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Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 209-213

Non-islet cell tumor hypoglycemia in a patient with pleural tumor and hypoinsulinemic hypoglycemia: A case report

Department of Diabetology, Dr. Mohan’s Diabetes Specialities Centre & Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India

Date of Submission25-May-2020
Date of Decision25-Jun-2020
Date of Acceptance07-Jul-2020
Date of Web Publication1-Sep-2020

Correspondence Address:
Dr. Muthukrishnan Varalakshmi
Consultant Diabetologist, Department of Diabetology, Dr. Mohan’s Diabetes Specialities Centre & Madras Diabetes Research Foundation, No. 4, Conran Smith Road, Gopalapuram, Chennai, Tamil Nadu.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JOD.JOD_39_20

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Non-islet cell tumor hypoglycemia (NICTH) is a relatively rare paraneoplastic syndrome associated with tumors of mesenchymal and epithelial cell origin. Hypoglycemia can be the presenting symptom of NICTH or can appear later in the disease course. The cause of NICTH is stated to be due to secretion of poorly processed insulin-like growth factor (IGF)-2 and in most previous reported cases, the diagnosis of NICTH is made based on the identification of this fraction of IGF-2 or an increased ratio between total IGF-2 and IGF-1. However, in clinical setting, especially in developing countries, such tests cannot be readily available and a diagnosis of NICTH should not be delayed in a patient with a combination of solid tumor, recurrent fasting hypoglycemia, and a low serum insulin and C-peptide level. We describe in our report an 87-year-old man with a history of a pleural tumor presenting with recurrent episode of hypoglycemia. Although surgical removal of the tumor is the ideal management, it is often not feasible as exemplified in our report. In such cases, treatment with glucocorticoid is effective in alleviating the symptoms of hypoglycemia.

Keywords: Hypoglycemia, insulin, non-islet cell tumor hypoglycemia, tumor

How to cite this article:
Natarajan H, Varalakshmi M, Mohan V. Non-islet cell tumor hypoglycemia in a patient with pleural tumor and hypoinsulinemic hypoglycemia: A case report. J Diabetol 2020;11:209-13

How to cite this URL:
Natarajan H, Varalakshmi M, Mohan V. Non-islet cell tumor hypoglycemia in a patient with pleural tumor and hypoinsulinemic hypoglycemia: A case report. J Diabetol [serial online] 2020 [cited 2021 May 7];11:209-13. Available from: https://www.journalofdiabetology.org/text.asp?2020/11/3/209/294044

  Introduction Top

Non-islet cell tumors are second only to insulinoma as a cause of spontaneous chronic hypoglycemia in nondiabetic adults.[1] Numerous tumors, mainly of mesenchymal or epithelial origin, are associated with hypoglycemia.[2] Several mechanisms for hypoglycemia have been described in the literature, including secretion of substances interfering with glucose metabolism such as insulin receptor antibodies,[3] insulin,[4] and secretion of insulin-like growth factor (IGF)-1,[5] and extensive destruction of the liver and adrenal gland by tumor infiltration. However, the major cause appears to be high-molecular-weight insulin-like growth factor (IGF)-2, derived from the tumor.[2],[6-9] Regardless of the mechanism, the diagnosis of non-islet cell tumor hypoglycemia (NICTH) is fairly straightforward in a patient with known tumor burden and recurrent hypoglycemic episodes. The ideal management is prompt and complete tumor resection.[10] However, when resection is not feasible, glucocorticoid therapy is found to be effective in suppressing the abnormal secretion of high-molecular-weight IGF-2.[11] This case report describes an elderly patient with a pleural tumor and recurrent episodes of hypoglycemia.

  Case Report Top

An 87-year-old male presented to our hospital with episodes of giddiness, excess hunger, and sweating for the past 2 months which was relieved by having food. Low blood sugars with reading as low as 25mg/dL had been documented. Further questioning revealed that the patient had a history of pleural leiomyoma 20 years earlier which was surgically excised.

Two months earlier, the patient had visited a local hospital with complaints of dry cough and fever. A chest computed tomography (CT) was done which revealed a pleural tumor of size 18.0cm x 15.0cm x 11.5cm with bilateral pneumonitis. A possible recurrence of the leiomyoma was considered and the patient was advised biopsy. However, due to his age, the patient deferred further workup of the tumor at that time and was therefore discharged after the appropriate management of pneumonitis.

