INTRODUCTION:
Diabetes insipidus (DI) is a condition characterized by excessive
thirst and excretion of large amounts of severely dilute urine, with reduction
of fluid intake having no effect on the concentration of the urine. Patients
with diabetes insipidus have abnormal water and electrolyte balance which need
to be taken care of.(1) It is essential to assess the patient followed by a
proper treatment and reevaluation. The treatment varies depending upon the
source of origin of the defect. (3,4) .The extracellular fluid toxicity is
maintained by intake of water regulation. Proper cell functioning depends upon
this water balance.(16)Water balance in-turn depends upon intact thirst
mechanism, vasopressin synthesis and the response of renal tubules to
vasopressin action.(18,19) There are two different types of diabetes insipidus
such as central and nephrogenic.(21).Central diabetic insipidus is rare in
children and young adults and up to 50 percent of cases are idiopathic. (22)
TYPES OF DIABETES INSIPIDUS:
Central Diabetic Insipidus:
Central diabetes insipidus results due to the defective
production, transport and release of ADH. It is prevalent in both genders.
(6)The symptoms are polyuria and polydipsia. Water deprivation for even a short
period of time causes dehydration and thirst. Thirst is severe in this
case.(7). This is a heterogenous condition due to the deficiency of arginine
vasopressin. In many cases, it is cause by the neuronal destruction that
originate in the supra optic and paraventricular nuclei of the hypothalamus.
(22)Some of the causes of the neuronal destruction include inflammatory, autoimmune,
vascular diseases, trauma due to accidents and genetic defects in the synthesis
of vasopressin.(23). Arginine vasopressin is transported from the hypothalamus
through the neuronal component of the pituitary stalk and stored in nerve
terminals in the posterior pituitary.(18) Children are also affected by central
diabetes insipidus. The cause for it is multifactorial which includes trauma to
the base of the brain, and fracture of sella turcica.(19)
Nephrogenic Diabetes Insipidus:
In nephrogenic diabetes insipidus, increased plasma osmolality
stimulates posterior pituitary which in turn produces a sufficient amount of
ADH, but the kidneys cannot respond to the ADH resulting in the production of
dilute urine.(8) This may lead to hypernatraemia and hyperchloraemia.(40)As a
result of this, the tubular reabsorption in the distal convoluted tubules and
collecting duct is affected resulting in osmotic diuresis. It varies with
patients having complete form and partial form.(42,43)
CAUSES OF DIABETIC INSIPIDUS
Causes of Central Diabetic
Insipidus:
Damage to the hypothalamo-neurohypohyseal region:-
The damage of this region results in central diabetes insipidus.
Damage caused may be multifactorial which includes trauma, surgery or
metastatic tumours.(9). Tumour associated diabetes insipidus was not diagnosed
in children less than five years of age. However familial form of disorder was
diagnosed by the age of seven.(25). The onset of CDI is abrupt in trauma cases
and gradual in other non- trauma cases. Severe neonatal forms are rarely
described in children with CDI.(26)Proximal lesions account for 30% to 40% of
all cases of post traumatic aand post operative diabetes insipidus, whereas
distal lesions account for 50% to 60%. (10,11).The magnetic resonance imaging
of the hypothalamus and pituitary helps in locating the neuronal damage which
helps in the assessment of functional significance of lesions.(12)
IDIOPATHIC:
In this case there is degeneration of neurohypophysos as well
as supra optic and paraventricular nuclei.
GENETIC:
Mutation in the neurophysin 2 coding region of the ADH gene leads
to CDI. Eons 1 and 3 are normal , but in exon 2 , thymine is substituted for
guanine at nucleotide 1884. This in turn causes the substitute of a glycine for
valine in the ADH molecule.(12) Affected patients have both the mutant and
normal alleles. Abnormal ADH accumulates in the posterior pituitary leading to
the destruction of entire of the entire cells finally resulting in central
diabetes insipidus.
Substitution of valine for alanine in the genes for the signal
peptide for ADH- neUrophysin 2/ copeptide precursor. Hereditary forms are rare
and accounts only upto 1% to 2% of all cases of central diabetes insipidus.(13)
CAUSES OF NEPHROGENIC DIABETES INSIPIDUS:
Acquired form:
They are more common than the familial forms. This results due to
the structural and functional alteration of the kidney. Among the systemic
circumstances leading to acquired nephrogenic diabetes insipidus are
hypokalemia, hypercalcemia ,various types of renal diseases and sickle
cell anemia.(13)
Hypokalemia results due to less dietary intake or due to the loss
of potassium as a result of polyuria in this case. (3,4)
Chronic hypercalcemia results from interstitial calcification and fibrosis.(14)
During pregnancy, the desmopressin is delaminates at the N- terminal which
makes the effector vassopressinase resistant resulting in transient diabetes
insipid us.(15)
Drug induced diabetes insipdus:
Drug-induced diabetes insipidus is always of the nephrogenic type,
i.e. unresponsiveness of the kidneys to the action of antidiuretic hormone.
