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Diabetes insipidus is a disorder characterized by the excretion of abnormally large volumes (<30 ml/kg body weight/day for an adult patient) of dilute urine (<250 mmol/kg). Four basic defects can be involved. The most common, a deficient secretion of the antidiuretic hormone (ADH) arginine vasopressin (AVP), is referred to as neurogenic (or central, neurohypophyseal, cranial, or hypothalamic) diabetes insipidus. Diabetes insipidus can also result from renal insensitivity to the antidiuretic effect of AVP, which is referred to as nephrogenic diabetes insipidus (NDI). Excessive water intake can result in polyuria, which is referred to as primary polydipsia: It can be due to an abnormality in the thirst mechanism, referred to as dipsogenic diabetes insipidus; it can also be associated to a severe emotional cognitive dysfunction, referred to as psychogenic polydipsia. Finally, increased metabolism of vasopressin during pregnancy is referred to as gestational diabetes insipidus.
Keywords
Hereditary diabetes insipidus; AVPR2; AQP2; Osmoregulation; AVP; Genetic Testing; Central and peripheral osmoreceptors, vasopressin receptors, Brattleboro rats, neurogenic diabetes insipidus, nephrogenic diabetes insipidus, Wolfram syndrome, Bartter’s syndrome, diabetes insipidus during pregnancy, dehydration testing for diabetes insipidus, plasma vasopressin measurements, magnetic resonance imaging of the brain in diabetes insipidus
Nonapeptides of the vasopressin family are the key regulators of water homeostasis in amphibia, reptiles, birds, and mammals. Since these peptides reduce urinary output, they are also referred to as antidiuretic hormones. Oxytocin and AVP ( Figure 46.1 ) are synthesized in separate populations of magnocellular neurons of the supraoptic and paraventricular nuclei. Oxytocin is most recognized for its key role in parturition and milk letdown in mammals. The axonal projections of AVP- and oxytocin-producing neurons from supraoptic and paraventricular nuclei reflect the dual function of AVP and oxytocin as hormones and as neuropeptides, in that they project their axons to several brain areas, and to the neurohypophysis. The regulation of the release of AVP from the posterior pituitary is primarily dependent, under normal circumstances, on tonicity information relayed by central osmoreceptor neurons expressing TRPV1 ( Figure 46.2 ) and peripheral osmoreceptor neurons expressing TRPV4. AVP and its corresponding carrier, neurophysin II, are synthesized as a composite precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus (for review see ). The precursor is packaged into neurosecretory granules and transported axonally in the stalk of the posterior pituitary. En route to the neurohypophysis, the precursor is processed into the active hormone. Pre-provasopressin has 164 amino acids, and is encoded by the 2.5 kb AVP gene located in chromosome region 20p13. The AVP gene (coding for AVP and neurophysin II) and the OXT gene (coding for oxytocin and neurophysin I) are located in the same chromosome region, at a very short distance from each other (12 kb in humans) in head-to-head orientation. Data from transgenic mouse studies indicate that the intergenic region between the OXT and the AVP genes contains the critical enhancer sites for cell-specific expression in the magnocellular neurons. It is phylogenetically interesting to note that cis and trans components of this specific cellular expression have been conserved between the Fugu isotocin (the homolog of mammalian oxytocin) and rat oxytocin genes. Exon 1 of the AVP gene encodes the signal peptide, AVP, and the NH 2 -terminal region of neurophysin II. Exon 2 encodes the central region of neurophysin II, and exon 3 encodes the COOH-terminal region of neurophysin II and the glycopeptide. Provasopressin is generated by the removal of the signal peptide from pre-provasopressin, and from the addition of a carbohydrate chain to the glycopeptide ( Figure 46.3 ). Additional post-translational processing occurs within neurosecretory vesicles during transport of the precursor protein to axon terminals in the posterior pituitary, yielding AVP, neurophysin II, and the glycopeptide. The AVP–neurophysin II complex forms tetramers that can self-associate to form higher oligomers. Neurophysins should be seen as chaperone-like molecules facilitating intracellular transport in magnocellular cells. In the posterior pituitary, AVP is stored in vesicles. Exocytotic release is stimulated by minute increases in serum osmolality (hypernatremia, osmotic regulation), and by more pronounced decreases in extracellular fluid (hypovolemia, non-osmotic regulation). Oxytocin and neurophysin I are released from the posterior pituitary by the suckling response in lactating females.
