Case Study Of Mr XZ: Aetiology, Pathophysiology, And Management Of Central Diabetes Insipidus

Physiological functions of endogenous hormone vasopressin

Discuss about the Case Study of Mr XZ.

The paper deals with the case study of Mr XZ, a 43-year-old man diagnosed with central diabetes insipidus. In the previous 3 months, he was complaining of polyuria, polydipsia, and nocturia. The water deprivation test confirms the illness and eliminates diabetes mellitus. In response to the case study, the paper discusses the aetiology and pathophysiology of the diabetes insipidus. The difference between the central and nephrogenic diabetes insipidus is discussed along with the diagnostic tool available. The paper also highlights the physiological functions of endogenous hormone vasopressin, and agents available for the treatment of DI, with reference to the pharmacological basis for their therapeutic effects. Lastly, the reasonable management strategies for XZ are proposed.

Hypothalamus synthesises vasopressin and is then transferred to the posterior pituitary as the neurosecretory vesicles. The hormone is released into the circulation that is maintained by the plasma osmolality. The function of the hormone is to concentrate the urine in the distal renal tubules. The deficiency of the hormone leads to failure of urine concentration in the renal tubules. This contributed to the passage of the copious volume of dilute urine, which can be more than 3 litres of urine in 24 hours and with low osmolality (Hagiwara et al. 2014).

In healthy people, ADH is released when the bodily fluids are depleted. The hormone released from the pituitary gland prevents the excretion of fluids from the body in the form of urine. The hormone increases the water permeability of the distal convoluted tubule and in the collecting duct of the kidney. The hormone functions to activate the transmembrane protein channels called aquaporins to open and allow water into the collecting ducts. The collecting ducts are the tubules receiving the diluted urine by nephrons, the functional unit of the Kidney.  Vasopressin induces the translocation of the aquaporin CD water channels to increase the permeability of the collecting ducts. Thus, the blood absorbs more water and urine volume is reduced and is concentrated. This functioning is hampered during deficiency of hormone. In short, the main functions of this hormone are to constrict the blood vessels and to retain the water in the body (Qureshi et al. 2014).

Vasopressin also increases arterial blood pressure by enhancing the peripheral vascular resistance. By regulating the blood glucose, water and salts, it maintains the homeostasis. Sometimes, vasopressin stored in the posterior pituitary is directly released into the brain and regulates social behaviour, pair bonding, stress response and sexual motivation (Juul et al. 2014).

Aetiology and pathophysiology of Diabetes Insipidus

According to Kalra et al. (2016), the abnormalities in the vasopressin gene present on chromosome 20 are responsible for the autosomal dominant form of the primary version of this disease. Even in the cases of genetic abnormalities, many cases are idiopathic. In rare cases, the disease can occur due to the genetic abnormality. The disease can also be secondary or acquired due to various lesions that may include cranial injuries, hypophysectomy, Langerhans cell histiocytosis, suprasellar and intrasellar tumours, lymphocytic hypophysitis, vascular lesions, granulomas, and infections. The primary central diabetes insipidus is marked by the profound decrease in the hypothalamic nuclei of the neurohypophyseal system (Oiso et al. 2013).

As per Bockenhauer and Bichet (2015), hypothalamic pituitary disorder contributes to central diabetes insipidus. It is characterised by the large volume of dilute urine that is less than 300mOsm/kg. The primary storage site and release of vasopressin is the posterior lobe of pituitary gland. However, the hypothalamus is the synthesis site of vasopressin. Until the hypothalamic nuclei and the neurohypophyseal tract are functional or intact, the newly synthesised hormone can be released into the circulation. In order to avoid this condition, the intact nature of the 10% of neurosecretory neurons is enough. Hence, the pathology of central diabetes insipidus always involve  supraoptic, and paraventricular nuclei of the hypothalamus or at least a major part of the pituitary tract should be intact. A complete central diabetes insipidus is indicated by the absence of vasopressin, or it may be partial when the body has an insufficient level of ADH (Rutishauser et al. 2016). 

