A “growing cause” of diabetic ketoacidosis

Abstract

The progress of a young woman presenting with diabetic ketoacidosis is described. She was managed as for a new presentation of type 1 diabetes, but was subsequently diagnosed with acromegaly due to a large pituitary tumour. Following treatment for this, and relative normalisation of growth hormone levels, she was able to stop insulin completely. Subsequently, an oral glucose tolerance test showed no evidence of abnormal glucose tolerance and she remains non-diabetic.

BACKGROUND

The differentiation between type 1 and type 2 diabetes can sometimes be difficult, particularly as type 2 diabetes is commonly being diagnosed at a younger age. Ketosis-prone type 2 diabetes accounts for less than 1% of presentations of diabetes, although it is suggested that up to 10% of Afro-Caribbean patients may present in this way.¹ The condition is characterised by episodic ketosis, without immunological markers of type 1 diabetes, insulin dependence at the time of diagnosis and a subsequent lack of insulin requirement, frequently for years.

Acute hyperglycaemia can be the initial presentation for a number of conditions and the following secondary causes of diabetes mellitus should always be considered:

• Chronic pancreatitis

• Cystic fibrosis

• Haemochromatosis

• Fibrocalculus diabetes

Endocrine disease:

• Cushings syndrome

• Acromegaly

• Hyperparathyroidism

• Phaeochromocytoma

• Conn’s syndrome

• Glucagonoma

Drug induced:

• Corticosteroids

• Thiazides

• Beta-blockers

• Atypical anti-psychotics

Infections:

• Cytomegalovirus

• Congenital rubella

Genetic syndromes:

• Turner’s syndrome

• Friedreich’s ataxia

• Dystrophia myotonica

• Prader Willi syndrome

• Down’s syndrome

• Huntingdon’s disease

• Porphyria.

Although acromegaly is a rarely reported cause of diabetic ketoacidosis, this case highlights the need to consider secondary causes of diabetes and also highlights an under-recognised form of diabetes, described as ketosis-prone type 2 diabetes.

CASE PRESENTATION

A 31-year-old, Caucasian female clerk presented to the emergency department with a 1 day history of abdominal pain and nausea. She described polyuria, polydipsia and a significant weight loss of 2 stone over 2 months. She had no significant past medical or family history and was not on any regular medication. On examination she was afebrile, dehydrated, blood pressure was 110/60 mmHg, pulse 110 regular and respiratory rate 30 per minute. Her weight was 81.5 kg (body mass index (BMI) 28.4 kg/m²). Further clinical examination was initially reported as unremarkable. There was no family history of type 1 or type 2 diabetes.

INVESTIGATIONS

Arterial pH was 7.2 and plasma glucose was 24.8 mmol/l. Urinalysis revealed heavy ketonuria and glycosuria, and urine beta-human chorionic gonadotropin was negative. Electrolytes showed sodium 133 mmol/l, potassium 3.7 mmol/l, urea 2.6 mmol/l and creatinine 66 μmol/l. Full blood count was normal. Subsequent tests revealed glycated haemoglobin of 12.7% (normal range: 4.8–6.4%) and negative glutamic acid decarboxylase (GAD) antibodies.

DIFFERENTIAL DIAGNOSIS

Type 1 diabetes mellitus complicated by ketoacidosis. Ketosis-prone type 2 diabetes mellitus.

TREATMENT

She was treated with intravenous insulin and fluid and electrolyte replacement, and made a rapid clinical recovery. It was noted she required very large doses of insulin to control plasma glucose levels. She was subsequently converted to a standard basal bolus insulin regime requiring over 200 units of subcutaneous insulin per day.

