Diabetes insipidus E23.2

In 1590, the Dutch anatomist Pieter Pauw (1564 - 1617) was the first to describe the clinical picture of diabetes insipidus in an 18-year-old girl who died in the course of the disease (Kivelä 1998).

In 1981, Zerbe et al. presented a test to differentiate between D.I. and primary polydipsia, in which direct AVP measurement was performed after osmotic stimulation. This showed the following result (Christ- Crain 2020):

• in the case of central D.I. the AVP values were below the normal range
• in nephrogenic D.I. above the normal range
• with primary polydipsia in the normal range

Diabetes insipidus (D. i.) is a condition in which the kidneys are unable to produce concentrated urine when dehydrated (Herold 2021).

The urine volume comprises > 50 ml / kg bw per day (Kasper 2015).

D.I. is divided (Kasper 2015) into:

• 1. central (pituitary) diabetes insipidus (ZDI).

This is caused by ADH deficiency.

• 2. renal / nephrogenic diabetes insipidus (NDI).

In the renal form, the kidneys do not respond to ADH.

• 3. gestational diabetes insipidus
• 4. primary polydipsia:
  • dipsogenic D.i.
  • psychogenic polydipsia
  • iatrogenic polydipsia

In primary polydipsia, there is a physiological ADH concentration and an adequate renal response to ADH. In this case, there is primarily polydipsia, which then leads to polyuria.

The disease occurs predominantly in the context of psychiatric comorbidities such as addiction, depression, etc.. However, a prospective study of 156 patients by Fenske (2018) showed a similar prevalence for psychiatric comorbidities in patients with diabetes insipidus (Christ- Crain 2020).

With a prevalence of 1: 25,000 (Crist- Crain 2020), D.I. is one of the rare diseases and affects both sexes with equal frequency (Lehnert 2010).

The ZDI is the more common form, while the NDI occurs only rarely (Herold 2021).

• Causes of ZDI can be:
  • idiopathic
  • secondary

for more details see central diabetes insipidus

• Causes of NDI can be (Herold 2021):
  • Congenital form due to genetic changes
  • Acquired form due to kidney disease with tubular damage

for more details see nephrogenic diabetes insipidus

D.I. can also occur according to Kasper 2015:

• in the course of pregnancy due to a primary plasma ADH deficiency as so-called gestational diabetes insipidus.

Primary polydipsia:

In this case, there is excessive fluid intake due to impaired thirst perception (Kasper 2015).

A distinction is made between 3 forms:

• 1. dipsogenic D.i.: In this case, the inadequate increase in thirst is caused by a reduction in the target value in the osmoreceptor regulatory mechanism (can occur in the context of meningitis, neurosarcoidosis, multiple sclerosis, etc.).
• 2. Psychogenic polydipsia: In psychogenic polydipsia, there is primarily no increased feeling of thirst; polydipsia rather occurs in the context of psychoses or obsessive-compulsive neuroses.
• 3. iatrogenic polydipsia: This form of polydipsia arises from recommendations (medical or tabloid) that one should drink a lot because it has preventive or therapeutic benefits (Kasper 2015).

Pathophysiology of central or nephrogenic diabetes insipidus s. d.

• Primary polydipsia:

In primary polydipsia, excessive fluid intake causes an increase in body water, which decreases ADH- secretion, serum osmolality/sodium, and urine concentration.

Urine dilution causes a compensatory increase in free water diuresis. This stabilizes plasma osmolality / serum sodium to a level only 1% - 2% below basal. Unless the polydipsia is very severe, no marked hyponatremia is found clinically.

(Kasper 2015)

The clinical presentation of diabetes insipidus and primary polydipsia do not differ (Christ- Crain 2020).

• Polydipsia
• Polyuria (in 50 % of patients an excretion of 4 - 8 l / d is found, in 25 % > 12 l / d and in individual cases up to 40 l / d [Siegenthaler 2006])
• Daytime fatigue due to nocturnal polyuria
• Enuresis (Kasper 2015)
• nocturia (if this is absent, a D.I. is practically excluded)
• Asthenuria (the ability to concentrate urine is absent [Herold 2021]).