Polyuria, polydipsia, nocturia is the predominant clinical manifestations of the disease. In mammals, including humans, central or nephrogenic diabetes insipidus is caused by a deficiency in any part of this endocrine system and are manifested as polyuria and dilute urine.  The same has been observed in the case of the patient MR. XZ. The previous three months of the patient showed these manifestations. The production of the very dilute urine or Polyuria is caused by the poor level or lack of anti-diuretic hormone or ADH, also known as vasopressin (De Fost et al. 2015).  The low volume of ADH fails to function, activate the aquaporins, and subsequently allow the water into the collecting duct. Thus, blood cannot reabsorb the water, increasing the urine volume and decreasing its concentration.

Polyuria is followed by polydipsia, a condition of excessive thirst to prevent the circulatory collapse. With the greater loss of body fluid, a patient feels dehydrated, with more urge to drink water. With polyuria and polydipsia, a person has to suffer from nocturia, a condition characterised by waking up at night frequently for voiding (Kalra et al. 2016). 

Differentiating central and nephrogenic DI and the diagnostic tools available

The central diabetes insipidus is characterised by the decrease in secretion of ADH. The nephrogenic diabetes insipidus is impairment in the urine concentration process, caused by the resistance to ADH function in the Kidney.  The diagnosis by the water deprivation test show poor ability to concentrate urine maximally. The causes of the central diabetes insipidus differ from the nephrogenic form. The principal causes of the central diabetes insipidus are the idiopathic, malignant tumours, head trauma, and crania surgery (Kalra et al. 2016). 

Water deprivation test distinguishes the central form of insipidus to the nephrogenic form as in later the injection of vasopressin does not reverse the existing symptoms.  The low vasopressin levels are diagnostic but are difficult to measure. Moreover, these tests are not routinely available. Nocturia is diagnosed by taking the patient’s nocturnal urine volume. It excludes the last void before sleeping but includes the first in the morning (Abbas et al. 2016). Prior to water deprivation test, the urine is tested for sugar to rule out diabetes mellitus. In addition to high sodium level, many electrolytes are found to be abnormally high. In addition to the water deprivation tests, another form of diagnosis of central diabetes insipidus is urinalysis and magnetic resonance imaging (MRI). Urinalysis is the physical and the chemical examination of urine. In central diabetes, inispdius urine is less concentrated if the water is high in comparison to the other excreted substances(Robertson 2016). MRI is the non-invasive technique where the magnetic field and radio waves are used to get the detailed view of the brain tissues and detect any abnormalities (Cull et al. 2014).

In the idiopathic cases, destruction of the hypothalamus cells is more common. With the advancement of the imaging techniques, and identification of the antibodies against secreting cells, the idiopathic cases have decreased. However, this leads diagnostic confusion as these antibodies are also found on the people with Langerhans cell histiocytosis. Thus, Serial contrast-enhanced brain MRIs (every 3-6 months for the first 2 years) is mandatory for diagnosis. Craniopharyngioma and other primary tumours are the common manifestations of the central diabetes insipidus. Central diabetes insipidus is also the common manifestation of subarachnoid haemorrhage (Kreutz et al. 2017). In 10% of the cases, this disease is familial and may be under diagnosed.  The autosomal dominant inheritance and result from a defect in the AVP-NP2 gene on chromosome 20p13. Genetic testings are recommended to determine the specific aetiology and answer the recurrence risk questions (Bernal et al. 2016).  Additional causes can be cancer, cardiac arrest, granulomatous disease and vascular lesions. CT and MRIs are successful brain  imaging techniques to identify   any abnormal findings

On the other hand, the nephrogenic diabetes insipidus is caused by the metabolic factors such as high blood sugar, calcium and low potassium. In adults, this condition mostly develops due to hypocalcaemia or lithium toxicity. In 20% of the cases, where the patient is taking lithium, experiences impairment in urine concentration. The contributing factor of this condition is the dysregulation of the aquaporin system in the collecting duct having principal cells.  The urine concentrating ability is also declined by the prolonged elevation of the serum calcium level that is more than 11 mg/dL (Bockenhauer and Bichet 2015).

