Non-islet cell tumour hypoglycaemia in a patient with a gastrointestinal stromal tumour

Tumour induced hypoglycaemia is a rare paraneoplastic phenomenon. Insulinomas are the most common tumours associated with hypoglycaemia. The incidence of these insulin secreting tumours is estimated at 0.5 to 4 per million people per year [1], [2]. However, hypoglycaemia may also occur in solid tumours of epithelial or mesenchymal origin. Hypoglycaemia caused by these types of tumours is referred to as non-islet cell tumour hypoglycaemia (NICTH). NICTH is generally attributable to the secretion of large amounts of incompletely processed insulin-like growth factor II (IGF-II), also called ‘big’-IGF-II [3].

In this report, we describe the case of a patient with metastatic gastrointestinal stromal tumour (GIST) who presented with a loss of consciousness due to hypoglycaemia caused by increased concentrations of ‘big’-IGF-II.

Case report

A 50-year old man was admitted to the hospital because of loss of consciousness. He was known for a large retroperitoneal GIST diagnosed three years earlier as a recurrence of a previously resected sarcoma, at that time interpreted as a leiomyosarcoma. In the summer of 2001, the patient was enrolled in a clinical trial with the tyrosine kinase inhibitor imatinib mesylate (gleevec®). From that moment, stable disease was established during a year, followed by local tumour progression. At that time, debulking of the tumour was performed. Three months later, a CT-scan revealed multiple liver metastases. Subsequently, the patient was included in a phase I study. However, during the following months he showed further disease progression.

On admission, physical examination revealed a comatose patient with a Glascow Coma Score of 1-4-1. A CT-scan was performed because a neurological cause was considered. However, his serum glucose level was 1.0 mmol/l (normal fasting glucose 4.0–5.4 mmol/l). Further laboratory investigation showed normal kidney function, slightly abnormal liver function tests and low insulin (<2 mU/l) levels. He recovered quickly after glucose infusion. A carbohydrate rich diet could hardly prevent more hypoglycaemic events and prednisolone 30 mg per day was started. The patient died a month later.

Because NICTH was suspected, serum samples obtained during the phase of stable disease, disease progression and a month prior to admission were analysed. IGF-I and IGF-binding protein 3 (IGFBP-3) levels were reduced and the concentration of IGFBP-2 was elevated a month prior to admission (Table I). In contrast, the levels of these proteins at the other time points fell within the normal range. The amount of total IGF-II was not deviated from normal control at all the time points. However, levels of pro-IGF-IIE[68–88] (‘big’-IGF-II) were markedly elevated a month before admission.

Table I.  IGF and IGFBP levels^* at various time points.

	Stable disease	Disease progression	Prior to admission
IGF-I (nmol/L)	10.6 (−1.19)^†	19.5 (1.10)	3.9 (−4.56)
IGF-II (nmol/L)	49.4 (−0.83)	71.2 (1.16)	48.5 (−0.92)
Pro-IGF-IIE[68-88] (nmol/L)	6.24 (0.16)	7.13 (0.35)	21.9 (5.23)
IGFBP-2 (nmol/L)	12.8 (1.89)	11.6 (1.65)	23.6 (3.27)
IGFBP-3 (nmol/L)	44.7 (−1.49)	55.0 (−0.64)	22.3 (−4.44)

^* Serum concentrations were determined by Jaap van Doorn, Laboratory of Endocrinology, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

^† Standard deviation scores (Z-scores) are given between hedges.

Discussion

There are several mechanisms by which solid tumours can cause hypoglycaemia: (1) insulin secreting insulinomas, (2) non-islet cell tumours secreting aberrant IGF-II and (3) liver and adrenal failure due to tumour invasion [2]. Our patient had elevated levels of ‘big’-IGF-II that is associated with NICTH and had no signs of liver failure.

Both IGF-II and IGF-I are structurally and functionally related to insulin [4], [5]. They can exert an insulin-like activity by binding to the insulin receptor and IGF-receptor type 1 [6]. This insulin-like activity is only 5% of insulin but the total serum concentration of IGFs is about 1000-fold higher than the mean insulin concentration. Hypoglycaemia does not occur, however, because of binding to IGFBPs. Under physiological conditions, 75–80 percent of the IGFs are bound to IGFBPs, mostly IGFBP-3, and an acid-labile subunit (ALS). The remainder is bound to IGFBP-3 alone as a binary complex or, less than 1 percent, circulates in a free form. The ternary complex has a molecular mass of about 150 kDa and is not able to pass the capillary membrane. In this way the availability of IGFs to their target tissues is limited [7]. IGF-I, IGFBP-3 and ALS are produced by the liver and their production is stimulated by growth hormone (GH) secretion. GH, in turn, is negatively regulated by IGF-I and IGF-II. In contrast, IGF-II is produced by various tissues, which is GH-independent [6].

