Abstract
Hyperparathyroidism leading to hypercalcaemia is a rare cause of acute pancreatitis with debatable association. The diagnosis of hyperparathyroidism is frequently overlooked or delayed as symptoms are non-specific and serum calcium is not routinely measured in acute pancreatitis. Early diagnosis and treatment of hyperparathyroidism may reduce the chances of complications. We report a 35-year-old woman, who was admitted with recurrent episodes of acute pancreatitis. She was previously diagnosed with gall-stone induced acute pancreatitis, had undergone laparoscopic cholecystectomy, but the recurrence of acute pancreatitis suggested an alternative aetiology and provoked extensive investigations. Serum calcium was found to be elevated. No additional risk factor for pancreatitis was found. Further workup revealed primary hyperparathyroidism, which was due to a functioning parathyroid adenoma. She has undergone parathyroidectomy followed by an uneventful recovery. She subsequently conceived and is now in her first trimester, without any recurrence of acute pancreatitis since her surgery.
Keywords: endocrine system, gastrointestinal system, pancreatitis, calcium and bone
Background
Gall-stones and alcohol are the most common causes of acute pancreatitis. Among other causes, hypercalcaemia is rarely associated with acute pancreatitis and the cause–effect relationship is still controversial. Primary hyperparathyroidism (PHPT) and malignancy are the two most important causes of hypercalcaemia. PHPT is characterised by uncontrolled secretion of parathyroid hormone (PTH) from the parathyroid gland resulting in biochemical abnormalities like hypercalcaemia and hypophosphataemia.1 In most cases, patients remain asymptomatic and it is detected on routine biochemical screening. In symptomatic patients, it usually presents as recurrent renal calculi or skeletal manifestations.2
The following case report describes the association of PHPT leading to hypercalcaemia and recurrent attacks of acute pancreatitis in a middle-aged woman.
Case presentation
A 35-year-old non-hypertensive, non-diabetic, euthyroid woman was admitted in a tertiary care hospital in Eastern India on November 2019 with problems of severe upper abdominal pain radiating to back along with constipation for 2 days prior to admission. She had no history of alcohol intake or any addiction/substance abuse. She had a history of gall stone pancreatitis in June 2018 following which she underwent laparoscopic cholecystectomy. She also had a midline neck swelling for last 2 years with recent increase in size over last 1 month. There was no family history of any pancreatic disorder or any other significant illness. She denied any history of bone pains, fractures, neuropsychiatric symptoms or muscle weakness.
On admission, she was conscious, with a pulse rate of 102/min, blood pressure (BP) 100/60, respiratory rate 18/min and a firm midline neck swelling (3 cm × 2 cm) was noted without any lymphadenopathy. She had epigastric tenderness, without hepatosplenomegaly. Intestinal peristaltic sounds were audible. Other systemic examinations were unremarkable.
Investigations
Blood investigations revealed mild anaemia with neutrophilic leukocytosis. There was no significant alteration of liver and renal function tests. Serum amylase and lipase were significantly elevated. Ultrasonography (USG) of whole abdomen revealed irregular swollen appearance of pancreas suggestive of acute pancreatitis. Serum Calcium was found to be elevated. Normally, hypocalcaemia is expected during an attack of acute pancreatitis. So, hypercalcaemia found in our case was a strong clue for suspecting PHPT. The other suggestive parameters were low serum phosphorus, elevated intact parathyroid hormone, low 25-hydroxy vitamin D, elevated urinary calcium and urinary calcium–creatinine ratio. Contrast-enhanced CT abdomen revealed bulky pancreas with heterogenous attenuation, peripancreatic fat stranding with ascites (figure 1). No calcification or dilatation of main pancreatic duct was noted. Those features were suggestive of acute severe pancreatitis (modified CT severity index of 6). Diffusely oedematous pancreas with no evidence of pancreatic divisum was seen in magnetic resonance cholangiopancreatography. No abnormalities were noted in fasting lipid profile.
Figure 1.
Contrast-enhanced CT abdomen showing bulky pancreas with heterogenous attenuation, peripancreatic fat stranding with ascites.
After the episode of acute pancreatitis subsided, serum corrected calcium was repeated, and it was found to be persistently elevated (13.1 mg/dL).
USG neck revealed a well-defined smoothly marginated heterogenous hyperechoic lesion in relation to the left lobe of thyroid and isthmus measuring 25 mm × 14 mm. Single-photon emission CT (SPECT)—parathyroid 99m TC sestamibi scan revealed features suggestive of parathyroid adenoma in relation to the left lobe and isthmus of thyroid gland (figure 2).