In addition to Lithium, there are other drugs that reduce the concentration of the urine in the distal renal tubule. It may include Amphotericin B,
Orlistat, cidofovir, Demeclocycline, and Ofloxacin. The other causes of the nephrogenic diabetes insipidus include transient pregnancy, Hypokalemia, renal disease (amyloidosis, sickle cell anaemia), and hyperglycemia (Bockenhauer and Bichet 2015). The hereditary factors responsible for this form of the disease are rare. When occurs, it is attributed to the mutations in the AVP receptor 2 genes (AVPR2) on chromosome Xq28. The resistance to the ADH is caused by the defects in the AVP receptor. It is an X-linked disorder, hence, mostly males are affected by this disease.  In case of females, this disease is reported occasionally due to skewed X inactivation (Moeller et al. 2013). The familial nephrogenic DI cases are contributed by the mutation in AQP2, aquaporin 2. This gene is present on chromosome 12q13, that expresses water channel in the collecting ducts of Kidneys.  In nephrogenic diabetes insipidus, both Autosomal recessive and autosomal dominant forms are reported (Bockenhauer and Bichet 2015).

The central diabetes insipidus is commonly diagnosed by water deprivation test to examine the blood electrolyte levels, urine production, and weight for 12 hours. After dehydration, the patients cannot maximally concentrate urine but can do so after receiving exogenous ADH. In this test, the patient is not allowed to take fluid for stipulated time say 8-12 hours. If the morning void is not concentrated, then it can be diagnosed as central diabetes insipidus (Robertson 2016). It is also confirmed by the decrease in blood pressure, loss of more than 5% body weight and increase in heart rate. By injecting vasopressin, these effects are reversed (Kalra et al. 2016).

The primary treatment goals include rectification of water deficit that is persisting and reduction of the ongoing excessive urinary water losses. The treatment depends on the speed of the onset of the symptoms. In case, the patient has the presence of any associated hypernatremia (Valenti and Tamma 2016). To promote rehydration, the level of dehydration in Mr XZ must be assessed and ongoing losses. Accordingly, the rehydration therapy can be commenced. In case the serum sodium is greater than  150mmol/L, rehydration therapy is immediately needed and the symptoms may improve within 48 hours.

Desmopressin as pharmacology therapy treats central diabetes insipidus. This agent is the longer acting form (synthetic analogue) of vasopressin. This physiologic replacement is effective for the hormonal deficiency.  It can be taken as the tablet, or nasal spray and dose can be adjusted as per the body’s requirement to maintain water balance and urine output. Both vasopressin and desmopressin when taken in excess amount lead to complications such as swelling, fluid retention and other problems. Injections of vasopressin are given to people undergoing surgery. For outpatient treatment of diabetes, insipidus desmopressin is preferred in comparison to the vasopressin as the former is easy to administer (dose can be precisely tailored) and has greater safety and tolerability (Bichet 2014).

The mechanism of action of both vasopressin and desmopressin is slightly different. Vasopressin exhibits its antidiuretic effect by the activation of the V2 R caused by the kidney reabsorption of water. This process is triggered via “Gs protein/adenylyl cyclases/cAMP pathway”. The cascade of events leads to the mobilisation of water channel aquaporin to the distal convoluted tubules of kidney nephron and the collecting duct. This action increases the permeability of the lipid bilayer of the cell membrane to water. On the other hand, the antidiuretic mode of action of the desmopressin is by greater antidiuretic potency and decreased pressor activity. In compared to natural hormone this agent has longer half-life and clearance in urine is strong during renal impairment (Ando et al. 2015).

