Constipation as an Atypical Presentation of Hyperparathyroidism: A Case Report

Introduction

Primary hyperparathyroidism (PHPT), namely the excess production of parathyroid hormone (PTH), is the third most common endocrine disorder after type 2 diabetes and disorders involving the thyroid [1]. PTH plays an important role in calcium and phosphate homeostasis, along with vitamin D (calcitriol) and fibroblast growth factor 23 [2]. PTH promotes osteoclastic activity at the bone level, resulting in calcium release into the bloodstream. Similarly, in the kidneys, PTH enhances calcium reabsorption and stimulates the activation of vitamin D, which in turn increases calcium absorption at the intestinal level. Its secretion is physiologically inversely proportional to serum calcium levels [3].

The etiopathogenesis of PHPT is typically straightforward, with most cases resulting from solitary adenomas [4]. Less than 15% of cases will present with hyperplasia of all the 4 glands, and even fewer will have multiple adenomas or a carcinoma, which is the rarest cause of PHPT [1,5]. Even though in most cases the proliferation of parathyroid tissue is localized at the gland level, about 1 in 10 patients will have ectopic adenomas [6,7]. A number of genetic conditions can also cause or predispose the patient toward PHPT, such as multiple endocrine neoplasia syndromes and familial hypocalciuric hypercalcemia [8–10].

In general, hyperparathyroidism is asymptomatic at early stages. In fact, during this commonly asymptomatic period, the only usual manifestation is fatigue. As such, the initial diagnosis is usually incidental, via routine laboratory examinations, which reveal mild hypercalcemia (calcium 10.5–11.9 mg/dL); some patients can remain asymptomatic even at moderate hypercalcemia levels (calcium 12.0–13.9 mg/dL), while severe hypercalcemia is defined as serum calcium levels over 14 mg/dL and is associated with potentially severe signs and symptoms, even coma [11,12]. It is therefore considered a medical emergency. When serum calcium levels exceed 12.8 mg/dL, calcifications can start to appear in vital organs, such as the heart, lungs, kidneys, stomach, and vessels, leading to significant complications, such as renal insufficiency, cardiac valve calcium deposition, and atherosclerosis [4,13].

It must be noted that even when the patient is symptomatic, the symptoms and signs themselves are nonspecific, commonly including fatigue, muscle weakness, mental confusion, depression, nausea, vomiting, constipation, and weight loss [4,14]. Therefore, PHPT is commonly underdiagnosed.

Herein, we present a compelling case of a 77-year-old patient who presented to our department with only general, nonspecific gastrointestinal symptoms, despite her elevated calcium levels ranging from 15.59 to 15.63 mg/dL. She eventually received a diagnosis of PHPT, due to parathyroid adenoma.

Case Report

A 77-year-old female patient without comorbidities, presented to our Emergency Department (ED) for left iliac fossa pain, accompanied by progressively more severe constipation in the past 3 months. The patient reported involuntary weight loss of approximately 15 kg in the same period. The patient also reported intermittent nausea and vomiting. The patient did not report any other comorbidities, past illnesses, history of surgical interventions, or childhood infections. There was nothing significant in the patient’s personal medical history and the family history, containing nothing of note or especially associated with the patient’s present condition.

On the clinical examination, she appeared depressed, although she was conscious and cooperative, with no difficulties in breathing. She was afebrile, with normal blood pressure of 120/70 mmHg, and a heart rate of 90 beats/min. Her abdomen was soft and regular, with sensitivity on palpation over the left iliac fossa, without signs of peritoneal irritation (no guarding). Bowel sounds were present, while the spleen and kidneys were not palpable. In the ED, we performed an electrocardiogram, which showed no abnormalities. There were no clinical signs or symptoms of severe dehydration that could have explained the constipation. Regarding paraclinical evidence, there was no hemoconcentration and no hypernatremia, and the blood urea nitrogen to creatinine ratio was less than 20: 1, thus ruling out dehydration [15]. Despite 2 adequate administrations of polyethylene glycol solution, there were no bowel movements, which would have been the case had the cause of constipation been dehydration.

