This case report highlights an unusual and interesting case of hypoglycemia, an uncommon clinical phenomenon outside of the diabetic population. Although it involves one clinical scenario of hypoglycemia, it outlines the systematic approach required to achieve diagnosis and the following discussion highlights pertinent points relating to the diagnosis of pathological hypoglycemia with particular attention to IGF2 mediated processes.
In patients without underlying diabetes, hypoglycemia is diagnosed on the basis of a blood glucose less than 3 mmol/L occurring in the context of Whipple’s triad [1, 5]. This includes symptoms or signs related to hypoglycemia, a laboratory confirmed low blood glucose and improvement of clinical status following treatment of hypoglycemia [1]. Once criteria are fulfilled, investigation as to the cause of hypoglycemia proceeds according to the classification outlined in the Endocrine Society Practice Guideline [1] and detailed in Table 3.
Tumour-induced hypoglycemia is a rare clinical entity encompassing a variety of underlying pathophysiological mechanisms. Eutopic insulin secretion originates from tumours in the pancreatic β-cell but ectopic non-islet cell tumours also occur less commonly [1, 2]. The latter, non-islet cell tumour hypoglycemia (NICTH), encompasses tumour secretion of IGF2, both mature and incompletely processed forms, and less commonly IGF1, somatostatin and glucagon-peptide 1, which stimulate glucose consumption through different mechanisms [2, 6]. The phenomenon of tumour-induced hypoglycemia is observed in cases of significant neoplastic disease as a consequence of increased glucose consumption, liver infiltration and/or pituitary or adrenal gland destruction in the absence of a humoral mediator of hypoglycemia.
The first case of NICTH with IGF2-immunostain positive tumour resection with compatible biochemistry was described in 1988 by Daughaday et al. [7] A 67-year-old presented with recurrent hypoglycemia which resolved after resection of a thoracic leiomyosarcoma with large molecular weight (big) insulin-like growth factor 2 detected on histopathology and in serum. In the interim, further clinical cases with various underlying neoplasm have been described. Traditionally it is believed to be a rarer phenomenon than hypoglycemia due to insulinoma [8]; although this has more recently been challenged due to increased recognition of hypoglycemia in patients with hepatocellular carcinoma [9].
NICTH has been described in a broad range of epithelial and mesenchymal tumours [3]. Hepatocellular carcinoma as reported in the original case description of IGF-2 mediated hypoglycemia in 1929 [8], is the most prevalent neoplasm causing NICTH [3]. Most tumours are large with one review of 78 patients observing tumour diameter of more than 10 cm in 70% [10]. Both benign and malignant pathology is observed [3]. Importantly, hypoglycemia is not a predictor of the size or aggressiveness of the tumour [11].
NICTH is almost exclusively secondary to excessive secretion of IGF-2 or the prohormone, pro-IGF-2. Abnormal activation of promotor regions in the IGF-2 gene, located on the short arm of chromosome 11, results in excessive pro-IGF2 production [3]. Elevated pro-IGF-2 levels oversaturate the prohormone convertase enzyme responsible for conversion of pro IGF-2 to mature IGF-2 [12]. This can lead to a disproportionate rise in big-IGF-2.
Physiologically, IGF-2 forms a 150 kDa complex bound to insulin like growth factor binding protein 3 (IGFBP-3) and acid labile subunit (ALS) [3]. This accounts for 70% of its circulating form with the remaining 30% forming a smaller 50 kDa complex of IGF-2 and IGFBP-3 [3]. Pro-IGF-2 has a lower affinity for binding proteins such as IGF-BP3 and acid labile subunit (ALS). Therefore, big IGF2 forms a lower molecular weight complex. This relatively lower molecular weight results in increased bioavailability of IGF-2 in circulation and increased binding to insulin receptors with subsequent increased peripheral glucose consumption and decreased glycogenolysis, gluconeogenesis and ketogenesis at hypothalamic and hepatic levels [3, 10].
Hypoglycemia generally occurs in the fasting state [13]. Autonomic features such as sweating and tremor, can be blunted in the setting of recurrent episodes of hypoglycemia. Neuroglycopenic symptoms such as confusion, amnesia and seizures tend to predominate [13]. As demonstrated by Jannin et al. in a case series, confusion was the presenting symptom of IGF2-mediated hypoglycemia in three of six patients [14]. This illustrates the importance of recognising hypoglycemia as a reversible cause of confusion and consequent morbidity in the elderly. Hypoglycemia in the setting of IGF-2 excess is associated with increased symptom severity due to lack of ketogenesis as activation of the insulin receptor by IGF-2 not only stimulates glucose utilisation but also suppresses free fatty acid release therefore limiting brain energy supply [15]. NICTH should be considered in any patient with an established oncological diagnosis as well as cerebral metastasis, opioid use and infection which can mimic a presentation of hypoglycemia [16].
Hypokalaemia is a feature in approximately half of all cases at presentation, as was the case with our patient, however is generally only recognised in retrospect [10]. The mechanism for this is not established. Acromegaloid features as a consequence of IGF receptor activation have been described in the context of a pelvic clear cell sarcoma [17]. The woman presented with skin tags and course facial features which subsequently settled after tumour resection. These features are hypothesized to arise from IGF-2-mediated stimulation of insulin-related and IGF-1-related receptors [3].