This condition is easily diagnosed by administration of a modified antidiuretic
hormone, desmopressin, to demonstrate the renal unresponsiveness.(7,8) Drug-induced
nephrogenic diabetes insipidus is not a common disorder except in patients
receiving treatment with lithium salts for affective disorders.(5)
Demeclocycline, an antibiotic of the tetracycline group, is commonly used by
der- matologists to treat acne. It results in polyuria and polydipsia. These
side effects might not manifest immediately after the use of drug. It's effect
on kidney is gradual. And the kidney might not restore to its normal
functioning immediately after the termination of the drugs. Restoring kidney's
function to normal take a long time.(6)
Familial nephrogenic diabetes insipidus:-
V2 receptor mutations:- Mutations in the gene encoding the ADH type 2
receptor cause an X-linked form of the disease.(13)
Aquaporin-2 mutations:- Mutations in the gene encoding the ADH-dependent water
channel aquaporin-2 are responsible for an autosomal-recessive form, and in
some cases an autosomal-dominant type of the disease.(14)
METHODS OF DIAGNOSIS OF DIABETES
INSIPIDUS:
Laboratory diagnosis:
The initial step in the diagnosis of DI is to ascertain the
presence of polyuria which can be established with an accurate 24 hours urine
output measurement by the direct collection of urine. Urine output more than 4
ml/kg/hr in infants and children and more than 6ml/kg/hr in newborns is
suggestive of polyuria. Urine analysis for the presence of glucosuria,
hypercalciuria or uremia is done.(18) This is done to rule out solute diuresis.
Presence of polyuria in the absence of solute diuresis should raise the
suspicion of diabetes insipidus.(16) The specific gravity of urine is very
essential because urinary specific gravity of more than 1.010 makes the
possibility of DI less likely. Since infants generally exhibit a constitutional
hyposthenuria, the process of distinguishing normal and pathological inability
to concentrate urine may be difficult.(19)Thus, simultaneous measurement of
serum osmolality,urine osmolality and serum electrolyte is essential in
paediatric age group.(17) It can also be diagnosed by collecting 2 days urine
sample assessing the fluid intake followed by the intra venous application of
DDAVP.(35) Urine volume and osmolality as well as serum electrolyte
concentration and osmolality was determined before and after administration of
DDAVP(37).Various studies suggest that the combination of water deprivation
test and direct AVP determination would allow the diagnosis of more than 95% of
all cases of diabetes insipidus correctly.(19)
Magnetic resonance imaging of pituitary:
MRI of pituitary ia an important tool for the assessment of
etiology of CDI. It should be performed after the administration of gadolinium
injection. It is to check for any abnormality in the stalk. MRI should
performed even after the hydration of the patient.(20)
Renal sonography:
It helps rule out primary renal disorders like polycystic kidney
disease , ureteral obstruction , etc..... Massive hydronephrosis and mega
ureters are seen in children with polyuria - polydypsia long standing
duration.(20)
Gene testing:
Gene testing for the familial forms of CDI and NDI are not
commercially available.
TREATMENT :
Treatment of CDI:
The primary goals of the treatment include reducing polyuria
and decreasing the thirst for a proper development and maintenance of normal
life cycle .
It is achieved by:
Free access to water:
This facilitates maintenance of tonicity. However excessive intake of water may
lead to hydronephrosis and hydroureter. It may also lead to fluorosis if the
fluoride content of the water is high. In case of infants and neonates the
management is done only with fluids since they have a high obligatory oral
fluid intake.(17)
ADH replacement:
The earliest preparation of ADH includes a crude
acetone dried extract from bovine administered by nasal insufflation. Problems
with this preparation includes irritation of the nasal mucosa.
Subsequently, a more purified preparation of ADH was developed,
known as Pitressin .This is given intra- muscularly every 2 to 4 days and
provides relief for 24 to 72 hours. Its side effects include abdominal
cramping, hypertension, and angina.(1)
VASOPRESSIN:
In people with CDI aqueous vasopressin , lysine vasopressin , de- amino, D
arginine vasopressin may be used to minimize water excretion.(20)
DESMOPRESSIN:
It is the current drug of choice for long term therapy of CDI. It has more
specific antiduretic action, negligible pressor activity and long half life
than other molecules. It can be administered parenterally,orally or
intranasally. Oral tablets are less potent than intra nasal forms.(16) The
desmo- pressin dosage and scheduling should be adjusted individually according
to the degree of polyuria.
