How should you approach this case involving extreme thirst with a normal HbA1c?

Clinical conundrum: In the next in our series exploring tricky cases, GPwSI in diabetes Dr Patrick Holmes advises on potential causes and appropriate investigations in this case of a woman presenting with extreme thirst but a normal HbA1c result.

The case: You see a 48-year-old woman who complains of intense thirst that she has been experiencing for some months. She seems otherwise well, is on no medication, and has no other particular symptoms. Having Googled her symptoms, she has become very worried that she might have diabetes mellitus. You arrange an HbA1c and this is completely normal. She is relieved to hear this but then asks what else might be making her thirsty.

When might HbA1c be falsely reassuring?

While this patient’s HbA1c appears genuinely normal, it’s worth noting scenarios where HbA1c might be misleadingly low. HbA1c may not reflect recent hyperglycaemia, particularly when symptoms are of short duration or with drug-induced diabetes from steroids, antipsychotics or checkpoint inhibitors.¹ HbA1c can also be falsely low with recent blood loss, haemolysis or iron replacement therapy.² However, when symptoms have been present for months and HbA1c is normal, non-diabetic causes should be considered.

What, other than diabetes mellitus, are likely causes of polydipsia? How common are they?

When blood glucose is genuinely normal, several non-diabetic conditions can cause polydipsia. The key is distinguishing true polyuria (more than 3L daily) from urinary frequency.

• Diabetes insipidus. Though uncommon (prevalence of around 1 in 25,000), this is an important diagnosis not to miss. Cranial diabetes insipidus results from inadequate anti-diuretic hormone (ADH) secretion, often following head trauma, neurosurgery, or brain tumours, though 30% are idiopathic.³ Nephrogenic diabetes insipidus occurs when kidneys don’t respond to ADH, commonly due to lithium therapy, hypercalcaemia, or genetic causes. Both present with large-volume, dilute urine and intense thirst.
• Primary polydipsia. A common cause when glucose is normal. Affects up to 20% of psychiatric patients but also occurs in healthy individuals. Excessive fluid intake suppresses ADH release. It can be psychogenic (anxiety, stress, psychiatric conditions) or dipsogenic (hypothalamic dysfunction). Unlike diabetes insipidus, patients can concentrate urine when fluid is restricted.
• Bladder and urinary tract causes. Very common presentations in primary care. UTIs, interstitial cystitis and overactive bladder syndrome cause frequent small-volume voiding rather than true polyuria. These patients often describe urgency and dysuria. Consider if frequency predominates over thirst.
• Medications. Lithium is the classic drug cause and can impair urinary concentrating ability in a substantial proportion of long-term users. Diuretics are another common cause of polyuria, and are often overlooked when a patient presents. Anticholinergics and some antipsychotics can also cause polydipsia.
• Kidney, metabolic and endocrine causes. Hypercalcaemia impairs renal concentrating ability and increases thirst, often with bone pain and depression. Hyperthyroidism causes heat intolerance and compensatory fluid intake alongside weight loss, palpitations, and anxiety. Chronic kidney disease with advancing impairment develops concentrating defects, nocturia, and increased thirst.

What further investigations should the GP consider and how should these be interpreted?

A systematic approach helps differentiate between causes and guides appropriate referral decisions.

First-line investigations

• Basic tests.FBC, U&Es including calcium, glucose, and thyroid function tests. Urine dipstick for glucose, leucocytes and specific gravity if available. These identify most common metabolic causes.
• Urine osmolality and serum sodium are crucial.Low urine osmolality (<300 mOsm/kg) indicates inappropriately dilute urine, but is not by itself diagnostic of diabetes insipidus. Low sodium supports primary polydipsia, while elevated sodium supports diabetes insipidus.⁴ (Note that paired serum and urine osmolality is the standard test for diabetes insipidus, but in practice this can be difficult to coordinate and it has been superseded by other tests in secondary care. Therefore an elevated serum sodium is sufficient to guide referral for further investigation of this.) Results in the normal range are less specific and may require specialist assessment.
• 24-hour urine collection.Volumes above 3L daily confirm polyuria rather than frequency. This helps distinguish diabetes insipidus and primary polydipsia from bladder causes.

Specialist investigations

• Water deprivation testing.A specialist investigation used to help diagnose diabetes insipidus and distinguish it from primary polydipsia. Requires specialist supervision due to dehydration risk.
• Copeptin testing is increasingly used as an alternative to water deprivation.
• Other investigations may include MRI.

Which patients require referral and what safety netting should be provided?

Urgent referrals

• Severe hypercalcaemia (>3.0 mmol/L), severe hypernatraemia (>150 mmol/L), or suspected malignancyrequire urgent medical assessment due to risk of arrhythmias, altered consciousness, or need for cancer investigation pathways.

Routine specialist referrals

• Suspected diabetes insipidus.Endocrinology referral for patients with dilute urine (<300 mOsm/kg), high-normal or elevated sodium and true polyuria (>3L daily).
• Primary polydipsia with psychiatric features.Consider psychiatry referral if excessive water drinking appears related to anxiety or obsessive behaviours.
• Unexplained polyuria.If basic investigations are normal but symptoms persist, endocrinology referral helps exclude rare causes.

Safety netting

• Ongoing monitoring.Regular monitoring of electrolytes and symptoms. If symptoms change or weight loss develops, reassess with glucose-based testing.
• Fluid intake guidance. Patients with primary polydipsia need counselling about gradually reducing fluid intake under medical supervision.

Practical plan for this patient

1. Initial investigations.FBC, U&Es including calcium, thyroid function tests, and urine osmolality. Urine dipstick. 24-hour urine collection to quantify polyuria.

2. Interpret results together.Combine urine osmolality and serum sodium findings. Dilute urine with elevated sodium suggests diabetes insipidus.

3. Referral decision.If investigations suggest diabetes insipidus, refer to endocrinology. If basic tests are normal and symptoms mild, consider watchful waiting.

4. Patient education. Reassure about normal HbA1c but explain other causes of thirst. Provide clear guidance about when to seek urgent medical attention.

Key learning points

• Primary polydipsia is a common cause of polydipsia when glucose is genuinely normal in primary care.
• True polyuria is more than 3 L daily and should be distinguished from urinary frequency due to bladder pathology.
• Combined interpretation of urine osmolality and serum sodium helps differentiate diabetes insipidus from primary polydipsia.
• HbA1c may not reflect recent hyperglycaemia, but fingerprick glucose will identify acute diabetes.
• Water deprivation testing requires specialist supervision due to risk of severe dehydration.

Dr Patrick Holmes is a GPwSI in diabetes in Darlington

References

1. NICE CKS. Type 2 diabetes. 2023
2. Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med 2014;29:388-394
3. Christ-Crain M, Bichet DG, Fenske WK. Diabetes insipidus. Nat Rev Dis Primers 2019;5:54
4. Ball SG, Iqbal Z. Diagnosis and treatment of diabetes insipidus. Best Pract Res Clin Endocrinol Metab 2016;30:205-218