Immunocytochemical and radioimmunologic studies have demonstrated that oxytocin and vasopressin are synthesized in separate populations of the supraoptic nuclei and the paraventricular nuclei neurons, the central and vascular projections of which have been described in great detail. Some cells express the AVP gene and other cells express the OXT gene. Immunohistochemical studies have revealed a second vasopressin neurosecretory pathway that transports high concentrations of the hormone to the anterior pituitary gland from parvocellular neurons to the hypophyseal portal system. In the portal system, the high concentration of AVP acts synergistically with corticotropin-releasing hormone (CRH) to stimulate adrenocorticotropic hormone (ACTH) release from the anterior pituitary. More than half of parvocellular neurons co-express both CRH and AVP . In addition, while passing through the median eminence and the hypophyseal stalk, magnocellular axons can also release AVP into the long portal system. Furthermore, a number of neuroanatomic studies have shown the existence of short portal vessels that allow communication between the posterior and anterior pituitary. Therefore, in addition to parvocellular vasopressin, magnocellular vasopressin is able to influence ACTH secretion.
Mammals are osmoregulators: they have evolved mechanisms that maintain extracellular fluid (ECF) osmolality near a stable value. Yet, although mammals strive to maintain a constant ECF osmolality, values measured in an individual can fluctuate around the set-point owing to intermittent changes in the rates of water intake and water loss (through evaporation or diuresis), and to variations in the rates of Na intake and excretion (natriuresis). In humans, for example, 40 minutes of strenuous exercise in the heat or 24 hours of water deprivation causes plasma osmolality to rise by more than 10 mosmol kg −1 . In a dehydrated individual, drinking the equivalent of two large glasses of water (~850 ml) lowers osmolality by approximately 6 mosmol kg −1 within 30minutes. Similarly, ingestion of 13 g of salt increases plasma osmolality by approximately 5 mosmol kg −1 within 30 minutes. Although osmotic perturbations larger than these can be deleterious to health, changes in the 1–3% range play an integral part in the control of body fluid homeostasis. Differences between the ECF osmolality and the desired set-point induce proportional homeostatic responses according to the principle of negative feedback. ECF hyperosmolality stimulates the sensation of thirst to promote water intake, and the release of vasopressin to enhance water reabsorption in the kidney. By contrast, ECF hypoosmolality suppresses basal VP secretion in rats and humans.
As summarized elegantly by Bourque, early studies provided clear evidence that “cellular dehydration” (that is, cell shrinking) was required for thirst and vasopressin release to be stimulated during ECF hyperosmolality: these responses could be induced by infusions of concentrated solutions containing membrane-impermeable solutes, which extract water from cells, but not by infusions of solutes that readily equilibrate across the cell membrane (such as urea). Verney coined the term “osmoreceptor” to designate the specialized sensory elements. He further showed that these were present in the brain, and postulated that they might comprise “tiny osmometers” and “stretch receptors” that would allow osmotic stimuli to be “transmuted into electrical” signals. Osmoreceptors are therefore defined functionally as neurons that are endowed with an intrinsic ability to detect changes in ECF osmolality, and it is now known that both cerebral and peripheral osmoreceptors contribute to the body fluid balance.
Although magnocellular neurons are themselves osmosensitive, they require input by glutamatergic afferents from the lamina terminalis to respond fully to osmotic challenges ( Figure 46.2 ).
Hypertonicity is sensed by Organum Vasculosum Lamina Terminalis (OVLT) neurons expressing TRPV1 (Transient Receptor Potential Vanilloid-1, vide infra ): OVLT serves as the brain’s primary osmoreceptor area, and neurons in this nucleus transduce hyperosmotic conditions into proportional increases in action-potential firing rate. The information encoded by the electrical activity of these neurons is then relayed synaptically to diverse subsets of homeostatic effector neurons that induce appropriate osmoregulatory responses such as thirst, natriuresis, and antidiuretic hormone release. The mechanical modulation of TRPV1 is well-demonstrated.
