Total T4 (Total Thyroxine)

Tetraiodothyronine/T4 (Total Thyroxine)

T4 is a thyroid hormone, and too much or too little of it can indicate an issue with the thyroid. A T4 (thyroxine) test is a blood test that helps diagnose thyroid conditions.

Thyroxine, also known as T4 and tetraiodothyronine, is the main hormone secreted by the thyroid gland and released into the bloodstream. The thyroid also releases small amounts of triiodothyronine (T3). T4 and T3 work together and are commonly referred to as "thyroid hormone". Hormones are chemicals that coordinate different functions in the body by carrying messages through the blood to the organs, muscles and other tissues. These signals tell the body what to do and when to do it. 

Thyroxine (T4) plays an important role in the hypothalamic-pituitary system of thyroid regulation and has an influence on general metabolism. T4 results from the coupling of two molecules of 3,5-diiodotyrosine, is bound to thyroglobulin and remains in the cells of the thyroid follicles, from where it is excreted under the action of TSH.

Other names when referring to a T4 test may include: free thyroxine, total T4 concentration, thyroxine screen, free T4 concentration, free T4 index (FTI).

The thyroid is a small, butterfly-shaped gland located at the front of the lower neck, above the clavicle. It's a part of the endocrine system and it makes hormones that control the way the body uses energy. These hormones affect nearly every organ in the body and control many of the body's most important functions. For example, they affect the breathing, heart rate, weight, digestion, and mood. In children, thyroid hormones affect growth, too. The thyroid gland makes and releases thyroid hormones in the blood, which then travel to the organs to exert their effect.

Most thyroxine circulates in the blood bound to proteins. Since the concentration of serum carrier proteins is subject to exogenous and endogenous influences (for example, it increases during pregnancy and after oral contraceptives and decreases in nephrotic syndrome), their status should be taken into account when assessing the T4 level. 

There are two forms of T4 in the blood:

- Free T4 is the active form of thyroxine hormone that enters the body tissues where it is needed;

- Bound T4 is thyroxine that attaches or binds to certain proteins which prevent it from entering the body tissues. It stays in the bloodstream as a "backup supply" until the tissues need it.

T4 is the main hormone that the thyroid makes. The T4 that the thyroid releases is inactive, meaning that it doesn't affect the body's cells. However, the liver and kidneys convert most of this thyroxine into triiodothyronine (T3), which is an active hormone that impacts the cells in the body. 

Together, T4 and T3 play vital roles in regulating various bodily functions, such as:

- Metabolic rate (the rate at which the body transforms the food that is eaten into energy);

- Heart and digestive functions;

- Muscle control;

- Brain development;

- Bone maintenance.

T4 levels can be measured with either a free T4 test or a total T4 test:

- A free T4 test measures the amount of free T4 in the blood. This form "freely" enters the body's tissues where it's needed. Medical experts believe this test is more accurate than a total T4 test, so it's used more often;

- A total T4 test measures free and bound T4 together; Bound T4 attaches to proteins, which prevents it from entering the body's tissues.

Because of this, there are a few different tests that measure T4 levels. A T4 test alone can't provide enough information to diagnose thyroid problems. A blood test that measures both free and bound T4 is called a total T4 test. Some blood tests measure just free T4. Healthcare providers most often use a free T4 test to assess thyroid function because it's more accurate than a total T4 test. Aditionally, T4 analysis is usually done with a TSH blood test. TSH stands for thyroid stimulating hormone. It's a hormone made by the pituitary gland, a small gland at the base of the brain. TSH tells the thyroid how much hormone to make. Normally, if the T4 levels are too low, the pituitary makes more TSH to make the thyroid work harder. If the T4 levels are too high, the pituitary stops making TSH.

A TSH test is the best way to initially assessing the thyroid function. In fact, T4 tests more accurately reflect thyroid function, when combined with a TSH test. Measuring T4 levels might not be necessary in all thyroid conditions.

Recommendations for T4 determination:

- diagnosis of hyper- and hypothyroidism (primary or secondary);

- monitoring of TSH suppressive treatment.

Patient preparation: fasting (without food); if the patient is on treatment with hypolipidemic drugs containing thyroxine, blood sampling for T4 determination will be done 4-6 weeks after its discontinuation. Specimen collected: venous blood.  

 

Why is it a T4 (thyroxine) test needed?

Healthcare providers may use T4 tests to assess how well the thyroid is working. The provider may order a T4 test (in addition to a TSH test) for any of the following reasons:

- To follow up on an abnormal thyroid-stimulating hormone (TSH) test result;

- To diagnose hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid);

- To monitor T4 levels if taking thyroid hormone replacement therapy (medication);

- To screen for an underactive thyroid in newborns;

- To evaluate other conditions, such as goiter, thyroid nodules and issues with the pituitary gland or hypothalamus;

- To evaluate for low thyroid hormone levels from a pituitary cause (central hypothyroidism).

Again, providers more commonly order free T4 tests than total T4 tests. In certain situations, such as pregnancy, a total T4 test might be necessary rather than a free T4 test.

T4 (Total Thyroxine) Reference Values:

- are based on age:

Age:                             Value (nmol/L):                         Value (µg/dL):

0 - 6 days                     64.9 - 239                                   5.04 - 18.5

6 days - 3 months        69.6 - 219                                   5.41 - 17

3 - 12 months              73 - 206                                      5.67 - 16

1 - 6 years                   76.6 - 189                                   5.95 - 14.7

6 - 11 years                  77.1 - 178                                  5.99 - 13.8

11 - 20 years                76.1 - 170                                  5.91 - 13.2

> 20 years                    66.0 - 181                                  5.13 - 14.1

In pregnancy, T4 level increases by 40-60%, starting with weeks 11-12, due to the increase in TGB:

1st trimester: 94.4 - 191 nmol/L (7.33 - 14.8 µg/dL);

2nd trimester: 102 - 208 nmol/L (7.93 - 16.1 µg/dL);

3rd trimester: 89.5 - 202 nmol/L (6.95 - 15.7 µg/dL).

Detection limit - 5.40 nmol/L (0.42 µg/dL).

