REMISSION OF LONGSTANDING INSULIN-TREATED DIABETES MELLITUS FOLLOWING SURGICAL RESECTION OF PHEOCHROMOCYTOMA

Abstract

Objective:

To describe the case of a woman with a longstanding misdiagnosis of type 1 diabetes mellitus (T1DM), in whom diabetes remission was achieved following surgical resection of adrenal pheochromocytoma.

Methods:

We present a case report with accompanying biochemical, histologic, and genetic investigation results.

Results:

We report the case of a 57-year-old woman with a 13-year history of apparent T1DM, and her presentation with intermittent exertional nausea. An abdominal ultrasound scan identified a rounded heterogeneous mass measuring 120 × 110 × 104 mm superior to her left kidney. Plasma metanephrine levels were markedly elevated with normetaneprhine at 17,856 pmol/L (reference range is 120 to 1,180 pmol/L), metanephrine >25,000 pmol/L (reference range is 80 to 510 pmol/L), 3-methoxytyramine at 1,393 pmol/L (reference range is 0 to 180 pmol/L). The mass demonstrated marked uptake on an iodine-123-meta-iodobenzylguanidine scan. The patient's hypertension was managed with phenoxybenzamine, and she underwent adrenalectomy. Following surgery, she was able to discontinue all diabetes medications and has maintained a hemoglobin A1c value <48 mmol/mol for over 12 months.

Conclusion:

The case illustrates that remission of T1DM is possible even after prolonged insulin treatment upon surgical resection of pheochromocytoma. It highlights the potential benefits of reevaluating the diagnostic classification of T1DM in the light of new clinical information.

INTRODUCTION

Pheochromocytomas (PCCs) are catecholamine-secreting neoplasms arising from adrenal chromaffin cells (1), or, in about 10% of cases, from extra-adrenal chromaffin tissue (paranganglioma). It is a rare condition, with an annual incidence reported at about 2 to 8 cases per million people (2). Disorders of glucose tolerance and hyperglycemia are relatively common with PCC due to elevated circulating catecholamine levels, and a high proportion of such patients achieve remission of diabetes mellitus following surgical resection of PCC.

This report describes an unusual case of a patient who had received a clinical diagnosis of type 1 diabetes mellitus (T1DM) 13 years prior to presentation with PCC, and who achieved remission of T1DM following surgery.

CASE REPORT

A 57-year-old woman presented to her primary care physician reporting a 13-year history of progressively worsening nausea and vomiting associated with physical exercise such as cycling. She provided written, informed consent for this case report. Her past medical history included a clinical diagnosis of T1DM made about 13 years previously as well as hypertension and gastritis. In addition, she had been seen on several occasions in secondary care by cardiology specialists with intermittent palpitations and an associated sensation of unease, which resulted in a series of investigations including a 24-hour ambulatory electrocardiogram demonstrating intermittent sinus tachycardia, and cardiac magnetic resonance imaging which showed mild left ventricular hypertrophy. Her regular medication included twice daily insulin detemir with a total daily dose of 24 units, insulin aspart with meals at a typical dose of 2 to 4 units, candesartan at 32 mg once daily, modified-release diltiazem at 240 mg, and simvastatin at 40 mg once daily.

On review, the clinical records do not state the rationale for the diagnosis of T1DM, but it appears the diagnosis was likely made based on a normal body mass index, relatively young age, and absence of a family history of diabetes mellitus. There was no history of diabetic ketoacidosis. Glycemic control was suboptimal, reflected in a hemoglobin A1c value of 79 mmol/mol.

To investigate her symptoms, her primary care physician ordered an ultrasound of the abdomen and a series of blood tests. Serum cortisol was measured to investigate for adrenal insufficiency in the context of apparent T1DM and recurrent nausea and vomiting; it was 1,278 nmol/L (reference range is 170 to 540 nmol/L). This raised cortisol level prompted a referral to the endocrinology service.

At review in the endocrinology outpatient clinic, the patient was hypertensive with a blood pressure of 199/93 mm Hg. Her body mass index was 22.5 kg/m². Clinical examination was otherwise unremarkable, and there were no cushingoid features.

The abdominal ultrasound scan showed a 120 × 110 × 104-mm, heterogeneous mass with cystic components and evidence of internal vascularity situated above the left kidney. An urgent computer tomography scan further described this mass as being of heterogeneous density, with solid and cystic components, in close relationship with the upper pole and lateral margin of the left kidney (Fig. 1). Further laboratory analysis demonstrated markedly elevated catecholamine levels with normetaneprhine at 17,856 pmol/L (reference range is 120 to 1,180 pmol/L), metanephrine >25,000 pmol/L (reference range is 80 to 510 pmol/L), and 3-methoxytyramine at 1,393 pmol/L (reference range is 0 to 180 pmol/L). Although the patient did not fully suppress her cortisol with 2 mg of dexamethasone on overnight suppression testing, her urinary free cortisol and plasma adrenocorticotropic hormone levels were within their normal ranges. The mass demonstrated marked uptake on an iodine-123-meta-iodobenzylguanidine (MIBG) uptake scan, with no evidence of further MIBG-avid disease identified.

Fig. 1.