On examination, clubbing, skin tags, and diminished breath sounds over the lower half of the right hemithorax were noted. There was no other significant finding in physical examination. Medication-induced hypoglycemia was ruled out through a careful review of medications. Renal and hepatic causes of hypoglycemia were ruled out through a comprehensive metabolic panel which showed normal liver and renal functions. Based on the history of a pleural tumor and recurrent hypoglycemia, a provisional diagnosis of NICTH was made. Regular oral carbohydrate intake along with continuous glucose monitoring was planned and the patient was advised to follow-up after 2 days with 8-AM serum cortisol, fasting insulin, and C-peptide assay. Serum IGF-1 and IGF-2 levels will not be measured due to lack of availability of the assay in our hospital. During the follow-up visit, 8-AM serum cortisol was found to be normal (21.9 microgram/dL) ruling out adrenal insufficiency. Fasting insulin and C-peptide were found to be below normal providing further evidence in favor of NICTH. Continuous glucose monitoring using iPro 2 (Medtronics) showed several episodes of hypoglycemia despite regular oral carbohydrate intake [Figure 1]. Definitive interventions including surgery and chemotherapy were discussed which the patient declined. Hence, glucocorticoid therapy was initiated. Prednisolone at a dose of 30mg/day was started and home continuous glucose monitoring was continued.
Figure 1: Continuous glucose monitoring showing several episodes of hypoglycemia despite regular oral carbohydrate intake

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The patient had no episodes of hypoglycemia for the first week and the dose of the steroid was reduced to 25mg/day for the next week which kept the patient free of symptoms. Any further reduction in the dose of prednisolone caused recurrence of hypoglycemia and hence a dose of 25mg/day was maintained. The patient was on weekly follow-up and remained symptom-free for a month when he suddenly lost consciousness and was rushed to a nearby hospital. He was diagnosed with an episode of severe hypoglycemia and treated with intravenous 25% dextrose which provided immediate relief. The patient then consented for surgical and other definitive management of the tumor and was referred to a facility specializing in oncology. Contrast-enhanced CT scan of the chest and abdomen was done which revealed the tumor had enlarged to a size of 33cm x 20cm x 15cm extending into the upper abdomen across the right hemidiaphragm which was not clearly delineated [Figure 2]. The tumor was considered inoperable and hence chemotherapy was contemplated. Ultrasound-guided needle biopsy was performed to understand the nature of the tumor. Microscopic examination of the biopsy specimen showed a poorly differentiated malignant tumor with large round cells in clusters and many cells with vacuolated cytoplasm resembling lipoblasts, suggestive of poorly differentiated liposarcoma/soft tissue sarcoma [Figure 3]A and [B]. Due to inadequacy of the amount of tissue sample obtained, immunohistochemistry could not be performed and a repeat biopsy was requested by the pathologist. However, before this could be done, the patient’s general health started to deteriorate and he was shifted to the intensive care unit where he was started on oxygen and Ryle’s tube feed. However, despite all efforts, the patient’s health continued to worsen. In accordance with the will of the patient, he was discharged home with palliative care, where he succumbed to the illness.
Figure 2: Contrast-enhanced CT scan of the chest and abdomen showing a large 33cm x 20cm x 15cm lobulated, heterogeneously enhancing circumscribed soft-tissue attenuation lesion with central nonenhancing necrotic areas in the lower right hemithorax extending onto to the upper abdomen across the right hemidiaphragm which is not clearly delineated. Laterally, the lesion is seen insinuating across the intercostal space projecting into the deep subcutaneous plane

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Figure 3: (A) High-power photomicrograph (40x, HandE) showing poorly differentiated large round cells with hyperchromatic nucleus in cluster surrounding a blood vessel. Occasional mitotic figures are seen (shown by arrow). (B) Low-power photomicrograph (10x, HandE) showing cells with vacuolated cytoplasm resembling lipoblasts

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  Discussion Top

NICTH is a rare paraneoplastic syndrome. It was first described in 1929 by Nadler and Wolfer in a patient with hepatocellular carcinoma.[12] Since then, several cases have been reported worldwide. It is mainly seen in tumors of mesenchymal or epithelial cell origin and is more likely to develop in those with a large tumor burden. Hypoglycemia can either be the presenting symptom of the tumor or it can occur later during the course of the disease. In addition to hypoglycemia, acromegaloid skin changes such as excessive oiliness of the skin, skin tags, and rhinophyma, have been described in some case reports.[13],[14]