Clinical alert values - low level: <26 nmol/L (possibility of myxedema coma); high level: >258 nmol/L (possibility of "Thyroid storm").

Limitations and interferences

In the first 2 months of life, T4 shows values much higher than in normal adults.

Elevated T4 values can also be found in dysalbuminemic familial hyperthyroxinemia - albumins bind T4 more avidly than normal, but not T3, causing laboratory changes similar to those in thyrotoxicosis, but the patients are not clinically thyrotoxic.

Normal T4 values can be found in hyperthyroid patients who present T3 thyrotoxicosis or artificial hyperthyroidism due to T3.

What are normal free T4 levels?

Normal levels of free T4 vary based on the age. In general, normal ranges of free T4 for healthy people include:

- Children up to 5 years old: 0.8 - 2.8 nanograms per deciliter (ng/dL);

- Children 6 to 15 years old: 0.8 - 2.1 ng/dL;

- Male adolescents 16 to 17 years old: 0.8 - 2.8 ng/dL;

- Female adolescents 16 to 17 years old: 0.8 - 1.5 ng/dL;

- Adults over 18 years old: 0.9 - 1.7 ng/dL.

Normal value ranges for free T4 may vary slightly among different laboratories. One should check the lab report's reference range on the lab results. If there are questions about the results, the patient should ask the healthcare provider.

What happens when T4 (thyroxine) levels are too high?

If the patient has higher-than-normal T4 or free T4 levels, it could indicate thyrotoxicosis. This can result from several situations and conditions, including hyperthyroidism (overactive thyroid), thyroid inflammation (thyroiditis) and taking excessive amounts of thyroid medication.

Thyrotoxicosis speeds up the metabolism, which can be dangerous to the patient's health. Symptoms of thyrotoxicosis include:

- Unexplained weight loss;

- Increased bowel movements;

- Rapid or irregular heartbeat (arrhythmia).

If one is experiencing symtoms of thyrotoxicosis, it's important to contact the healthcare provider.

Other conditions that could cause elevated total T4 levels with normal free T4 levels include pregnancy and estrogen-containing birth control pills. This is because estrogen levels are high in those two scenarios. Estrogen increases the proteins bound to T4 and causes the total T4 (which is free T4+ binding proteins) to be high.

What happens when T4 (thyroxine) levels are too low?

If a patient has lower-than-normal T4 levels, it usually indicates hypothyroidism (underactive thyroid). Hypothyroidism has several causes, including certain autoimmune diseases, poor iodine intake in the diet and the use of certain medications.

Hypothyroidism slows down the metabolism. Symptoms include:

- Fatigue;

- Intolerance of cold temperatures;

- Low heart rate;

- Weight gain.

If symptoms of hypothyroidism are experienced, it's important to talk to the healthcare provider.

If the T4 test results are irregular, the provider may order more thyroid tests to help make a diagnosis. These tests may potentially include:

- T3 (triiodothyronine) test (another thyroid hormone);

- A TSH (thyroid-stimulating hormone) test;

- Tests to diagnose Graves disease, an autoimmune disease that causes hyperthyroidism;

- Tests to diagnose Hashimoto disease, an autoimmune disease that causes hypothyroidism.

How are TSH (thyroid-stimulating hormone) and T4 (thyroxine) levels related?

TSH and T4 are related, since thyroid-stimulating hormone (TSH) triggers the production of thyroxine (T4) and temporarily elevated levels of T4 prevent the release of TSH. TSH and T4 levels directly affect each other. 

When one gets their blood tests that check the thyroid function and TSH level, different levels of each hormone can indicate different conditions. 

Low TSH and normal T4

Having low TSH levels and normal T4 levels is usually considered subclinical hyperthyroidism. "Subclinical" means the condition doesn't cause any symptoms or symptoms haven't yet started. Studies estimate that subclinical hyperthyroidism affects up to 16% of the population. If the blood test report reveals these results, the healthcare provider will likely continue to monitor the levels to see if they change and result in clinical hyperthyroidism.

Low TSH and high T4

Having low TSH levels and high T4 levels typically indicate hyperthyroidism. This is because excess T4, due to an issue with the thyroid, is preventing the hypothalamus from releasing TSH.

Low TSH and low T4

Having low TSH and low T4 levels may indicate that one is having an issue with the pituitary gland, such as large pituitary adenoma, that's preventing it from releasing enough TSH to trigger T4 production. This is a less common result combination. 

High TSH normal T4

When a patient is having high TSH levels and normal T4 levels, it's usually considered subclinical hypothyroidism (also called mild thyroid failure). This condition occurs in 3% to 8% of the population.

If the blood test report reveals these results, the healthcare provider will likely continue to monitor the levels to see if they change and result in clinical hypothyroidism.

High TSH and low T4

Having high TSH and low T4 levels usually indicates hypothyroidism, an underactive thyroid due to a primary thyroid problem. This is a lack of T4 production due to an issue with the thyroid that's causing the pituitary gland to release excess TSH to try to stimulate the thyroid into making more T4.

High TSH and high T4

Having high TSH and high T4 levels may indicate that the patient has an issue with the pituitary gland that's causing it to release too much TSH, and thus triggering the thyroid to make excess T4. This is an extremely rare result combination.

Patients should know that thyroid conditions are fairly common, especially hypothyroidism, and are treatable. The healthcare provider will let the patient know if there is a need to undergo further tests to determine the cause of the abnormal T4 level. Patients should ask more questions if there are, to their healthcare provider.

What a T4 test is used for? Summary

A T4 is usually used with other thyroid tests to help diagnose and monitor thyroid disease and to gather more information about other conditions that may affect the thyroid. It may be used to:

- Diagnose: 

                - Hypothyroidism;

                - Hyperthyroidism.

- Help learn more about:

                     - Other thyroid conditions, such as if a patient has thyroid nodules (growth on the thyroid that aren't cancer) or a goiter (an enlarged thyroid that may make the neck look swollen). Sometimes these conditions can cause high T4 levels;

              - Disorders of the pituitary gland; abnormal T4 levels are usually caused by thyroid problems, but sometimes they are a sign of a pituitary problem that causes too much or too little TSH;

                     - Disorders of the hypothalamus, an area of the brain that controls the pituitary gland and other body functions.