OUTCOME AND FOLLOW-UP

She was reviewed shortly after admission by the endocrine team and was noted to have physical features of acromegaly and a bitemporal haemianopia. Insulin-like growth factor-1 (IGF-1) was 1001 ng/ml (age-related normal range 56–280 ng/ml; median 176 ng/ml). On five point testing, mean growth hormone burden was 250 miu/l (normal range <5 miu/l). Imaging revealed a pituitary macroadenoma extending to the optic chiasm and laterally into the sphenoid sinus (fig 1). She underwent transphenoidal hypophysectomy followed by external beam radiotherapy and medical treatment with cabergoline. Due to only a modest reduction in the growth hormone burden and IGF-1, and intolerance of somatostatin analogues, she was started on pegvisomant (a growth hormone receptor antagonist), following which IGF-1 fell to 450 ng/ml. Her diabetes was well-controlled on insulin, and she was troubled by recurrent hypoglycaemia. Her weight had risen to 93 kg, and BMI to 32.5 kg/m². Insulin treatment was discontinued 18 months after diagnosis. An oral glucose tolerance test confirmed that she no longer had diabetes mellitus (fasting glucose 4.4 mmol; 120 minute glucose 3.0 mmol/l). While this indicated she was not diabetic, the reactive hypoglycaemia 2 hours after a glucose load is not infrequently seen in people at subsequent risk of type 2 diabetes. She subsequently underwent gamma knife radiosurgery targeted to the remaining pituitary disease. Her most recent IGF-1 is 253 ng/ml which indicates good control of the disease. She remains without diabetes.

Figure 1.

MRI scan of pituitary fossa showing large pituitary tumour (arrowed).

DISCUSSION

This case highlights a number of learning points. First, diabetes mellitus can be the presenting feature of other, less common, conditions, and secondary causes of diabetes should always be considered. Second, it illustrates a case of a relatively under-recognised form of diabetes: ketosis-prone type 2 diabetes. This form of diabetes has been described for many years and has a number of pseudonyms (type 1a, atypical, type 1½, J-type or flatbush diabetes).² The largest case series published of this type of diabetes has followed 233 patients over 10 years diagnosed with ketosis-prone type 2 diabetes (as defined as presenting with new onset diabetes without a precipitating cause, heavy ketonuria or ketoacidosis, and GAD antibody negative).¹ Despite initial insulin treatment, all patients came off insulin but there was a 90% relapse rate of ketosis over 10 years. Half of the patients remained insulin dependent and 40% became non-diabetic. The aetiology of this condition is not clearly understood. It appears to be more common among people of African-Caribbean descent and among people treated with atypical antipsychotics.³ An association with low glucose-6 phosphate dehydrogenase activity has been noted.⁴ This may suggest a susceptibility to oxidative stress leading to beta cell dysfunction and, hence, acute insulin deficiency, which is reversed when the oxidative stress is removed.

Acromegaly can commonly present with hyperglycaemia and an association with type 2 diabetes is well recognised.⁵ However, presentation with ketoacidosis is uncommon and we have found 12 previous cases reported in the literature.⁵ The previous reports involve patients aged from 16–78 years, most of whom were Caucasian, followed up for 1–10 years. Insulin was been used as initial treatment in all, but around 60% were able to stop insulin once the acromegaly was treated. Our patient had severe acromegaly. Growth hormone induces hyperglycaemia by a variety of mechanisms, including increase in hepatic gluconeogenesis and reduced peripheral use of glucose. We postulate that the ketoacidosis seen in some cases of acromegaly may be induced by increased lipolysis, leading to increased ketone production via the Randal cycle, probably due to a direct effect of very high growth hormone levels inhibiting normal fatty acid metabolism. In addition, high levels of glucose may contribute to beta cell failure (glucotoxicity), which improves with improved glycaemic control. This is also the proposed mechanism by which ketosis occurs in ketosis-prone type 2 diabetes.

LEARNING POINTS

• Diabetic ketoacidosis is a rare presenting feature of acromegaly.

• Ketosis-prone type 2 diabetes is an under-recognised form of diabetes characterised by acute ketosis followed frequently by insulin independence.

• Secondary causes of diabetes should always be considered.