Article Text

Rare disease
When a nephrectomy cures hypoglycaemia
  1. Aonghus O’Loughlin1,
  2. Frank Waldron-Lynch1,
  3. Kevin Christopher Cronin1,
  4. Sean Dinneen2,
  5. John Lee3,
  6. Damian Griffin4,
  7. Mary Casey5,
  8. N Nusrat6,
  9. Syed Jaffrey6,
  10. Timothy O’Brien2,
  11. Fidelma Dunne2
  1. 1
    University Hospital Galway, Diabetes Mellitus, Newcastle Road, Galway, Ireland
  2. 2
    University Hospital Galway, Endocrinology, Newcastle Road, Galway, Ireland
  3. 3
    University Hospital Galway, Gastroenterology, Newcastle Road, Galway, Ireland
  4. 4
    University Hospital Galway, Biochemistry, Newcastle Road, Galway, Ireland
  5. 5
    University Hospital Galway, Pathology, Newcastle Road, Galway, Ireland
  6. 6
    University Hospital Galway, Urology, Newcastle Road, Galway, Ireland
  1. Aonghus O’Loughlin, aonghus_o_loughlin{at}hotmail.com

Summary

A 40-year-old woman presented with a 10 day history of episodic vagueness, speech disturbance and blurred vision. Episodes typically occurred in the morning after awaking from sleep and resolved with food ingestion. She had no past medical history, did not drink alcohol and was not on any medication. Physical examination was normal with no evidence of endocrinopathy. After 10 h of fasting, she became hypoglycaemic with evidence of neuroglycopenia, which resolved with intravenous dextrose. Biochemical investigations revealed decreased glucose, insulin and C-peptide values with an increased excess insulin-like growth factor II: excess insulin-like growth factor I (IGF-II: IGF-I) ratio. Radiological examinations of the abdomen and pelvis revealed a heterogenous 10.5 cm left renal mass. The patient underwent a radical left nephrectomy. She had complete resolution of hypoglycaemic events. Histology revealed a renal sarcoma, grade 2/3. This is the first report in the literature involving a renal sarcoma causing non-islet cell tumour hypoglycaemia via excess IGF-II secretion.

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BACKGROUND

Hypoglycaemia may be a complication of malignancy. There are several mechanisms, but non-islet cell tumour hypoglycaemia (NICTH) should be considered in this clinical scenario. The biochemical results point to NICTH and further investigations for malignancy should be undertaken. With respect to this case, radiological imaging was undertaken.

In addition, this is the first case described in the literature involving a renal sarcoma causing NICTH via excess insulin-like growth factor II (IGF-II) secretion.

CASE PRESENTATION

A 40-year-old woman presented to a university teaching hospital with a 10 day history of episodic vagueness, speech disturbance and blurred vision. The episodes occurred in the morning upon waking and resolved with food. She denied headache or vertigo. She did not drink or smoke and was not taking any medication. Her medical and family history was unremarkable.

On examination the patient appeared healthy. Her heart rate was 70/min normal sinus rhythm, blood pressure was 120/80 mm Hg with no postural drop, and her body mass index (BMI) was 28 kg/m2. Cardiovascular, respiratory, and neurological examinations were normal. On abdominal examination a smooth non-tender immobile mass, palpable over the left renal area, was detected. There was no associated bruit.

INVESTIGATIONS

An electrocardiogram (ECG), chest x ray, full blood count, and serum renal, bone and liver profiles were normal. A short synacthen test demonstrated a normal response of 652 nmol/l at 30 min. Thyroid function tests, gonadotrophins and prolactin values were within the normal range. She was fasted overnight and after 10 h of fasting, she became confused and could not follow simple commands. Her symptoms quickly resolved with intravenous 5% dextrose. Blood tests taken before dextrose administration revealed: plasma glucose 1.8 mmol/l (normal range (NR) 3.9–7.8), insulin <1.4 pmol/l (NR 17.8–173), C-peptide 23.2 pmol/l (NR 370–1470), growth hormone <1 mU/l, β-hydroxybutyrate 200 μmol/l (NR 20–270) and insulin-like growth factor I (IGF-I) 3.5 nmol/l (NR 13–50). These data (table 1) are consistent with NICTH.