Because the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) lie outside the blood–brain barrier, they can integrate this information with endocrine signals borne by circulating hormones, such as angiotensin II (Ang-II), relaxin, and atrial natriuretic peptide (ANP). While circulating angiotensin II and relaxin excite both OT and vasopressin magnocellular neurons, ANP inhibits vasopressin neurons. The non-osmotic pathways are more physiologically described now as “osmoregulatory gain,” since angiotensin II amplifies osmosensory transduction by enhancing the proportional relationship between osmolality, receptor potential, and action potential firing in rat supraoptic nucleus neurons ( Figure 46.4 ). Modifications in osmoregulatory gain induced by angiotensin explain why the changes in the slope and threshold of the relationship between plasma osmolality and vasopressin secretion are potentiated by hypovolemia or hypotension, and are attenuated by hypervolemia or hypertension ( Figure 46.5 ).
The osmotic stimulation of AVP release by dehydration or hypertonic saline infusion, or both, is regularly used to test the AVP secretory capacity of the posterior pituitary. This secretory capacity can be assessed directly by comparing the plasma AVP concentration measured sequentially during a dehydration procedure with the normal values, and then correlating the plasma AVP with the urinary osmolality measurements obtained simultaneously ( Figure 46.6 ).
The AVP release can also be assessed indirectly by measuring plasma and urine osmolalities at regular intervals during the dehydration test. The maximum urinary osmolality obtained during dehydration is compared with the maximum urinary osmolality obtained after the administration of vasopressin or 1-desamino-8-D-arginine vasopressin (dDAVP; Pitressin: 5 units subcutaneously (SQ) in adults; 1 unit SQ in children or dDAVP 1–4 mg intravenously over 5 to 10 minutes).
The nonosmotic stimulation of AVP release can be used to assess the vasopressin secretory capacity of the posterior pituitary in a rare group of patients with the essential hyponatremia and hypodipsia syndrome. Although some of these patients may have partial central diabetes insipidus, they respond normally to nonosmolar AVP release signals such as hypotension, emesis, and hypoglycemia. In all other cases of suspected central diabetes insipidus, these nonosmotic stimulation tests will not give additional clinical information.
The osmotic regulation of the release of AVP from the posterior pituitary is primarily dependent, under normal circumstances, on tonicity information relayed by central osmoreceptor neurons expressing TRPV1, and peripheral osmoreceptor neurons expressing TRPV4.
The cellular basis for osmoreceptor potentials has been characterized using patch-clamp recordings and morphometric analysis in magnocellular cells isolated from the supraoptic nucleus of the adult rat. In these cells, stretch-inactivating cationic channels transduce osmotically evoked changes in cell volume into functionally relevant changes in membrane potential. In addition, magnocellular neurons also operate as intrinsic Na + detectors. The N-terminal variant of the transient receptor potential channel (TRPV1) is an osmoticaly activated channel expressed in the magnocellular cells producing vasopressin, and in the circumventricular organs, the OVLT, and the SFO. Since osmoregulation still operates in Trpv 1 −/− mice, other osmosensitive neurons or pathways must be able to compensate for loss of central osmoreceptor function. Afferent neurons expressing the osmotically-activated ion channel, TRPV4, in the thoracic dorsal root ganglia that innervate hepatic blood vessels and detect physiological hypoosmotic shifts in blood osmolality have recently been identified. In mice lacking the osmotically-activated ion channel, TRPV4, hepatic sensory neurons no longer exhibit osmosensitive inward currents, and activation of peripheral osmoreceptors in vivo is abolished. In a large cohort of human liver transplantees, who presumably have denervated livers, plasma osmolality is significantly elevated compared to healthy controls, suggesting the presence of an inhibitory vasopressin effect of hyponatremia, perceived in the portal vein from hepatic afferents. TRPV1 (expressed in central neurons) and TRPV4 (expressed in peripheral neurons) thus appear to play entirely complementary roles in osmoreception. Lechner et al. have thus identified the primary afferent neurons that constitute the afferent arc of a well-characterized reflex in man and more recently also in rodents. This reflex engages the sympathetic nervous system to raise blood pressure and stimulate metabolism. Of clinical interest, it has already been demonstrated that orthostatic hypotension and postprandial hypotension respond to water drinking. Moreover, water drinking in man can prevent neutrally-mediated syncope during blood donation or after prolonged standing. Finally, water drinking is also associated with weight loss in overweight individuals. Other peripheral sensory neurons expressing other mechanosensitive proteins may also be involved in osmosensitivity.
