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An elderly man with pleural effusion and abnormal behaviour

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Q1: What is the cause of this patient's hypoglycaemia?

The cause of the hypoglycaemia is non-islet cell tumour hypoglycaemia (NICTH). IGF concentrations confirm this diagnosis. Other common causes like insulin or sulphonylurea therapy are not supported by history. Liver failure, an insulinoma, and adrenal failure are refuted by investigation results. Undetectable insulin and C peptide concentrations during hypoglycaemia, with normal liver and adrenal function tests, suggest the diagnosis of NICTH.

Box 1: Potential causes of NICTH

Tumours of mesodermal origin
  • Fibroblastomas.

  • Fibromas.

  • Fibrosarcomas.

  • Haemangioendotheliomas.

  • Histiocytomas.

  • Leiomyosarcomas.

  • Mesenchymal tumours of the diaphragm, pancreas, and pleura.

  • Mesoblastic nephromas.

  • Mesotheliomas.

Tumours of epithelial origin
  • Adrenal carcinomas.

  • Carcinomas of the gastrointestinal tract, lung, or prostate.

  • Hepatomas.

  • Medullary thyroid carcinoma.

Tumours of haemopoietic origin
  • Leukaemia (chronic myelocytic leukaemia).

  • Lymphoma.

Tumours of neuroectodermal origin
  • Neuroblastoma.

Box 2: Learning points

Key diagnostic points for NICTH
  • Reduced ratio of IGF-I: IGF-II.

  • Raised “big” IGF-II.

Treatment options in NICTH
  • Recombinant human growth hormone can ameliorate symptoms.

  • Steroids help symptomatically by diminishing bioavailability of IGF-II.

  • Debulking or complete removal of tumour leads to symptom remission.

Q2: What pharmacological agents may alleviate his hypoglycaemia?

Recombinant human growth hormone increases IGF-I and IGFBP-3 concentrations, and therefore reduces the bioavailability of “big” IGF-II. Prednisolone helps by increased binding of “big” IGF-II to the acid labile subunit, and there is reduced secretion of “big” IGF-II, thus leading to diminished bioavailability of IGF-II.1 Both these therapies are synergistic in controlling hypoglycaemia.

Q3: What is the role of surgery in management of this patient?

Debulking or partial removal helps symptomatically in patients of mesothelioma presenting with hypoglycaemia. This situation obtains in most of the malignant or locally infiltrating tumours. Complete alleviation of hypoglycaemic symptoms is possible in cases where the tumour can be completely excised.

Discussion

Patients with large mesotheliomas (particularly sarcomatoid) weighing 1–10 kg may develop hypoglycaemia, particularly with fasting.2 Headache, fatigue, confusion, or seizures may occur. Patients with a large mesothelioma and hypoglycaemia are likely to have NICTH. Some of these mesenchymal (non-islet cell) tumours produce and release “big” IGF-II,3 a prohormone form of IGF-II, which binds to insulin receptors as well as to IGF-I and IGF-II receptors, and leads to hypoglycaemia. “Big” IGF-II directly stimulates the uptake of glucose by the tumour and by insulin responsive tissues like fat and muscle. Hepatic glucose production and insulin secretion are decreased by hypoglycaemia and by the direct inhibitory effects of big IGF-II on the pancreatic β cells.4 “Big” IGF-II inhibits the secretion of pituitary growth hormone, which in turn decreases the synthesis and secretion of the ternary complex of IGF-I, IGFBP-3, and the acid labile subunit.4 Diminished concentrations of IGFBP-3 augment the effects of circulating IGF-II. Big IGF-II interacts poorly with the IGFBP complex, and the resulting increase in unbound IGF-II causes hypoglycaemia by inhibiting hepatic glucose production and enhancing the disposal of glucose into muscle.4 Surgical removal of the tumour or radiotherapy reduces the excess IGF-II, thereby ameliorating the hypoglycaemia.4

Once adrenal and hepatic diseases have been excluded in a patient with significant hypoglycaemia, insulin and C peptide concentrations should be measured. High insulin with suppressed concentrations of C peptide raises the possibility of exogenous insulin administration.5 Insulinoma, sulphonylureas, and sulphonamides (in the presence of renal disease) lead to high insulin and C peptide concentrations.6 If insulin concentrations are low (hypoinsulinaemic hypoglycaemia), like our patient, then what is reducing the glucose? IGFs can do this and checking IGF-I, IGF-II, and IGFBP-3 will help to clinch the issue. Another possibility is due to insulin receptor antibodies, where growth hormone is raised, IGF-I and IGF-II are normal (unlike our patient), and insulin receptor antibodies are present.

Follow up

This patient was treated with recombinant human growth hormone subcutaneously and oral prednisolone. Tumour debulking was done by right pleurectomy. He is on postoperative radiotherapy at present as an outpatient; this has decreased his hypoglycaemic episodes. He is on oral feeds during the day. He needs occasional nocturnal intramuscular glucagon for hypoglycaemic episodes.

Final diagnosis

Non-islet cell tumour hypoglycaemia.

References

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