Diabetes insipidus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

Diabetes insipidus (DI) is a syndrome characterized by the excretion of abnormally large volumes of dilute urine. It can be classified into three fundamentally different types that must be distinguished from one another in order to facilitate appropriate diagnosis and treatment. These are central DI (also called neurogenic DI), which occurs due to inadequate production and secretion of antidiuretic hormone, arginine vasopressin (AVP); nephrogenic DI, which occurs due to renal insensitivity to the antidiuretic effect of AVP; and primary polydipsia (also known as psychogenic DI), which occurs due to the suppression of arginine vasopressin secretion by excessive fluid intake. Patients with DI typically present with excessive day and nighttime urination and excessive fluid intake in order to compensate for the lost fluids in urine, which may lead to electrolyte imbalances such as hypo– or hypernatremia. The causes of diabetes insipidus are unique to each variation of the disease, and a treatment plan should be targeted toward the underlying cause of the disease.

The history of diabetes insipidus dates back as the early 1670s when Thomas Willis noted that there was a difference in the taste of urine produced by different patients who presented with polyuria and polydipsia. This marked the beginning of the research into the difference between the popularly known diabetes mellitus and diabetes insipidus.

Diabetes insipidus can be classified into three types: Central, nephrogenic, and psychogenic diabetes insipidus. Some rare types of diabetes insipidus include gestational diabetes insipidus which occurs only in pregnancy; autoimmune diabetes insipidus caused by an autoimmune reaction and thirst related diabetes insipidus.

The posterior pituitary consists of paraventricular and the supra-optic nuclei that synthesizes oxytocin and arginine vasopressin respectively. In Central DI, there is an absence of vasopressin which is responsive to the exogenous administration of desmopressin. On the contrary, in nephrogenic DI, solute excretion and all filtration functions of the kidney are normal but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of both endogenous and exogenous administration of vasopressin. More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of AVP have been identified in familial central diabetes. Many conditions have been associated with the development of diabetes insipidus such as Wolfram syndrome also known as DIDMOAD, Langerhans cell histiocytosis (LCH), sickle cell disease and amyloidosis.

Diabetes insipidus is caused by a variety of factors. The causes for each subtype of diabetes insipidus is classically different. It is important to identify these underlying causes of the various forms in order to appropriately diagnose and treat each type.

Diabetes insipidus must be differentiated from other diseases that cause polyuria which is defined as a urine output exceeding 3 L/day in adults and 2 L/m2/day in children, increased frequency or nocturia and polydipsia. It is important to know that levels of hypo or hypernatremia is not sufficient to describe the underlying cause of diabetes insipidus.

The prevalence of diabetes insipidus is estimated to be 3:100,000 individuals worldwide. The prevalence and incidence of both central and nephrogenic DI does not vary by gender. Similarly, no significant racial predilection in prevalence among ethnic groups have been found.

With both central and nephrogenic DI, inherited causes account for approximately 1-2% of all cases. An incidence of about 1 in 20 million births for nephrogenic DI caused by AQP2 mutations has been documented.

The risk factors in the development of diabetes insipidus vary depending on the type of DI caused. There are a few risk factors in the development of central DI which include genetic mutations, pituitary disorders, hypothalamic injury, head tumors. The most potent risk factor in the development of nephrogenic diabetes insipidus is lithium use; as lithium has a very narrow therapeutic index of 0.4-0.8 mmol/L . Excessive water intake has been identified to be the only risk factor associated with psychogenic DI; also pregnancy is the for gestational DI.

According to the USPSTF screening for diabetes insipidus is not recommended.

Diabetes insipidus if left untreated results in an elevation in serum sodium and osmolality. The hyperosmolarity seen in these patients may also present with neurologic symptoms such as confusion, altered mental status, seizures, coma and death. The two major complications of diabetes insipidus are dehydration and electrolyte imbalance. Some research also demonstrates that there is decrease in bone mineral density seen in patients with diabetes insipidus. However the mechanism of development is not clearly understood neither is the treatment clearly accounted for because treatment of diabetes insipidus does not reverse the disorder.

Clinical examination may provide important clues to possible underlying diagnoses. The age at which symptoms develop together with the pattern of fluid intake, may influence subsequent investigation of diabetes insipidus. The primary symptoms are persistent polyuria and polydipsia, and young children may have severe dehydration, vomiting, constipation, fever, irritability, sleep disturbance, failure to thrive and growth retardation.