In NICTH, increased expression of the IGF-2 gene by the tumor is seen. Normally, the maternal allele of IGF-2 is imprinted. Loss of imprinting leads to increased expression of IGF-2 gene in the tumor cells. The translation product of IGF-2 mRNA is a 180 amino acid precursor, pre-pro IGF-2, which is modified post-translation to pro-IGF-2 and then to the IGF-2 protein. Abnormal processing often occurs in these tumors likely due to augmented levels of pro-IGF-2 synthesized, resulting in increased production and secretion of pro-IGF-2E (or “big IGF-2”).[2]

In normal individuals, the IGF-2 protein forms a150-kDa ternary complex with IGF binding protein (IGFBP)-3 and an 85-kDa glycoprotein termed the acid-labile subunit (ALS), which cannot cross the capillary membrane. However, in NICTH, the big IGF-2 forms a 50-kDa binary complex with IGFBP-3 but fails to form a complete complex with ALS due to steric hindrance. This abnormal binary complex can cross the capillary membrane and interact with insulin and IGF receptors causing hypoglycemia.[2] [Figure 4] summarizes the pathogenesis of hypoglycemia in NICTH.
Figure 4: Pathogenesis of hypoglycemia in NICTH

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Biochemical features of NICTH are low serum insulin, C-peptide, IGF-1, and growth hormone (GH). Abnormality in the biochemical parameters can be explained by feedback inhibition. The excess levels of big IGF-2 secreted by the tumor cells suppres the secretion of GH, IGF-1, and insulin. The secretion of the normal fraction of IGF-2 is also suppressed, although not to the extent of IGF-1 leading to an increased ratio between total IGF-2 and IGF-1.[15] However, in clinical practice, especially in developing countries, an assay of serum IGF-1 and IGF-2 may not be readily available and a diagnosis of NICTH can be made from a carefully elicited history and low serum insulin and C-peptide levels in a patient with a solid tumor and recurrent hypoglycemia, as shown by Maji and Ghosh[16] and further elucidated in our case report.

Hypoglycemia in an unconscious patient or a patient unable to ingest carbohydrate can be managed acutely by subcutaneous or intramuscular injection of glucagon (0.5–1.0mg). In the hospital setting, it can be treated more quickly by giving 25% dextrose intravenously. The mainstay of long-term management of NICTH, however, is to reduce the tumor size by surgery, radiotherapy, or chemotherapy. Although prompt and complete tumor resection represents the ideal management,[10] most of these cases occur in elderly patients, and surgery as an option is often not feasible because of the diffuse nature of the tumor or impracticality in this patient population, or both.[11] In such situations where the underlying malignancy cannot be treated, initial management of hypoglycemia involves a frequent and increased calorie and carbohydrate intake.[10] When conservative management with oral carbohydrate feeding fails, medical therapy is required to prevent hypoglycemia. Glucocorticoid therapy, glucagon, and high-dose recombinant growth hormone (rhGH) are effective options. Glucocorticoid therapy is considered a reasonable initial medical therapy as it has an immediate beneficial effect on symptomatic hypoglycemia and it has also shown to decrease the production of big IGF-2 and correct underlying biochemical dysfunction.[11] Because the response to glucocorticoid varies among patients, careful titration of the steroid dosing is required to prevent hypoglycemia.[2]

Our patient showed an excellent response to prednisolone at a dose of 25mg/day. When glucocorticoids fail to adequately control hypoglycemia, long-term intravenous glucagon (0.06–0.30mg/hour) is considered, if the patient has an adequate hepatic glycogen reserve indicated by a good glycemic response to glucagon (a rise in serum glucose of >30mg/dL after a 1mg infusion of glucagon).[17] rhGH at supraphysiologic dosages of 3–12 mg daily is another effective option in treating hypoglycemia. GH at high doses increases serum IGFBP-3 and ALS, which bind IGF-2 and prevents its interaction with insulin receptor.[2] However, long-term usage of rhGH has the potential to increase serum levels of IGF-1 and insulin, as well as undo the beneficial action of glucocorticoid therapy on big IGF-2.[11] By increasing levels of IGF-1, rhGH also presents a theoretical risk of stimulating tumor growth.