The neurohypophyseal hormone AVP has multiple actions, including the inhibition of diuresis, contraction of smooth muscle, platelet aggregation, stimulation of liver glycogenolysis, modulation of adrenocorticotropic hormone release from the pituitary, and central regulation of somatic and higher functions (thermoregulation, blood pressure, autonomic expression of fear, neurobiology of attachment). These multiple actions of AVP could be explained by the interaction of AVP with at least three types of G-protein-coupled receptors: the V1a (vascular hepatic) and V1b (anterior pituitary) receptors act through phosphatidylinositol hydrolysis to mobilize calcium ; and the V2 (kidney) receptor is coupled to adenylate cyclase.
The transfer of water across the principal cells of the collecting ducts is now known at such a detailed level that billions of molecules of water traversing the membrane can be represented; see useful teaching tools at http://www.mpibpc.gwdg.de/abteilungen/073/gallery.html and http://www.ks.uiuc.edu/research/aquaporins . The 2003 Nobel Prize in chemistry was awarded to Peter Agre and Roderick MacKinnon, who solved two complementary problems presented by the cell membrane: how does a cell let one type of ion through the lipid membrane to the exclusion of other ions; and how does it permeate water without ions? This contributed to a momentum and renewed interest in basic discoveries related to the transport of water, and indirectly to diabetes insipidus. The first step in the action of AVP (synthesized by du Vigneaud, Nobel Prize in Chemistry 1955) on water excretion is its binding to arginine vasopressin type-2 receptors (hereafter referred to as V2 receptors) on the basolateral membrane of the collecting duct cells ( Figure 46.7 ). The human AVPR2 gene that codes for the V2 receptor is located in chromosome region Xq28, and has three exons and two small introns. The sequence of the cDNA predicts a polypeptide of 371 amino acids with seven transmembrane, four extracellular, and four cytoplasmic domains. The activation of the V2 receptor on renal collecting tubules stimulates adenylyl cyclase via the stimulatory G-protein (Gs) (1994 Nobel Prize in Physiology and Medicine to Rodbell and Gilman for signal transduction and G-proteins), and promotes the cyclic adenosine monophosphate (cAMP)-mediated incorporation of water channels into the luminal surface of these cells. E. Sutherland and T. Rall isolated cyclic adenosine monophosphate in 1956, and Sutherland was awarded the Nobel Prize in Physiology or Medicine in 1971. There are two ubiquitously expressed intracellular cAMP receptors: (1) the classical protein kinase A (PKA) that is a cAMP-dependent protein kinase; and (2) the recently discovered exchange protein directly activated by cAMP that is a cAMP-regulated guanine nucleotide exchange factor. Both of these receptors contain an evolutionally-conserved cAMP-binding domain that acts as a molecular switch for sensing intracellular cAMP levels to control diverse biological functions. Several proteins participating in the control of cAMP-dependent AQP2 trafficking have been identified; for example, A-kinase anchoring proteins tethering PKA to cellular compartments; phosphodiesterases regulating the local cAMP level; cytoskeletal components such as F-actin and microtubules; small GTPases of the Rho family controlling cytoskeletal dynamics; motor proteins transporting AQP2-bearing vesicles to and from the plasma membrane for exocytic insertion and endocytic retrieval; SNAREs inducing membrane fusions, hsc70, a chaperone important for endocytic retrieval. These processes are the molecular basis of the vasopressin-induced increase in the osmotic water permeability of the apical membrane of the collecting tubule.
AVP also increases the water reabsorptive capacity of the kidney by regulating the urea transporter variants UT-A1/3, which are present in the inner medullary collecting duct, predominantly in its terminal part. AVP also increases the permeability of principal collecting duct cells to sodium. In summary, as stated elegantly by Ward and colleagues, in the absence of AVP stimulation, collecting duct epithelia exhibit very low permeabilities to sodium urea and water. These specialized permeability properties permit the excretion of large volumes of hypotonic urine formed during intervals of water diuresis. In contrast, AVP stimulation of the principal cells of the collecting ducts leads to selective increases in the permeability of the apical membrane to water (P f ), urea (P urea ), and Na (P Na ).