Symptoms in infancy or childhood of a hereditary cause of D.I. may include:

• Vomiting
• Diarrhoea (Herold 2021)
• fevers
• failure to thrive
• strongly fluctuating body weight(Lentze 2014)

In cases of marked polyuria, the following may develop:

• Dilatation of the urinary tract
• hydronephrosis
• megacystis (Lentze 2014)

In the case of the above-mentioned symptoms, glucosuria should first be excluded diagnostically.

The following procedure is then recommended:

• 24 h urine collection
• Measurement of Copeptin

For more details see "Laboratory"

(Kasper 2015)

MRI

MRI can provide clues to differentiate central or nephrogenic diabetes insipidus and primary polydipsia.

The posterior pituitary lobe appears on cerebral MRI in healthy adults and children as a hyperintense signal, a so-called "bright spot" (Christ- Crain 2020). This is reduced or absent in patients with cerebral and also nephrogenic diabetes insipidus. In patients with primary polydipsia, however, the bright spot is usually present (Kasper 2015).

In a recent study by Fenske (2018), however, it was shown that the bright spot was also absent in 39% of patients with primary polydipsia.

Laboratory values of central D.I. s. d.

Laboratory values of nephrogenic D.I. s. d.

• Laboratory values in primary polydipsia:

Increase in body water results in the following changes:

• Sodium drops (due to free water diuresis, the value usually stabilizes at 1 % - 2 % below the basal value).
• ADH secretion decreases
• Serum osmolality decreases

(Kasper 2015)

The ability to form a concentrated urine is usually between 500 - 600 mosmol / l (Krebs 2018), which is below the normal value of 800 mosmol / kg, because the osmotic gradient in the kidney is lost due to the high flow values (Kuhlmann 2015).

• 24 h collection- urine:

If an excretion volume of > 50 ml / kg bw (corresponds to > 3500 ml at 70 kg) and an osmolality of > 300 mosmol / l are present here, this confirms the diagnosis of D.i.

To identify the type of D.I., further diagnostic measures are required.

Further diagnostics regarding central or nephrogenic diabetes insipidus s. d.

For the diagnosis of primary polydipsia are available:

• 1. measurement of copeptin:

Measurement of copeptin is best for further differentiation and is now considered the gold standard in differentiating a D. I. (Christ- Crain 2020).

Copeptin can be used to mirror the vasopressin (ADH) concentration in the circulation. To diagnose primary polydipsia, the test requires stimulation. This can be done by hypertonic saline (osmotic stimulation) or by arginine (non-osmotic stimulation).

The copeptin test shows a sensitivity of 93% and a specificity of 100% in primary polydipsia (Crist- Crain 2020).

Test performance:

• Stress test with NaCl:

This involves first determining copeptin, then infusing a hypertonic 3% NaCl solution and measuring copeptin again.

• Urine osmolality:

Remains low in ZDI and NDI, increases in primary polydipsia.

• Plasma osmolality:

rises in ZDI and NDI, remains normal in primary polydipsia.

• Copeptin i. S.:

remains low in ZDI, rises in RDI and primary polydipsia.

NaCl- test is more reliable than dehydration test at 95%.

(Herold 2021)

• Dehydration:

Copeptin - level is measured after 8 hours of dehydration in the morning fasting.

It lies in:

• renal diabetes insipidus > 20 pmol / l
• central diabetes insipidus < 2,6 pmol / l

If the determined value is between 2.6 - 20 pmol / l, a further fasting blood sample is required after 16 h of dehydration, in which serum sodium is determined in addition to copeptin. The copeptin index is calculated from these values. If this is < 20, it is a case of central diabetes insipidus partialis and if values are > 20, it is a case of primary polydipsia.

(Kasper 2015)

• 2. fluid deprivation in primary polydipsia:

The test begins in the morning at a well-defined time. The patient is allowed a light breakfast and fluid ad libitum.

The patient is then weighed and a urine sample is taken to determine urine osmolarity, a blood sample is taken to determine plasma osmolality, sodium concentration, ADH or copeptin concentration.

This is followed by the 12-hour thirst phase during which 1 x / h is measured:

• Urine volume
• urine osmolality
• Plasma osmolality
• Serum sodium
• body weight
• Pulse
• Blood pressure

After the end of the test, electrolytes and ADH / Copeptin are measured in addition to the above data.

