Adipsia

In humans, the thirst center is located in the hypothalamus. The primary physiological stimuli for thirst are hypertonicity (osmotic) and hypovolemia. After infancy, an additional social stimulus for thirst is usually observed, which is viewed as secondary.

Osmoreceptors in the anterior wall of the third ventricle, near the organum vasculosum mediate the osmotic regulation of thirst, near to or even common to the osmoreceptors that regulate secretion of aqueous vasopressin (AVP). This stimulus is known as osmotic thirst.[2]

In general, the threshold for AVP secretion is a small increase in serum osmolality from 280-290 mOsm/kg H2 O. In contrast, the stimulus for osmotic thirst stimulation is set much higher, typically when near-maximal urine concentrations are achieved (ie, at serum osmolalities around 295 mOsm/Kg H2 O). The purpose of this dichotomy appears to be so that thirst can act as a back up mechanism, when pituitary and renal mechanisms are insufficient to keep plasma osmolality within a tight 1-2% range. If thirst were the primary system, humans would need to constantly divert attention towards seeking water.

After activation of osmotic thirst, downregulation of this stimulus occurs in 2 phases: (1) an immediate but short-lived downregulation of thirst by the oropharynx and upper GI tract and (2) a less immediate but more sustained downregulation by drop in serum osmolality (negative feedback).

Hypovolemia and hypotension may also stimulate thirst through the activation of low-pressure (venous) and high-pressure (arterial) vascular stretch receptors (hypovolemic thirst). Impulses from these receptors are transmitted by the vagus and the glossopharyngeal nerves to the medulla and from there to the hypothalamus. In addition, the hypothalamus is directly stimulated by angiotensin II. Such a hypovolemic thirst occurs with depletion of plasma volume by at least 4-8% in humans and 10-15% in some species.

Thirst abnormalities may result either from specific functional lesions that impair the activation of thirst by hypertonicity or hypovolemia or from generalized lesions that impair the cognitive processes required for thirst perception.

Any lesion, congenital or acquired, that affects the anterior hypothalamus may lead to the abolition of thirst. Because the center for AVP secretion occupies a contiguous area, lesions of the thirst center may also affect AVP (also known as antidiuretic hormone [ADH]) production, storage, or secretion), leading to impaired urinary concentrating ability. Therefore, patients may present with a combination of adipsia and central diabetes insipidus (ie, absence of AVP secretion), also known as adipsic diabetes insipidus.[3, 4] Such patients can develop severe hypernatremia, though it is chronic and therefore asymptomatic in many cases.[5] However, these patients have a much higher risk of infection and death.[6] . In adipsia, AVP secretion may be either completely unaffected, partially abolished, or completely abolished. In a normal situation, AVP acts along with thirst to maintain serum osmolality within tight control.

In rats, areas within the caudate nucleus appear to regulate water intake through norepinephrine-sensitive alpha receptors.[7] In a single case report in a dog, antithyroid antibodies led to hypothyroidism and adipsia, both of which resolved with levothyroxine therapy.[8] "Sickness behavior" is a condition in animals in which systemic infection leads to a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia. The neuroimmune communication may involve the interaction of cytokines with peripheral nerves.[9] In rat models, lipopolysaccharide is used to induce adipsia as part of sickness behavior.[10]

Although many different diseases can affect the anterior hypothalamus, adipsia is seen very infrequently even among patients with known anterior hypothalamic lesions. The reason adipsia is uncommon in such situations and the instances when adipsia is more likely to occur remain unknown.

Rarely, some children have adipsia without a definable structural lesion (essential adipsia).[11, 12, 13] A constellation of adipsia, obesity, hyperprolactinemia, and hypothyroidism was reported in one child.[13]

In hypodipsia, the exact pathological abnormalities are not known. AVP levels are normal, suggesting that neuronal pathways affecting thirst are selectively affected, either at the osmoreceptor level or further downstream.