The actions of vasopressin in the distal nephron are possibly modulated by prostaglandin E2, nitric oxide, and by luminal calcium concentration. PGE 2 is synthesized and released in the collecting duct, which expresses all four E-prostanoid receptors (EP1–4). Both EP2 and EP4 can signal via increased cAMP. Olesen et al. hypothesized that selective EP receptor stimulation could mimic the effects of vasopressin, and demonstrated that, at physiological levels, PGE 2 markedly increased apical membrane abundance and phosphorylation of AQP2 in vitro and ex vivo , leading to increased cell water permeability. In their experiments, both EP2 and EP4 selective agonists were able to mimic these effects. Furthermore, an EP2-agonist was able to positively regulate urinary-concentrating mechanisms in an animal model of nephrogenic diabetes insipidus where AVPR2 receptors were blocked by Tolvaptan, a non-peptide V2-antagonist. These results reveal an alternative mechanism for regulating water transport in the collecting duct that has major importance for understanding whole body water homeostasis, and provide a rationale for investigations into EP receptor-agonist use in X-linked nephrogenic diabetes insipidus treatment.
The animal model of diabetes insipidus that has been most extensively studied is the Brattleboro rat. Discovered in 1961, the rat lacks vasopressin and its neurophysin, whereas the synthesis of the structurally-related hormone oxytocin is not affected by the mutation. Its inability to synthesize vasopressin is inherited as an autosomal recessive trait. Schmale and Richter isolated and sequenced the vasopressin gene from homozygous Brattleboro rats, and found that the defect is due to a single nucleotide deletion of a G residue within the second exon encoding the carrier protein neurophysin ( Figure 46.8 ). The shift in the reading frame caused by this deletion predicts a precursor with an entirely different C-terminus. The messenger RNA (mRNA) produced by the mutated gene encodes a normal AVP, but an abnormal NPII moiety which impairs transport and processing of the AVP-NPII precursor and its retention in the endoplasmic reticulum of the magnocellular neurons where it is produced. Homozygous Brattleboro rats may still demonstrate some V2 ( vide infra ) antidiuretic effects, since the administration of a selective non-peptide V2-antagonist (SR 121463 A, 10 mg/kg i.p.) induced a further increase in urine flow rate (200 to 354±42 mL/24 h) and a decline in urinary osmolality (170 to 92±8 mmol/kg). This decline in urine osmolality following the administration of a non-peptide V2 receptor antagonist could also be secondary to the “inverse agonist” properties of SR121463A: the intrinsic activity or “tone,” of the V2R would be deactivated by the SR121463A compound (for the inverse agonist properties of SR121463A see ). There is also an alternative explanation to this relatively high urine osmolality of 170 since, in Brattleboro rats, low levels of hormonally-active AVP are produced from alternate forms of AVP preprohormone. Due to a process called molecular misreading, one transcript contains a 2 bp deletion downstream from the single nucleotide deletion that restores the reading frame, and produces a variant AVP preprohormone that is smaller in length by one amino acid and differs from the normal product by only 13 amino acids in the neurophysin II moiety. Oxytocin, which is present at enhanced plasma concentrations in Brattleboro rats, may be responsible for the antidiuretic activity observed. Oxytocin is not stimulated by increased plasma osmolality in humans.
A useful strategy to establish the physiological function of a protein is to determine the phenotype produced by pharmacological inhibition of protein function or by gene disruption. Transgenic knockout mice deficient in AQP1, AQP2, AQP3, AQP4, and CLCNK1, NKCC2, NFAT5, AVPR2 or AGT have been engineered. Angiotensinogen (AGT)-deficient mice are characterized by both concentrating and diluting defects secondary to a defective renal papillary architecture. The Aqp3 , Aqp4 , Clcnk1 , and Agt knockout mice have no identified human counterparts. Of interest, AQP1 -null individuals have no obvious symptoms. Yang et al. have generated an AQP2-T126M “conditional knock-in” model of NDI, to recapitulate the clinical features of the naturally occurring human AQP2 mutation T126M. The conditional knock-in adult mice showed polyuria, urinary hypoosmolality, and ER retention of AQP2-T126M in the collecting duct. Screening of candidate protein folding “correctors” in AQP2-T126M-transfected kidney cells showed increased AQP2-T126M plasma membrane expression with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), a compound currently in clinical trials for tumor therapy. 17-AAG increased urine osmolality in the AQP2-T126M mice (without effect in AQP2 null mice), and partially rescued defective AQP2-T126M cellular processing. These proof-of-concept findings suggest the possibility of using existing drugs for therapy in some forms of NDI.
