyperparathyroidism-induced acute pancreatitis; Multiple endocrine neoplasia type 1

Core Tip: Primary hyperparathyroidism-induced acute pancreatitis during pregnancy is a rare condition and can cause maternal and fetal adverse outcomes. Therefore, early diagnosis and appropriate therapeutic intervention are essential. This article comments on the recent systematic review of this condition published in the World Journal of Gastroenterology. In addition, multiple endocrine neoplasia screening is recommended for the better prognosis of the cases.

TO THE EDITOR

A recently published article authored by Augustin et al[1] presented a systematic review on primary hyperparathyroidism (PHPT)-induced acute pancreatitis in pregnant women. Various etiologies can induce acute pancreatitis; PHPT being one of the causes. Since acute pancreatitis in the pregnancy period could lead to maternal as well as fetal adverse outcomes, accurate diagnosis and appropriate treatment are crucial. Therefore, knowledge and understanding of the condition is very important. Since acute pancreatitis induced by hyperparathyroidism in the pregnancy period is a relatively rare condition, sufficient information has not been summarized in the literature to date. Hence, a systematic review of this pathology was necessary to establish diagnostic and treatment algorithms. Augustin et al[1] concluded that examining the serum calcium level is the key to early diagnosis and therapeutic intervention of PHPT-induced acute pancreatitis. Recently, the guidelines for the clinical practice to manage the PHPT have been published, as it involves multiple organs and is complicated with various symptoms[2-5]. In addition, approximately 10% of PHPT is associated with various syndromes and genetic diseases, such as multiple endocrine neoplasia type 1 (MEN1)[6,7]. MEN is an autosomal dominant inherited tumor syndrome that is characterized by multiple tumors affecting the parathyroid glands, pituitary glands, and pancreas. Therefore, further screening, including genetic diagnosis, might be beneficial for pregnant women and their babies for accurate prediction of additional tumor onset and other symptoms.

Management of PHPT-induced acute pancreatitis in pregnancy

Although biliary tract stones and alcohol abuse are the major etiologies of acute pancreatitis, it can also be caused by hypertriglyceridemia, hypercalcemia, autoimmune diseases, endoscopic retrograde cholangiopancreatography, and trauma[8,9]. Among various factors that cause hypercalcemia, PHPT is reported to be associated with acute pancreatitis occurrence with approximately a 5%-6% rate[10]. Misgar et al[10] reviewed the records of 242 PHPT cases and reported that pancreatitis was the only presenting complaint, and PHPT screening was important for any patient with pancreatitis with high serum calcium levels, particularly when the other common etiologies of pancreatitis are present. The major pathology of PHPT-induced acute pancreatitis is the deposition of calcium in the pancreatic duct, thereby obstructing it. In addition, the direct toxic action of parathyroid hormone (PTH) and conversion of trypsinogen to trypsin triggers pancreatitis in individuals with PHPT[11,12]. Early diagnosis and management of PHPT is important since it can cause various complications and symptoms, including kidney stones, weakened bones, hypertension, nausea, and constipation[6,10]. Furthermore, some cases of PHPT are related to inherited conditions, such as MEN1, involving the parathyroid glands[6,7]. Carsote et al[6] reviewed 1375 cases of hypercalcemia-induced pancreatitis in 9 studies and summarized that MEN1 with PHPT has been reported in 85%-90% of the subjects. Therefore, an accumulation of symptomatic PHPT case information will contribute to establishing diagnostic and treatment algorithms and facilitating the early detection of MEN[1-7].

PHPT in the pregnancy period is a rare occurrence, with approximately 1% reported incidence[13,14]. However, the number of case reports has increased in recent years, and more information is available[15,16]. Diagnosis of PHPT is difficult during pregnancy due to the nonspecific symptoms; however, careful screening is necessary to prevent adverse outcomes for the mother and fetus, as well as the neonate, especially when serum calcium levels are elevated. Incidents of acute pancreatitis during pregnancy are further rare, which have been reported to range between 0.1% and 0.01%[17-20]. However, considering the serious complications for both mother and fetus, it is important to diagnose properly and provide appropriate therapeutic options. PHPT is one of the causes of acute pancreatitis in the pregnancy period as well as in non-pregnant cases[3,8-12]. Therefore, although rare, the information regarding PTPH-induced acute pancreatitis during pregnancy was an unmet need for accurate diagnosis and therapeutic intervention for a better outcome for the mother, fetus, and neonate. For this condition, Augustin et al[1] reviewed 54 cases of PTPH-induced acute pancreatitis in pregnancy from 51 studies in 55 years since 1968. The study collected and reviewed the largest number of cases reported to date. Among these cases, for treating PHPT, surgical treatment was performed in 33 cases during pregnancy and 12 cases after delivery. No detailed information was available for the remaining nine cases. Histological analyses revealed the parathyroid adenoma (46 cases), carcinoma (2 cases), and hyperplasia (1 case).