Non-islet cell tumours causing hypoglycaemia contain elevated levels of mRNA for IGF-II [8], [9]. IGF-II is thought to act as an autocrine growth factor in various tumours [8], [10]. It is produced as a pre-prohormone. During intracellular processing, tumour cells fail to cleave the large E-domain from pro-IGF-II, which leads to the secretion of an extraordinary large amount of uncleaved peptide, the so-called ‘big’-IGF-II [11]. In NICTH, high serum concentrations of ‘big’-IGF-II are associated with a shift in the distribution of IGFs from high-molecular-weight ternary complexes to binary complexes and to the unbound form [9], [12]. Therefore, it seems likely that abundant ‘big’-IGF-II leads to an impaired formation of the ternary complex. This could be due to several factors. In the first place, it has been reported that the aberrant form of IGF-II and IGFBP-3 have the inability to form complexes with ALS [13]. Furthermore, an increase in circulating ‘big’-IGF-II levels could suppress GH secretion. As a consequence, IGFBP3 and ALS production by the liver is decreased, leading to a further decrease in ternary complexes [9]. Binary complexes and unbound IGF can easily cross the capillary membrane. ‘Big’-IGF-II has the same affinity to the insulin and IGF receptor type 1 as normal IGF-II [9]. Excessive receptor stimulation causes increased peripheral glucose uptake and suppressed hepatic glucose output, resulting in hypoglycaemia [14].

Laboratory investigation can confirm the diagnosis NICTH. Low insulin and C-peptide levels are detected, related to a low glucose concentration. GH, IGF-I and IGFBP-3 levels are typically decreased. An elevated level of IGFBP-2 is also a characteristic finding in patients with NICTH, although the mechanisms by which it is increased are unclear [15]. The concentration of E-domain containing forms of IGF-II is increased [11]. However, total IGF-II levels are usually within the normal range, which is probably due to increased turnover rates. Furthermore, an IGF-II:IGF-I molar ratio > 10 is also considered pathognomic of NICTH [2]. All these characteristic laboratory findings were retrospectively found in our patient, including markedly elevated big-IGF-II levels (standard deviation score 5.23) and a IGF-II:IGF-I molar ratio of 12.4 (Table I).

Data on the exact incidence of NICTH are not available. It has been estimated that NICTH is four times less common than insulinoma, but the true incidence is probably higher [2]. In most of the cases, NICTH is caused by a tumour of mesenchymal origin. These tumours are usually large and can be both benign and malignant. The most common histological types causing hypoglycaemia are fibrosarcomas, mesotheliomas, leiomyosarcomas, and hemangiopericytomas [3].

Our patient suffered from a large GIST with multiple liver metastases. GISTs are a group of mesenchymal neoplasms, showing differentiation towards the interstitial cells of Cajal, also known as the pacemaker cells of the gastrointestinal tract. Virtually all GISTs overexpress the receptor tyrosine kinase KIT that, in most cases, contains mutations leading to ligand-independent activation of the receptor. Until recently, stromal tumours of the gastrointestinal tract were regarded as leiomyomas, leiomyosarcomas or leiomyoblastomas. However, these tumours do not express KIT and nowadays GISTs are considered as a distinct clinicopathological entity [16]. The introduction of imatinib mesylate, an inhibitor of KIT, has dramatically improved the life expectancy of patients with metastatic GIST [17]. Recently, Beckers et al. have described a patient with NICTH due to a GIST. This report is the second one about this topic. There are several reported cases about hypoglycaemia caused by a leiomyosarcoma of the stomach or bowel [19], [20]. Advances in KIT immunostaining have revealed that leiomyosarcomas of stomach and bowel are extremely rare. Therefore, there is a strong suggestion that these tumours should have been GIST and probably more cases associated with hypoglycaemia will be reported in the near future.

In order to treat the hypoglycaemia, a short-term effect is best achieved with infusion of glucose and dietary guidelines. The best long-term treatment is to reduce the tumour by surgery, irradiation or chemotherapy [6]. In our patient, frequent carbohydrate rich meals could not prevent the recurrence of new hypoglycaemic events. When tumour reduction can not be established and dietary measurements and infusion of glucose is not sufficient, administration of glucocorticoids, glucagon and high dose GH can be tried [21–23].

In conclusion, in unconscious cancer patients – especially those diagnosed with mesenchymal tumours – apart from vascular events and brain metastases, NICTH should be considered.