Depending on the time of presentation, patients with diabetes insipidus usually appear generally weak without any focal neurologic findings. However, physical examination of patients with diabetes is usually remarkable for signs of dehydration, such as tachycardia, tachypnea, hypotension, and dry mucus membranes.

There are a couple of laboratory investigations that can be carried out in order to diagnose diabetes insipidus. Some of them include plasma sodium and urine osmolality, measurement of urine output, plasma and urine ADH measurement.

There are no electrocardiogram findings associated with diabetes insipidus.

There are no chest X ray findings associated with diabetes insipidus.

There are no CT scan findings associated with diabetes insipidus.

There are no MRI findings associated with diabetes insipidus.

There are no echocardiography or ultrasound findings associated with diabetes insipidus.

There are no other imaging findings associated with diabetes insipidus.

There are no other diagnostic studies recommended for diabetes insipidus.

The hallmark symptoms of both central and nephrogenic diabetes insipidus (DI) are polyuria, nocturia, and polydipsia due to a concentrating defect. Treatment of central diabetes insipidus is primarily aimed at decreasing the urine output, usually by increasing the activity of antidiuretic hormone (ADH, also called arginine vasopressin or AVP). However, nephrogenic diabetes insipidus (DI) results from resistance of the kidney to the actions of antidiuretic hormone(ADH). As a result, patients with this disorder are not likely to have a good response to hormone administration (as DDAVP) or to drugs that increase either the renal response to ADH or ADH secretion and so other treatment options must be explored.

Surgical intervention is not recommended for the management of diabetes insipidus.

Majority of the cause of diabetes insipidus are idiopathic. However, for the ones in which the causes are known, prevention of the causes can help in avoiding diabetes insipidus.

The secondary prevention of diabetes insipidus is same as its primary prevention.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The history of diabetes insipidus dates as far back as the early 1670s, when Thomas Willis noted that there was a difference in the taste of urine produced by different patients who presented with polyuria and polydipsia. This marked the beginning of the research into the difference between the popularly known diabetes mellitus and diabetes insipidus.

• Thomas Willis was first noted the difference diabetes mellitus from diabetes insipidus in 1670.^[1]
• Johann Peter Frank was first introduced the term “diabetes insipidus“; described polyuric patients excreting nonsaccharine urine in 1794.^[1][2]
• In 1913, a historical milestone was achieved when Farini successfully used posterior pituitary extracts to treat diabetes insipidus.
• In the early 1920s the available evidence indicated that diabetes insipidus was a disorder of the pituitary gland.
• In 1928, De Lange first observed that some patients with diabetes insipidus did not respond to posterior pituitary extracts.
• In 1945, Forssman and Waring established that the kidney played a critical role in the forms of diabetes insipidus that were resistant to this treatment.
• In 1947, Williams and Henry introduced the term nephrogenic diabetes insipidus for the congenital syndrome characterized by polyuria and renal concentrating defect resistant to vasopressin.
• In 1955, du Vigneaud received the 1955 Nobel Prize in chemistry for the first synthesis of the hormone vasopressin, which represented a milestone in the development of treatment for central diabetes insipidus.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

Diabetes insipidus can be classified into three types: central, nephrogenic, and psychogenic diabetes insipidus. Some rare forms of the disease include gestational diabetes insipidus, which occurs only in pregnancy, and autoimmune diabetes insipidus, which is caused by an autoimmune reaction.

• CDI is caused by the destruction or degeneration of neurons originating in the supraoptic and paraventricular nuclei, which disrupts the normal storage and release of ADH.
• The most common cause of central diabetes insipidus (CDI) is idiopathic diabetes insipidus (DI), which accounts for the vast majority of cases of CDI.^[1][2]

• The most common causes of ADH resistance severe enough to produce polyuria are hereditary nephrogenic DI (in children) and chronic lithium ingestion and hypercalcemia (in adults).
• Acquired causes are often partially reversible with cessation of the offending drug or correction of hypercalcemia.^[3][4][5]

