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Diabetes insipidus
PITUITARY DISORDERS
Diabetes insipidus
What’s new?
Stephen Ball C
C
Abstract C
Diabetes insipidus (DI) describes the excess production of dilute urine. It is caused by the lack of production or action of the hormone vasopressin (AVP). Diagnosis requires a targeted history and examination. Confirmation requires referral to specialist services with expertise in diagnosis and management. Lack of AVP can be treated with synthetic vasopressin analogues. Additional approaches may be needed for specific forms of DI. Combined defects in AVP production and thirst perception require a structured programme of fluid intake and antidiuresis. Clinicians need to be aware of both systemic and locally progressive pathologies that can present with DI.
Dipsogenic diabetes insipidus (DDI, primary polydipsia): inappropriate, high fluid intake in excess of ability to excrete free water. Hypothalamic diabetes insipidus Presentation with HDI occurs when 80% of hypothalamic magnocellular neurone AVP production has been lost. Several pathological processes can be involved. All lead to either the destruction of AVP neurones, or the interruption of the transport or processing of AVP as it moves along the axons of these neurones for release at nerve terminals in the posterior pituitary (Table 1). The condition can appear for the first time or become worse in pregnancy as residual AVP is degraded by increased placental (vasopressinase) enzyme activity. Up to 50% of children and young adults with HDI have an underlying tumour or CNS malformation.3 Familial HDI comprises 5% of cases.4
Keywords adipsia; diabetes insipidus; hypernatraemia; hyponatraemia; polydipsia; polyuria; vasopressin
Diabetes insipidus (DI) is characterized by excess production of dilute urine e more than 40 ml/kg/24 hours in adults and more than 100 ml/kg/24 hours in children. Urine concentration is regulated by vasopressin (AVP), a nineamino-acid peptide produced by magnocellular neurones within the supra-optic nucleus (SON) and para-ventricular nucleus (PVN) of the hypothalamus. AVP is released into the circulation from nerve terminals in the posterior pituitary gland. Production is directly related to plasma osmolality and inversely related to plasma volume. The principal site of action of AVP is the kidney, where it increases the synthesis and assembly of water channels (aquaporin 2, AQP2), leading to increased free water reabsorption. These effects are mediated through interaction with a Gprotein coupled cell surface receptor (AVP-R2), found on target cells lining the luminal surface of the distal nephron.1
Nephrogenic diabetes insipidus Renal resistance to AVP can be the result of the adverse effects of specific drugs (e.g. lithium toxicity). These effects may be temporary, but sometimes persist. NDI may also occur following obstructive nephropathy, acute kidney injury and electrolyte disturbances (e.g. hypokalaemia, hypercalcaemia). Prolonged polyuria of any cause can result in partial NDI through disruption of the intra-renal solute gradient that is an obligatory requirement for production of concentrated urine. X-linked familial NDI results from loss-of-function mutations in the renal AVP-R2 receptor. Autosomal recessive NDI is caused by loss-of-function mutations in the AVP-dependent water channel, AQP2.5
Classification and aetiology There are three sub-types of DI, each reflecting a specific element of the physiology and/or pathophysiology of the AVP axis.2 Cranial or hypothalamic diabetes insipidus (HDI): relative or absolute lack of AVP. Nephrogenic diabetes insipidus (NDI): partial or total resistance to the renal antidiuretic effects of AVP.
Dipsogenic diabetes insipidus Persistent inappropriate fluid intake leads to appropriate polyuria. If it exceeds the limit of renal free water excretion it may result in hyponatraemia. DDI can be associated with the following abnormalities in thirst perception: low threshold for thirst exaggerated thirst response to osmotic challenge inability to suppress thirst at low plasma osmolalities. Structural lesions may be present, but neuroimaging is normal in most cases. DDI is associated with affective disorders.
Stephen Ball BSc PhD FRCP is Senior Lecturer and Honorary Consultant, Newcastle University and Newcastle Hospitals NHS Trust, UK. SB studied Basic Science at Birmingham University before pursuing undergraduate and postgraduate Medical Studies in London. Middle grade training in Diabetes and Endocrinology included a period in the USA as a Medical Research Council (UK) and Howard Hughes Fellow. He combines clinical medicine, research and teaching. He is a member of Council of the Society for Endocrinology and a Senior Editor of Clinical Endocrinology. He is also a European Endocrine Society representative within European Guideline groups. Conflicts of interest: none declared.