The most common neoplastic lesions associated with adipsia are germinomas,[14] histiocytomas, and gliomas.

Congenital lesions that are associated with adipsia include the following:

• Microcephaly

• Ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome

• Empty sella syndrome

• Malformation of the septum pellucidum

• Holoprosencephaly

The following can also produce adipsia:

• Meningoencephalitis

• Subarachnoid hemorrhage

• Hydrocephalus

• Pseudotumor cerebri

• Psychogenic abnormalities[15]

International statistics

Adipsia is an extremely rare condition. Fewer than 200 cases have been reported worldwide, although more cases are likely unreported. Mavrakis et al collated and described 70 reported cases in which thirst and AVP secretion were both abolished.[16]

Interestingly, a number of cases are reported in the veterinary literature, largely due to intracranial tumors, similar to causes in humans.

Age-related demographics

Adipsia occurs in all age groups. Congenital malformations and traumatic lesions predominate in children, neoplastic lesions occur in all age groups, and psychogenic causes are more common in adults, particularly elderly persons. In children, adipsia without demonstrable structural lesions is very rare and has been reported in only 6-7 patients.[17]

Prognosis is unfavorable unless behavioral therapy is successful. Most patients remain homebound or institutionalized and may develop further neurological handicaps.

Morbidity/mortality

Adipsia leads to considerable difficulty in the management of water balance. Its common consequence is hypernatremic dehydration, which, when severe, is associated with hemodynamic and CNS manifestations. Adipsia has a higher morbidity than diabetes insipidus, in which the thirst mechanism is intact.[18]

Complications

Existing neurological deficits can be exacerbated by acute episodes of severe hypernatremia and cerebral hemorrhage.

Extrarenal losses of volume during episodes of gastroenteritis, more common in children, may lead to rehospitalization for worsening hypernatremia or other disorders of serum electrolytes.

In most situations, patients with adipsia present with obtundation caused by hypernatremic dehydration.

Information regarding the quantity and type of fluid intake may reveal the lack of thirst, pointing to the diagnosis. The presence of an inappropriately high urinary output is highly suggestive of concomitant central diabetes insipidus.

A history of brain tumors or congenital malformations suggests the possibility of a hypothalamic lesion.

No physical signs are specific for adipsia. The most prominent physical signs are referable to alterations in brain water content due to hypernatremia. These alterations include the following:

• Hyperpnea

• Muscle weakness

• Restlessness

• High-pitched cry

• Insomnia

• Lethargy

• Coma

• Convulsions (uncommon, except in cases of overly rapid rehydration)

Loss of skin turgor and dry mucous membranes are evident but may not be commensurate with the grade of dehydration.

Physical signs indicative of an underlying abnormality are often evident. Examples of such physical signs include the following:

• Cleft palate

• Other midline facial defects

• Hydrocephalus

• A scar from a previous tumor surgery

The following studies are indicated in patients with adipsia:

• Serum electrolytes, BUN, and serum creatinine levels

  • Suspicion of adipsia frequently results from serum electrolyte abnormalities.

  • Hypernatremia is a hallmark of clinically significant water deficit that may be due to adipsia.

  • Volume depletion that is associated with adipsia also causes elevations in BUN and creatinine levels and an increase in the BUN/creatinine ratio.

• Serum osmolality: The water deficit results in a markedly elevated serum osmolality.

• Urine electrolyte levels and osmolality

  • Simultaneous measurements of urine electrolytes and osmolality are critical in determining the central, rather than renal, nature of the defect in water homeostasis.

  • In adipsia, the fractional excretion of sodium is less than 1%, unless a coexisting defect in aqueous vasopressin (AVP) secretion is present.

  • Urine osmolality is very high, unless a coexisting defect in AVP secretion is present.

  • In diabetes insipidus, the concentration of urine is submaximal, even in the face of high serum osmolality. In salt intoxication, the urine sodium concentrations are very high and fractional excretion of sodium is greater than 1%.