• This type of DI is characterized primarily by excessive water intake. This disorder is most often observed among young women and mentally unstable patients with psychiatric illnesses, including those taking a phenothiazine, which can lead to the sensation of a dry mouth.^[6]
• Other identifiable causes of psychogenic diabetes insipidus include sarcoidosis and lesions to the hypothalamic pituitary axis, which may disrupt the thirst center, thereby increasing the sensation of thirst and water consumption.^[7]

• This type of diabetes insipidus occurs only during pregnancy. Gestational DI occurs when an enzyme made by the placenta destroys ADH produced in the mother.
• Most cases of gestational DI can be successfully treated with desmopressin.^[6]
• In rare cases, however, an abnormality in the thirst mechanism causes gestational DI, and desmopressin should not be used.^[8]

• This type of diabetes insipidus is very rare. It results from an autoimmune cause.^[7]
• It is usually associated with other autoimmune diseases and typically affects women of childbearing age.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The posterior pituitary consists of the paraventricular and supraoptic nuclei, which synthesize oxytocin and arginine vasopressin, respectively. In cases of central DI, there is an absence of vasopressin, which is responsive to the exogenous administration of desmopressin. On the contrary, in cases of nephrogenic DI, solute excretion and all filtration functions of the kidney are normal, but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of both endogenous and exogenous administration of vasopressin. More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of ADH have been identified in familial central diabetes. Many conditions have been associated with the development of diabetes insipidus such as Wolfram syndrome (also known as DIDMOAD), Langerhans cell histiocytosis (LCH), sickle cell disease, amyloidosis, and several others.

The posterior pituitary consists of the paraventricular and supraoptic nuclei that synthesize oxytocin and arginine vasopressin, respectively. The axons of these hormones project to the neurohypophysis, where the hormones are secreted into the bloodstream to allow for maximum anti-diuresis over the course of 5–10 days. The maintenance of water balance in healthy humans is achieved principally by three interrelated determinants:

• Thirst
• AVP
• Kidney function

ADH acts on the kidney, where it increases urine osmolality. It binds to the V2 receptors in the basolateral membrane of the renal collecting tube and activates the Gs-adenyl cyclase system, increasing intracellular levels of cyclic 3′,5′-adenosine monophosphate (cAMP) and thus activating protein kinase A, which in turn phosphorylates preformed AQP2 water channels localized in intracellular vesicles.^[1]

In cases of nephrogenic DI, solute excretion and all filtration functions of the kidney are normal, but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of endogenous vasopressin. Abnormalities in the medullary osmotic gradient, directed by antidiuretic hormone (ADH) or arginine vasopressin (AVP) and inhibition of the action of ADH on the renal tubules, are both thought to be mechanisms by which nephrogenic DI develops. The lack of response to ADH is due to the inhibition of adenylate cyclase and the resultant decreased formation of cAMP. cAMP serves as a second messenger to protein kinase A and facilitates the fusion of aquaporin storage vesicles to the luminal cell wall, which in turn allows the collecting ducts to become permeable and reabsorb water.

This disorder is also known as factitious diabetes insipidus, a condition whereby, due to some psychological disorder, a patient drinks an excessive amount of water, thereby decreasing the plasma osmolarity and suppressing the release of ADH. This leads to polyuria. The presence of a psychoneurotic disorder, the absence of a preference for iced fluids, and prompt antidiuresis in response to the administration of hypertonic saline, nicotine, or water deprivation will usually establish the diagnosis.

This disorder is classically identified during pregnancy in a woman of childbearing age. Gestational diabetes insipidus (DI) is a very rare complication of pregnancy. Undiagnosed and untreated cases may lead to serious complications in both the mother and the fetus. Gestational DI results when an enzyme made by the placenta destroys ADH in the mother. The placenta is the system of blood vessels and other tissues that develops with the fetus. The placenta allows for the exchange of nutrients and waste products between mother and fetus. Most cases of gestational DI can be treated with desmopressin. In rare cases, however, an abnormality in the thirst mechanism causes gestational DI, and desmopressin should not be used.^[2]

More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of AVP have been implicated in the development of familial central diabetes.^[3] The majority of relevant genetic mutations have an autosomal dominant form of inheritance.^[4]

Conditions associated with DI include:

• Langerhans cell histiocytosis (LCH)
• Wolfram syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness)
• Sickle cell disease
• Amyloidosis
• Obstructive uropathy
• Electrolyte disturbances (e.g., hypokalemia and hypercalcemia)
• Pregnancy
• Conditions induced by a drug (e.g., lithium, demeclocycline, amphotericin B, and vincristine)
  • Lithium is the most common cause of drug-induced nephrogenic DI

There are no gross pathology findings associated with diabetes insipidus.