Figure 2.
Single-photon emission CT suggestive of parathyroid adenoma in relation to left lobe and isthmus of thyroid gland.
Relevant investigations have been documented in table 1.
Table 1.
Relevant laboratory investigations of the patient
| Parameters | Values | Reference range |
| Haemoglobin | 9.8 | 12–15 g/dL |
| Total leucocyte count | 11.5×109 | 4–11 × 109 |
| Differential leucocyte count | Neutrophil 83%, lymphocyte 5%, eosinophil 5%, monocyte 7% | Neutrophil 40%–75% Lymphocyte 20%–40% Eosinophil 0%–6% Monocyte 2%–8% |
| Urea | 22 | 17–43 mg/dL |
| Creatinine | 91 | 59–104 µmol/L |
| Total bilirubin | 0.6 | 0.1–1.2 mg/dL |
| AST | 25 | 8–48 IU/L |
| ALT | 26 | 18–35 IU/L |
| ALP | 88 | 40–129 IU/L |
| Total protein | 5.5 | 4–6 g/dL |
| Albumin | 3.4 | 3.4–5.4 g/dL |
| Amylase | 931 | <100 U/L |
| Lipase | 3670 | <160 U/L |
| Calcium | 12.37 | 9–11 mg/dL |
| Corrected calcium | 12.8 | 8.5–10.2 mg/dL |
| Phosphorous | 1.44 | 3.5–4.5 mg/dL |
| iPTH | 82.8 | 15–65 pg/mL |
| 25-hydroxy vitamin D | 31.0 | 25–80 ng/mL |
| Urinary calcium | 407.1 | 100–250 mg/day |
| Urinary calcium–creatinine ratio | 0.27 | <0.14 |
| Triglyceride | 146 | <150 mg/dL |
| LDL cholesterol | 106 | <100 mg/dL |
ALP, alkaline phosphatase; ALT, alanine transainase; AST, aspertate transaminase; iPTH, intact parathyroid hormone; LDH, low density lipoprotein.
Differential diagnosis if relevant
Our patient was non-alcoholic. She has undergone cholecystectomy and no intraluminal calculi or dilatation of common bile duct was found in imaging. So, the two most common causes of recurrent acute pancreatitis were excluded. Other differentials in our case were hypertriglyceridaemia (point against: no alteration of lipid profile), drug induced (point against: no such history of drug intake), occult disease of the biliary tree or pancreatic ducts, neoplasm and anatomic variations like pancreas divisum (point against: no such features on imaging), autoimmune (point against: no clinical evidence of autoimmune disease and imaging was also not suggestive), hereditary (point against: family history not suggestive). Biochemical parameters and SPECT parathyroid 99m TC sestamibi scan clinched the diagnosis of PHPT secondary to a functioning parathyroid adenoma.
Treatment
Patient was managed with intravenous fluids aggressively, analgesics and other supportive measures. Vital parameters and urine output were monitored closely. Patient’s clinical condition gradually improved; investigations were done to look for aetiology of recurrent acute pancreatitis.
Hypercalcaemia workup revealed PHPT, due to parathyroid adenoma.
As serum calcium was persistently elevated, intravenous frusemide was administered after adequate hydration to increase urinary calcium excretion. Bisphosphonates (zoledronic acid 4 mg) was also administered to correct hypercalcaemia. Patient was referred to the department of endocrine surgery for necessary surgical intervention.
Outcome and follow-up
The patient improved steadily and was discharged within a span of 7 days. The patient had undergone parathyroidectomy subsequently and the histopathology of the tissue confirmed a parathyroid adenoma. Her postoperative recovery was uneventful and her calcium levels returned to baseline (9.1 mg/dL). She did conceive in the next few months. Now, she is in her first trimester of pregnancy and no episode of recurrence of acute pancreatitis have been reported after her surgery.