Mice lacking the AVPR2 receptor failed to thrive and died within the first week after birth due to hypernatremic dehydration. Li et al. generated mice in which the Avpr2 gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Adult mice displayed all characteristic symptoms of X-linked NDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE 2 receptors might compensate for the lack of renal V2R activity in X-linked NDI mice, and both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI. This beneficial effect is likely secondary to the intracellular generation of cAMP at the principal cell level by EP4 PGE 2 receptors.
As reviewed by Rao and Verkman, extrapolation of data in mice to humans must be made with caution. For example, the maximum osmolality of mouse (<3000 mOsm/kg H 2 O) is much greater than that of human urine (1000 mOsmol/kg H 2 O), and normal serum osmolality in mice is 330 to 345 mOsmol/kg H 2 O, substantially greater than that in humans (280–290 mOsm/kg H 2 O). Protein expression patterns, and thus the interpretation of phenotype studies, may also be species-dependent. For example, AQP4 is expressed in both proximal tubule and collecting duct in mouse, but only in collecting duct in rat and human.
Ethylnitrosourea-mutagenized mice heterozygous for the F204V mutation in the Aqp2 gene have been described, and mice from the Jackson Laboratory with congenital progressive hydronephrosis bear the S256L mutation in Aqp2 which affects its phosphorylation and apical membrane accumulation.
Diabetes insipidus is characterized by the excretion of abnormally large volumes of hypoosmotic urine (<250 mmol/kg). This definition excludes osmotic diuresis, which occurs when excess solute is being excreted, as with glucose in the polyuria of diabetes mellitus. Other agents that produce osmotic diuresis are mannitol, urea, glycerol, contrast media, and loop diuretics. Osmotic diuresis should be considered when solute excretion exceeds 60 mmol/hour. The quantification of water excretion (free water clearance, osmolar clearance, free electrolyte water reabsorption, effective water clearance) is described elsewhere in this textbook.
Failure to synthesize or secrete vasopressin normally limits maximal urinary concentration and, depending on the severity of the disease, causes varying degrees of polyuria and polydipsia. Experimental destruction of the vasopressin-synthesizing areas of the hypothalamus (supraoptic and paraventricular nuclei) causes a permanent form of the disease. Similar results are obtained by sectioning the hypophyseal hypothalamic tract above the median eminence. Sections below the median eminence, however, produce only transient diabetes insipidus. Lesions to the hypothalamic–pituitary tract are frequently associated with a three-stage response in experimental animals and in humans : (1) an initial diuretic phase lasting from a few hours to 5 to 6 days; (2) a period of antidiuresis unresponsive to fluid administration (this antidiuresis is probably due to vasopressin release from injured axons and may last from a few hours to several days; because urinary dilution is impaired during this phase, continued water administration can cause severe hyponatremia); and (3) a final period of diabetes insipidus. The extent of the injury determines the completeness of the diabetes insipidus and, as already discussed, the site of the lesion determines whether the disease will be permanent.
Twenty-five percent of patients studied after transsphenoidal surgery developed spontaneous isolated hyponatremia, 20% developed diabetes insipidus, and 46% remained normonatremic. Normonatremia, hyponatremia, and diabetes insipidus were associated with increasing degrees of surgical manipulation of the posterior lobe and pituitary stalk during surgery. Central diabetes insipidus observed after transphenoidal surgery is often transient, and only 2% of patients need long-term treatment with dDAVP.
The causes of central diabetes insipidus in adults and in children are listed in Table 46.1 . Rare causes of central diabetes insipidus include leukemia, thrombotic thrombocytopenic purpura, pituitary apoplexy, sarcoidosis and Wegener granulomatosis, xanthoma disseminatum, septooptico dysplasia and agenesis of the corpus callosum, metabolic anorexia nervosa, lymphocytic hypophysitis, and necrotizing infundibulo-hypophysitis. Maghnie et al. studied 79 patients with central diabetes insipidus: additional deficits in anterior pituitary hormones were documented in 61% of patients, a median of 0.6 years (range, 01–18.0 years) after the onset of diabetes insipidus. The most frequent abnormality was growth hormone deficiency (59%), followed by hypothyroidism (28%), hypogonadism (24%), and adrenal insufficiency (22%). Seventy-five percent of the patients with Langerhans cell histiocytosis had an anterior pituitary hormone deficiency that was first detected a median of 3.5 years after the onset of diabetes insipidus. None of the patients with central diabetes insipidus secondary to AVP mutations developed anterior pituitary hormone deficiencies.