There are no microscopic findings associated with diabetes insipidus.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

Diabetes insipidus is caused by a variety of factors. The causes for each subtype of diabetes insipidus are classically different. It is important to identify these underlying causes of the various forms in order to appropriately diagnose and treat each type.

• CDI is caused by the destruction or degeneration of neurons originating in the supraoptic and paraventricular nuclei. Central DI results from damage to the pituitary gland, which disrupts the normal storage and release of ADH. The most common cause of central diabetes insipidus (CDI) is idiopathic diabetes insipidus (DI), which accounts for the vast majority of cases.^[1][2]

• Others causes include:^[2]

• Familial and congenital diseases
  • Familial CDI^[3]
  • Wolfram syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness)^[4]
  • Congenital hypopituitarism^[5]
  • Septo-optic dysplasia^[6]
• Neurosurgery or trauma^[7][8]
• Cancer^[1]
• Hypoxic encephalopathy
• Infiltrative disorders^[9][10]
  • Langerhans cell histiocytosis (LCH)
  • Eosinophilic granuloma
• Post-supraventricular tachycardia^[11]
• Anorexia nervosa^[12]

The most common causes of ADH resistance severe enough to produce polyuria are hereditary nephrogenic DI (in children) and chronic lithium ingestion and hypercalcemia (in adults). Acquired causes are often partially reversible with cessation of the offending drug or correction of hypercalcemia. Other causes include:

• Hereditary nephrogenic diabetes Insipidus^[13]
  • Vasopressin V2 receptor gene mutation^[14][15]
  • Aquaporin-2 gene mutation^[16]
• Lithium toxicity^[17]
• Hypercalcemia^[18]
• Hypokalemia^[19]
  • Persistent severe hypokalemia (plasma potassium concentration usually below 3 meq/L) can impair urinary concentrating ability
• Other — Nephrogenic DI has been described in a number of other clinical settings
  • Renal disease
    • Sickle cell disease or trait
    • Autosomal dominant polycystic kidney disease
    • Medullary cystic kidney disease
    • Renal amyloidosis^[20]
    • Sjögren’s syndrome^[21]
  • Drugs^[22]
    • Cidofovir
    • Foscarnet
    • Amphotericin B
    • Demeclocycline
    • Ifosfamide
    • Ofloxacin
    • Orlistat
    • Didanosine
  • Pregnancy^[23]
  • Bardet-Biedl syndrome^[24]
  • Bartter syndrome^[25]

Psychogenic DI (also known as dipsogenic DI, primary polydipsia, or factitious diabetes insipidus) is characterized by a primary increase in water intake. Some of the major causes include:

• Psychiatric illnesses
• Use of phenothiazine, which can lead to the sensation of a dry mouth
• Hypothalamic lesions that directly affect the thirst center
• Infiltrative disease such as sarcoidosis

Gestational diabetes insipidus is a very rare complication of pregnancy. However, undiagnosed and untreated cases may lead to serious complications in both mother and fetus. The only cause that has been associated with this disorder is pregnancy. It usually causes mild polyuria, which can be treated with desmopressin; if left untreated, it can progress to more severe complications.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The most important differential diagnosis for diabetes insipidus include: Central diabetes insipidus, acquired, Trauma (surgery, deceleration injury), Vascular (cerebral hemorrhage, infarction, anterior communicating artery aneurysm or ligation, intra-hypothalamic hemorrhage), Neoplastic (craniopharyngioma, meningioma, germinoma, pituitary tumor or metastases), Granulomatous (histiocytosis, sarcoidosis), Infectious (meningitis, encephalitis), Inflammatory/autoimmune (lymphocytic infundibuloneurohypophysitis), Drug/toxin-induced (ethanol, diphenylhydantoin, snake venom), hydrocephalus, Idiopathic, congenital, Congenital malformations, nephrogenic diabetes insipidus: Acquired, drug-induced (demeclocycline, lithium, cisplatin, methoxyflurane, etc.), Hypercalcemia, hypokalemia, infiltrating lesions (sarcoidosis, amyloidosis, multiple myeloma, Sjogren’s disease), Vascular (sickle cell disease), congenital, X-linked recessive, primary polydipsia,Psychogenic, dipsogenic (downward resetting of thirst threshold), gestational diabetes insipidus, Diabetes mellitus.

