Pituitary Disorders:3Diabetes Inspidus & Pan hypopituitarism

Professor Tariq WaseemDr. Hina Latif

Apollo Bay Melbourne Australia 2013

Case Scenario 1.

Twenty two years old university student presents with 3 months history of excessive thirst. She consumes about 20-25 glasses of water in a day and wakes up 5-6 times at night to pass urine and drink water. She is constipated but her appetite is normal and she has not lost weight. Her wedding is scheduled in two months and she is quite apprehensive about it.

What is differential diagnosis?

Major Symptoms are:

PolydipsiaNocturiaPolyuriaAnxiety

Psychogenic PolydipsiaDiabetes MellitusDiabetes Inspidus

Diabetes Inspidus

Defined as the passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg).

Central (neurogenic, pituitary) DI, results from decreased secretion of antidiuretic hormone ADH

Nephrogenic DI, occurs due to decreased ability to concentrate urine because of resistance to ADH action in the kidney

Central Diabetes Inspidus (CDI)

Results from any condition that impairs the synthesis, transport, or release of antidiuretic hormone (ADH), also known as arginine vasopressin (AVP).

ADH deficiency may be complete or partial.

VasopressinVasopressin normally controls the expression and

cell surface targeting of the apical water channel aquaporin-2 (AQP2) in connecting tubules(CNT) and Connecting ducts (CD).

The CNT and CD are also the site of amiloride-sensitive sodium reabsorption via the epithelial sodium channel (ENaC).

Both AQP2 and ENaC are regulated by vasopressin via V2-receptor-dependent cAMP production.

Exogenous application of vasopressin efficiently corrects the reduced AQP2 expression and the urinary concentration defect in central DI.

Diabetes Inspidus

Lack of water reabsorption in the collecting ducts of the kidneys due to decreased secretion of ADH results in polyuria.

The urine output can range from 3 L/day in mild partial DI to over 15 L/day in patients with severe disease.

CDI worsen or first diagnosed during pregnancy since vasopressinases released from placenta increase ADH catabolism.

Etiology

Idiopathic DI (most common)Brain traumaPrimary or metastatic brain tumors Infiltrative diseases NeurosurgeryHypoxic or ischemic encephalopathyFamilial DI Radiation to the brain Infection such as meningitis or encephalitisCerebral edema Intracranial hemorrhage

Etiology

Wolfram syndrome (or DIDMOAD syndrome):

An autosomal recessive disorder with incomplete penetrance.

DI: Diabetes InspidusDM: Diabetes MellitusOA: Optic atrophyD: Deafness.

CDI is due to loss of ADH-secreting neurons in the hypothalamus and impaired processing of ADH precursors.

SymptomsPolyuria and Polydipsia.Urine output of over 3 L/day in adults.

D/D Nocturia/Frequency of micturition, (Not associated with an increase in total urine output).

The onset of polyuria is usually abrupt in CDI but always gradual in Nephrogenic DI and Primary or Psychogenic Polydipsia.

Symptoms

Nocturia is often the first sign of CDI.

Urine mostly gets concentrated in the morning due to lack of fluid ingestion overnight.

Lack of ADH and resulting loss of concentrating ability results in NOCTURIA.

A relatively dilute urine is excreted, with a urine osmolality of less than 200 mOsmol/kg.

Dry skin and constipation are other symptoms that may occur in CDI.

Laboratory

Mild Hypernatremia (> 142 mEq/L).Plasma Osmolality >290 m osm/kg (Normal 280-295 mOsm/kg).

Why?

Initial loss of water results in concurrent stimulation of thirst, which minimizes the degree of net water loss.

Diagnosis

Water Deprivation Test:Helps differentiating central DI from

nephrogenic DI and primary polydipsia.Water restriction should raise the plasma

osmolality and stimulate ADH secretion and result in concentrated urine and an increased urinary osmolality to more than 1000-1200 m osmol/L in normal individuals.

Giving exogenous ADH does not raise urinary osmolality any further.

DiagnosisStimulation of thirst does not occur, however,

when CDI is due to a central lesion that impairs thirst causing hypodipsia or adipsia.

In such cases, the plasma sodium concentration can exceed 160 meq/L and the plasma osmolality will rise significantly also.

This also occurs if a patient has no access to water.

Withholding water in patients with CDI can result in severe dehydration.

Water Restriction Test

Method:Water restriction lasts 4 to 18 hours.

Overnight fluid restriction should be avoided, as severe volume depletion and hypernatremia can be induced in patients with severe polyuria.

Measure the urine volume and osmolality every hour and serum sodium concentration and osmolality every two hours.

Water Restriction Test

The test should be continued until one of the following occurs:The urine osmolality reaches above 600 mOsm/kg,

indicating that both ADH release and effect are intact.

The urine osmolality is stable on 2 or 3 successive measurements despite a rising plasma osmolality.

The plasma osmolality exceeds 295 to 300 mOsm/kg.Exogenous ADH is administered (10 microgm of dDAVP

nasally or 4 microgm sq).Urine osmolality is then measured every 30 minutes for

the next 3 hours.

Water Restriction TestIn patients with complete CDI:

Plasma osmolality is increased but urine osmolality remains below 290 mOsm/kg and does not increase.

Urine osmolality will increase by approximately 200 mOsm/kg in response to exogenous ADH.

In patients with partial CDI:Urine osmolality will increase somewhat to 400

to 500 mOsm/kg during water deprivation, but is still well below that of normal people.

Urine osmolality will increase by approximately 200 mOsm/kg in response to exogenous ADH.

Water Restriction TestsInterpretation:

Normal subjects and primary polydipsia: Urine osms are greater than plasma Osms after water

restriction. Urine osms increase minimally (<10%) after

exogenous ADH.