Computed tomograpy image showing a mass of heterogeneous density, with solid and cystic components, in close relationship with the upper pole and lateral margin of the left kidney.

The patient was managed with alpha-blockade with phenoxybenzamine, with the dose titrated to 30 mg 3 times per day to achieve good blood pressure control. The patient underwent an open left-sided adrenalectomy.

Following surgery, the patient was able to discontinue insulin. She has remained normoglycemic on no diabetes-related medication for over 12 months following adrenalectomy, with hemoglobin A1c values <42 mmol/mol. Her diabetes team has since measured anti-islet cell and anti-glutamic acid decarboxylase antibodies, neither of which were detectable before surgery.

Histology of the resected tumor showed findings in keeping with PCC, with immunohistochemistry demonstrating staining of the sustentacular cells for S100, and strongly positive immunostaining for succinate dehydrogenase-A with weaker staining for succinate dehydrogenase-B. The following genetic tests did not identify any known disease-causing variants: EGLN1 (egl-9 family hypoxia inducible factor 1), EGLN2 (egl-9 family hypoxia inducible factor 2), KIF1B (kinesin family member 1B), MAX (MYC-associated factor X), NF1 (neurofibromin 1), RET (ret proto-oncogene), SDHA (succinate dehydrogenase complex flavoprotein subunit A), SDHAF2 (succinate dehydrogenase complex assembly factor 2), SDHB (succinate dehydrogenase complex iron sulfur subunit B), SDHC (succinate dehydrogenase complex subunit C), SDHD (succinate dehydrogenase complex subunit D), TMEM127 (transmembrane protein 127), and VHL (von Hippel-Lindau tumor suppressor).

DISCUSSION

The clinical presentation of PCC can be insidious, subtle, and nonspecific, which may partly account for the reported average delay in diagnosis of about 3 years after the onset of symptoms (3). Case series show diabetes mellitus has a prevalence of 25 to 35% in patients with PCC, and case reports indicate that, for some patients, the diagnosis of diabetes mellitus precedes the diagnosis of PCC by a number of years (Table 1) (4,5).

Table 1.

Summary of Case Reports with Diabetes Mellitus Diagnosed before Pheochromocytoma

Reference number	Patient age (years)	Sex	Years of diabetes mellitus diagnosis prior to diagnosis of pheochromocytoma	Initial classification of diabetes	Remission of diabetes following surgical correction of pheochromocytoma?	Duration of insulin therapy (years)
14	31	Male	3	Type 1	Yes	3
20	36	Male	2	Type 2	Yes	not available
21	53	Male	12	Type 2	Yes	2
22	70	Male	3	Type 2	Yes	not available
23	65	Male	2	Type 2	Yes	<1
24	65	Male	2	Type 2	Yes	<2
25	41	Female	1	Type 2	Yes	not available

Hyperglycemia associated with of PCC is mediated by the action of elevated catecholamines through multiple mechanisms. For instance, there is a β-adrenergic mediated increase in hepatocyte gluconeogenesis and glycogenolysis (6). In addition, stimulation of α-2 receptors of pancreatic β cells has been shown to suppress insulin secretion (7,8). There is evidence that PCCs are associated with increased insulin resistance, as evidenced by the use of the euglycemic insulin clamp to show improved insulin sensitivity with pharmacological adrenergic blockade and further improvement following adrenalectomy (9,10).

It has long been known that surgical resection of PCCs can result in remission of diabetes mellitus (11). Retrospective studies have shown remission of diabetes mellitus is achieved in 79 to 90% of cases, with the caveat that there is variation within the study methodologies for length of follow-up and the method of determination of remission (12,13). Interestingly, patients with a lower body mass index are more likely to achieve remission. This may reflect the higher catecholamine levels seen in larger tumors, which could provide a more powerful diabetogenic impetus, or the weight-negative effects of elevated catecholamines. Alternatively, this difference may represent the higher prevalence of risk factors for type 2 diabetes mellitus through mechanisms independent of PCC in more overweight patients.

The mistaken diagnosis of T1DM in cases of PCC has been reported (14), but this case is unusual because of the duration of the woman's insulin-treated T1DM prior to her surgery. It has been established that plasma metanephrine levels are normally elevated for several years prior to diagnosis with PCC, with 1 longitudinal retrospective study reporting the first elevation in metanephrine above the upper limit of the reference range was evident at a median of 6.6 years prior to diagnosis (15). Given our case's clinical history of duration of adrenergic symptoms, new-onset of diabetes mellitus and hypertension, it is likely she has had significantly elevated catecholamine levels for more than 13 years (since prior to diagnosis).

This case illustrates the potential benefits in revisiting even long-established diagnostic labels when new clinical information becomes available. This is important as the misclassification of diabetes mellitus is common and has been reported to affect 7 to 15% of patient with diabetes mellitus (16–18), although the true extent of misclassification may be even greater (19).

CONCLUSION

This case illustrates that remission of diabetes mellitus is possible even after prolonged insulin treatment upon surgical resection of PCC. Such cases serve to remind the clinician of the benefits of critically reevaluating the diagnostic classification of diabetes mellitus in the light of new clinical information.

Abbreviations:

PCC

pheochromocytoma

T1DM

type 1 diabetes mellitus