Chlorpropamide (Diabinese), an anti-diabetes drug, decreases the clearance of
solute- free water, but only if the neurohypophysis has some residual secretory
capacity.
Carbamazepine (Tegretol), an anticonvulsant , reduces the sensitivity of the
osmoregulatory system of ADH secretion and simultaneously raises the
sensitivity of the collecting duct to the hydro-osmotic action of the hormone.
Clofibrate (Atromid-S), a lipid-lowering agent, stimulates residual ADH
production in patients with partial CDI.(1,2)
Other management in Central DI:-
Glucocorticoids are essential for insertion of water channels
independent of vasopressin.(19)
Treatment of nephrogenic diabetes insipidus:-
It is a severe form of DI and very difficult to treat. Despite
adequate control, mental and growth retardation is often found on long term
follow up.(18)
It can be managed by:
Dietary management:
Modification in the diet is helpful in decreasing solute load to
the kidneys and has been shown to be useful especially in NDI. Diet with low
sodium,protein with high calories is recommended.(11,12)
Hydrochlorthiazide:- It is the most useful therapy in NDI, it
works by enhancing sodium excretion at the expense of water.(40,41)
Amelioride is given additionally which has a similar effect as
that of hydrochlorthiazide but is useful in preventing hypokalemia.(17)
No adverse effects as a result of the treatment with hydrochlorothiazide/amiloride
were re- ported, either by the patients or their parents. Repeated medical
examinations did not reveal any adverse reactions either.(37,38)
Long-term treatment with indomethacin is often limited by gastric adverse
effects, as in the described case, whereas long-term treatment with thiazide
diuretics is usually considered to be safe. (46,47)
CONCLUSION:
DI is not a common endocrine disorder. Water deprivation test is useful in
establishing a diagnosis of DI and helps differentiating between NDI and CDI.
Desmopressin is the drug of choice for CDI therapy, oral formulation being more
preferred. Drugs such as thiazides and indomethacin also helps in decreasing
the water excretion. DDAVP is an effective and safe adjunct for treating
patients who are at risk for excessively rapid correction of hyponatreamia(17).
REFERENCES:
1 Cagno JM. Diabetes insipidus. Crit Care Nurse 1989; 9:86–93.
2 Singer I, Oster JR, Fishman LM. The management of diabetes
insipidus in adults. Arch Intern Med 1997; 157:1293–1301.
3 Adam P. Evaluation and management of diabetes insipidus. Am Fam
Physician 1997; 55:2146–2153.
4 Kovacs L, Lichardus B. Vasopressin, Disturbed Secretion and Its
Effects. Prague: Kluwer Academic Publishers, 1989.
5 Ueta Y, Taniguchi S, Yoshida A, et al. A new type of familial
central diabetes insipidus caused by a single base substitution in the neuro-
physin II coding region of the vasopressin gene. J Clin Endocrinol Metab 1996;
81:1787–1790.
6 Rauch F, Lenzner C, Nurnberg P, Frommel C, Vetter U. A novel
muta- tion in the coding region for neurophysin-II is associated with autoso-
mal dominant neurohypophyseal diabetes insipidus. Clin Endocrinol (Oxf) 1996;
44:45–51.
7 Repaske DR, Medlej R, Gultekin EK, et al. Heterogeneity in
clinical manifestation of autosomal dominant neurohypophyseal diabetes
insipidus caused by a mutation encoding Ala-1 —> Val in the signal peptide
of the arginine vasopressin/neurophysin II/copeptin precursor. J Clin Endocrinol
Metab 1997; 82:51–56.
8 Lam KS, Wat MS, Choi KL, Ip TP, Pang RW, Kumana CR.
Pharmacokinetics, pharmacodynamics, long-term efficacy, and safety of oral
1-deamino-8-D-arginine vasopressin in adult patients with cen- tral diabetes
insipidus. Br J Clin Pharmacol 1996; 42:379–385.
9 Gregerman RI. Selected endocrine problems. In: Barker LR,
Burton JR, Zieve PD, editors. Principles of Ambulatory Medicine, 3rd edition.
Baltimore, MD: Williams and Wilkins Publishers, 1991:997–998.
10 Seckl JR, Dunger DB. Diabetes insipidus. Current treatment recom-
mendations. Drugs 1992; 44:216–224.
