A change for good may not be always good! An interesting case of recurrent hypoglycaemia.

Good control of plasma glucose levels always remains a desired goal for both diabetic patients and their physicians. However, unintended tight glucose control should always be alarming to the treating physician, although, it may seem to be a blessing to the patient. A downward trend in blood glucose profile in an elderly male with long standing diabetes generally points to developing renal insufficiency. Apart from that, other causes responsible for lowering of blood glucose have to be considered at times when clinical scenario is slightly different. Here, we present a case of an elderly man who presented with an unintended tight control of blood glucose over a period of few months, which upon neglecting culminated into recurrent hypoglycaemia. The etiology of recurrent hypoglycaemia in this patient was non-islet cell tumor hypoglycaemia (NICTH). The causes, pathophysiology, and management of NICTH are discussed briefly.

INTRODUCTION

Achieving target glycaemic goals while avoiding hypoglycaemia is a major challenge in the management of elderly patients with diabetes mellitus. While dealing with an elderly patient with repeated hypoglycaemic episodes, it is imperative to focus on the etiologies that are exclusive to this group like compromised renal function, polypharmacy or pharmacy error due to impaired cognition. Rare causes like coexisting hypoadrenalism or hypopituitarism, malignancy, and hypoglycaemia of islet or non islet cell origin are considered lower in the list once the common precipitating factors are ruled out. Here, we present a case of recalcitrant hypoglycaemia of non-islet cell origin.

CASE REPORT

A 62-year-old man presented with fever, cough, dyspnoea, and unintentional weight loss of 3 kgs within 3 months. Chest X-ray revealed some scattered pulmonary shadows for which a CT scan of chest was planned. During the hospital stay patient developed documented symptomatic and asymptomatic hypoglycaemia almost daily especially in morning hours including two episodes of severe hypoglycaemia for which endocrine opinion was taken.

On reviewing the history, the patient was on metformin 500 mg and glimepride 1 mg, each twice a day after meals since 8 yrs. His blood glucose and other metabolic parameters were well controlled on this medication and he was very regular with regards to his diabetic diet and physical exercise. He did regular self blood glucose monitoring with a periodically calibrated glucometer and maintained a good record of his data. He had never been hospitalized for hypoglycaemia or ketoacidosis, so far. The patient had never recorded any severe hypoglycaemic events, so far. However, he noticed that his blood glucose values started to follow a downward trend since last 6 months with an appreciable drop of his fasting capillary blood glucose values by an average of 10-15 mg/dl, despite of regular and relatively liberal diet. Patient also confirmed some of these relatively low values with laboratory plasma glucose values. At this point of time the patient self adjusted his medications by gradually reducing the doses of Oral Hypoglycaemic Agent (OHA) or oral antidiabetic agents. Due to persistent low blood glucose values despite of liberalized diet, he stopped all OHA after 3 months. There was no history suggestive of any renal, hepatic disorder, alcohol consumption, diabetic retinopathy or any other underlying autoimmune disorder. The patient was not on angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) ACEI or ARBs, fluoroquinolones, sulphonamides. He was receiving paracetamol and cefuroxime for his current illness.

On examination, patient had a BMI of 23.5 kg/m2. He had no stigmata of chronic kidney disease. However, he had a palpable liver of two finger breadths below the costal margin which was non-tender but there were no other features suggestive of chronic liver disease.

On investigation, liver function tests were normal and his serum creatinine was 1.04 mg/dl with a clearance of 88 ml/min. CT scan of the chest performed to diagnose his chest pathology revealed right lower lobe consolidation with multiple pulmonary densities with pleural effusions in both lobes along with a large hypodense mass occupying almost entire right lobe of liver consistent with the provisional diagnosis of hepatocellular carcinoma with pulmonary metastasis, which was confirmed with biopsy [Figure 1].