Under fluid deprivation there is an increase in serum osmolality and sodium level. ADH release is adequate.

However, the concentration capacity of the urine is usually not immediately restored due to the persistent polyuria (Kasper 2015). The values are 500 - 600 mosmol / l (in healthy > 800 mosmol / l ).

(Krebs 2018)

However, the diagnostic reliability is poor in primary polydipsia, as shown in studies by Fenske in 2011 and 2018 (Christ- Crain 2020).

• nephrogenic diabetes insipidus
• central diabetes insipidus
• primary polydipsia
• diabetes mellitus (in which case there is osmotic diuresis)
• diuretic abuse
• hypercalcemic crisis
• dry mouth (indicated by medications such as anticholinergics)

(Herold 2021)

• chronic renal failure
• interstitial nephritis
• vesicoureteral reflux
• obstructive uropathies
• Lithium therapy
• hypokalemia
• hypercalcaemia

(Kröner 2010)

• nephrogenic diabetes insipidus s. d.
• central diabetes insipidus s. d.
• Primary polydipsia:

Persistent polydipsia results in down-regulation of aquaporin- 2 channels, also known as the wash-out phenomenon (Crist- Crain 2020).

Medications are available, depending on the cause of D.I. for symptomatic treatment:

• ADH preparations such as:
  • Desmopressin
• Drugs that enhance the release of ADH such as:
  • Clofibrate
  • Carbamazepine
• Medications that supplement the action of ADH such as:
  • Chlorpropamide
  • Carbamazepine
• Drugs that decrease the amount of drinking such as:
  • Thiazides
  • non-steroidal anti-inflammatory drugs

(Kuhlmann 2015)

For more details on drug therapy, see central D.I. and nephrogenic D.I.

• Primary polydipsia

There is no effective therapeutic measure for primary polydipsia.

Treatment with a vasopressin analogue (e.g. desmopressin) or other antidiuretics is not possible, as this does not reduce the feeling of thirst and consequently hyponatremia occurs after 8-24 hours as a sign of water intoxication.

Patients should be informed that they must not take thiazide diuretics and carbamazepine-containing anticonvulsants such as Tegretal, as otherwise water intoxication may occur.

(Kasper 2015)

• central D.I. s. d.
• nephrogenic D.I. s. d.
• primary polydipsia

Prognosis depends on the cause precipitating the polydipsia.

1. Christ- Crain M (2020) Copeptin- value in the diagnosis of polyuria- polydipsia syndrome. J Clin Endocrinol. Stoffw. 13, 142 - 150 https://doi.org/10.1007/s41969-020-00106-9
2. Fenske W, Refardt J, Chifu I et al (2018) A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med 379: 428 - 439
3. Hegele A et al (2015) Urology: intensive course for continuing education. Thieme Publishers
4. Herold G et al (2021) Internal medicine. Herold Publishers 803 - 804
5. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 64e - 3, 304, 2275 - 2279
6. Kasper D L et al (2015) Harrison's internal medicine. Georg Thieme Publishers 2796 - 2799
7. Keller C K et al (2010) Practice of nephrology. Springer Verlag
8. Kivelä T et al. (1998) Diabetes insipidus and blindness caused by a suprasellar tumor: Pieter Pauw's observations from the 16th century. JAMA 279 (1) 48 - 50
9. Krebs M (2018) Clarification in polyuria. J Clin Endocrinol. Stoffw. 11, 104-106 https://doi.org/10.1007/s41969-018-0026-7
10. Kröner C et al (2010) Basic knowledge of pediatrics. Springer Verlag 317
11. Kuhlmann U et al. (2015) Nephrology: pathophysiology - clinic - renal replacement procedures. Thieme Verlag 263 - 265
12. Lehnert H et al (2010) Rational diagnostics and therapy in endocrinology, diabetology and metabolism 48 - 50.
13. Lentze M J (2014) Pediatrics: basic principles and practice. Springer Verlag 585 - 588
14. Risler T et al (2008) Specialist nephrology. Elsevier Urban and Fischer Publishers 153 - 155, 381 - 385, 752.
15. Siegenthaler W et al (2006) Clinical pathophysiology. Thieme Verlag 260 - 262