MEDICINE 41:9
Better understanding of the regulation of vasopressin secretion and its mechanism of action New insights into the molecular genetics of inherited diabetes insipidus Evolving approaches and novel tools to aid differential diagnosis
Epidemiology DI is rare. Prevalence of HDI is estimated at 1/25,000 with equal gender distribution. The prevalence of the other forms is unclear. While most cases present in adults, familial HDI and NDI characteristically present in childhood.
519
Ó 2013 Elsevier Ltd. All rights reserved.
PITUITARY DISORDERS
Diagnosis and classification of diabetes insipidus by measurement of plasma vasopressin in response to graded hyperosmolar stimulation
Aetiology of hypothalamic diabetes insipidus Genetic
Developmental syndromes Idiopathic Secondary Trauma Tumour
Inflammatory
Vascular
Wolfram’s syndrome, autosomal dominant, autosomal recessive Septo-optic dysplasia
20
Plasma vasopressin (pmol/litre)
Primary
Head injury, post-surgery (transcranial, trans-sphenoidal) Craniopharyngioma, germinoma, metastases, pituitary macroadenoma Sarcoidosis, histiocytosis, meningitis, encephalitis, infundibuloneurohypophysitis, GuillaineBarre syndrome, autoimmune Aneurysm, infarction
15
Nephrogenic Dipsogenic Hypothalamic
10
5
0
280
290
300
310
320
Plasma osmolality (mOsmol/kg) The shaded area depicts the normal-range response of plasma vasopressin as plasma osmolality is raised. Patients with hypothalamic diabetes insipidus have a response below the normal range. Those with dipsogenic diabetes insipidus have a normal response. Patients with nephrogenic diabetes insipidus have a response at the top of the reference range but coincident urine osmolalities that are dilute, consistent with vasopressin resistance.
Classification describes primary and secondary (acquired) causes. All result in decreased production of vasopressin (AVP) through direct or indirect damage to hypothalamic AVP magnocellular neurones.
Figure 1
Table 1
Diabetes insipidus and hypernatraemia There is a close neuroanatomical relationship between the hypothalamic structures responsible for osmoregulation of thirst and AVP production. Certain structural, neurovascular and neuro-developmental lesions are thus associated with combined defects in both processes. Absent or reduced thirst (adipsia) in association with HDI predisposes to hypernatraemic dehydration. Diagnosis follows the protocol for HDI, but benefits from the parallel assessment of thirst perception.8
Diagnosis and investigations DI presents with polyuria and polydipsia. History and examination may reveal important features suggestive of: systemic disease associated endocrinopathy an associated neurological problem suggestive of structural disease drug toxicity. Polyuria must be distinguished from simple frequency without excess urine volume. The initial approach should be to confirm excess urine volume and exclude simple metabolic causes such as hyperglycaemia and hypercalcaemia. Definitive diagnosis requires referral to an endocrine service for testing of AVP production and action in response to osmolar stress. The water deprivation test measures renal concentrating capacity in response to dehydration, and is an indirect assessment of the AVP axis. It is usually followed by assessment of renal response to the synthetic AVP analogue DDAVP. Characteristic findings are as follows. In DDI, urine concentration is normal in response to dehydration. In HDI, urine concentration fails in response to dehydration, but not to DDAVP. In NDI, urine concentration fails in response to both manoeuvres. In practice, many results are indeterminate.6 Direct measurement of AVP production during graded hyperosmolar stimulation is the gold-standard method for diagnosing and classifying DI (Figure 1). Recent data suggest that measurement of co-peptin, an inactive fragment of the AVP precursor that is released in proportion to AVP, may prove to be an alternative.7 Confirmation of HDI should lead to further pituitary function testing and cranial MRI. NDI requires renal tract imaging and additional renal function studies.
