DIABETES INSIPIDUS

Perie Adorable-Wagan, MD

Objectives
To evaluate patients presenting with polyuria To present a diagnostic approach in a patient suspected with Diabetes insipidus To briefly review pathophysiology of Diabetes insipidus To discuss management of Diabetes insipidus

IDENTIFYING DATA
30 year old Female Single Roman Catholic OFW Nurse Quezon City Jan 25, 2006

CHIEF COMPLAINT

Increase urine output

HISTORY OF PRESENT ILLNESS

5 months (+) polyuria every 2 hours (+) polydipsia 4-6L/day 5 days - (+) polyuria (+) polydipsia (+) disrupted work (+) IGT

TMC

Review of Symptoms
Skin: supple skin,no skin pigmentation HEENT: no headache,no dizziness,no seizures, no visual changes or eye pain, no photophobia, no tinnitus, no hearing loss, no nose bleeding, no hoarseness, no dysphagia. Respiratory: no shortness of breath, no cough, no hemoptysis

Review of Symptoms
Cardiovascular: no easy fatigability, no palpitation ,No chest pain, orthopnea, , no paroxysmal nocturnal dyspnea Gastrointestinal: no abdominal pain, nausea,vomiting Genitourinary: (+)urinary frequency due to her increase water intake , no dysuria, no hematuria

Review of Symptoms
Neuromuscular: no proximal muscle weakness Metabolic : no heat intolerance, no weight loss, regular appetite

Past Medical History

Non-Hypertensive, Non diabetic. No history of asthma,no history of head trauma

Family Medical History:

(+) Hypertension-Maternal relative (+) DM-paternal relative (+) Asthma- Maternal relative

Personal and Social History:

Non- smoker, occasional drinker

PHYSICAL EXAMINATION
BP: 130/80 HR: 100 RR: 130/80 Temp: 37 wt: 51kg Skin supple skin, no skin pigmentation HEENT: anicteric sclera, pink conjunctivae, moist lips and buccal mucosa, no neck vein distention,no palpable neck mass, no cervical lympadenopathy

PHYSICAL EXAMINATION
HEART: adynamic precordium, regular rate regular rhythm, no murmur Abdomen: soft, normoactive bowel sound, no tenderness Extremities: no tremors, no cyanosis, no edema

SALIENT FEATURES
30 year old female No known medical comorbidities Polyuria and polydipsia

ADMITTING IMPRESSION

DIABETES INSIPIDUS

EVALUATION OF POLYURIA
1. Is This True Polyuria or Just Urinary Frequency? 2. If True Polyuria, is this a Water Diuresis or a Solute Diuresis? 3. If If a Water Diuresis, Is This Diabetes Insipidus or Primary Polydipsia?

True Polyuria vs Urinary frequency

Frequently voiding large volumes of dilute (colorless or pale) urine, (colorless or pale) urine, both day and night, suggests true polyuria,

Frequent voiding of small volumes of concentrated urine is indicative of bladder dysfunction caused by infection or other local disease.
A 24-hour urine collection provides objective confirmation of true polyuria when the volume exceeds 3 L or 50 mL/kg.

Primary care Medicine 2009

WATER DIURESIS OR SOLUTE DIURESIS ?

and Total Solute

Solute diuresis

>350 mOsm/L concentrated urine

Water diuresis

<250 mOsm/L dilute urine

Primary care Medicine 2009

Differential Diagnosis of Polyuria/Polydipsia

Solute Diuresis Diabetes Mellitus Diuretics Water Diuresis Diabetes Insipidus Nephrogenic Primary Polydipsia

Evaluation of Polyuria
Polyuria >3L/24hrs

UoSm > 300 Hyperglycemia

UoSm < 200

Diabetes Mellitus

Diabetes Insipidus Suspect

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006

COURSE IN THE WARD

Polyuria Polydipsia

Uosm 59mOsm/kg

Posm 293mOsm/kg

Serum Na 140

Water Deprivation Test Jan. 27, 2006

Baseline Body weight: 51Kg Target Body weight: (5%) 49k Time Started: 8am

Interpretation
Normal response Urine osmolality 2-4x greater than that of plasma osmolality With Exogenous vasopressin resulting in less than 9% further increase in urine osmolality
Endocrine Protocols 2011 1st edition

Interpretation
Complete Central Diabetes Insipidus Urine osmolality is low compared to plasma osmolalilty in response to water deprivation but more than 50% increase in urine osmolality after vasporessin administration

Endocrine Protocols 2011 1st edition

Interpretation
Partial Central DI Increase 9-50% urine osmolality after vasopressin Nephrogenic DI Urine osmolality fail to increase to greater than plasma osmolality with exogenous vasopressin. Increase < 10% urine osmolality
Endocrine Protocols 2011 1st edition

Interpretation
Primary Polydipsia Concentrate urine only slightly Less than 9% rise in urine osmolality

Endocrine Protocols 2011 1st edition

Patients result

DIAGNOSTIC ALGORITHM

DIAGNSOTIC ALGORITHM

DIAGNOSTIC ALGORITHM

Management
1. ADH replacement a.)Pitressin(vasopressin tannate in oil). IM Every 2 to 4 days and provides relief 24 to 72 hours. Its side effects include abdominal cramping, hypertension, and angina. The disadvantages of these preparations prompted the development of oral agents to aid in antidiuresis.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006

Management
b.)Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) Drug of choice for long-term therapy of central diabetes insipidus. synthetic V2R (ADH receptor) agonist It can be given IV, PO, intranasally. For all dosage forms, the starting dosage is 10 g at night to relieve nocturia. A morning dose can be added if symptoms persist during the day.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006

Management
c.)Chlorpropamide (Diabinese) decreases the clearance of solute free water, but only if the neurohypophysis has some residual secretory capacity. Its antidiuretic effect is likely due to raising the sensitivity of the epithelium of the collecting duct to low concentrations of circulating ADH. d.)Carbamazepine (Tegretol) reduces the sensitivity of the osmoregulatory system of ADH secretion raises the sensitivity of the collecting duct to the hydroosmotic action of the hormone.
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006

Management
d.) Clofibrate (Atromid-S) stimulates residual ADH production in patients with partial central diabetes insipidus. e.)Thiazide diuretics decreasing sodium and chloride absorption in the distal tubule, therefore allowing more sodium absorption and therefore water absorptionin the proximal tubule.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006

DIABETES INSIPIDUS
Disorder of a large volume of urine (diabetes) that is hypotonic, dilute, and tasteless (insipid). Four pathophysiologic mechanisms related to vasopressin produce large volumes of dilute urine and polydipsia:

1. Hypothalamic (central or neurohypophyseal) diabetes insipidus with inability to secrete and usually to synthesize vasopressin in the neurohypophyseal system 2. Nephrogenic diabetes insipidus wherein there is an inappropriate renal response to vasopressin 3. Transient diabetes insipidus of pregnancy produced by the accelerated metabolism of vasopressin 4. Primary polydipsia wherein the initial pathophysiology is the ingestion of fluid rather than the excretion of fluid
Kronenberg: Williams Textbook of Endocrinology, 11th ed.

WATER DEPRIVATION TEST

Procedure: 1. Patient should not eat or smoke 2 hours before the test and during the test 2. Nothing per orem at 6:00 hr until the end of the procedure 3. Place patient on a recumbent position for 30 mins during which subsequent steps can be carried out 4. Measure and record urine volume at baseline and hourly thereafter. 5. Weigh patient and record urine volume at baseline and hourly thereafter

Endocrine Protocol First Edition 2011

WATER DEPRIVATION TEST

Compute for the 3% and 5% decrease in body weight Terminate test if any of the following endpoints are reached: a.) 3-5% of body weight is lost b.) serum osmolality reaches 295-300 mOsm/kg H20 c.) urine osmolality plateus with hourly increase < 30mOsm/kg water for 3 successive hours d.) urine osmolality > 600mOsm/kg Upon termination of the test based on the criteria above, give 5 units of aqueous vasopressin sq, or 1 mcgDDVAP sq, IM, or IV then measure urine and serum osmolality after one hour

Copeptin in the Differential Diagnosis of the Polydipsia-Polyuria Syndrome Revisiting the Directand Indirect Water Deprivation Tests
J Clin Endocrinol Metab, May 2011, 96(5):15061515
Wiebke Fenske,* Marcus Quinkler,* Daniela Lorenz, Kathrin Zopf, Ulrike Haagen,Jana Papassotiriou, Andreas F. H. Pfeiffer, Martin Fassnacht, Stefan Stork,and Bruno Allolio

Copeptin
Background: The water deprivation test (WDT) with direct or indirect measurement of plasma arginine vasopressin (AVP) is the method of choice for the differential diagnosis of the polydipsia polyuria syndrome. In theory, direct measurement of AVP is highly attractive but is hampered by technical difficulties.

J Clin Endocrinol Metab, May 2011

Copeptin
Objective: The aim of the studywasto evaluate the utility of copeptin, a surrogate of AVPsecretion, in the diagnostic work-up of the polyuria-polydipsia syndrome and to compare its performance with the current diagnostic standard. Setting and Design: In two tertiary referral centers, 20 healthy subjects and 50 patients with polydipsia-polyuria syndrome underwent WDT with measurements of both plasma AVP and copeptin levels. The reference diagnosis was based on clinical information and treatment response
J Clin Endocrinol Metab, May 2011

Copeptin
C-terminal part of the AVP precursor cosecreted with AVP from the neurohypophysis higher ex vivo stability much easier to measure than AVP Recently developed copeptin assay demonstrated excellent and robust performance with an analytical detection limit of 0.4 pmol/liter

J Clin Endocrinol Metab, May 2011

Patients and Methods

May 2007 and November 2009 20 control 50 adult patients referred and screened for polydipsia polyuria syndrome Water deprivation test Direct test (AVP, copeptin)

J Clin Endocrinol Metab, May 2011

Results

J Clin Endocrinol Metab, May 2011

Results:
Baseline cut-off value >20pmol/L Nephrogenic DI
Primary Polydipsia Sensitivity 82% specificity 92%

> 3pmol/L

J Clin Endocrinol Metab, May 2011

Diagnostic performance of copeptin in the polydipsia-polyuria syndrome

According to this direct test, copeptin measurement correctly diagnosed

4 out 9 CDI

Copeptin levels far below normal range

11 out 17 PDI Copeptin levels below normal range

19 out 22 PP
Copeptin levels within normal range and above

2 out 2 NDI

Copeptin levels far above normal range

36 of the 50 (72%) diagnosed correctly

J Clin Endocrinol Metab, May 2011

Results
Nonetheless, due to the substantial overlap of baseline and stimulated copeptin data points between primary poly-dipsia and partial central DI patients the discriminative value of a single copeptin measurement turned out to be limited.

J Clin Endocrinol Metab, May 2011

Limitation of the study

1.Missing correlation between plasma AVP and copeptin levels correlation might be related to different half-lives of AVP and copeptin 2. The authors cannot fully exclude the possibility that the well-known technical difficulties of AVP measurement might also have contributed to the lack of correlation 3. Finally, the clinical reference standard based on follow-up assessments and retrospective judgment is not well standardized.
J Clin Endocrinol Metab, May 2011

Authors Summary
In summary, copeptin a promising diagnostic potential. If confirmed in additional series, determination of baseline copeptin may become a simple method to identify patients with nephrogenic DI and severe forms of central DI

J Clin Endocrinol Metab, May 2011

References:
1. 2. 3. 4. Baylis,Peter. Posterior Pituitary 1997 The Medicine Group (Journals) Villa,Michael. Endocrine Protocols. Handbook of Interpreation of results. 2011 Slovik, David. Evaluation and Management of Adult patient with Polyuria. Williams and Wilkins 2009 Nils G. Morgenthaler,* Joachim Struck, Christine Alonso, and Andreas Bergmann Assay for the Measurement of Copeptin, a Stable Peptide Derived from the Precursor of Vasopressin: Clinical Chemistry 52:1 112119 (2006) AMGAD N. MAKARYUS, MD, SAMY I. McFARLANE, MD, MPH Diabetes insipidus: Diagnosis and treatment of a complex disease : CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006 Wiebke Fenske,* Marcus Quinkler,* Daniela Lorenz. Copeptin in the Differential Diagnosis of the Polydipsia-Polyuria SyndromeRevisiting the Direct and Indirect Water Deprivation Tests. J Clin Endocrinol Metab, May 2011, 96(5):15061515

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7. Robert W. Schrier. Body Water Homeostasis: Clinical Disorders of Urinary Dilution and Concentration. 2006 by the American Society of Nephrology 8. Y. EDOUTE1, M.R. DAVIDS2, C. JOHNSTON3 and M.L. HALPERIN An integrative physiological approach to polyuria and hyponatraemia. Q J Med 2003; 96:531540