The average magnitude, duration of the effect of the intravenous infusion of desmopressin, following 2 hour on urine osmolality and urine flow is dose dependent and clearly reciprocal.  The magnitude of the antidiuretic effect of the desmopressin is limited due to a concentrating capacity of the Kidney which is bunted in the patient with central diabetes insipidus as they were already deficient in vasopressin. Thus, at an IV dose of 250 ng the average maximum urine osmolality achieved was 850 mOsm/kg, and the rate of urine output reduced to 1.4 L/day, which is almost the normal range (Kataoka et al. 2015). The action of the agent is prolonged by doubling the dose of desmopressin.

When administering the DDAvasopressin orally, maximum plasma concentration can be obtained at 90 minutes. Treating vasopressin orally for 5 years as long-term treatment has been found to control diuresis in 8 of the 9 patients. When treated with this agent the patients should be started with the lowest dose possible, and subsequent titration should be followed based on the clinical response. Prior to giving further dosage polyuria should be allowed to develop as sometimes diuresis is transient may be nullified by single dosage.   Thus, both the agents are safe therapeutic agents and can be effective to cure Mr. XZ. It is a good alternative treatment for central diabetes insipidus. These agents greatly simplify the management of the disease (Murakami et al. 2014).  The patients undergoing pituitary surgery can experience diuresis as they are administered with the large volume of fluids. These patients also exhibit the posttraumatic decrease in AVP levels. These symptoms become difficult to distinguish with central diabetes insipidus. They are also challenging to manage. In such cases, the patients are administered with DDAVP if polyuria is continued with low urine osmolality (Behan et al., 2015). 

The medication management in chronic central diabetes insipidus requires “individually tailored dosing schedule”. Initially starting with the low dose, the doses are subsequently increased based on the clinical response. Per dose, the average duration of action is between 6-18 hours. However, in some cases single dose at night is sufficient. The dose should be titrated to control nocturia The accredited registered nurses should administer the therapeutic agents. The nurses must inform the managing team if te Mr. XZ is found to have urine output greater than 4mls/kg/hr for two consecutive hours. It indicates the need of repeated serum. There is a need of notifying the management if the serum electrolytes are not in normal range after drug administration (Behan et al. 2015).

It is very rare to expect spontaneous or complete recovery from the illness as overcoming hormonal deficiency is uncommon. Reversible in symptoms is seen after neurosurgery. Other drugs that stimulate the body production of the vasopressin are carbamazepine, thiazide diuretics, chlorpropamide, and clofibrate. These drugs provide relief in the severe form of diabetes insipidus.  These are the non-hormonal agent, and sometimes-nonsteroidal anti-inflammatory drugs are prescribed. The latter is mainly prescribed in the nephrogenic DI, as a last resort (Arima et al. 2013). 

The nurses must educate the patient (XZ) about increasing the prescribed dosage of drugs based on the thirst level and urinary output. To offload the excess water and diuresis the patients may be advised to delay the dose by one per week, prevent the hyponatraemia, and then take subsequent dosage as normal. For Mr. XZ to have normal lifestyle decreasing thirst and Polyuria is the primary goal (Gleeson et al. 2016). 

The patients of central diabetes insipidus must be educated about the side effects of desmopressin such as a headache, runny nose, nosebleeds, stomach pain, feeling bloated or dizziness.  Mr. XZ must be aware of the symptoms of hypernatremia, which are confusion, nausea and vomiting, and prolonged headache. Desmopressin should be discontinued if the patient is experiencing hyponatremia (Gleeson et al. 2016).

The management of the patients with central diabetes insipidus includes monitoring of fluid retention. During initial therapy, the XZ needs to be monitored for hyponatremia, and if confirmed then intravenous fluids may be required. The patient should be observed for the volume of water intake, the volume of urine output and frequency, serum sodium, specific gravity and level of thirst. Mr. XZ should be requested for follow up visits post-hospitalisation (Verbalis 2016).