Regarding the maternal and fetal mortality of 9.3%, the authors analyzed various factors. For maternal outcomes of alive or death, age, various factors including, previous pregnancies, previous deliveries, pancreatitis occurrence in gestational week, pancreatitis postpartum, amylase, lipase, calcium, phosphorus, number of abortion, complex delivery, delivery occurrence week, and fetal/child death and no difference in the two groups were shown. It should be noted; however, that the maternal death rate was observed to be higher in cases where surgical intervention was required for pancreatitis management compared with the cases treated conservatively (60.0% vs 16.3%). Moreover, maternal deaths were associated with elevated PTH levels (910 pg/mL vs 302 pg/mL). Regarding fetal/child outcomes, when the five cases of mortality group was compared with the survivors, the mortality group demonstrated statistically elevated calcium (4.1 mmol/L vs 3.3 mmol/L) and PTH (1914 pg/mL vs 302 pg/mL) levels. The need for surgical intervention for acute pancreatitis was similar in both groups (20.0% vs 20.4%)[1].

Previous studies have reported that maternal hypercalcemia can induce premature birth, intrauterine growth retardation, suppression of fetal parathyroid gland development, and neonatal hypocalcemia, which results in tetany that can persist for several weeks. High maternal PTH levels also result in elevated maternal blood pressure, increasing the risk of preeclampsia[21,22]. These pathologies induced by elevated serum calcium and PTH levels contribute to the increased mortality. Further analysis by Augustin et al[1], using a multivariable logistic regression model, demonstrated that serum lipase levels at the time of acute pancreatitis, and the timing of delivery are related to the risk of maternal mortality in PHPT-induced acute pancreatitis. Complex delivery was found to be a risk factor for fetal/child mortality.

According to the reports[13-16] and guidelines from The American Association of Endocrine Surgeons, surgical treatment is recommended for symptomatic cases, cases having serum calcium levels of greater than 1 mg/dL, and cases complicated with nephrolithiasis, nephrocalcinosis, hypercalciuria, impaired renal function, osteoporosis, or fragility fracture[23]. In addition, a single-center study has demonstrated that PHPT can be managed conservatively in pregnancy with calcium levels of < 2.85 mmol/L when no complications such as acute pancreatitis or other hypercalcemia syndrome are present[24]. No consensus currently exists regarding the treatment of PHPT in pregnancy; however, parathyroidectomy performed in the second trimester is preferred when the patient is symptomatic or if the calcium level is high (> 2.75 mmol/L)[16,17,25,26]. Calcitonin, cinacalcet, and bisphosphonate could be used; however, due to the lack of long-term safety data no guidelines on medications are currently available. Particularly, as cinacalcet and bisphosphonates cross the placenta and might be embryotoxic (Figure 1)[21].

Figure 1 Parathyroid hormone and serum calcium levels in primary hyperparathyroidism during pregnancy and its treatment options. PTH: Parathyroid hormone.

Serum calcium levels decrease during pregnancy, primarily due to hemodilution, decreased serum albumin levels, and calcium transport from the mother to the fetus[21,22,27]. Therefore, elevated serum calcium levels during pregnancy might indicate the presence of a pathophysiological condition. Augustin et al[1] concluded that early diagnosis of PTPH-induced acute pancreatitis with the serum calcium test is warranted for detecting acute pancreatitis during pregnancy. This is because higher calcium and PTH values increase the risk of fetal and child mortalities, abortions, and complex deliveries. Meanwhile, in this review, the screening workup for MEN was reported in only three cases. Most PHPT cases are sporadic, and their incidence is estimated to be 0.3% in the general population[10]; on the other hand, 5%-10% of PHPT patients might have syndromes and hereditary diseases, including MEN1. MEN1 is an autosomal dominant inherited tumor syndrome that is characterized by the presence of pancreatic, parathyroid, and pituitary gland tumors[2]. Imaging studies, including computed tomography, parathyroid scintigraphy with ^99mTc, and magnetic resonance imaging, assist in the diagnosis[28]. Parathyroid tumors are the most common cause of hyperparathyroidism and are detected in > 90% of patients with MEN1[2,3,28]. MEN1 can be fatal if not accurately diagnosed and treated. To date, information regarding the impact of MEN1 on pregnancy is insufficient, and further reports, including actual case experiences, are warranted[27]. According to published reports, MEN1-induced endocrinopathies affect pregnancies, with a high incidence of complications related to PHPT, while non-parathyroid symptoms are less frequent. Additionally, maternal calcium and blood glucose levels are key factors for screening and monitoring hypercalcemia and gestational diabetes, which are the major complications of pregnancy in MEN1 cases[27]. Magnetic resonance imaging and ultrasonography are useful for diagnosing parathyroid tumors in pregnant women due to their sensitivity and lack of exposure to ionizing radiation. Hypercalcemia results in maternal complications such as renal stones, arrhythmia, pancreatitis, miscarriage, and preeclampsia[21,22,29]. Therefore, parathyroidectomy in the second trimester of pregnancy is recommended to reduce maternal and fetal mortality caused by these clinical symptoms and to minimize the risk of complications[21,22,29]. Therefore, screening for MEN1 is also essential for the cases diagnosed with PHPT-induced acute pancreatitis in pregnancy.

CONCLUSIONS

Understanding PHPT-induced acute pancreatitis and its occurrence in pregnancy is important for the early diagnosis and appropriate therapeutic intervention to prevent maternal and fetal adverse outcomes. Further consideration of MEN screening could be considered for the PHPT etiology for a better prognosis.