Discussion
PHPT is a frequent cause of asymptomatic hypercalcaemia. It is a generalised disorder of calcium, phosphate and bone metabolism due to an increased secretion of PTH. The disease has a peak incidence between the third and fifth decades, but occurs in young children and in the elderly. The diagnosis is typically made by detecting an elevated immunoreactive PTH level in a patient with asymptomatic hypercalcaemia. Preoperative 99m Tc sestamibi scans with SPECT are used to predict the location of hypersecreting focus.3
The involvement of pancreas in hypercalcaemia secondary to PHPT may be in the form of acute, subacute or chronic calcific pancreatitis.4 The prevalence of hypercalcaemia-induced acute pancreatitis is estimated to be between 1.5% and 7%.5 Proposed mechanisms include deposition of calcium salts in the pancreatic duct and calcium mediated activation of trypsinogen within the pancreatic parenchyma resulting in autodigestion of the pancreatic cells.6 The low incidence of acute pancreatitis in chronic hypercalcaemia suggests that factors other than the serum calcium level per se (eg, acute elevations of serum calcium) are responsible for pancreatitis. Another explanation for the association is that hypercalcaemia leads to formation of pancreatic calculi resulting in ductal obstruction and subsequent attacks of acute pancreatitis. In addition, factors like genetic predisposition may also increase the risk.
Serum calcium level is usually low during attacks of acute pancreatitis. Normal or higher calcium levels during acute or chronic pancreatitis should always draw attention to complementary explorations in search of endocrine or malignant cause.7 However, in literature, the association between hypercalcaemia and acute pancreatitis has been mentioned even when hypocalcaemia was seen on initial presentation in acute pancreatitis.8 The mean calcium values were reported to be higher among patients with PHPT and pancreatic disease than those in patients with PHPT without pancreatic involvement. So, estimation of serum calcium is very important in acute pancreatitis to minimise the delay in diagnosis of secondary causes.
The occurrence of acute pancreatitis in PHPT is rare and the cause–effect relationship is also controversial. However, a cause and effect relationship is suggested by the fact that parathyroidectomy seems to prevent recurrence of pancreatitis in some cases.9 The only opportunity for permanent cure is surgical removal of the abnormal gland(s) and it is still is the treatment of choice for those patients who do present with recurrent nephrolithiasis, clinically overt bone disease or severe hypercalcaemia.3 As per literature, nearly 100% patients have reported resolution of pancreatitis symptoms after the cause of PHPT has been addressed.10
Intravenous bisphosphonates have been employed successfully in the urgent therapy of hypercalcaemia due to PHPT.11
In our case, the diagnosis was confirmed by SPECT-CT parathyroid 99m TC sestamibi scan which revealed a parathyroid adenoma. Intravenous bisphosphonates were also administered to correct hypercalcaemia in our patient. Moreover, the histopathological confirmation of parathyroid adenoma with uneventful postoperative recovery, without any further recurrence of attacks of pancreatitis may establish a causal relationship between PHPT and RAP in our case.
A report published from The Mayo Clinic between 1950 and 1975 described that only 1.5% of all the patients of PHPT had coexisting pancreatitis, and alternative aetiologies for pancreatitis were found in many patients.12 A study from south India by Agarwal et al described that pancreatitis was associated with around 6.8% of cases of PHTP (6 out of 87 patients). Among them, 5 patients presented with acute pancreatitis.13
The data obtained via a study in South India in 2006 suggest a causal association between the pancreatic disease and PHPT, attributed to high serum calcium.14 Until more information is available, it would be prudent to check serum calcium in all patients presenting with unexplained pancreatic disease. The pooled clinical and experimental data in a study done in USA in 2012 also suggest an association between PHPT and pancreatitis.15
Thus, for clinicians, it is important to recognise pancreatitis in patients with PHPT and, conversely, to consider PHPT by checking serum calcium levels in patients, who present with recurrent unexplained pancreatitis.
Patient’s perspective.
I am thankful to the almighty that I got diagnosed with a treatable condition. I used to think that with this illness, I will never be able to live my dream of becoming a mother, but thankfully the doctors cured me. God bless them.
Learning points.
Hypercalcaemia is a rare yet important cause of recurrent acute pancreatitis.
Measurement of serum calcium during an acute attack of pancreatitis may be helpful while investigating a case of recurrent acute pancreatitis.
Hypercalcaemia in a background of recurrent acute pancreatitis may be suggestive of primary hyperparathyroidism, though the cause effect relationship is debatable.
Primary hyperparathyroidism is usually asymptomatic or may present with renal calculi or musculoskeletal complications.
Footnotes
Contributors: PKK thoroughly evaluated the case and carried out all relevant investigations to arrive at the final diagnosis. He also supervised the manuscript. SB prepared the manuscript and collected relevant data and investigations. UC was the direct care giver of the patient and also helped in revising the manuscript. AC supervised the entire manuscript and also helped in case analysis and reaching to a definite conclusion.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed.
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