11 Posner L, Mokrzycki MH. Transient central diabetes insipidus in
the setting of underlying nephrogenic diabetes insipidus associated with
lithium use. Am J Nephrol 1996; 16:339–343.
12 Navarro JF, Quereda C, Quereda C, et al. Nephrogenic diabetes
insipidus and renal tubular acidosis secondary to foscarnet therapy. Am J
Kidney Dis 1996; 27:431–434.
13 Knoers NV, van Os CH. Molecular and cellular defects in
nephrogenic diabetes insipidus. Curr Opin Nephrol Hypertens 1996; 5:353–358.
14 Earm JH, Christensen BM, Frokiaer J, et al. Decreased
aquaporin-2expression and apical plasma membrane delivery in kidney collecting
ducts of polyuric hypercalcemic rats. J Am Soc Nephrol 1998; 9:2181–2193.
15 Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect of hydrochloro-
thiazide in lithium-induced nephrogenic diabetes insipidus is associat- ed with
upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium
channel. J Am Soc Nephrol 2004; 15:2836–2843.
16 Ranadive SA, Rosenthal SM. Pediatric disorders of water balance.
Endocrinol Metab Clin North Am. 2009;38:663–72. [PubMed]
17 Colaco P. Disorder of water and electrolyte homeostasis. In:
Desai MP, Menon PS, Bhatia V, editors. Pediatric Endocrine Disorders. 2nd ed.
New Delhi: Orient Long13. Saborio P, Tipton GA, Chan JC. Diabetes Insipidus.
Pediatr Rev. 2000;21:122–9. quiz 129. [PubMed]
18 Muglia LJ, Majzoub JA. Disorders of the posterior pituitary. In:
Sperling MA, editor. Pediatric Endocrinology. 3rd ed. Philadelphia: Saunders;
2008. pp. 356–73.
19 Siggaard C, Christensen JH, Corydon TJ, Rittig S, Robertson GL,
Gregersen N, et al. Expression of three different mutations in arginine
vasopressin gene suggests genotype-phenotype correlation in familial
neurohypophyseal diabetes insipidus kindreds. Clin Endocrinol (Oxf)
2005;63:207–16. [PubMed]
20 Masera N, Grant DB, Stanhope R, Preece MA. Diabetes insipidus
with impaired osmoregulation in septo-optic dysplasia and agenesis of corpus
callosum. Arch Dis Childhood. 1994;70:51–6. [PMC free article] [PubMed](2)Man Pvt
Ltd; 2008. pp. 445–57.
21. Mootha SL, Barkovich AJ, Grumbach MM, et al.
Idiopathic hypotha- lamic diabetes insipidus, pituitary stalk thickening, and
the occult intracra- nial germinoma in children and adolescents. J Clin Endocrinol
Metab 1997;82:1362-7.
22 Maghnie M, Villa A, Aricò M, et al. Correlation between
magnetic res- onance imaging of posterior pituitary and neurohypophyseal
function in children with diabetes insipidus. J Clin Endocrinol Metab
1992;74:795-800.
23. Maghnie
M, Aricò M, Villa A, Genovese E, Beluffi G, Severi F. MR of the
hypothalamic-pituitary axis in Langerhans cell histiocytosis. AJNR Am J
Neuroradiol 1993;13:1365-71.
24 Imura H, Nakao K, Shimatsu A, et al. Lymphocytic
infundibuloneuro- hypophysitis as a cause of central diabetes insipidus. N Engl
J Med 1993; 329:683-9.
25 Maghnie M, Genovese E, Sommaruga MG, et al. Evolution of child-
hood central diabetes insipidus into panhypopituitarism with a large hypo-
thalamic mass: is “lymphocytic infundibuloneurohypophysitis” in children a
different entity? Eur J Endocrinol 1998;139:635-40.
26 Verbalis JG, Robinson AG, Moses AM. Postoperative and
post-traumat- ic diabetes insipidus. Front Horm Res 1985;13:247-65.
27 Robinson AG, Fitzsimmons MD. Diabetes insipidus. Adv Endocrinol
Metab 1994;5:261-96.
28 Robertson GL. Diabetes insipidus. Endocrinol Metab Clin North Am
1995;24:549-72.
29 Hansen LK, Rittig S, Robertson GL. Genetic basis of familial
neurohy- pophyseal diabetes insipidus. Trends Endocrinol Metab 1997;8:363-72.
10. Blotner H. Primary or idiopathic diabetes insipidus: a system disease.
Metabolism 1958;7:191-200.
