CASE 1:
POLYURIA AND POLYDIPSIA
INTRODUCTION
CAUSES
History
A 45-year-old woman with a history of hypothyroidism presents to her GP with a three-month history of passing urine more frequently, including up to three times at night. She finds that her constant desire to drink fluids, particularly cold water, and her frequent need to visit the toilet are bothersome since she works as a teacher. Apart from hypothyroidism, she has no other health problems and takes no regular medications.
Examination
Peripherally, the patient is warm and well perfused, with no evidence of dehydration.
Examination of her heart, lungs, and abdomen is unremarkable.
Neurologic examination is normal.
Urine dipstick is negative.
INVESTIGATIONS
Haemoglobin 13.5
White cells 8.3
Platelets 325
Sodium 144
Potassium 4.2
Urea 6.5
Creatinine 100
Fasting glucose 6.0
Corrected calcium 2.25
Questions
1. What is the differential diagnosis for this presentation, and what further tests are required?
2. What are the principles of a water deprivation test, and how should the results shown in Figure 1.1 be interpreted?
3. Discuss the pathophysiology of the likely diagnosis, and suggest how the patient may be treated.
ANSWER 1
This woman presents with polyuria, nocturia and polydipsia.
These symptoms have four important differential diagnoses:
(1) diabetes mellitus
(2) diabetes insipidus, which may either be central or nephrogenic in origin
(3) hypercalcaemia, which may present like the above in an acute setting
(4) primary polydipsia (PP)
Therefore, investigations need to be directed at elucidating one of the above diagnoses.
For diabetes mellitus
a fingerprick glucose may be performed, but formal fasting or random serum glucose is needed to make a diagnosis.
Simple urinalysis may show the presence of glucose, which would point towards this diagnosis.
Measurement of corrected serum calcium is needed to look for hypercalcaemia. Diabetes insipidus is a relatively rare disease characterized by the excretion of large volumes of dilute urine as a result of either a deficiency of or a resistance to the actions of the posterior pituitary hormone antidiuretic hormone (ADH), also known as arginine vasopressin (AVP).
ADH is released into the circulation from the posterior pituitary gland in responseto an increase in serum osmolality, and acts to increase reabsorption of water by causing the insertion of aquaporin 2 (AQP2) channels into the apical membrane of the distal parts of the nephron. Deficiency of ADH leads to central diabetes insipidus (CDI), while failure of the kidney to respond to its actions causes nephrogenic diabetes insipidus (NDI).
Diagnosis of diabetes insipidus includes basic laboratory investigations and a fluid deprivation test. Hypernatraemia may be found secondary to dehydration, while urinalysis may show a low specific gravity (<1.005).
Serum osmolality is increased due to excess free water loss. It may be formally measured, or estimated using the formula: 2 × [Na+] + [urea] + [glucose], as these are the main solutes in plasma. (For this patient, estimated serum osmolality would be around 300 mOsm/kg.) Similarly, urine osmolality will be low, generally less than 200 mOsm/kg, due to inadequate reabsorption of water from the distal parts of the nephron.
When the diagnosis is equivocal, a fluid deprivation test may be performed. Patients are withheld from fluid intake under close supervision for a period of 8 hours, with hourly measurement of body weight, urine volume and urine osmolality. After allowing a sufficient time for dehydration, desmopressin (synthetic ADH) is administered subcutaneously, and a final urine sample is taken one hour afterwards to measure urine osmolality.
The table below shows how the results may be interpreted:
Urine osmolality (mOsm/kg) Diagnosis
After fluid deprivation After desmopressin
<300 >750 CDI
<300 <300 NDI
>750 >750 PP
300–750 <750 Non-diagnostic
The essence of the test is that with CDI, urine will become more concentrated once the deficient ADH is replaced, whereas with NDI, the inability of the kidney to respond to ADH means that any further replacement by ADH has no effect.
CDI is commonly idiopathic though autoantibodies against ADH-secreting cells of the hypothalamus are found in several cases. Moreover, these patients tend to exhibit other
autoimmune conditions, so the patient in our case is most likely to fall into this category,since she has a background of hypothyroidism. Other causes of CDI include benign or
malignant tumours of the brain (such as germinomas and craniopharyngiomas), neurosur-
gery, head injury, and infiltrative conditions (such a Langerhans cell histiocytosis).
There are also genetic forms of the disease, with the majority being inherited in an autosomal dominant fashion with mutations in the ADH gene.
Treatment of diabetes insipidus depends on whether it is cranial or nephrogenic in origin.
CDI responds well to ADH replacement, usually via the synthetic analogue, desmopressin (DDAVP).
High-dose DDAVP may be used for mild cases of NDI, but treatment of NDI requires management of the underlying cause (e.g. correcting metabolic abnormalities, discontinuing any offending drugs). In any case, treatment is required only if the patient is suffering from severe dehydration, with urine volumes >4 L per day.
KEY POINTS
• Causes of polyuria and polydipsia include diabetes mellitus, diabetes insipidus, hypercalcaemia and primary polydipsia.
• Diabetes insipidus is due either to inadequate central production of ADH or failure of the kidneys to respond to ADH.
• Central diabetes insipidus is frequently idiopathic and managed with synthe
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Reference