The most important differential diagnosis for diabetes insipidus include:^[1][2][3]

Type of DI	Subclass	Disease	Defining signs and symptoms	Lab/Imaging findings
Central	Acquired	Histiocytosis	Bone lysis and fracture Purulent otitis media Diabetes insipidus and delayed puberty Maxillary, mandibular, and gingival disease Rash and maculoerythematous skin lesions Scaly, erythematous scalp patches Lung involvement GI bleeding Lymph node enlargement[4]	CD1a and CD45 + Interleukin-17 (ILITA)
		Craniopharyngioma	Headache Endocrine dysfunction Diabetes insipidus Hypothyroidism Adrenal failure Diabetes insipidus (e.g., excessive fluid intake and urination) Growth failure and delayed puberty	Suprasellar calcified cyst on MRI
		Sarcoidosis	Systemic complaints Fever Anorexia Arthralgias Pulmonary complaints Dyspnea on exertion Cough Chest pain, Hemoptysis (rare) Diabetes mellitus	Hypercalcemia Hypercalciuria (noncaseating granulomas) Elevated alkaline phosphatase Serum amyloid A (SAA) ACE levels may be elevated
	Congenital	Hydrocephalus	Cognitive deterioration Headaches Neck pain Blurred vision Unsteady gait Incontinence such as polyuria	Dilated ventricles on CT and MRI
		Wolfram Syndrome (DIDMOAD)	Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness	Negative islet cell antibodies Optic atrophy on electroretinogram Deafness on audiogram Atrophy of brain stem on MRI
Nephrogenic	Acquired	Drug-induced (demeclocycline, lithium)	Polyuria Polydipsia Nocturia	Urine osmolality <100 mmol/ Arginine vasopressin level >4.6 pmol/ Little or no response to administration of exogenous arginine vasopressin
		Hypercalcemia	Polyuria Polydipsia Gastrointestinal disturbances Pathological fractures Confusion Palpitations and cardiac arrhythmias	Ca levels greater than 11 meq/L
		Hypokalemia	Polyuria Hyporeflexia Palpitations and cardiac arrhythmias	K levels less than 3meq/L on CBC
		Multiple myeloma	Pathologic bone fractures Bleeding Hypercalcemia leading to polyuria Infection Hyperviscosity Anemia	IgG or IgA spike on serum protein electrophoresis Monoclonal M spike Disordered plasma cell proliferation on bone marrow biopsy
		Sickle cell disease	Chronic pain Anemia Aplastic crisis Splenic sequestration Infection Isosthenuria presenting with polyuria	Hemoglobin level is 5-9 g/dL Hematocrit is decreased to 17-29% Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes MRI can demonstrate avascular necrosis of the femoral and humeral heads
Primary polydipsia		Psychogenic	Polyuria Polydipsia Nocturia	Dry mucus membrane History of psychiatric disorders
Gestational diabetes insipidus			Polyuria Polydipsia Nocturia Pregnancy	Dry mucus membranes Pregnancy
Diabetes mellitus			Polyuria Polydipsia Nocturia Weight gain	Elevated blood sugar levels >126 Elevated HbA1c > 6.5

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The prevalence of diabetes insipidus is estimated to be 3 cases per 100,000 individuals worldwide. The prevalence and incidence of both central and nephrogenic DI does not vary by gender. Similarly, no significant racial predilection in prevalence has been observed. With both central and nephrogenic diabetes inispidus, inherited causes account for approximately 1-2% of all cases. The incidence of nephrogenic diabetes insipidus caused by AQP2 mutations is about 1 in 20 million births.

The prevalence of diabetes insipidus is estimated to be 3 cases per 100,000 individuals worldwide.^[1]

The incidence of diabetes insipidus is 1 in 20 million births for nephrogenic diabetes insipidus caused by AQP2 mutations.^[1]

The case-fatality rate of diabetes insipidus is unknown.

Diabetes insipidus has been identified in all age groups from infancy to adulthood.

