Ectopic parathyroid adenoma causing hyperparathyroidism-induced psychosis: A case report

Abstract

Primary hyperparathyroidism is a disease with multisystemic and heterogeneous manifestations, characterized by underlying high parathormone concentrations. Despite neuropsychiatric involvement being one of the manifestations, psychosis is rare. This is the case of a 68-year-old female with a 10-day clinical course of anorexia, mutism, dysphagia, constipation, and weight loss. The patient had disorganized speech associated with paranoid delusions. Prior to this visit, the patient was recently diagnosed with a mixed anxiety-depressive disorder. For this reason, treatment with antidepressants in combination with atypical antipsychotics was administered without a satisfactory response. Neuroimaging, infectious panel, and toxicology screening showed no abnormal findings. Hypercalcemia secondary to a retropharyngeal ectopic parathyroid adenoma was the causative etiology of her primary hyperparathyroidism, and hypercalcemia treatment resolved the psychotic episode. We highlight the importance of recognizing psychosis as a possible initial presentation of hyperparathyroidism and hypercalcemia. Ruling out organic etiologies prior to diagnosing a primary cause of psychosis is crucial, as their treatment can reverse the psychotic symptoms.

Introduction

Psychosis is a symptom defined by impaired reality testing and characterized further by hallucinations, delusions, disorganized speech, thinking, or behavior.^1,2 Primary psychiatric etiologies account for only 40% of psychotic episodes, while the remaining 60% are attributed to underlying organic etiologies (secondary psychosis). ³ More specifically, electrolyte imbalance, cerebrovascular disease, infections, traumatic brain injury, brain tumors, temporal lobe epilepsy, storage diseases, and mitochondrial disorders can present as new-onset psychosis. ⁴ A significant number of patients with misdiagnosis of schizophrenia have been reported to have an organic cause of psychotic symptoms; thus, excluding secondary causes of psychotic symptoms is fundamental. ⁵

Among endocrine conditions that can manifest as psychosis, Cushing’s syndrome and thyroid diseases account for most cases, while primary hyperparathyroidism (pHPT) remains a relatively rare cause. ⁶ pHPT is characterized by abnormally high parathyroid hormone (PTH) levels, resulting in calcium homeostasis imbalances. Functional adenomas (80% of cases) and multiple-gland hyperplasia are the leading causes of PTH hypersecretion. ⁷ Although pHPT usually presents as asymptomatic hypercalcemia, a wide variety of musculoskeletal, renal, and neuropsychiatric symptoms can occur secondary to hypercalcemia. ⁸ Asymptomatic and non-specific presentations can delay the diagnosis, resulting in more severe manifestations, complications, and sequelae. Therefore, pHPT should be suspected in cases of weakness, nausea, polydipsia, polyuria, abdominal pain, irritability, and acute psychosis. ⁶

In this case, we present an infrequent clinical scenario of new-onset psychosis induced by pHTP in a patient with a history of a mixed psychiatric disorder. The clinical course was notable for an unusually located ectopic adenoma, which resulted in a delayed diagnosis.

Case report

A 68-year-old female with a past medical history of well-controlled hypertension presented with a 10-day clinical course of paranoid delusions, anorexia, mutism, dysphagia, constipation, and disorganized behavior and speech.

The patient had no personal or family history of psychiatric illness; however, 2 months prior to the index presentation, she was evaluated due to anhedonia, non-specific gait abnormalities, and a 5-kg weight loss. The onset of these symptoms was related to a traumatic event in which she and her husband were simultaneously hospitalized for severe COVID-19, requiring critical care. Although the patient made a full recovery, her husband died, and due to her critical condition, she did not find out until several weeks later. In that previous consultation, she was diagnosed with a mixed anxiety-depressive disorder with psychotic symptoms for which treatment with antidepressants (sertraline 50 mg/day) and atypical antipsychotics (levomepromazine 5 drops/day) was started without an adequate response. The symptoms persisted after 6 weeks, even after the addition of a second antipsychotic (risperidone 2 mg/day). She reported being adherent to treatment and denied recreational drug use or other remarkable personal or familial psychiatric history.