Central Diabetes Insipidus: Urine osms remain less than plasma osms after water

restriction. After ADH is given, urine osms increase 100% in

complete CDI and over 50% in partial CDI.

Nephrogenic Diabetes Insipidus: Urine osms remain less than plasma osms. After ADH, urine osms increase by less than 50%.

Treatment

Fluid Replacement is most important.

Encourage oral water intake IV Fluids such as D5W if the patient is unable to

take fluids by mouth.

Why not 0.9% Normal Saline?Why not IV Sterile water?

Treatment.

Desmopressin is the drug of choice for long-term therapy of CDI to control polyuria.

Available in subcutaneous, IV, intranasal, and oral preparations. Generally, it can be administered 2-3 times per day.

It is safe during pregnancy for both the mother and the fetus.

Monitoring & Follow up

Monitor for fluid retention and hyponatremia during initial therapy.

Keep record of volume of water intake and the frequency and volume of urination, and inquire about thirst

Monitor serum sodium, 24-hour urinary volumes, and specific gravity.

Follow-up visits with the patient every 6-12 months

Other Drugs

Chlorpropamide:Carbamazepine:Clofibrate:Prostaglandin inhibitorsThiazide diuretics:

Antidiuretic effect of Diuretics

Thiazide diuretics inhibit the NaCl co-transporter (NCC/TSC) in the renal distal convoluted tubule (DCT). The DCT is water impermeable and considered to be part of the diluting segment

Antidiuretic effect of Diuretics

 The antidiuretic action of thiazides is

secondary to increased renal sodium excretion. The renal sodium loss causes extracellular volume contraction leading to lowered GFR and increased proximal tubular sodium and water reabsorption. Hence, less water and solutes are delivered to the distal tubule and collecting duct and are lost as urine.

Bridge on River Yarra Melbourne

CASE SCENARI0: 2o Mr. A 54 years old man underwent

transsphenoidal surgery, following a history of tonic-clonic seizures and a diagnosis of pituitary tumor.

o 6 month later he reported to his GP C/O of fatigue, lethargy, decreased exercise capacity, dry skin, decreased sweating, depressive mood, impaired social function and low self-esteem

o A diagnosis of Depression was made and SNRI were started.

Case Scenario:2 ………contdThree months later he reported decreased

libido, impotence and decreased body hair . Next one year he complained of cold

intolerance, dry skin, mental dullness, constipation, hoarseness.

In next few months he developed weakness, nausea, vomiting, anorexia, weight loss, low grade fever, postural hypotension, frequent hypoglycemic spells, and noticed fairness of his complexion.

Physical Examination

Slightly overweight fine, pale, and smooth skin with fine wrinkling on the face deficient or absent body and pubic hair,

Atrophy of genitalia decreased muscle strength, Postural hypotension,

Bradycardia, Delayed deep tendon reflexes

Diagnosis??

labsAnemiaHyponatremiaHypoglycemiaLow FT3,FT4,TSHLow ACTH,& Cortisol.Low FSH and LH,

Etiology

• Head injuries • Brain tumor • Brain surgery • Radiation treatment • Autoimmune inflammation (hypophysitis) • Stroke• Infections of the brain, such as meningitis • Tuberculosis

Signs and SymptomsHypopituitarism is often

progressive. Although the signs and symptoms can occur suddenly, usually they tend to develop gradually. They are sometimes vague and subtle and may be overlooked for many months or even years.

Signs & Symptoms

• Depend on which pituitary hormones are deficient.

• Fatigue • Headaches• Low tolerance for stress• Muscle weakness • Nausea • Constipation • Weight loss or gain • A decline in appetite

• Abdominal discomfort • Sensitivity to cold or difficulty staying warm • Visual disturbances• Loss of underarm and pubic hair• Joint stiffness• Hoarseness • Facial puffiness • Thirst and excess urination • Low blood pressure • Lightheadedness when standing

Presenting Complaints in hypopituitarism

DEPEND ON HORMONES LOST

1. Lack of FSH LH : 1. Hypogonadim: amenorrhea 2. Lack of TSH: hypothyroidism3. Lack of ACTH: adrenocortical insufficiency4. Prolactin deficiency: FAILURE OF POSTPARTUM LACTATION5. If all of the above: PANHYPOPITUITARISM6. In children: GH: short stature

Testing Anterior .Pituitary Function

1. Baseline studies: TSH, ACTH, FSH, LH, prolactin GH

2). Stimulation tests: 1) TRH 2) LH-RH 3) Insulin hypoglycemia3. Radiological :

Imaging

- Lat skull x=ray- CT- MRI

TREATMENT OF HYPOPITUITARIM

1. Remove cause 2. REPLACEMENT THERAPY; depends on hormone lost3. THYROXINE in 2° hypothyroidism4. Hydrocortisone for 2° hypoadrenalism

20 mg at AM 10 mg at PM

5. Growth hormone : for children 6. Testosterone: monthly injections7. Estrogen + progesterone8. For induction of ovulation FSH + LH

Follow upMr. A is currently on1. Thyroxine 200 microgram daily2. Prednisolone 7.5 mg/dayInj testosterone 250 mg IM every month

He also developed DM three years ago and is on Pre-mix insulin.

He needs dose adjustments whenever he has URTI.

He is under follow up for past 12 years.Last month he underwent laparoscopic

cholecystectomy under GA and is doing fine.

Case Scenario 3A 30 years old lady reports failure to

conceive after her first childbirth that was 5 years ago.

Her mother in law reports heavy postpartum bleeding after her previous delivery and that she did not have lactation and her baby had to be started on formula feed.

She also describes multiple episodes of fainting on standing from sitting, has become isolated and uninterested, lost 8 Kg of her weight, and has amenorrhea since last child birth.

DIAGNOSIS??

MCG Melbourne