- Check a newborn for congenital hypothyroidism, which is hypothyroidism that is present at birth;

- Check the T4 levels, if the patient is taking thyroid hormone medicine to treat hypothyroidism.

In certain cases, a T4 test may be done as part of a group of thyroid tests called a thyroid panel.

Why does a patient need a thyroxine (T4) test? Summary

A patient may need a T4 test if:

          - the patient had abnormal results on a TSH test;

         - the patient has symptoms of hypothyroidism. Not having enough thyroid hormone slows down the body functions. The symptoms can vary from person to person and may include:

                    - Fatigue

                    - Weight gain

                    - Being very sensitive to cold

                    - Joint and muscle pain

                    - Dry skin

                    - Dry, thinning hair

                    - Heavy or irregular menstrual periods

                    - Fertility problems in women

                    - Slow heart rate

                    - Depression

                    - Constipation

            - the patient has symptoms of hyperthyroidism. Having too much thyroid hormone speeds up the body's functions. The symptoms can vary from person to person and may include:

                    - Weight loss, even though the patient may be eating more than usual

                    - Rapid or irregular heartbeat

                    - Feeling nervous or irritable

                    - Trouble sleeping

                    - Fatigue

                    - Shaky hands, muscle weakness

                    - Sweating or being very sensitive to heat

                    - Frequent bowel movements (pooping a lot) or diarrhea

                    - Goiter

         - a member of the patient's family has had thyroid disease. Thyroid disease tends to run in families;

             - the patient is taking thyroid hormone medicine for hypothyroidism. A T4 test may be used to check how well the treatment is working;

             - the patient has symptoms that could be caused by another thyroid condition or a problem with the pituitary gland.

What do the results mean?

If the patient had a free T4 test, the test results may be reported as "free T4". If the patient had a total T4 test, the results may be reported as "free T4 index (FTI)". FTI is the amount of free T4 in the blood, based on a calculation using the total T4 test results.

To fully understand the results, the healthcare provider will usually need to compare them with the results of other thyroid tests.

If the T4 results are abnormal, the patient may need more testing to find the cause. But abnormal T4 levels don't always mean that the patient has a severe medical condition.

T4 and pregnancy

Thyroid disease can develop during pregnancy, but it's not common. If this happens, the healthcare provider will treat the patient, if necessary. After the woman gives birth, she would usually have the thyroid checked again.

If a patient had thyroid disease, she should tell her healthcare provider if she is pregnant or if she is thinking about becoming pregnant.   

Aldosterone

ALDOSTERONE - steroid hormone, mineralocorticoid hormone

Many important physiological functions of vertebrates are controlled by steroid hormones. Aldosterone is a steroid hormone secreted by the adrenal glands and a component of the renin-angiotensin-aldosterone system, involved in sodium and potassium homeostasis and in the maintenance of blood pressure. Aldosterone serves as the principal regulator of the salt and water balance of the body and thus is also categorized as a mineralocorticoid. It has effects on the metabolism of fats, carbohydrates, and proteins.  

Aldosterone is a mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex that influences water and salt regulation in the body. Aldosterone is created from cholesterol within the zona glomerulosa of the adrenal glands. Aldosterone's primary function is to act on the late distal tubule and collecting duct of nephrons in the kidney, favoring sodium and water reabsorption and potassium excretion while also contributing to acid-base balance. To execute these tasks, it influences epithelial sodium channels, sodium-potassium exchange pumps, hydrogen ion ATPases, and bicarbonate-chloride antiporters. Cholesterol interacts sequentially with the enzymes 3-beta-hydroxysteroid dehydrogenase, 21-alpha-hydroxylase, 11-beta-hydroxylase, and steroid 18-hydroxylase (also called aldosterone synthase) to produce 11-beta, 21-dihydroxy-3, 20-dioxopregn-4-en-18-al (aldosterone). These enzymes also function in the production of other steroid hormones from cholesterol in the adrenal glands, including glucocorticoids (corticosterone and cortisol) and androgen hormones (estrone, estradiol, and dihydrotestosterone). 

 

Mineralocorticoids (Aldosterone): Source and Control of Secretion

Like glucocorticoids, mineralocorticoids are a mixture of steroid hormones from the adrenal cortex.

Aldosterone secretion is controlled by four negative feedback mechanisms that operate through the kidney. These mechanisms help maintain homeostasis by regulating blood pressure, osmotic pressure, and blood levels of sodium and potassium.

In the most influential of these mechanisms, aldosterone secretion increases when the kidney secretes renin in response to low blood pressure, high osmotic pressure, or adverse changes in sodium concentrations. Aldosterone increases sodium and water reabsorption and retention by the kidneys, causing an increase in blood pressure and adjustments to osmotic pressure and sodium concentrations. Conversely, high blood pressure, low osmotic pressure, and the opposite changes in sodium concentration can suppress renin secretion and aldosterone production. 

Aldosterone secretion is regulated secondarily by the effects of blood levels of sodium and potassium on the adrenal cortex, by a hormone (atrial natriuretic factor) secreted by the heart when blood volume is high, and by a hormone (ACTH) secreted by the anterior pituitary gland during stress. In each case, the adjustment in aldosterone secretion helps maintain proper blood pressure, osmotic pressure, and blood levels of sodium and potassium.

Age changes and aldosterone

Though aldosterone secretion decreases with aging, blood levels remain steady under ideal body conditions because the decline in secretion is accompanied by a compensatory decrease in elimination. However, aging is accompanied by a decrease in the ability to raise aldosterone secretion and blood levels when needed, leading to a decrease in aldosterone reserve capacity.

These changes are not due to age changes in the adrenal cortex, which largely retains the ability to increase aldosterone levels when needed. The age-related decrease in aldosterone reserve capacity is due primarily to the declining ability of the kidneys to secrete renin when needed. Aging is also accompanied by a declining ability to increase aldosterone secretion during stress. There is an age-related decrease in kidney sensitivity to aldosterone.

Because of the interrelationships between aldosterone secretion and kidney functioning, there is age-related decrease in the ability to maintain normal conditions when faced with adverse conditions such as low blood pressure, dehydration, and disease. Body conditions that are likely to become abnormal include blood pressure; osmotic pressure; concentrations of sodium and potassium; and acid/base balance. 