30 Bode HH. Disorders of posterior pituitary. In: Kaplan SA, ed.
Clinical pediatric endocrinology. Philadelphia: W.B. Saunders, 1990:63-86.
31 Omarède R, Czernichow P, Rappaport R, et al. Le
diabète insipide pitresso-sensible de l’enfant. II. Etude de 93 cas
observés entre 1955 et 1978. Arch Fr Pediatr 1980;37:37-44.
32 Czernichow P, Pomarede R, Brauner R, Rappaport R. Neurogenic
diabetes insipidus in children. Front Horm Res 1985;13:190-209.
33 Greger NG, Kirkland RT, Clayton GW, Kirkland JL. Central diabetes
insipidus: 22 years’ experience. Am J Dis Child 1986;140:551-4.
34 Wang LC, Cohen ME, Duffner PK. Etiologies of central diabetes
insipidus in children. Pediatr Neurol 1994;11:273-7.
35 Tien R, Kucharczyk J, Kucharczyk W. MR imaging of the brain in
pa- tients with diabetes insipidus. AJNR Am J Neuroradiol 1991;12:533-42.
36. Moses AM, Clayton B, Hochhauser L. Use of T1-weighted MR imag- ing
to differentiate between primary polydipsia and central diabetes insip- idus.
AJNR Am J Neuroradiol 1992;13:1273
37. Bichet DG, Oksche A, Rosenthal W. Congenital nephro- genic diabetes
insipidus. J Am Soc Nephrol 1997;8:1951–8.
38. Knoers N, Monnens LA. Nephrogenic diabetes insipidus: clinical
symptoms, pathogenesis, genetics and treatment.Pediatr Nephrol 1992;6:476–82.
39 Reeves WB, Andreoli TE. Nephrogenic diabetes insipidus.
In: Scriver, CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular
bases of inherited disease. New York: McGraw Hill 1995:3045–71.
40. Stevens S, Brown BD, McGahan JP. Nephrogenic diabetes insipidus: a
cause of severe nonobstructive urinary tract dilatation. J Ultrasound Med
1995;14:543–5.
41 Uribarri J, Kaskas M. Hereditary nephrogenic diabetes insipidus and
bilateral nonobstructive hydronephrosis. Nephron 1993;65:346–9.
42 Crawford JD, Kennedy GC. Chlorothiazide in diabetes insipidus.
Nature 1959;183:891–2.
43 Morgan DB, Davidson C. Hypokalaemia and diuretics: an analysis of
publications. BMJ 1980;280:905–8.
44 McMahon FG, Ryan JR, Akdamar K, Ertan A. Upper gastrointestinal
lesions after potassium chloride supplements: a controlled clinical trial.
Lancet 1982;2: 1059–61.)5
45 Bichet DG. Nephrogenic diabetes insipidus. Am J Med 1998; 105:
431–442
46 Schulz A, Sangkuhl K, Lennert T et al. Aminoglycoside
pretreatment partially restores the function of truncated V(2) vasopressin
receptors found in patients with nephrogenic diabetes insipidus. J Clin
Endocrinol Metab 2002; 87: 5247– 5257
47 Pasel K, Schulz A, Timmermann K et al. Functional
characterization of the molecular defects causing nephrogenic diabetes
insipidus in eight families. J Clin Endocrinol Metab2000; 85: 1703–1710
48 Rosenthal W, Seibold A, Antaramian A et al. Molecular
identification of the gene responsible for congenital nephro-
genic diabetes insipidus. Nature 1992; 359: 233–235
49 Knoers NV, Deen PM. Molecular and cellular defects in nephrogenic
diabetes insipidus. Pediatr Nephrol 2001; 16: 1146–1152
50 Sui H, Han BG, Lee JK, Walian P, Jap BK. Structural basis of water-specific
transport through the AQP1 water channel.Nature 2001; 414: 872–878
51 Kamsteeg EJ, Wormhoudt TA, Rijss JP, van Os CH,Deen PM. An
impaired routing of wild-type aquaporin-2 after tetramerization with an
aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. EMBO J
1999; 18: 2394–2400
52 Schmieder RE, Delles C, Messerli FH. Diuretic therapy and the
risk for renal cell carcinoma. J Nephrol 2000; 13: 343–346
53 Messerli FH. Risk factors for renal cell carcinoma: hyperten-
sion or diuretics? Kidney Int 2005; 67: 774–775
54 Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS. Neonatal
mortality in an aquaporin-2 knock-in mouse modelM. Zaki et al.of recessive
nephrogenic diabetes insipidus. J Biol Chem 2001; 276: 2775–2779)10