Initial evaluation for the presence of Whipple’s triad is essential. Hypoglycemia can be the presenting feature of hypopituitarism and hypoadrenalism as well as acute presentations of hepatic or renal failure, sepsis and starvation [18]. A clinical review, including thorough history and examination to elucidate features of systemic disease and medication use completes initial work up. Biochemical assessment of glucose, insulin, c-peptide, proinsulin and β-hydroxybutyrate during a hypoglycemic episode will differentiate pathologies [1]. The hypoglycemic event can be spontaneous or provoked by a prolonged supervised fast of up to 72 hours or a mixed meal test.
NICTH is potentially misdiagnosed or underdiagnosed due to its rarity, non-classical clinical presentation and potentially ambiguous biochemical profile [19]. IGF-2-mediated hypoglycemia, the main aetiology of NICTH, involves the secretion of both mature IGF2 and incompletely processed forms, namely ‘big IGF2’ [3]. The timing of the clinical detection of hypoglycemia in the setting of an IGF-2-oma is variable. Initial tumour presentation with hypoglycemia was observed in 48% of patients in a retrospective review, as was the case with our patient, while in the remaining 52%, tumour detection preceded the recognition of hypoglycemia [10].
Patients with IGF-2 mediated hypoglycemia manifest low serum insulin, proinsulin, c-peptide and B-hydroxybutyrate during hypoglycemia [10]. Serum IGF-1 and GH levels are low which differs from other causes of hypoglycemia which generally precipitate an increase in serum GH [10, 20]. Measurement of serum IGF-2 levels in isolation is of limited diagnostic value as a normal value does not exclude diagnosis [21]. In a review, 58% (18/31) of serum IGF2 measurements in patients with IGF2-producing NICTH were within normal reference range [10]. Concurrent measurement of serum IGF-1 allows calculation of a ratio of IGF-2 to IGF-1. In health, a normal ratio is 3:1. In the setting of recurrent hypoglycemia, a molar ratio of greater than 10 confirms NICTH [21]. Of note, false positive ratio elevation can be seen in the setting of malnutrition and sepsis but individual IGF-1 and IGF-2 values are below reference range [22]. Furthermore, IGF-2/IGF-1 ratio is influenced by IGFBP-3 and therefore renal failure, through a reduction of IGFBP-3 levels, can result in a false negative IGF-2/IGF-1 ratio [3].
A review of the profile of circulating glucose-regulatory hormone in 37 patients with big IGF2-mediated hypoglycemia reported lower random growth hormone level during hypoglycemic episodes and suggested that this may be a useful indicator for the presence of IGF-2 producing NICTH [23]. Plasma cortisol levels when measured during hypoglycemia were significantly reduced in this group also. The pathophysiology for this is not clearly understood. It is suggested that this may be related to the attenuation of counter-regulatory hormonal response to repeated hypoglycemia as observed in the diabetic and insulinoma cohort [23].
Initial treatment of hypoglycemia involves oral and potentially parenteral glucose therapy. Once hypoglycemia is corrected in the acute sense, further episodes are avoided through glucocorticoid therapy [24]. Steroids increase hepatic gluconeogenesis, inhibit peripheral uptake of glucose and promote lipolysis but use is limited by an ongoing dose titration requirement. Glucocorticoid effectiveness is only achieved when steroid dose exceeds a patient specific threshold and reduction or withdrawal of therapy can lead to recurrence of hypoglycemia [24]. Diazoxide has been successfully used in the short term to stimulate hepatic glycogenolysis [25]. Glucagon infusion pumps are also efficacious however use is limited to the shorter term [25]. Recombinant growth hormone (rGH) is a useful agent for glucocorticoid-refractory cases not amenable to operative intervention [26]. It increases gluconeogenesis and peripheral glucose uptake as well as increasing IGFBP-3. Large 150 kDa complexes of IGF2 bound to IGFBP3 reduce the bioavailability of IGF2. Somatostatin therapy has not been effective in controlling hypoglycemia in the context of IGF2-mediated process [27]. Although reports have suggested that inhibition of the mammalian target of rapamycin (mTOR) pathway improves hypoglycemia associated with malignant insulinoma, it has not been replicated in IGF2 mediated hypoglycemia [28]. Surgery with the goal of complete tumour resection is necessary to alleviate hypoglycemia in the long term [2]. Debulking is considered where complete surgical excision is not feasible. Neoadjuvant chemoradiation and arterial embolization has been described in the literature in the context of a non-resectable solitary fibrous tumour [29].
In conclusion, this case demonstrates the caveats in achieving a diagnosis of IGF-2 mediated hypoglycemia and highlights a novel case involving two separate neoplastic processes. Although an incidental finding of serous carcinoma was made, the paradox in this case is that the apparently benign solitary fibrous tumour accounted for the patient’s morbidity, through secretion of IGF2 and without treatment, posed a significant mortality risk.