Aldosterone secretion is stimulated by the following mechanism: decreased plasma volume and renal perfusion lead to increased renin secretion, which converts angiotensinogen into angiotensin I. Angiotensinogen is an α2-globulin derived from the liver, present in serum. Angiotensin I is converted in the lung to angiotensin II. Finally, angiotensin II stimulates aldosterone synthesis. Aldosterone acts at the distal and collecting tubules of the nephron to stimulate sodium reabsorption and potassium and hydrogen ion excretion.

On the other hand, elevated plasma potassium concentrations can directly stimulate adrenal aldosterone production. Under physiological conditions, pituitary adrenocorticotropic hormone (ACTH) is not a major factor in regulating aldosterone secretion. Physiologically, plasma aldosterone levels vary with body position (ortho- or clinostatism) and salt intake. Aldosterone concentration also follows a circadian rhythm that is similar to that of cortisol, but less pronounced. Thus, the hormone level peaks in the early morning hours.

Aldosterone is involved in blood volume and pressure control through regulation of sodium and potassium homeostasis. It affects blood pressure by regulating the sodium gradient in the nephron to either increase or decrease the water reabsorbed to contribute to the volume of the extracellular fluid (ECF). This, however, is not to be confused with the effect of anti-diuretic hormone (ADH), also referred to as vasopressin. ADH is often released simultaneously with aldosterone in order to support water reabsorption to the ECF by mobilizing aquaporin channels to the apical (lumen-facing) membrane of principal cells in the collecting tubule. Overall, aldosterone is a key player in the multi-factorial regulation of salt, potassium, blood pressure, and acid-base balance.

Aldosterone is synthesized in the body from corticosterone, a steroid derived from cholesterol. Production of aldosterone (in adult humans, about 20–200 micrograms per day) in the zona glomerulosa of the adrenal cortex, is regulated by the renin-angiotensin system. 

The biological action of aldosterone is to increase the retention of sodium and water and to increase the excretion of potassium by the kidneys (and to a lesser extent by the skin and intestines). It acts by binding to and activating a receptor in the cytoplasm of the renal tubular cells. The activated receptor then stimulates the production of ion channels in the renal tubular cells, thereby increasing sodium reabsorption into the blood and increasing potassium excretion into the urine.

The effects of aldosterone secretion are mediated by genomic and nongenomic mechanisms. The genomic effects are linked to the binding of aldosterone to intracellular receptors with consequent transcriptions of genes involved in the regulation of vascular tone and in hydro-electrolyte balance; nongenomic effects are due to the direct binding of aldosterone to specific membrane receptors in heart, vessels, and kidney tissues. Aldosterone excess is caused by renin-independent production due to primary aldosteronism (PA) or hyperactivation of the renin-angiotensin-aldosterone system (RAAS) as in heart failure (HF) in the context of secondary aldosteronism. In both cases, fluid and sodium retention result in volume expansion, vasoconstriction, and consequent potassium depletion that are related to the development of hypertension. Moreover, aldosterone induces oxidative stress and decreased nitric oxide bioavailability, leading to reduced vascular compliance, accentuated by aldosterone-mediated vascular fibrosis. Mineralocorticoid receptors (MRs) are present in coronary artery smooth muscle cells. Hypersecretion of aldosterone is associated with vascular and cardiac remodeling, myocardial fibrosis, endothelial dysfunction with consequent increased risk of cardiovascular events and cardiovascular mortality.

The synthesis and release of aldosterone is controlled by:

- the renin-angiotensin-aldosterone system (the main regulatory factor);

- plasma potassium concentration (an increased level stimulates aldosterone secretion);

- ACTH;

- blood pressure.

Aldosterone increases blood pressure by:

- stimulating water and sodium reabsorption in the distal renal tubules;

- secreting potassium into the urine;

- increasing circulating blood volume.

Aldosterone's clinical significance

Chronic hyperproduction and secretion of aldosterone causes hypertension, with aldosterone determination being one of the important laboratory tests used in the differential diagnosis of hypertension.

Aldosterone measurement is useful in investigating primary aldosteronism (e.g. adrenal adenoma/carcinoma, adrenocortical hyperplasia) and secondary aldosteronism (renovascular disease, salt depletion, potassium overload, heart failure with ascites, pregnancy, Bartter syndrome).

Pathways in the biosynthesis of steroid hormones 

The major pathway involved in the biosynthesis of steroid hormones is the renin-angiotensin system. The renin-angiotensin system is a physiological system that regulates blood pressure.

Renin is an enzyme secreted into the blood from specialized cells that encircle the arterioles at the entrance to the glomeruli of the kidneys (the renal capillary networks that are the filtration units of the kidney). The renin-secreting cells, which compose the juxtaglomerular apparatus, are sensitive to changes in blood flow and blood pressure. The primary stimulus for increased renin secretion is decreased blood flow to the kidneys, which may be caused by loss of sodium and water (as a result of diarrhea, persistent vomiting, or excessive perspiration) or by narrowing of a renal artery. Renin catalyzes the conversion of a plasma protein called angiotensinogen into a decapeptide (consisting of 10 amino acids) called angiotensin I. An enzyme in the serum called angiotensin-converting enzyme (ACE) then converts angiotensin I into an octapeptide (consisting of eight amino acids) called angiotensin II. Angiotensin II acts via receptors in the adrenal glands to stimulate the secretion of aldosterone, which stimulates salt and water reabsorption by the kidneys, and the constriction of small arteries (arterioles), which causes an increase in blood pressure. Angiotensin II further constricts blood vessels through its inhibitory actions on the reuptake into nerve terminals of the hormone norepinephrine.

Aldosterone levels in clinical laboratory

- can vary based on age and other factors.

Normal Range: The normal range for aldosterone levels varies by age:

0-6 days: 5.0 - 102.0 ng/dL

1-3 weeks: 6.0 - 179.0 ng/dL

1-11 months: 7.0 - 99.0 ng/dL

1-2 years: 7.0 - 93.0 ng/dL

3-10 years: 4.0 - 44.0 ng/dL

11-14 years: 4.0 - 31.0 ng/dL

15 years and older: ≤31.0 ng/dL.