Table 1

Biochemistry results on fasting with non-islet cell tumour hypoglycaemia

The serum IGF-II was 118.6 nmol/l and the IGF-II:IGF-I ratio was 33.9 (NR 0–10). Immunoglobulin G insulin antibodies were within normal range. Computed tomography (CT) (fig 1) and magnetic resonance imaging (MRI) of the abdomen and pelvis revealed a heterogenous 10.5 cm left renal mass. An isotope bone scan and MRI of the brain were normal.

Figure 1

Contrast enhanced computed tomographic image revealing renal sarcoma.

DIFFERENTIAL DIAGNOSIS

A blunted morning cortisol response to a low serum glucose (table 1) raised the possibility of adrenocortical insufficiency; however, a normal synacthen test and brain MRI discounted this possibility.

The increased IGF-II in conjunction with a decreased insulin and decreased C-peptide in the presence of hypoglycaemia indicated that NICTH secondary to an IGF-II secreting tumour was likely. Subsequent imaging and histology confirmed this.

TREATMENT

The patient underwent a radical left nephrectomy and had an uneventful postoperative recovery with complete resolution of hypoglycaemic episodes. Intraoperative IGF-II was 83.4 nmol/l and postoperative IGF-II and IGF-II:IGF-I ratio was 37.8 nmol/l and 1.7, respectively.

OUTCOME AND FOLLOW-UP

Histology revealed an encapsulated cream white tumour (115 × 80 mm), present centrally in the kidney, consistent with a renal sarcoma grade 2/3.

Immunohistochemistry demonstrated the tumour cells to be positive for vimentin, BCL2 (B cell leukaemia/lymphoma 2) and weak to negative for epithelial markers including EMA (epithelial membrane antigen) and cytokeratins OSCAR (osteoclast associated, immunoglobulin-like receptor) and the cytokeratin monoclonal antibody cam 5.2, oestrogen receptor, inhibin and CD 34.

Immunohistochemistry for WT-1 (Wilms tumour suppressor gene), MIC-2 (a gene over-expressed in Ewings sarcoma and primitive neuroectodermal tumours), melan A (over-expression detected in melanoma), human melanoma black 45(also detected in melanoma) actin, and c-kit (tyrosine kinase receptors associated with gastrointestinal stromal tumours) were negative.

The patient made a full recovery. At 6 months postoperatively, she remains symptom-free. She subsequently had a normal full body FDG positron emission tomography (PET) scan. The IGF-II values and IGF-II: IGF-I ratio remain within the normal range.

She was reviewed at the Memorial Sloane-Kettering Cancer Centre in New York, and agreement was reached on the diagnosis of a renal sarcoma grade 2/3.

Her follow-up is with CT imaging of thorax, abdomen and pelvis every 3 months for 2 years and PET every 6 months. There is no role for postoperative chemotherapy or radiotherapy.

DISCUSSION

The low insulin and C-peptide results ruled out an insulin or sulfonylurea mediated hypoglycaemia. The decreased IGF-I and growth hormone are accounted for by inhibition of the somatotroph axis.1 The blunted growth hormone response to hypoglycaemia is observed in NICTH and is considered one of the mechanisms leading to hypoglycaemia (suppression of growth hormone regulatory action).2

In addition with NICTH, free IGF-II is able to bind to insulin-like growth factor receptors as well as to insulin receptors (with which it cross-reacts), that are present on liver and all peripheral cells. Severe hypoglycaemia results from suppression of hepatic glucose output and an increased peripheral uptake of glucose.3 Retroperitoneal sarcomas are known to cause hypoglycaemia via excess IGF-II secretion and are the most common tumours causing hypoglycaemia,4 although in the vast majority of cases the patient is unwell at presentation.

This is the first case described in the literature involving a renal sarcoma causing NICTH via excess IGF-II secretion. Hypoglycaemia may be a complication of malignancy. There are several mechanisms, but NICTH should be considered in this clinical scenario.

LEARNING POINTS

  • Hypoglycaemia may be a manifestation of malignancy, through excess insulin-like growth factor II (IGF-II) secretion.

  • Hypoglycaemia with co-existent decreased serum insulin and serum C-peptide rules out an insulin or sulfonylurea mediated cause and should prompt IGF-II level assessment.

  • A renal sarcoma can give rise to non-islet cell tumour hypoglycaemia (NICTH), via excess IGF-II secretion.

REFERENCES

View Abstract

Footnotes

  • Competing interests: none.

  • Patient consent: Patient/guardian consent was obtained for publication

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