Children (%) | Children and Young Adults (%) | Adults (%) | |
---|---|---|---|
Primary brain tumor a | 49.5 | 22.0 | 30.0 |
Before surgery | 33.5 | 13.0 | |
After surgery | 16.0 | 17.0 | |
Idiopathic (isolated or familial) | 29.0 | 58.0 | 25.0 |
Histiocytosis | 16.0 | 12.0 | – |
Metastatic cancer b | – | 8.0 | |
Trauma c | 2.2 | 2.0 | 17.0 |
Postinfectious disease | 2.2 | 6.0 | – |
a Primary malignancy: craniopharyngioma, dysgerminoma, meningioma, adenoma, glioma, astrocytoma.
b Secondary: metastatic from lung or breast, lymphoma, leukemia, dysplastic pancytopenia.
Lacombe and Weil described a familial non-X-linked form of diabetes insipidus without any associated mental retardation. The descendants of the family described by Weil were later found to have autosomal dominant neurogenic diabetes insipidus. Hereditary neurogenic diabetes insipidus (OMIM 125700) is a well-characterized entity, secondary to mutations in AVP (OMIM 192340). Patients with autosomal dominant neurogenic diabetes insipidus retain some limited capacity to secrete AVP during severe dehydration, and the polyuropolydipsic symptoms usually appear after the first year of life, when the infant’s demand for water is more likely to be understood by adults. In hereditary neurohypophyseal diabetes insipidus, termed familial neurohypophyseal diabetes insipidus (FNDI), levels of AVP are insufficient, and patients show a positive response to treatment with dAVP. Growth retardation might be observed in untreated children with autosomal dominant FNDI. Over 60 mutations in the prepro-arginine-vasopressin-neurophysin II AVP gene located on chromosome 20p13 have been reported in dominant FNDI (adFNDI). Knock-in mice heterozygous for a nonsense mutation in the AVP carrier protein neurophysin II showed progressive loss of AVP-producing neurons over several months correlated with increased water intake, increased urine output, and decreased urine osmolality. The data suggest that vasopressin mutants accumulate as fibrillar aggregates in the endoplasmic reticulum and cause cumulative toxicity to magnocellular neurons, explaining the later age-of-onset. To date, recessive FNDI, with early polyuric manifestations, has only been described in three studies. Very early (first week of life) polyuric states are usually nephrogenic, but we and others have observed autosomal recessive central diabetes insipidus patients with early polyuria, dehydration episodes responding to dDAVP with specific mutations of the AVP gene. A study by Christensen examined the differences in cellular trafficking between dominant and recessive AVP mutants, and found that dominant forms were concentrated in the cytoplasm, whereas recessive forms were localized to the tips of neurites. The expression of regulated secretory proteins such as granins and prohormones, including pro-vasopressin, generates granule-like structures in a variety of neuroendocrine cell lines due to aggregation in the trans-Golgi. Co-staining experiments unambiguously distinguished between these granule-like structures and the accumulations by pathogenic dominant mutants formed in the ER, since the latter, but not the trans-Golgi granules, co-localized with specific ER markers. As studies concerning both dominant and recessive FNDI accumulate, it is becoming evident that FNDI exhibits a variable age-of-onset, and this may be related to the cellular handling of the mutant AVP. This progressive toxicity, sometimes called a toxic gain-of-function, shares mechanistic pathways with other neurodegenerative diseases, such as Huntington’s and Parkinson’s.
Of interest, errors in protein folding represent the underlying basis for many inherited diseases and are also pathogenic mechanisms for AVP , AVPR2 , and AQP2 mutants. Why AVP-misfolded mutants are cytotoxic to AVP-producing neurons is an unresolved issue. Protein misfolding, an “unfolded protein response” in cells, and the accumulation of excess misfolded protein leading to apoptotic cell death are well-documented for autosomal dominant retinitis pigmentosa.
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