Clinical Significance: Elevated aldosterone levels can indicate conditions like primary aldosteronism, which is often caused by a benign tumor on the adrenal glands. This condition can lead to hypernatremia (high sodium levels) and hypokalemia (low potassium levels).

Measurement: Aldosterone levels are typically measured in nanograms per deciliter (ng/dL) and are influenced by factors such as sodium intake, potassium levels, and other medical conditions. 

Serum aldosterone measurement is useful both for detecting primary or secondary hyperaldosteronism and for evaluating patients suspected of having secondary hypertension. For the differential diagnosis between these two conditions, plasma renin should be tested simultaneously and the aldosterone/renin ratio calculated; thus, renin is low in primary hyperaldosteronism and high in secondary hyperaldosteronism.

Inappropriate aldosterone secretion results in hypertension, muscle pain and cramps, tetany, paralysis, polyuria, proteinuria, and ultimately renal failure. Primary hyperaldosteronism is commonly caused by adrenal adenoma, unilateral or bilateral hyperplasia, and much less commonly by glucocorticoid-suppressible familial hyperaldosteronism.

Low serum aldosterone (hypoaldosteronism) may result from primary adrenal insufficiency (Addison's disease). Less common cause include hereditary defects in aldosterone biosynthesis, such as 21-hydroxylase deficiency, the salt-wasting form of adrenogenital syndrome. When hypoaldosteronism is the result of a primary defect in adrenal steroid biosynthesis, plasma renin levels are elevated.

Aldosterone deficiency can also occur in association with chronic kidney disease, especially tubulointerstitial disease and diabetic nephropathy. Most patients have low renin levels, a condition called hyporeninemic hypoaldosteronism.

Regardless of the cause, hypoaldosteronism causes hyperkalemia.

   

Aldosterone's importance in development

During fetal development, aldosterone plays a role in maternal volume expansion necessary to accommodate fetal perfusion and may also increase the expression of placental growth factors.

Congenital issues of concern related to aldosterone synthesis include autosomal recessive deficiencies in the enzymes responsible for adrenal hormone production. Congenital adrenal hyperplasia (CAH) can take many forms, depending on which enzyme is deficient. The three main enzymes that affect aldosterone are 21-hydroxylase, 11-beta-hydroxylase, and aldosterone synthase. A deficiency of any of these enzymes will halt aldosterone production. The production of aldosterone occurs in an interconnected pathway that produces mineralocorticoids, glucocorticoids, and androgens. The inability for aldosterone production to proceed leads to a buildup of intermediary products and cholesterol to be funneled down the glucocorticoid and androgen hormone production pathways instead. Depending on the severity of the enzyme deficiency, this can result in hyponatremia, hyperkalemia (due to the inability to exchange sodium for potassium in the nephron), and hypovolemia (low sodium causes a decrease in extracellular fluid). In aldosterone synthase deficiency, many of the functional losses are mitigated by the continued production of corticosterone, which acts similarly to aldosterone. The shunting of cholesterol towards the 17-alpha-hydroxylase pathway (androgen hormone production pathway) can result in virilization and ambiguous genitalia in females. Conversely, in the case of 17-alpha-hydroxylase deficiency, cholesterol is shunted towards mineralocorticoid production while glucocorticoid and androgen production is impaired, causing ambiguous genitalia in genetic males and lack of secondary sexual development in genetic females.

Organ Systems Involved 

The organs involved in the production, utilization, and regulation of aldosterone are the adrenal glands, kidneys, and lungs, due to the pulmonary conversion of angiotensin 1 to angiotensin 2 in the renin-angiotensin-aldosterone system.

Function

When a stimulus such as low blood pressure or low serum sodium triggers the RAAS, first renin is secreted from the renal juxtaglomerular cells, then angiotensinogen is cleaved into angiotensin I. Angiotensin-converting enzyme (ACE) from the lungs then converts angiotensin I to angiotensin II, which in turn stimulates the production of aldosterone.

Aldosterone is a mineralocorticoid steroid hormone that modulates activity directly and indirectly in the aldosterone-sensitive distal nephron which includes the late distal convoluted tubule, the connecting tubule, and the collecting duct system. Because this region is so distal, aldosterone affects the final stages of electrolyte and water absorption within the nephron before the tubule contents are excreted in the urine. This only accounts for about 5-10% of total sodium reabsorption.

Depending on the specific physiologic parameters, aldosterone may:

- increase sodium reabsorption

- increase water retention

- increase potassium excretion

- increase acid (H+) excretion

- increase bicarbonate (HCO3-) excretion and chloride reabsorption

Although predominantly known for its activity in the kidney, aldosterone may act at mineralocorticoid receptors in other tissues as well such as the gastrointestinal tract, respiratory epithelium, myocardium, and vascular smooth muscle.

Mechanism

As with all steroid hormones, aldosterone passes through cell membranes to bind to cytoplasmic receptors which translocate to the nucleus to influence mRNA transcription and subsequently protein synthesis. The mineralocorticoid receptor (MR) may have higher or lower affinity for aldosterone, depending on whether or not it is phosphorylated. In the phosphorylated state, MR has lower affinity for aldosterone, therefore phosphorylation of MR in a given cell inhibits aldosterone activity.

Within the principal cells of the late distal tubule and collecting ducts, MR is largely in a non-phosphorylated state. In principal cells, aldosterone increases the expression of sodium channels and sodium-potassium ATPase in the cell membrane. The sodium channels are on the luminal side of the principal cells and allow sodium to passively diffuse into the principal cells due to the transepithelial potential difference of -50 mV. This gradient is maintained by the sodium-potassium ATPase on the basolateral side, which uses ATP to actively transport sodium into the blood and potassium into the cell. Meanwhile, potassium channels on the luminal side of the cell that allow passive diffusion out of the cell into the lumen of the kidney whenever a sodium ion enters the cell. The net effect of this process is sodium absorption from the lumen, which allows for water absorption, assuming ADH is present to make the cells permeable to water. This directly results in an increase in osmolality within the blood, causing water to flow down its concentration gradient.