Figure 1

CT chest showing large hypodense space occupying lesion in right lobe of liver (red arrow)

Biochemical tests done during hypoglycaemia (blood glucose 44 mg/dl) showed a serum cortisol level of 36.5 μg/dl, suppressed serum insulin 0.6 IU/ml (3-35 μIU/ml, RIA) and C-peptide level 0.2 ng/ml (0.85-3.3 ng/ml, RIA) with negative serum ketones [Table 1], which ruled out endogenous hyperinsulinism. IGF-1 done was normal. In the given clinical scenario, ectopic secretion of big IGF-2 from the tumor mass was suspected but big IGF-2 assay was not available. Hence, a provisional diagnosis of non-islet cell hypoglycaemia as a part of paraneoplastic syndrome due to IGF-2 secreted by hepatocellular carcinoma was made.

Table 1

Serum insulin levels and C-peptide levels with corresponding plasma glucose values during three episodes of hypoglycemia in the patient

DISCUSSION

Non-slet cell tumor hypoglycaemia (NICTH) associated with the aberrant production of pro-IGF-2 (‘big’-IGF-2) resulting in a persistent insulin-like activity was first described in a patient with leiomyosarcoma by Daughaday.[1] NICTH-causing tumors abundantly express IGF-2 mRNA2. ‘Big’-IGF-2 acts on IGF-1 and insulin receptors on skeletal muscles and contributes to the glucose-lowering effect and an enhanced insulin-like activity.[12]

NICTH is a fasting hypoglycaemia, characterised by (1) diminished hepatic glucose production due to inhibition of glycogenolysis and gluconeogenesis (2) diminished lipolysis in adipose tissue resulting in low serum free fatty acids (3) increased peripheral glucose consumption. Circulating levels of big IGF-2 are determined by size-exclusion acid chromatography or immunoblot analysis by polyacrylamide gel method.[2] Increased production of ‘big’- IGF-2 by the tumor displaces free IGFs from the IGFBPs leading to increased serum concentrations of free, unbound IGFs hence contributing further to hypoglycaemia. Insulin levels are generally low in NICTH.[3]

In addition, sometimes patients with NICTH do not have elevated ‘big’- IGF-2 levels and hypoglycaemia may be caused by the increased secretion of mature instead of ‘big’-IGF-2, IGF-1, insulin or other peptides with insulin-like activity or a combination of cachexia, renal, and hepatic dysfunction, and glucose consumption by the tumor.[2]

True incidence of NICTH is probably higher, as many cases go unrecognized, especially concerning patients with disseminated disease. NICTH mainly occurs in patients with solid tumors of mesenchymal and epithelial origin, but rarely also in patients with tumors of haematopoietic and neuroendocrine origin[3] [Table 2]. Cases of NICTH in diabetics are reported rarely. In this case, the inadvertent and unexpected tight blood glucose control was a hint to underlying pathology. In addition to hypoglycaemic symptoms, acromegaloid skin changes, such as skin tags, excessive oiliness of the skin, and rhinophyma have been described in patients with NICTH.

Table 2

Prevalence of non-islet cell tumor hypoglycaemia in various types of neoplastic conditions. Data extracted from Zapf (1993), Frystyk et al., (1998), Marks and Teale (1998), Fukuda et al., (2006) and Tsuro et al. (2006)

As shown in Table 3, treatment options include intake of oral carbohydrates, parenteral glucose, GH therapy, octreotide, steroids or glucagon and others.[4]

Table 3

Review of cases of non-islet cell tumor hypoglycemia in the literature with their etiology and treatment given in each case. HCC-hepatocellular carcinoma, GH-growth hormone

To conclude, increased frequency of hypoglycemic episodes without any apparent pharmacological, metabolic (renal and hepatic) or facticious reasons should be carefully evaluated as a change apparently for good may not be actually good. NICTH should be considered in any cancer patient diabetic or nondiabetic without signs of vascular events or brain metastases especially in mesenchymal or malignant epithelial tumor. Low serum insulin in combination with elevated levels of ‘big’-IGF-2 and an increased IGF-2/IGF-1 ratio would confirm the diagnosis.