In the ED, we performed an abdominal ultrasound, in which the only abnormal findings were gallbladder sludge and microcalcifications, with intense abdominal meteorism. Thoracic and abdominal computed tomography (CT) scans were also performed. In the abdominal CT, calcified and non-calcified mixed plaques were visible in the lumen of the aorta (Figure 1) and superior mesenteric artery (Figure 2), presenting approximately 50% lumen reduction, along with fecal loading changes throughout the entire colon. While these calcifications could have been age-related, their extent did not correlate well with the rest of the cardiovascular profile of the patient. Furthermore, calcifications at the level of the superior mesenteric artery are most probably suggestive of impaired calcium metabolism, in the absence of cardiovascular risk factors [16]. Also, at the level of the liver parenchyma, a few diffusely distributed microcalcifications were noted. The digital rectal examination was normal. After admission to the hospital, having left the ED, a colonoscopy was attempted. This could not be performed, due to the high volume of the immovable feces, although the adequate colonoscopy preparation had been performed at least 2 times. An endoscopy, performed to specifically rule out gastrointestinal ulcers, which are often associated with nausea and vomiting, did not reveal any such pathology.

A laboratory examination revealed nothing beyond normochromic normocytic anemia, elevated ferritin levels, and increased creatinine levels (1.28 mg/dL, reference range: 0.514.95 mg/dL). Such findings did not correlate with the clinical presentation of the patient or with the echography findings.

Subsequently, a larger number of biochemical values were determined, and severe hypercalcemia, with a serum calcium level of 15.59 mg/dL, was revealed. Serum phosphorus levels were normal at 2.8 mg/dL, while serum vitamin D levels were not determined. Several hours later, along with the total serum calcium level, which was 15.63 mg/dL, the PTH values were 1028.3 pg/mL (reference range: 15–65 pg/mL).

Based on the levels of the laboratory test results for PTH and serum calcium levels, the patient received a diagnosis of PHPT. The potential for a malignancy had already been excluded after the abdominal and thoracic CT scans were performed. At that moment, the patient was treated with zoledronic acid (intravenous [i.v.] bisphosphonates) and i.v. saline solution, in an initial attempt to decrease the very high levels of calcium in the blood.

The patient was then referred to the Endocrinology Department, where she had a scintigram of the parathyroid glands, and the final diagnosis of a primary parathyroid adenoma was established. The subsequent CT revealed the adenoma to have a diameter of 2.99 cm (Figure 3); it was located at the left inferior parathyroid gland. The parathyroid adenoma was then surgically removed successfully, and the serum calcium levels returned to normal. Although the potential of an undiagnosed malignancy was very low, as mentioned, we sent a sample of the parathyroid for an anatomopathological examination following its removal, but no signs of malignancy were found. The presence or absence of a malignancy at this stage would not have altered our treatment course, as the objective was the removal of the parathyroid gland in order to restore calcium levels to normal. Given that the urine output was normal, there was no indication for hemodialysis.

Discussion

As already mentioned, the absence of signs and symptoms or their nonspecific character, if present, leads to an underdiagnosis of PHPT [4]. When considering that muscle weakness, fatigability, vomiting, constipation, and weight loss are fairly common manifestations of a number of pathologies – frequent and rare – the difficulty of a differential diagnosis becomes apparent.

For a patient presenting solely with gastrointestinal symptoms, the spectrum of probable pathologies is even more extensive, and such a presentation will naturally point medical personal toward causes other than PHTP. In our case report, a 77-year-old woman presented to our Gastrointestinal Department with only nausea, vomiting, constipation, and weight loss. Given these symptoms, a variety of gastrointestinal diseases were initially considered. There was no evidence either clinically or in the patient’s medical history that raised the possibility of other underlying causes. Although the patient was female – placing her at higher risk for PHPT than men – she was outside the typical peak incidence age range of 50 to 60 years.

A laboratory examination revealed nothing beyond normochromic normocytic anemia, elevated ferritin levels, and increased creatinine levels (1.28 mg/dL, reference range: 0.51–0.95 mg/dL). Although anemia has been described in the context of hyperparathyroidism [17], and ferritin and creatinine abnormalities can be seen in secondary hyperparathyroidism [18], on their own, such abnormalities do not raise suspicion for PHPT in a patient with no known history or other signs and symptoms. It has been reported in medical literature that hypercalcemia can be associated with gastric ulcers [19]; this possibility was ruled out following an upper gastrointestinal endoscopy.

As previously mentioned, the attempted colonoscopy was unsuccessful. It was performed because newly developed constipation and weight loss are commonly suggestive of colorectal malignancy [20]. Subsequently, an abdominal CT was performed, which unfortunately did not provide a specific diagnosis but confirmed a large bowel full of feces.

After we ruled out most primary gastrointestinal diseases, the next logical assumption was a functional gastrointestinal disorder, aside from the depressive disorder diagnosed by the Psychiatry Department. Several hours later, an electrolyte assessment revealed critically high calcium levels that were indicative of a hypercalcemic crisis (15.59 mg/dL). Repeat testing of PTH levels (1028 pg/mL, reference range: 15–65 pg/mL) confirmed the diagnosis of hyperparathyroidism. Collaboration with the Endocrinology Department led to the identification of primary hyperparathyroidism due to a parathyroid gland adenoma.