Within intercalated cells, MR is often in a phosphorylated state, therefore the dephosphorylation of MR in the presence of angiotensin II enables intercalated cells to be responsive to aldosterone. This conditional response of intercalated cells results in seemingly paradoxical effects of aldosterone dependent upon whether or not angiotensin II is present.

In alpha-intercalated cells (A-intercalated, acid-secretory), aldosterone increases the expression of apical hydrogen ATPases to stimulate hydrogen ion (proton) excretion into the lumen. Additionally, the sodium resorption from adjacent principal cells creates a more negatively charged lumen space which further encourages acid secretion from the intercalated cells to compensate.

Within the non-A intercalated cells (beta-intercalated, and non-A non-B intercalated cells), aldosterone increases the activity of apical bicarbonate-chloride exchangers, which reabsorb chloride from the lumen into the cell and excrete bicarbonate from the cell into the lumen.

Aldosterone-related Testing

The most common test to assess disturbances of the aldosterone pathway is the aldosterone: renin ratio. This determines whether there is an isolated aldosterone problem or there is a disturbance within renin-angiotensin system. If an aldosterone problem is suspected, and the results show no elevation in either aldosterone or renin, then congenital adrenal hyperplasia is suspected. If both aldosterone and renin are increased, and their ratio is less than 10, then the differential includes renovascular hypertension. If the renin value is normal, the aldosterone level is elevated, and the ratio is greater than 30, the differential includes Conn syndrome. This can be confirmed with a salt suppression test, an MRI of the adrenal glands, and adrenal vein sampling.

Aldosterone's Clinical Significance

Aldosterone is clinically significant for two reasons. An increase or decrease in aldosterone can cause disease and medications affecting its function alter blood pressure. Changes in the concentration of aldosterone, either too much (Conn syndrome and renovascular hypertension) or too little (certain types of Addison's disease and congenital adrenal hyperplasia), can result in disastrous effects on the body.

Hyperaldosteronism is caused by either a primary tumor within the adrenal gland (Conn syndrome) or via renovascular hypertension. A primary tumor within the adrenal gland causes an uncontrolled production and release of aldosterone. Renovascular hypertension increases aldosterone through two primary mechanisms: fibromuscular dysplasia (usually in young females) and atherosclerosis (usually in older individuals). Both decreased perfusion to the afferent arterioles of the kidney causes the renin-angiotensin system to be activated. This causes uncontrolled hypertension and hypokalemia.

Addison’s disease is characterized by a hypo-functioning adrenal gland. However, depending on the cause of Addison’s disease, the regulation of aldosterone may be unaffected. Aldosterone is only affected by Addison’s disease when the adrenal gland undergoes destruction, for example, in autoimmune-mediated destruction. Aldosterone is controlled by the renin-angiotensin system, while the rest of the adrenal glands' hormone production is controlled by adrenocorticotropic hormone (ACTH). Therefore, in cases of Addison’s disease caused by pituitary dysfunction, adrenal insufficiency will exist, but with appropriate aldosterone levels. This is due to the fact that the renin-angiotensin system remains intact.

Contraction alkalosis is a side effect of increased absorption of water via aldosterone and ADH pathways during a volume-depleted state. The body senses a low mean arterial blood pressure when the ECF is low. Therefore the renin-angiotensin system is activated. This causes an increase in water absorption as well as activation of aldosterone. Aldosterone causes sodium to be absorbed and potassium to be excreted into the lumen by principal cells. In alpha intercalated cells, located in the late distal tubule and collecting duct, hydrogen ions and potassium ions are exchanged. Hydrogen is excreted into the lumen, and the potassium is absorbed. This mechanism prevents the body from losing too much potassium, which causes a relative depletion of hydrogen ions in the blood causing an alkalotic state.

Antidiuretic Hormone/ADH/Vasopressin/Arginine Vasopressin

Antidiuretic Hormone (ADH): Physiology, Pathophysiology, Diagnostic Evaluation, and Clinical Implications

AntiDiuretic Hormone (ADH) is a neuropeptide secreted from the hypothalamus in response to hypovolemia and elevated plasma osmolality. 

ADH, also known as vasopressin or arginine vasopressin, plays a critical role in regulating water balance, blood pressure, and vascular resistance. It is essential for maintaining homeostasis and is involved in various pathophysiological conditions, including cardiovascular diseases and diabetes insipidus. Understanding the function of vasopressin is vital for developing therapeutic strategies targeting these conditions.

Neurohypophisars: ADH/Vasopressin

ADH is a peptide hormone pivotal in maintaining fluid, electrolyte, and blood pressure homeostasis. ADH is synthesized by the supraoptic and paraventricular nuclei in the hypothalamus and transported to the posterior pituitary gland (is stored in the pituitary gland). ADH release: the neurohypophysis release ADH, in response to changes in blood osmolality and blood volume. Hence, it is secreted by the posterior pituitary in response to hyperosmolarity and hypovolemia, ADH promoting therefore water reabsorption in the kidneys and causing vasoconstriction. ADH acts on the kidneys to increase water reabsorption, reducing urine output and helping to maintain fluid balance and blood pressure. ADH's major action is on the distal or collecting tubules of the kidney where it promotes reabsorption of solute free water. Its tightly regulated mechanism ensures the preservation of effective arterial blood volume and osmotic equilibrium. ADH secretion is stimulated by an increase in plasma osmolality via osmoreceptors and by a decrease in plasma volume via volume receptors. The hormone's action is primarily mediated through the V2 receptors in renal principal cells, facilitating aquaporin-2 insertion and passive water transport, and through V1 receptors in vascular smooth muscle that increase peripheral resistance. Clinically, disorders of ADH secretion or response manifest in three primary conditions: syndrome of inappropriate ADH secretion (SIADH), central diabetes insipidus (CDI), and nephrogenic diabetes insipidus. Diagnostic evaluation involves serum and urine osmolality, electrolyte panels, water deprivation testing, and response to desmopressin. Understanding the physiological and pathological aspects of ADH is essential for diagnosing and managing a wide spectrum of endocrine, renal, and hematologic conditions.       

Antidiuretic Hormone (ADH) Test, Plasma

This test is useful for the differential diagnosis of patients with water balance disorders, including diabetes insipidus in conjunction with osmolality and hydration status.