At the index admission, the mental examination revealed diminished language production, altered introspection, and paranoid delusions. The rest of the physical and neurological examinations were unremarkable. The initial working diagnosis was probable schizoaffective features associated with the newly diagnosed psychiatric condition. However, the age and abruptness of onset, as well as the suboptimal response to medications, raised the suspicion of underlying organic pathology.

Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain showed no abnormal findings. Laboratory workup ruled out infections and ingestions. Moreover, an upper gastric endoscopy was performed due to dysphagia and weight loss, ruling out malignancies and other anatomical defects. The metabolic panel was remarkable for an elevated corrected total calcium (13.21 mg/dL, normal: 8.6–10.3 mg/dL), confirmed with ionized calcium (1.8 mmol/L, normal: 1.15–1.30 mmol/L). A workup for hypercalcemia ruled out malignancies with a negative serum protein electrophoresis and a normal thoracoabdominal CT. pHPT was diagnosed based on an elevated PTH (396 pg/mL, normal: 14–55 pg/mL), a normal 24-h urinary calcium (224 mg/day, normal: 100–300 mg/day), and the incidental finding of nephrolithiasis in the abdominal CT (laboratory results are presented in Table 1). Scintigraphy was performed and revealed a retropharyngeal ectopic parathyroid adenoma.

Table 1.

Laboratory test results.

Variables	Result	Normal range
Initial ionized calcium (mmol/L)	1.8	1.20–1.32
Corrected calcium (mg/dL)	13.21	8.5–10.2
PTH (pg/dL)	396	14–55
Serum phosphorus (mg/dL)	2.80	2.8–4.5
Serum creatinine (mg/dL)	0.97	0.59–1.04
25-Hydroxyvitamin D (mg/dL)	22	20–40
24-h urinary calcium excretion (mg/day)	224	100–300
Ionized calcium levels after medical interventions
Post-hydration ionized calcium (mmol/L)	1.78	1.20–1.32
Ionized calcium after unique zoledronic acid dose (mmol/L)	1.11	1.20–1.32

PTH: parathyroid hormone levels.

Intravenous fluids were used as first-line treatment of hypercalcemia, without improvement. Consequently, a single 4 mg dose of intravenous zoledronic acid was administered, achieving a decline in ionized calcium to 1.11 mmol/L in the following week. With the resolution of hypercalcemia, psychiatric symptoms subsided, delusions ceased, and dysphagia resolved.

Upon discharge, the antipsychotics were discontinued, and cinacalcet (30 mg daily) was started. She was referred to the head and neck surgery department for parathyroidectomy. However, in the context of the COVID-19 pandemic, surgery had to be deferred, and the patient was lost to follow-up.

Discussion

Multiple endocrine disorders such as Cushing’s and thyroid disorders can present with psychosis as their initial symptom. In adults, pHPT is rarely linked to these symptoms, and the explanation may be linked to the effect of hypercalcemia. Calcium plays a role in neurotransmitter release, monoamine metabolism, and the modulation of the dopaminergic and cholinergic regulatory systems.^9,10 Hypercalcemia has been thought to cause dysregulation of these processes, resulting in neuropsychiatric symptoms (mainly via the mesolimbic pathway). It is crucial to exclude it as a secondary cause of new-onset psychosis as it is reversible with appropriate treatment.

A cohort of 405 patients with pHTP reported an incidence of psychiatric symptoms of 4.2%. ¹¹ Out of this subgroup, psychosis was infrequent and heterogeneous, ranging between (a) confusional psychosis, (b) paranoid ideation and depression, and (c) somatic symptoms. ¹² Severe hypercalcemia is most likely to lead to psychosis, while moderate hypercalcemia is more commonly associated with depression and irritability. ¹³ Nevertheless, in pHPT cases, an exact correlation between the degree of hypercalcemia and the severity of psychosis is undetermined. Interestingly, mild hypercalcemia has been reported to cause psychiatric symptoms when hypertension, advanced age, white matter lesions, or cognitive impairment is present. ¹⁴ Few cases of pHPT-induced psychosis have been reported in the literature (Table 2). ⁶ ,15–20 As in our case, most patients had a rapid onset of psychosis (days to weeks) and poor response to psychiatric treatment alone, contrary to reported cases of primary psychosis with concomitant pHPT. ²¹

Table 2.

Comparison with similar cases.