We must note that a hypercalcemic crisis is a medical emergency and must be treated as soon as possible. PHPT is the most common cause of such crises [21], which manifest with oliguria to anuria, somnolence, or even coma [21]. Hemodialysis, or even continuous hemodialysis or continuous hemodiafiltration with special dialysates, are usually recommended in hypercalcemic crises [22]; however, clinicians must consider their potential for severe adverse effects, such as hypotension and arrhythmias [23,24].

Upon discovering elevated serum calcium levels, the differential diagnosis should include PHPT, paraneoplastic syndromes, hypervitaminosis D, prolonged immobilization, and other potential causes [25]. Following the determination of hypercalcemia, elevated PTH levels are enough to indicate PHPT. In the differential diagnosis, there was no reason to consider secondary hyperparathyroidism, as there were no associated conditions, such as the patient being in long-term hemodialysis [26]. Even more revealing, both the PTH and calcium levels in our patient were high, which is not characteristic of secondary hyperparathyroidism. It must be noted that other signs and symptoms characteristic of PHPT-induced hypercalcemia, such as diffuse osteoarticular pain, recurrent renal lithiasis, and unexplained fatigue fractures [25], were not found in our patient.

Gastrointestinal symptoms are the fourth most common presentation in patients with PHPT [27]. A few case reports describe predominantly gastrointestinal symptoms and signs as a result of undiagnosed PHPT, namely melena [28], progressive dysphagia [29], unexplained abdominal pain [27], and acute pancreatitis [30], and all such presentations are considered atypical.

Based on a PubMed and Google Scholar search using the keywords “primary hyperparathyroidism” and “atypical symptoms”, we found a number of cases in which PHPT presented with atypical symptoms. However, when adding the keyword “gastrointestinal symptoms”, only very few case reports were available, namely that of 1 patient presenting with severe hypercalcemia-induced dysphagia [29], 2 patients with dysphagia due to mechanical compressions of the esophagus by the parathyroid adenomas themselves [31,32], and 1 case of a woman presenting with a more complex, yet atypical, symptomatology comprising anorexia, mutism, and dysphagia [33]. A few other cases of dysphagia are also described in the literature [34–39]. A search for case reports of patients with PHPT presenting with constipation, among other PHPT-related symptoms, yielded few results [40–45]. While there are reports of rare pathological manifestations, although not gastrointestinal, in patients with chronic hyperparathyroidism [46], our patient did not have chronic PHPT.

The results of our search of relevant medical literature underscores that there are no such other clinical case reports of patients with parathyroid adenoma and only gastrointestinal symptoms as clinical manifestation. Even in other cases in which constipation is among the initial manifestations of PHPT, it is accompanied by other symptoms, as outlined in the aforementioned case reports. This establishes the uniqueness of our case report, in which PHPT-induced gastrointestinal symptoms necessitated the presentation of the patient to the ED.

This case highlights the challenges in diagnosing PHPT, especially when patients present with only general gastrointestinal symptoms. The prevalence of PHPT across all age groups varies between 0.2% and 1.3%, depending on different populations [47–50], and has been gradually increasing in the last years [50,51]. This increase may be true or be caused by increasingly accurate diagnoses [50]. Even if the prevalence of the disease is fairly low, PHPT is characterized often by an unusual diagnostic complexity, mainly due to its nonspecific symptoms or even lack thereof at initial stages.

Conclusions

We present a very rare case of PHPT presenting only with gastrointestinal symptoms, namely severe constipation, involuntary weight loss in the previous 3 months, and intermittent nausea and vomiting. While the initial checkup was inconclusive, the subsequent determination of PTH and calcium levels in the blood pointed toward PHPT. This diagnosis was confirmed by a parathyroid scintigram, which located the parathyroid adenoma. At the time of presentation, the patient already had significantly life-threatening hypercalcemia. The initial treatment of zoledronic acid and i.v. saline solution was successful in halting the increasing calcium levels. The parathyroid adenoma was then removed by surgery, and the patient made a full recovery. Our report promptly underscores the importance of the early suspicion of a parathyroid pathology in patients presenting with gastrointestinal symptoms, when there is other no apparent cause. Therefore, we recommend that gastroenterologists include serum calcium levels, or preferably a complete electrolyte panel, in their initial diagnostic evaluations in patients presenting with unexplained severe constipation or other gastrointestinal symptoms.