The assessment of circulating ADH levels is challenging because it is released in a pulsatile pattern and is rapidly cleared from plasma. Measurement of ADH is further complicated by the high ex vivo instability of the peptide.

Mixed forms of diabetes insipidus (DI) can exist, and both central and peripheral DI may be incomplete, complicating the interpretation of results.

Additional Information about ADH in Pathology

Diabetes insipidus (DI) is a rare disorder of water homeostasis characterized by the excretion of abnormally large volumes of hypotonic urine due to the inability to appropriately concentrate urine in response to volume and osmolar stimuli. The primary causes of DI are decreased ADH production (central DI) or decreased renal response to ADH (nephrogenic DI); both of which lead to hypotonic polyuria which is usually accompanied by polydipsia. Along with these etiologies, the differential diagnosis of hypotonic polyuria includes primary polydipsia. In primary polydipsia, there is no initial compromise in ADH secretion or renal action and instead, excessive fluid intake leads to a drop in plasma osmolality and a suppression of ADH synthesis. Primary polydipsia can be caused by an abnormality in the thirst center (dipsogenic polydipsia) or, more commonly, as the result of one of a number of psychiatric disorders (psychogenic polydipsia).

Historically, the primary diagnostic test for the evaluation of polyuria-polydipsia syndrome has been the standard water deprivation test. In healthy subjects, water deprivation causes the plasma osmolality to rise, leading to the release of ADH into the circulation. In this test, insufficient ADH secretion or effect is revealed by insufficient concentration capacity of the kidneys on osmotic stimulation, which is achieved by a prolonged period of thirsting and followed by assessment of the response to exogenous ADH administration (Desmopressin). 

The two major clinical syndromes of antidiuretic hormone secretion are neurogenic diabetes insipidus (DI), an ADH deficiency disorder, and the syndrome of inappropriate ADH secretion (SIADH), a disorder of excess ADH synthesis. The tests used for the differential diagnosis of DI and SIADH, are: serum sodium, plasma osmolality, urine osmolality, U/P osmol ratio, urine output. 

Laboratory tests and examinations (DI versus SIADH)

DI is the chronic excretion of very high volumes of hypo-osmotic urine due to ADH deficiency. Polyuria triggers the thirst mechanism resulting in increased polydipsia. If water intake is inadequate, dehydration occurs. DI can be categorized as neurogenic and nephrogenic. In neurogenic DI, ADH secretion by the pituitary or hypothalamus is decreased. ADH deficiency can be partial or complete, depending on the degree of disturbance to the hypothalamus or pituitary. In nephrogenic DI, ADH production and secretion are adequate and appropriate, but the kidneys do not respond to the hormone because of damage to the renal tubules.

Plasma osmolality, urine osmolality and serum sodium are the principal laboratory tests used to diagnose ADH abnormalities. Polyuria increases plasma osmolality to >295 mmol/L and serum sodium to >145 meq/L. Urine osmolality is <300 mmol/L. In partial neurogenic DI, urine osmolality may range between 300 and 800 mmol/L.

Diabetes insipidus can be confirmed with an overnight water deprivation test. This test should be done if a baseline serum osmolality is <295 mosmol. Fluid intake is restricted for 12 to 18 hours and the body weight, urine osmolality, volume and plasma osmolality are measured every 1-2 hours. The test should be discontinued if body weight falls by more than 3%. The objective is to obtain consecutive urine osmolality's which do not differ by more than 30 mosmol. 

One can also measure antidiuretic hormone levels at maximum dehydration, which helps differentiate neurogenic from nephrogenic DI. In neurogenic DI, ADH levels decrease as plasma osmolality increases. Conversely, in nephrogenic DI, ADH levels increase with increasing plasma osmolality.

SIADH is the clinical condition that results from inappropriate continued secretion of ADH in the presence of low serum osmolality. The low serum osmolality is due to the retention of water by the kidney in response to ADH. The low serum sodium concentration is due to the dilutional effect of water retention and to the loss of sodium in the urine. Initial symptoms include anorexia, nausea, vomiting, and headache. Cerebral symptoms begin to appear when serum sodium is less than 125 meq/L. Severe hyponatremia (sodium <110 meq/L) or rapidly developing hyponatremia can cause cerebral edema, which is expressed as irritability, confusion, disorientation, convulsions, hemiparesis, and coma.

The major causes of SIADH include neoplasia, pulmonary disorders, neurological disorders and certain drugs.

Laboratory test results that favor a diagnosis of SIADH include: serum sodium <120 meq/L, serum osmolality <280 mOsm, decreased BUN, decreased serum uric acid, urine osmolality >100 mOsm, and urine sodium >20 meq/L. Other diagnostic criteria include the absence of dehydration, edema, adrenal insufficiency, hypothyroidism or renal failure.

The Neurohypophysis: Endocrinology of Vasopressin and Oxytocin

The neurohypophysis consists of three parts: the supraoptic and paravetricular nuclei of the hypothalamus; the supraoptico-hypophyseal tract; and the posterior pituitary. The neurohypophysis is one component of a complex neurohumoral system coordinating physiological responses to changes in both the internal and external environment.

Two hormones made by the hypothalamus and posterior pituitary are vassopressin (AVP) and oxytocin (OT). These hormones have key roles in water balance and reproductive function.

The neurohypophysis is the structural foundation of a neuro-humoral system coordinating fluid balance and reproductive function through the action of the two peptide hormones, vasopressin and oxytocin. Vasopressin is the principle endocrine regulator of renal water excretion, facilitating adaptive physiological responses to maintain plasma volume and plasma osmolality.

Oxytocin is important in parturition and lactation. Data support a wider role for both peptides in the neuro-regulation of complex behaviour. Clinically, deficits in the production or action of vasopressin manifest as diabetes insipidus. An understanding of the physiology and pathophysiology of vasopressin is also critical in approaching the diagnosis and management of hyponatremia, the most common electrolyte disturbance in clinical practice.

                

Vasopressin receptors

There are three distinct AVP receptor (V-R) subtypes. All have seven transmembrane spanning domain, and all are G protein coupled. They are encoded by different genes and differ in tissue distribution, down-stream signal transduction and function. 