MEDICINE 41:9
Management Mild forms of HDI may not require treatment. Significant polyuria and polydipsia are treated effectively with oral or intranasal DDAVP. In NDI, causal drugs should be withdrawn where possible and precipitating electrolyte disturbances corrected. NDI may respond partly to high-dose DDAVP. Thiazide diuretics and nonsteroidal anti-inflammatory drugs can be of additional benefit, but may not normalize urine production. The only rational approach to DDI is reduction in fluid intake. DDAVP treatment must be avoided in DDI, because of the risk of hyponatraemia. Follow-up Following initiation of DDAVP, patients may require frequent review by an endocrine service for dose titration. Thereafter, they can be seen annually to assess symptom control and check serum sodium to avoid over-treatment. The combination of HDI with adipsia requires meticulous follow-up in a specialist service, with a structured approach to fluid intake and antidiuresis. Prognosis Isolated HDI has an excellent prognosis and patients should anticipate a normal quality of life. When HDI is associated with pituitary hormone deficiency, structural or systemic disease, prognosis is determined by the natural history of the underlying pathology and co-morbidities. HDI following trauma may resolve.9 NDI is difficult to treat, and the symptoms seldom
520
Ó 2013 Elsevier Ltd. All rights reserved.
PITUITARY DISORDERS
5 Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev 2013; 34: 278e301. 6 Ball SG, Barber T, Baylis PH. Tests of posterior pituitary function. J Endocrinol Invest 2003; 26(suppl): 15e24. 7 Fenske W, Quinkler M, Lorenz D, et al. Copeptin in the differential diagnosis of the polydipsia-polyuria syndromedrevisiting the direct and indirect water deprivation tests. J Clin Endocrinol Metab 2011; 96: 1506e15. 8 Ball SG, Vaidja B, Baylis PH. Hypothalamic adipsic syndrome: diagnosis and management. Clin Endocrinol 1997; 47: 405e9. 9 Behan LA, Thompson CJ, Agha A. Neuroendocrine disorders after traumatic brain injury. J Neurol Neurosurg Psychiatr 2008; 79: 753e9. 10 Fenske W, Allolio B. Current state and future perspectives in the diagnosis of diabetes insipidus: a clinical review. J Clin Endocrinol Metab 2012; 97: 3426e37.
respond completely. Future developments may further help early diagnosis and guide appropriate intervention.10 A
REFERENCES 1 Ball SG. Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin. Ann Clin Biochem 2007; 44: 417e31. 2 Ball SG, Baylis PH. The neurohypophysis. In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. Oxford: Oxford University Press, 2002; 87e99. 3 Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000; 343: 998e1007. 4 Babey M, Kopp P, Robertson GA. Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol 2011; 7: 701e14.
MEDICINE 41:9
521
Ó 2013 Elsevier Ltd. All rights reserved.
Diabetes insipidus
What’s new?
Stephen Ball C
C
Abstract C
Diabetes insipidus (DI) describes the excess production of dilute urine. It is caused by the lack of production or action of the hormone vasopressin (AVP). Diagnosis requires a targeted history and examination. Confirmation requires referral to specialist services with expertise in diagnosis and management. Lack of AVP can be treated with synthetic vasopressin analogues. Additional approaches may be needed for specific forms of DI. Combined defects in AVP production and thirst perception require a structured programme of fluid intake and antidiuresis. Clinicians need to be aware of both systemic and locally progressive pathologies that can present with DI.
Dipsogenic diabetes insipidus (DDI, primary polydipsia): inappropriate, high fluid intake in excess of ability to excrete free water. Hypothalamic diabetes insipidus Presentation with HDI occurs when 80% of hypothalamic magnocellular neurone AVP production has been lost. Several pathological processes can be involved. All lead to either the destruction of AVP neurones, or the interruption of the transport or processing of AVP as it moves along the axons of these neurones for release at nerve terminals in the posterior pituitary (Table 1). The condition can appear for the first time or become worse in pregnancy as residual AVP is degraded by increased placental (vasopressinase) enzyme activity. Up to 50% of children and young adults with HDI have an underlying tumour or CNS malformation.3 Familial HDI comprises 5% of cases.4
Keywords adipsia; diabetes insipidus; hypernatraemia; hyponatraemia; polydipsia; polyuria; vasopressin
Diabetes insipidus (DI) is characterized by excess production of dilute urine e more than 40 ml/kg/24 hours in adults and more than 100 ml/kg/24 hours in children. Urine concentration is regulated by vasopressin (AVP), a nineamino-acid peptide produced by magnocellular neurones within the supra-optic nucleus (SON) and para-ventricular nucleus (PVN) of the hypothalamus. AVP is released into the circulation from nerve terminals in the posterior pituitary gland. Production is directly related to plasma osmolality and inversely related to plasma volume. The principal site of action of AVP is the kidney, where it increases the synthesis and assembly of water channels (aquaporin 2, AQP2), leading to increased free water reabsorption. These effects are mediated through interaction with a Gprotein coupled cell surface receptor (AVP-R2), found on target cells lining the luminal surface of the distal nephron.1
Nephrogenic diabetes insipidus Renal resistance to AVP can be the result of the adverse effects of specific drugs (e.g. lithium toxicity). These effects may be temporary, but sometimes persist. NDI may also occur following obstructive nephropathy, acute kidney injury and electrolyte disturbances (e.g. hypokalaemia, hypercalcaemia). Prolonged polyuria of any cause can result in partial NDI through disruption of the intra-renal solute gradient that is an obligatory requirement for production of concentrated urine. X-linked familial NDI results from loss-of-function mutations in the renal AVP-R2 receptor. Autosomal recessive NDI is caused by loss-of-function mutations in the AVP-dependent water channel, AQP2.5
Classification and aetiology There are three sub-types of DI, each reflecting a specific element of the physiology and/or pathophysiology of the AVP axis.2 Cranial or hypothalamic diabetes insipidus (HDI): relative or absolute lack of AVP. Nephrogenic diabetes insipidus (NDI): partial or total resistance to the renal antidiuretic effects of AVP.