In conclusion, the diagnosis of NICTH is fairly straightforward in a patient with known mesenchymal or epithelial cell tumor suffering from recurrent fasting hypoglycemia. However, a high degree of clinical suspicion is necessary to identify NICTH when hypoglycemia is the presenting symptom. Removal of the tumor is the mainstay of therapy and is curative but when not feasible, treatment with glucocorticoid is effective in alleviating the symptoms as shown in our patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

LeRoith D, Clemmons D, Nissley P, Rechler MM Insulin-like growth factors in health and disease. Ann Intern Med 1992;116:854-62.  Back to cited text no. 1
Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL, et al. Tumors, IGF-2, and hypoglycemia: Insights from the clinic, the laboratory, and the historical archive. Endocr Rev 2013;34:798-826.  Back to cited text no. 2
Redmon B, Pyzdrowski KL, Elson MK, Kay NE, Dalmasso AP, Nuttall FQ Hypoglycemia due to a monoclonal insulin-binding antibody in multiple myeloma. N Engl J Med 1992;326:994-8.  Back to cited text no. 3
Kiang DT, Bauer GE, Kennedy BJ Immunoassayable insulin in carcinoma of the cervix associated with hypoglycemia. Cancer 1973;31:801-5.  Back to cited text no. 4
Nauck MA, Reinecke M, Perren A, Frystyk J, Berishvili G, Zwimpfer C, et al. Hypoglycemia due to paraneoplastic secretion of insulin-like growth factor-I in a patient with metastasizing large-cell carcinoma of the lung. J Clin Endocrinol Metab 2007;92:1600-5.  Back to cited text no. 5
Gorden P, Hendricks CM, Kahn CR, Megyesi K, Roth J Hypoglycemia associated with non-islet-cell tumor and insulin-like growth factors: A study of the tumor types. New Engl J Med 1981;305:1452-5.  Back to cited text no. 6
Shapiro ET, Bell GI, Polonsky KS, Rubenstein AH, Kew MC, Tager HS Tumor hypoglycemia: Relationship to high molecular weight insulin-like growth factor-II. J Clin Invest 1990;85:1672-9.  Back to cited text no. 7
Phillips LS, Robertson DG Insulin-like growth factors and non-islet cell tumorhypoglycemia. Metabolism 1993;42:1093-101.  Back to cited text no. 8
Zapf J, Futo E, Peter M, Froesch ER Can “big” insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? J Clin Invest 1992;90:2574-84.  Back to cited text no. 9
Bodnar TW, Acevedo MJ, Pietropaolo M Management of non-islet-cell tumor hypoglycemia: A clinical review. J Clin Endocrinol Metab 2014;99:713-22.  Back to cited text no. 10
Teale JD, Marks V Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH). Clin Endocrinol (Oxf) 1998;49:491-8.  Back to cited text no. 11
Nadler WH, Wolfer JA Hepatogenic hypoglycemia associated with primary liver cell carcinoma. Arch Intern Med 1929;44: 700-10.  Back to cited text no. 12
Trivedi N, Mithal A, Sharma AK, Mishra SK, Pandey R, Trivedi B, et al. Non-islet cell tumour induced hypoglycaemia with acromegaloid facial and acral swelling. Clin Endocrinol (Oxf) 1995;42:433-5.  Back to cited text no. 13
Dutta P, Aggarwal A, Gogate Y, Nahar U, Shah VN, Singla M, et al. Non-islet cell tumor-induced hypoglycemia: A report of five cases and brief review of the literature. Endocrinol Diabetes Metab Case Rep 2013;2013.  Back to cited text no. 14
de Groot JW, Rikhof B, van Doorn J, Bilo HJ, Alleman MA, Honkoop AH, et al. Non-islet cell tumour-induced hypoglycaemia: A review of the literature including two new cases. Endocr Relat Cancer 2007;14:979-93.  Back to cited text no. 15
Maji S, Ghosh I Recurrent neuroglycopenia: Do not forget non-islet cell induced tumorhypoglycemia. Middle East J Cancer 2018;9:344-7.  Back to cited text no. 16
Hoff AO, Vassilopoulou-Sellin R The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia. Cancer 1998;82:1585-92.  Back to cited text no. 17


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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