Case	Age (years)/sex	Clinical manifestations	Previous psychiatric diagnosis	Duration of symptoms (weeks)	Measurment of calcium at onset of psychiatric symptoms	Calcium (mg/dL)	Phosphorus (mg/dL)	iPTH (pg/mL)	Treatment for hypercalcemia	Clinical response (defined as the resolution of psychiatric symptoms)	Paraclinical response (defined as the normalization of calcium and PTH serum levels)
Our case	68/F	Anorexia, mutism, swallowing disorder, dysphagia, constipation, disorganized behavior, and speech, with paranoid delusion	Yes	2.5	No	13.2	2.8	396	Medical	Yes	Yes
Otsuki et al. 15	68/F	Insomnia, disorientation, auditory hallucinations, delusions, irritability	No	1	No	10.4	Non-reported	184.0	Surgery	Yes	Yes
Nagy et al. 16	58/F	Headache and change in mental status, including paranoia and auditory hallucinations	No	3	Yes	14.4	2.0	759	Medical and surgery	No	Yes
Singh et al. 6	Middle-age/F	Third- person auditory hallucinations, paranoid delusions, confusion, low mood, and amnesia for 2 weeks, somnolence, hyporexia	No	2	No	14.0	1.86	High (a different test was used)	Medical	Yes	Yes
Babar and Alemzadeh 17	17/M	Aggressive, hostile, and angry moods associated with paranoia, visual and auditory hallucinations	No	2–3	Yes	16.5	Non-reported	242.0	Medical and surgical	Yes	Yes
Park and Hieber 18	38/M	Anxiety, chest tightness, tinnitus, profuse sweating, and syncope, hyporexia, depressed mood, paranoia	Yes	16	No	11.0	Non-reported	106	None	No	Unknown
Papa et al. 19	72/M	Confusional state, psychomotor agitation, loss of short-term memory, and irritability, weakness, anorexia, and progressive depression, visual and auditory hallucinations	No	8	Yes	17.8	2.7	708.3	Medical and surgical	Yes	Yes
Watson and Marx 20	63/M	Altered behavior, paranoia, hyporexia, agitation	No	6–8	Yes	10.8	2.3	127	Medical and surgical	Yes	Yes

PTH: parathyroid hormone levels.

Treatment of hypercalcemia is recommended for all symptomatic patients and aims to decrease bone resorption and increase the renal elimination of calcium. Both hydration and loop diuretics are viable options to increase calciuresis in the acute setting. Definitive treatment of the underlying cause is fundamental to achieving control of hypercalcemia. Single parathyroid adenomas are the leading cause of pHPT as they increase secretion and decrease suppression of PTH. Around 15% of these tumors arise from ectopic parathyroid tissue. ²² During embryology, the parathyroid glands descend to their usual anatomical position, making it possible for them to be ectopically lodged at any point along this pathway. Ectopic parathyroid adenomas are usually mediastinal, thymic, retroesophageal, and intrathyroidal, while retropharyngeal adenomas have rarely been reported. ²³ The localization of the latter creates a diagnostic problem since they can be undetected on many occasions, resulting in recurrent or persistent pHPT. A delayed diagnosis can result in increased complications like psychosis, especially in the presence of confounding factors such as a previous psychiatric diagnosis, as depicted in our case.

Parathyroidectomy is the definitive treatment for symptomatic adenomas, independent of their location. Three randomized controlled trials (RCT) have shown partial improvement in some aspects of mental evaluation in patients with pHPT treated with surgery.^24–26 Conversely, a metanalysis showed no benefit. ²⁷ In all the cases reported of pHPT-induced psychosis, surgery was beneficial in the short term.

Non-surgical treatment can be an alternative when surgery is contraindicated or cannot be performed. Bisphosphonates have been shown to decrease hypercalcemia and increase bone resorption, but the evidence in pHPT is limited. Cinacalcet can be another option, as it reduces PTH secretion and increases calcium sensitivity in the parathyroid gland. Both zoledronic acid and cinacalcet were effective in our case. Nonetheless, the best treatment in these scenarios remains to be fully elucidated.

Conclusion

We present an unusual case of pHPT-induced psychosis due to an infrequent retropharyngeal ectopic parathyroid adenoma. This case shows the importance of evaluating hypercalcemia and other secondary causes in scenarios of acute new-onset psychosis, as its treatment could revert the symptoms.