There are no specific dietary considerations required for diabetes insipidus even when chronic. The patient Mr. XZ must be educated about adequate intake of water and the importance of the water and salt balance. The urine output can be decreased by taking low protein and sodium diet. The patient should be educated to take precautions when travelling to avoid diarrhoea and vomiting. Mr. XZ can avoid dehydration by travelling at night and preventing exertion from hot weather. Serious problems can be prevented in the patients if they are educated to avoid dehydration. It is necessary to carry water, and the medications support wherever one go, and if possible, it is effective to carry the medical alert card (Kalra et al. 2016).

Counselling sessions can be recommended for Mr. XZ. Any chronic illness disturbs emotional well being in addition to the physical well-being. It may be due to embarrassing symptoms such as polyuria. The expensive treatment along with the physical weakness adds to distress. Financial burden is the main source of anxiety and depression in most cases. Psychiatric counselling can be referred for Mr. XZ to relive anxiety and better manage the illness (Morton et al. 2017).

Conclusion

Hypothalamic pituitary disorder contributes to central diabetes insipidus and is indicated by the absence of vasopressin, or an insufficient level of ADH. The paper elucidated the aetiology and pathophysiology of the diabetes insipidus. The difference between the central and nephrogenic diabetes insipidus is discussed along with the diagnostic tools available. The paper also highlights the physiological functions of endogenous hormone vasopressin, and agents available for the treatment of DI, with reference to the pharmacological basis for their therapeutic effects. Lastly, the reasonable management strategies for XZ are proposed.

References

Abbas, M.W., Iqbal, M.A., Iqbal, M.N., Javaid, R. and Ashraf, M.A., 2016. Diabetes insipidus: the basic and clinical review. International Journal of Research in Medical Sciences, 4(1), pp.5-11.

Ando, T., Nozaki, A., Akazawa, S., Sagara, I.U., Horie, I., Imaizumi, M., Usa, T. and Kawakami, A., 2015. QOL in the Patients with Central Diabetes Insipidus Under Different Formulations of Desmopressin. In Health Outcomes/Quality Improvement Research (pp. THR-194). Endocrine Society.

Arima, H., Oiso, Y., Juul, K.V. and Nørgaard, J.P., 2013. Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study. Endocrine journal, 60(9), pp.1085-1094.

Behan, L.A., Sherlock, M., Moyles, P., Renshaw, O., Thompson, C.J.T., Orr, C., Holte, K., Salehmohamed, M.R., Glynn, N., Tormey, W. and Thompson, C.J., 2015. Abnormal plasma sodium concentrations in patients treated with desmopressin for cranial diabetes insipidus: results of a long-term retrospective study. European journal of endocrinology, 172(3), pp.243-250.

Bernal, A., Mahía, J. and Puerto, A., 2016. Animal models of Central Diabetes Insipidus: Human relevance of acquired beyond hereditary syndromes and the role of oxytocin. Neuroscience & Biobehavioral Reviews, 66, pp.1-14.

Bichet, D.G., 2014. Treatment of central diabetes insipidus. 2013-09-25)[2014-03-03] https://www. uptodate. com/contents/treatment-of-central-diabetes-insipidus, pp.1-52.

Bockenhauer, D. and Bichet, D.G., 2015. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nature Reviews Nephrology, 11(10), pp.576-588.

Cull, E.H., Watts, J.M., Tallman, M.S., Kopp, P., Frattini, M., Rapaport, F., Rampal, R., Levine, R. and Altman, J.K., 2014. Acute myeloid leukemia presenting with panhypopituitarism or diabetes insipidus: a case series with molecular genetic analysis and review of the literature. Leukemia & lymphoma, 55(9), pp.2125-2129.

De Fost, M., Oussaada, S., Endert, E., Linthorst, G., Serlie, M., Soeters, M., DeVries, J.H., Bisschop, P. and Fliers, E., 2015. The water deprivation test to differentiate diabetes insipidus from primary polydipsia. Endocrine Connections, pp.EC-14.