Dipsogenic diabetes insipidus Persistent inappropriate fluid intake leads to appropriate polyuria. If it exceeds the limit of renal free water excretion it may result in hyponatraemia. DDI can be associated with the following abnormalities in thirst perception: low threshold for thirst exaggerated thirst response to osmotic challenge inability to suppress thirst at low plasma osmolalities. Structural lesions may be present, but neuroimaging is normal in most cases. DDI is associated with affective disorders.
Stephen Ball BSc PhD FRCP is Senior Lecturer and Honorary Consultant, Newcastle University and Newcastle Hospitals NHS Trust, UK. SB studied Basic Science at Birmingham University before pursuing undergraduate and postgraduate Medical Studies in London. Middle grade training in Diabetes and Endocrinology included a period in the USA as a Medical Research Council (UK) and Howard Hughes Fellow. He combines clinical medicine, research and teaching. He is a member of Council of the Society for Endocrinology and a Senior Editor of Clinical Endocrinology. He is also a European Endocrine Society representative within European Guideline groups. Conflicts of interest: none declared.
MEDICINE 41:9
Better understanding of the regulation of vasopressin secretion and its mechanism of action New insights into the molecular genetics of inherited diabetes insipidus Evolving approaches and novel tools to aid differential diagnosis
Epidemiology DI is rare. Prevalence of HDI is estimated at 1/25,000 with equal gender distribution. The prevalence of the other forms is unclear. While most cases present in adults, familial HDI and NDI characteristically present in childhood.
519
Ó 2013 Elsevier Ltd. All rights reserved.
PITUITARY DISORDERS
Diagnosis and classification of diabetes insipidus by measurement of plasma vasopressin in response to graded hyperosmolar stimulation
Aetiology of hypothalamic diabetes insipidus Genetic
Developmental syndromes Idiopathic Secondary Trauma Tumour
Inflammatory
Vascular
Wolfram’s syndrome, autosomal dominant, autosomal recessive Septo-optic dysplasia
20
Plasma vasopressin (pmol/litre)
Primary
Head injury, post-surgery (transcranial, trans-sphenoidal) Craniopharyngioma, germinoma, metastases, pituitary macroadenoma Sarcoidosis, histiocytosis, meningitis, encephalitis, infundibuloneurohypophysitis, GuillaineBarre syndrome, autoimmune Aneurysm, infarction
15
Nephrogenic Dipsogenic Hypothalamic
10
5
0
280
290
300
310
320
Plasma osmolality (mOsmol/kg) The shaded area depicts the normal-range response of plasma vasopressin as plasma osmolality is raised. Patients with hypothalamic diabetes insipidus have a response below the normal range. Those with dipsogenic diabetes insipidus have a normal response. Patients with nephrogenic diabetes insipidus have a response at the top of the reference range but coincident urine osmolalities that are dilute, consistent with vasopressin resistance.
Classification describes primary and secondary (acquired) causes. All result in decreased production of vasopressin (AVP) through direct or indirect damage to hypothalamic AVP magnocellular neurones.