The prevalence and incidence of both central and nephrogenic diabetes insipidus does not vary by gender.^[1]

There is no racial predilection for diabetes insipidus.

Incidence, prevalence, and geographical distribution of both central diabetes insipidus and nephrogenic diabetes insipidus does not vary.

Incidence, prevalence, and geographical distribution of both central diabetes insipidus and nephrogenic diabetes insipidus does not vary.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The risk factors for the development of diabetes insipidus vary among different types of DI. risk factors for the development of central DI include genetic mutations, pituitary disorders, hypothalamic injury, and head tumors. The most potent risk factor for the development of nephrogenic diabetes insipidus is lithium use, as lithium has a very narrow therapeutic index of 0.4-0.8 mmol/L. Excessive water intake has been identified as the only risk factor associated with psychogenic DI, as pregnancy is the only risk factor for gestational DI.

The following are some of the common risk factors associated with the development of diabetes insipidus:^[1][2][3][4]

• Genetics
• Polycystic kidney disease
• Pituitary disorders
• Hypothalamic injury
• Hypercalcemia
• Head tumors
• Pregnancy
• Sickle cell disease
• Amyloidosis
• Lithium use

Less common risk factors include:^[5][6]

• Male gender
• Family history of nephrogenic diabetes insipidus
• Excessive water consumption
• Pregnancy
• Drugs like phenothiazine

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

According to the USPSTF, screening for diabetes insipidus is not recommended.

According to the USPSTF, screening for diabetes insipidus is not recommended.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

If left untreated, diabetes insipidus results in an elevation in serum sodium and osmolality. The hyperosmolarity seen in these patients may also present with neurologic symptoms such as confusion, altered mental status, seizures, coma, and death. The two major complications of diabetes insipidus are dehydration and electrolyte imbalance . Some research also demonstrates that there is decrease in bone mineral density seen in patients with diabetes insipidus. However, the mechanism of development is not clearly understood neither is the treatment clearly accounted for because treatment of diabetes insipidus does not reverse the disorder.

• Diabetes insipidus if left untreated results in an elevation in serum sodium and osmolality. The hyperosmolarity seen in this patients may also present with neurologic symptoms such as confusion, altered mental status, seizures, coma, and death.
• The serum sodium concentration in untreated central diabetes insipidus is often in the high to normal range. This is required in order to provide the sensation of thirst in a patient and stimulate drinking in order to replace the water lost in the urine. However, in patients that have some form of central nervous disorders, moderate to severe hypernatremia can develop as thirst is impaired or cannot be expressed. This can also occur in infants and young children who cannot independently access free water, and in the postoperative period in patients with unrecognized diabetes insipidus (DI).
• Patients with CDI may develop decreased bone mineral density at the lumbar spine and femoral neck, even in those treated with desmopressin (dDAVP).^[1] It is unclear how the deficiency of ADH results in bone loss, particularly since treatment fails to prevent bone disease. However, since ADH acts upon both V1 and V2 receptors and desmopressin principally upon V2 receptors, one possible mechanism is that activation of V1 receptors stimulates bone formation.

There are two major complications of untreated diabetes insipidus:

Due to the inability of the body to retain water, patients with diabetes insipidus are prone to dehydration if the water lost is not appropriately restored by giving IV fluids in the hospital as oral drinking of water may not be sufficient to restore lost water at the same rate especially in infants and the elderly. It is important to watch out for signs and symptoms of dehydration which include:

• Dizziness or light-headedness
• Headache
• Dry mouth and lips
• Sunken eyes and fontanelles in infants and children
• Confusion and irritability

Diabetes insipidus can also cause an electrolyte imbalance. Some of the electrolyte imbalances include:

• hypernatremia from polyuria (seen in both central and nephrogenic DI)
• hyponatremia from polydipsia (seen in psychogenic DI)
• hypokalemia
• hypercalcemia

Polydipsia can cause an increase in the concentration of these electrolytes simply because of decrease in the plasma concentration of the blood. Dehydration disrupts other functions of the body, such as the way muscles work. The most important symptoms that may be associated with electrolyte imbalance include:

• Headache
• Fatigue
• Irritability
• Myalgias
• Palpitations

The prognosis of diabetes insipidus is good as long as the underlying cause is identified early before the onset of complications and treated early.

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