  • Difficulties in diagnosis may arise when adipsia and diabetes insipidus coexist. In these patients, initial test results may be suggestive of diabetes insipidus; however, administration of AVP increases urine osmolality and diminishes the tendency for hypernatremia. The patient's history of absence of thirst points toward the coexistence of adipsia.

• Blood hormone levels

• AVP levels: In isolated adipsia, circulating AVP levels must be high, reflecting an appropriate response of the pituitary to hyperosmolality. In patients who have defects in thirst regulation and AVP secretion, serum AVP levels are low or absent.

• Plasma renin and aldosterone levels: These are elevated secondary to hypovolemia.

Brain imaging studies, such as CT scans and MRI studies, are indicated if the underlying cause for adipsia needs to be determined (eg, empty sella syndrome, tumor). They may also help to rule out complications of hypernatremia, such as intracranial hemorrhage.

Therapeutic challenge with intravenous AVP or nasal desmopressin acetate (DDAVP) is often required to confirm or rule out the diagnosis of diabetes insipidus. Perform these tests in consultation with experts in water metabolism.

Do not rapidly correct chronic hypernatremia in patients with adipsia. Correct hypernatremia over 48-72 hours, with no more than half of the calculated water deficit replaced during the first 24 hours of therapy. Drop in serum sodium level should be at rate of approximately 0.5 mEq/L/hour or 10-12 mEq/L/day.

• Long-term therapy

  • The underlying damage to the hypothalamic area is often irreversible.

  • The goal of medical care is to teach the patient and parents how to maintain adequate fluid intake.[19]

• Treatment options

  • No pharmacological therapy is currently available.

  • Behavioral procedures are successful in increasing water intake in some patients.

  • Electroconvulsive therapy has been used, with mixed results, in patients in whom the underlying cause is psychogenic.

  • When behavioral therapy fails, the only remaining option is long-term administration of fluids by nasogastric tube or G-button.

  • Nasal desmopressin acetate (DDAVP) therapy to limit urine output is useful in patients with coexisting central diabetes insipidus.[20]

  • In adipsic diabetes insipidus, recovery of thirst function after removal of underlying cause can be assessed by a visual analog scale after hypertonic saline infusion.[21]

Removal of tumors, hematomas, or cysts that compress the thirst center may be curative in selected cases.

Obtain the opinion of an oncologist, a neurosurgeon, or both for patients with space-occupying lesions.

Obtain the opinion of an endocrinologist in patients with associated central diabetes insipidus.

Diet

No dietary restrictions are necessary.

Frequent and scheduled water intake has to be maintained.

Activity

No restrictions on activity are necessary.

Further outpatient care

Monitor the serum electrolyte levels in order to ensure adequate fluid intake. The level of comprehension and compliance of the patient and parents determines the frequency of the visits.

In children with normal aqueous vasopressin (AVP) secretion, measuring urine osmolality may be sufficient for follow-up care. The goal of a urine osmolality is 400-600 mOsm/kg H2O.

Further inpatient care

Patients with adipsia must remain in the hospital until hypernatremia is diagnosed and corrected and until the patient is able to maintain fluid and electrolyte homeostasis.

Transfer

Patients who are unable to achieve an adequate fluid intake may be transferred to a chronic care facility where they can be kept under close supervision and receive behavioral therapy.

Class Summary

These agents are indicated when diabetes insipidus coexists. Desmopressin is a synthetic antidiuretic hormone with actions that mimic vasopressin. It is used to treat diabetes insipidus, which deprives the kidney of its capacity to produce concentrated urine. This results in large volumes of dilute urine (polyuria) and excessive thirst (polydipsia). Elevated sodium serum concentrations may occur, but hypernatremia is more likely to be severe when fluid is restricted.

Desmopressin acetate (DDAVP)

Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys.