PARHON’S SYNDROME

PREPARED BY: DR SHAKTI YEOH (NNSMA)

DEFINITION

• Parhon’s Syndrome is also known as: Syndrome of Inappropriate Secretion of Antidiuretic

Hormone (SIADH) Syndromum Hydropexicum (in Greek)

• Hydro – Water• Pexis – Attachment, Binding

• Characterized by the non-physiological release of ADH, resulting in impaired water excretion with normal sodium excretion

INTRODUCTION

ANTIDIURETIC HORMONE– Also known as Vasopressin and Argipressin– Synthesized by Hypothalmus and stored in Posterior

Pituitary Gland (together with Oxytoxin)

Thank God We are Blessed with ADH

^^

– Functions:• Regulate the body's retention of water• May increases peripheral vascular resistance

(vasoconstriction of arterioles) and thus increases arterial blood pressure

• Implicated in memory formation• Acts in conjunction with corticotropin-releasing

hormone (CRH) to modulate the release of corticosteroids from the adrenal gland in response to stress

• ADH controls the osmolarity and water excretion by :– Increasing the water permeability of distal tubule and

collecting duct cells in the kidney, thus allowing water reabsorption and excretion of more concentrated urine (antidiuresis) by means of water channels (Aquaporin-2) in the apical membrane of distal tubule and collecting duct epithelial cells.

– Aquaporins allow water to move out of the nephron, increasing the amount of water reabsorbed from the filtrate (forming urine) back into the bloodstream.

– Alcohol inhibits the secretion of ADH thereby causing diuresis

CONTROL OF ADH SECRETION

• ADH secretion regulated by plasma osmolarity (concentration of solutes in blood).

• Osmolarity is sensed in the hypothalamus by osmoreceptors which may stimulate secretion from the neurons that produce antidiuretic hormone.

• Normal range of osmolarity :280-300 (mOSm/kg)• Secretion of ADH is also stimulated by decreases in

blood pressure and volume• The hormone is destroyed as soon as its function is

over and is excreted out along with the urine

Let's not bother him by invoking thirst

unless the situation is bad enough that ADH cannot handle

it alone

CAUSES

• Caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or by ectopic production

Ectopic production of neoplasm• Pulmonary - Lung carcinoma and mesothelioma• Gastrointestinal - Carcinomas of the duodenum, pancreas, and

colon• Genitourinary - Adrenocortical carcinoma; carcinomas of cervix,

ureter/bladder, and prostate; and ovarian tumors• Other - Brain tumors, carcinoid tumors, Ewing sarcoma,

leukemia, lymphoma, nasopharyngeal carcinoma, neuroblastoma (olfactory), and thymoma

Infections• Bacterial or viral pneumonia, Lung or brain abcess, TB,

meningitis, encephalitis, AIDS Neurological

• Guillain – Barre syndrome : acute polyneuropathy, a disorder affecting the peripheral nervous system due to autoimmune reaction.

• Multiple Sclerosis• Hydrocephalus• Trauma

Pulmonary disorders• Acute bronchitis/bronchiolitis• Acute respiratory failure• Asthma• Atelectasis• Chronic obstructive lung disease• Cystic fibrosis• Pneumonia

Drugs that stimulate AVP release are as follows:• Acetylcholine• Antineoplastic agents• Barbiturates• Bromocriptine• Carbachol• Chlorpropamide• Clofibrate• Cyclopropane• Dibenzazepines (eg, carbamazepine, oxcarbazepine

PATHOPHYSIOLOGY

• SIADH divided into 2 types:– Type A SIADH– Type B SIADH

• In type A SIADH, the excessive vasopressin release is unrelated to serum osmolality.

• In type B SIADH the response of vasopressin to changes in serum osmolality is preserved and urine-diluting capacity is intact, but the osmotic threshold for vasopressin release is lowered.

• In general, the plasma Na+ concentration is the Primary Osmotic Determinant Of AVP Release.

• In persons with SIADH, the nonphysiological secretion of AVP results in enhanced water reabsorption, leading to Dilutional Hyponatremia.

• Volume receptors are activated and natriuretic peptides are secreted, which causes Natriuresis

• In addition to the inappropriate AVP secretion, persons with this syndrome may also have an inappropriate thirst sensation, which leads to an intake of water that is in excess of free water excreted.

• This increase in water ingested may contribute to the maintenance of hyponatremia.

• Ingestion of water is an essential prerequisite to the development of the syndrome; regardless of cause, hyponatremia does not occur if water intake is severely restricted.

NONPHYSIOLOGICAL ADH SECRETION

ENHANCED WATER REABSORPTION

EXPANSION OF EXTRACELLULAR FLUID VOLUME (INTERSTITIAL

FLUID AND BLOOD PLASMA)

DILUTIONAL HYPONATREMIA

(EUVOLEMIC HYPONATREMIA)

SECRETION OF NATRIURETIC PEPTIDES:

PEPTIDE WHICH INDUCES NATRIURESIS

(DISCHARGE OF SODIUM THRU URINE)

NATRIURESIS AGGRAVATES HYPONATREMIA

THIRST WORSENS HYPONATREMIA

CLINICAL MANIFESTATION

• Clinical Manisfestation Due to Water Retention Hyponatremia Due to Water Toxicity (Complication)

Due to Water Retention Oligouria Weight Gain Edema is rare unless water overload >4 L Thirst ( Due to ADH stimulation)

Due to Hyponatremia (Normal: 135 – 145 mEq/L)Sodium 125-134 mEq/L

• Thirst• Anorexia• Nausea• Fatigue• Weakness• Muscle cramps• Headaches

• Sodium 115-124 mEq/L• Weight gain• Oliguria• Progressive neurologic symptoms

Sodium <115 mEq/LMortality may reach 50%S/S related to Cerebral Edema

PapilledemaDeliriumHypoactive reflexesAtaxiaGait disturbanceSeizuresComaDeath

COMPLICATION

• Heart Failure– Due to fluid overload

• Cerebral edema secondary to water intoxification.– When sodium levels in blood become too low,

excess water enters cells and causes the cells to swell

DIAGNOSIS

• Classical criteria introduced by Bartter and Schwartz in 1967 for diagnosis of SIADH: Hyponatremia with corresponding Hypoosmolality Continued renal excretion of Na+

Urine less than maximally dilute Absence of clinical evidence of volume depletion - Normal

skin turgor, blood pressure within the reference range Absence of other causes of hyponatremia

Adrenal insufficiency (mineralocorticoid deficiency, glucocorticoid deficiency)

Hypothyroidism, cardiac failure, pituitary insufficiency Renal disease with salt wastage, hepatic disease, drugs that impair

renal water excretion Correction of hyponatremia by fluid restriction

• TEST TO DIAGNOSE SIADH• Serum Na+

– Hyponatremia (ie, serum Na+ < 135 mmol/L)

• Serum Potassium– Remains unchanged

• Serum Bicarbonate– Remains within the reference range despite hypotonic expansion of body

fluids

• Blood Urea Nitrogen– unusually low, usually below 10 mg/dL. – occurs secondary to volume expansion because urea is distributed in

total body water.

• Serum Uric Acid– Hypouricemia (uric acid < 4 mg/dL) – increase in fractional uric acid excretion (usually >9%) occurs as a result

of volume expansion and a decrease in distal tubular reabsorption

• Plasma Osmolality– serum hypo-osmolality (less than 280 mOsm/kg H2O)

• Urine Osmolality– urine osmolality of more than 100 mOsm with plasma hypo-osmolality

is sufficient to confirm ADH excess

• Urine Specific Gravity– More than 1.030

• Glomerular Filtration Rate– Rate increased as a result of extracellular water expansion induced by

water retention

• Urinary Na excretion– >220mEq/L in 24 hr without diuretics

• ADH– plasma ADH is typically elevated

LAB TEST NORMAL VALUE VALUE IN SIADH

Serum Sodium 135-145meq/L <135meq/L

Serum Osmolality 275-295mOsm/kg <280mOsm/kg

Urine Sodium 50-220 mEq/L in 24hr >220mEq/L in 24 hr

Urine Osmolality 500-800 mOsm/kg of H2O in 24 hour

300-900 mOsm/kg of H2O in random test 

>1000 mOsm/kg

Urine Specific Gravity

1.025-1.032 >1.032

BUN 6-22 mg/dl Low BUN

SUMMARY

TREATMENT

• Goal: Normalization of plasma osmolality and elimination overhydration.

• Tactics of treatment depends on– degree of hyponatremia,– on whether the patient is symptomatic– and on whether it is acute (< 48 h) or chronic

• Steps of treatment – Treatment of underlying medical condition if exists– Water restriction– Normalize serum sodium (130 meq/l and above) over 24 -48

hours (Max correction of 15meq/day)• Correcting hyponatremia too rapidly may result in central

pontine myelinolysis (CPM) with permanent neurologic deficits

– Normalize serum osmolality– Correct excess extravascular fluid volume

ACUTE SETTING• < 48 h since onset• Treatment options for the Hyponatremia

– Loop diuretics with saline (Furosemide)• increase the excretion of free water

– 3% hypertonic Sodium saline (NaCl 514 mEq/L)• Replacement of the excreted Na+

• To avoid a net Na+ loss while effecting a loss of free water– Vasopressin-2 receptor antagonists (aquaretics)

• reduces the number of aquaporin-2 water channels in the renal collecting duct and decreases the water permeability of the collecting duct

• Conivaptan– Load: 20 mg IV infusion over 30 minutes– 20 mg IV as continuous infusion over 24-hour period for 2-4 days

• Tolvaptan– 15 mg PO qDay– Maintenance: Increase after >24 hr to 30 mg qDay; may increase

further, not to exceed 60 mg qDay– Water restriction 500-1500 mL/d

• WHY? Because when urine output exceeds water intake, a net water loss occurs and the serum Na+ level returns towards normal.

• fluid restriction and V2 receptor antagonists• ADH inhibitors

– Demeclocycline IV 0.6 mg 1-2times/ day, for 5-7 days or until the clinical improvement

– Phenytoin IV 200-500 mg I-2times/ day for 5-7 days until clinical improvement

– After the normalization of a maintenance therapy with the use of urea (0.5 g/kg)

CHRONIC SETTING

• Evaluating the effectiveness of treatment• acute hyponatremia - increasing sodium in

the blood• chronic hyponatremia - normal levels of

sodium in the blood, serum osmolality and elimination overhydration.

THANK YOU !!DR SHAKTI YEOH