Figure 1
Table 1
Diabetes insipidus and hypernatraemia There is a close neuroanatomical relationship between the hypothalamic structures responsible for osmoregulation of thirst and AVP production. Certain structural, neurovascular and neuro-developmental lesions are thus associated with combined defects in both processes. Absent or reduced thirst (adipsia) in association with HDI predisposes to hypernatraemic dehydration. Diagnosis follows the protocol for HDI, but benefits from the parallel assessment of thirst perception.8
Diagnosis and investigations DI presents with polyuria and polydipsia. History and examination may reveal important features suggestive of: systemic disease associated endocrinopathy an associated neurological problem suggestive of structural disease drug toxicity. Polyuria must be distinguished from simple frequency without excess urine volume. The initial approach should be to confirm excess urine volume and exclude simple metabolic causes such as hyperglycaemia and hypercalcaemia. Definitive diagnosis requires referral to an endocrine service for testing of AVP production and action in response to osmolar stress. The water deprivation test measures renal concentrating capacity in response to dehydration, and is an indirect assessment of the AVP axis. It is usually followed by assessment of renal response to the synthetic AVP analogue DDAVP. Characteristic findings are as follows. In DDI, urine concentration is normal in response to dehydration. In HDI, urine concentration fails in response to dehydration, but not to DDAVP. In NDI, urine concentration fails in response to both manoeuvres. In practice, many results are indeterminate.6 Direct measurement of AVP production during graded hyperosmolar stimulation is the gold-standard method for diagnosing and classifying DI (Figure 1). Recent data suggest that measurement of co-peptin, an inactive fragment of the AVP precursor that is released in proportion to AVP, may prove to be an alternative.7 Confirmation of HDI should lead to further pituitary function testing and cranial MRI. NDI requires renal tract imaging and additional renal function studies.
MEDICINE 41:9
Management Mild forms of HDI may not require treatment. Significant polyuria and polydipsia are treated effectively with oral or intranasal DDAVP. In NDI, causal drugs should be withdrawn where possible and precipitating electrolyte disturbances corrected. NDI may respond partly to high-dose DDAVP. Thiazide diuretics and nonsteroidal anti-inflammatory drugs can be of additional benefit, but may not normalize urine production. The only rational approach to DDI is reduction in fluid intake. DDAVP treatment must be avoided in DDI, because of the risk of hyponatraemia. Follow-up Following initiation of DDAVP, patients may require frequent review by an endocrine service for dose titration. Thereafter, they can be seen annually to assess symptom control and check serum sodium to avoid over-treatment. The combination of HDI with adipsia requires meticulous follow-up in a specialist service, with a structured approach to fluid intake and antidiuresis. Prognosis Isolated HDI has an excellent prognosis and patients should anticipate a normal quality of life. When HDI is associated with pituitary hormone deficiency, structural or systemic disease, prognosis is determined by the natural history of the underlying pathology and co-morbidities. HDI following trauma may resolve.9 NDI is difficult to treat, and the symptoms seldom
520
Ó 2013 Elsevier Ltd. All rights reserved.
PITUITARY DISORDERS
5 Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev 2013; 34: 278e301. 6 Ball SG, Barber T, Baylis PH. Tests of posterior pituitary function. J Endocrinol Invest 2003; 26(suppl): 15e24. 7 Fenske W, Quinkler M, Lorenz D, et al. Copeptin in the differential diagnosis of the polydipsia-polyuria syndromedrevisiting the direct and indirect water deprivation tests. J Clin Endocrinol Metab 2011; 96: 1506e15. 8 Ball SG, Vaidja B, Baylis PH. Hypothalamic adipsic syndrome: diagnosis and management. Clin Endocrinol 1997; 47: 405e9. 9 Behan LA, Thompson CJ, Agha A. Neuroendocrine disorders after traumatic brain injury. J Neurol Neurosurg Psychiatr 2008; 79: 753e9. 10 Fenske W, Allolio B. Current state and future perspectives in the diagnosis of diabetes insipidus: a clinical review. J Clin Endocrinol Metab 2012; 97: 3426e37.
respond completely. Future developments may further help early diagnosis and guide appropriate intervention.10 A
REFERENCES 1 Ball SG. Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin. Ann Clin Biochem 2007; 44: 417e31. 2 Ball SG, Baylis PH. The neurohypophysis. In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. Oxford: Oxford University Press, 2002; 87e99. 3 Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000; 343: 998e1007. 4 Babey M, Kopp P, Robertson GA. Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol 2011; 7: 701e14.
MEDICINE 41:9
521
Ó 2013 Elsevier Ltd. All rights reserved.