Gleeson, H., Bonfield, A., Hackett, E. and Crasto, W., 2016. Concerns about the safety of patients with diabetes insipidus admitted to hospital. Clin Endocrinol (Oxf), 84, pp.950-1.

Hagiwara, D., Arima, H., Morishita, Y., Wenjun, L., Azuma, Y., Ito, Y., Suga, H., Goto, M., Banno, R., Sugimura, Y. and Shiota, A., 2014. Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus. Cell death & disease, 5(3), p.e1148.

Juul, K.V., Bichet, D.G., Nielsen, S. and Nørgaard, J.P., 2014. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. American Journal of Physiology-Renal Physiology, 306(9), pp.F931-F940.

Kalra, S., Zargar, A.H., Jain, S.M., Sethi, B., Chowdhury, S., Singh, A.K., Thomas, N., Unnikrishnan, A.G., Thakkar, P.B. and Malve, H., 2016. Diabetes insipidus: The other diabetes. Indian journal of endocrinology and metabolism, 20(1), p.9.

Kataoka, Y., Nishida, S., Hirakawa, A., Oiso, Y. and Arima, H., 2015. Comparison of incidence of hyponatremia between intranasal and oral desmopressin in patients with central diabetes insipidus. Endocrine journal, 62(2), pp.195-200.

Kreutz, J., Potorac, I., Lutteri, L., Gennigens, C., Martin, D., Daly, A.F., Bonneville, J.F., Tshibanda, L. and Beckers, A., 2017, May. Adipsic diabetes insipidus revealing a bifocal intracranial germinoma. In Annales d’Endocrinologie. Elsevier Masson.

Moeller, H.B., Rittig, S. and Fenton, R.A., 2013. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocrine reviews, 34(2), pp.278-301.

Morton, P.G., Fontaine, D., Hudak, C.M. and Gallo, B.M., 2017. Critical care nursing: a holistic approach. Lippincott Williams & Wilkins.

Murakami, T., Hatoko, T., Nambu, T., Matsuda, Y., Matsuo, K., Yonemitsu, S., Muro, S. and Oki, S., 2014. Desmopressin orally disintegrating tablet in Japanese patients with central diabetes insipidus: A retrospective study of switching from intranasal desmopressin. Endocrine journal, 61(8), pp.773-779.

Oiso, Y., Robertson, G.L., Nørgaard, J.P. and Juul, K.V., 2013. Treatment of neurohypophyseal diabetes insipidus. The Journal of Clinical Endocrinology & Metabolism, 98(10), pp.3958-3967.

Qureshi, S., Galiveeti, S., Bichet, D.G. and Roth, J., 2014. Diabetes insipidus: celebrating a century of vasopressin therapy. Endocrinology, 155(12), pp.4605-4621.

Robertson, G.L., 2016. Diabetes insipidus: Differential diagnosis and management. Best Practice & Research Clinical Endocrinology & Metabolism, 30(2), pp.205-218.

Rutishauser, J., Spiess, M. and Kopp, P., 2016. Genetic forms of neurohypophyseal diabetes insipidus. Best Practice & Research Clinical Endocrinology & Metabolism, 30(2), pp.249-262.

Umbricht, D., del Valle Rubido, M., Hollander, E., McCracken, J.T., Shic, F., Scahill, L., Noeldeke, J., Boak, L., Khwaja, O., Squassante, L. and Grundschober, C., 2017. A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder. Neuropsychopharmacology, 42(9), p.1914.

Valenti, G. and Tamma, G., 2016. History of diabetes insipidus. G Ital Nefrol, 33(S66), pp.1724-5590.

Verbalis, J.G., 2016. Diabetes Insipidus: Principles of Diagnosis and Treatment. In 2016 Meet-The-Professor: Endocrine Case Management (pp. 195-201). The Endocrine Society.