Vasopressin Receptor Subtypes:

- V1a: vascular smooth muscle, liver, platelets, CNS;

- V1b: pituitary corticotroph;

- V2: basolateral membrane of distal nephron.

Physiological effects of receptor subtypes:

- V1a: smooth muscle contraction, stimulation of glycogenolysis, enhanced platelet adhesion, neurotransmitter & neuromodulatory function;

- V1b: enhanced ACTH release;

- V2: increased synthesis & assembly of aquaporin-2.

Vasopressin and renal water handling

Although AVP has multiple actions, its principle physiological effect is in the regulation of water resorption in the distal nephron, the structure and transport processes of which allow the kidney to both concentrate and dilute urine in response to the prevailing circulating AVP concentration. Active transport of solute out of the thick ascending loop of Henle generates an osmolar gradient in the renal interstitium, which increases from renal cortex to inner medulla, a gradient through which distal parts of the nephron pass end route to the collecting system. AVP stimulates the expression of a specific water channel protein (aquaporin) on the luminal surface of the interstitial cells lining the collecting duct.

The presence of aquaporin (AQP) in the wall of the distal nephron allows resorption of water from the duct lumen along an osmotic gradient, and excretion of concentrated urine; 13 different AQPs are important in humans, seven of which (AQP1-4, AQP6-8) are found in the kidney. AQPs act as passive pores for small substrates and are divided into 2 families: the water only channels; and the aquaglyceroporins that can conduct other small molecules such as glycerol and urea. Most substrates are neutral. However, this is not always the case. For example, AQP6 is a gated ion channel. AQPs are involved in a variety of cell processes: small molecule permeation; gas conduction and cell-cell interaction.

As with other membrane channels, specific structural arrangements within the primary, secondary, and tertiary structure convey the three functional characteristics of permeation, selectivity, and gating. The structure of AQPs involves 2 tandem repeats, each formed from 3 transmembrane domains, together with 2 highly conserved loops containing the signature motif asparagine-proline-alanine (NPA). All AQPs form homotetramers in the membrane, providing 4 functionally independent pores with an additional central pore formed between the 4 monomers. Water can pass through all the 4 independent channels of water-permeable AQPs. AQP1 is constitutively expressed in the apical and basolateral membranes of the proximal tubule and descending loop of Henle, where it facilitates isotonic fluid movement. Loss of function mutations of AQP1 in man lead to defective renal water conservation. AQP2 is expressed on the luminal surface of collecting duct cells and is the water channel responsible for AVP-dependent water transport from the lumen of the nephron into the collecting duct cells. V2-R activation in collecting duct cells produces a biphasic increase in expression of AQP2. Ligand-receptor binding triggers an intracellular phosphorylation cascade, ultimately resulting in phosphorylation of the nuclear transcription factor CREB and expression of c-Fos. In turn, these transcription factors stimulate AQP2 gene expression through CRE and AP-1 elements in the AQP2 gene promoter. In addition, AVP stimulates an immediate increase in AQP2 expression by accelerating trafficking and assembly of pre-synthesized protein into functional, homo-tetrameric water channels.

Maximum diuresis occurs at plasma AVP concentrations of 0.5 pmol/l or less. As AVP levels rise, there is a sigmoid relationship between plasma AVP concentration and urine osmolality, with maximum urine concentration achieved at plasma AVP concentrations of 3-4 pmol/L. Following persistent AVP secretion, antidiuresis may diminish. Down-regulation of both V2-R function and AQP2 expression may be responsible for this escape phenomenon.

Figure (on the left side) representing the relationship of plasma AVP concentration to urine osmolality. Shaded area represents range of normal; single line indicates representative individual. AVP has additional effects at other sites in the nephron: decreasing medullary blood flow; stimulating active urea transport in the distal collecting duct; and stimulating active sodium transport into the renal interstitium.  As a final outcome, there is generation and maintenance of a hypertonic medullary interstitium, and augment AVP-dependent water resorption.

Regulation of vasopressin release

Osmoregulation of Vasopressin

Plasma osmolality is the most important determinant of AVP secretion. The osmoregulatory systems for thirst and AVP secretion, and in turn the actions of AVP on renal water excretion, maintain plasma osmolality within narrow limits of 284 to 295 mOsmol/kg. The relationship between plasma osmolality and plasma AVP concentration has 3 characteristics.

- The osmotic threshold or 'set point' for AVP release

- The shape of the line describing changes in plasma AVP concentration with changing plasma osmolality

- The sensitivity of the osmoregulatory mechanism coupling plasma osmolality and AVP release.

There are situations where the normal relationship between plasma osmolality and AVP concentration breaks down:

- Rapid changes of plasma osmolality: rapid increases in plasma osmolality result in exaggerated AVP release;

- During the act of drinking: drinking rapidly suppresses AVP release, through afferent pathways originating in the oropharynx;

- Pregnancy: the osmotic threshold for AVP release is lowered in pregnancy.

Additional Mechanisms Regulating Vasopressin Release

A number of other stimuli influence AVP release independent of osmotic and hemodynamic status: 

- Nausea and emesis

- Unspecific stress

- Pain

- Manipulation of abdominal contents

- Immune-response mediators and inflammatory triggers

These stimuli contribute to high plasma AVP values observed in acute illness and after surgery.

Additional effects of vasopressin

Thirst

Renal free water clearance can be reduced to a minimum by the antidiuretic actions of vasopressin, but water loss is not completely eliminated, and insensible water loss from respiration and sweating is a continuous process. To maintain water homeostasis, water must also be consumed to replace the obligate urinary and insensible fluid losses. This is regulated by thirst. Thirst and drinking are key processes in the maintenance of fluid and electrolyte balance. Thirst perception and the regulation of water ingestion involve complex, integrated neural and neurohumoral pathways. Other centers are involved in thirst perception. There is a linear relationship between thirst and plasma osmolalities in the physiological range. The mean osmotic threshold for thirst perception is 281 mOsm/kg, similar to that for AVP release. Thirsty occurs when plasma osmolality rises above this threshold. As with osmoregulated AVP release, the characteristics of osmoregulated thirst remains consistent within an individual on related testing, despite wide inter-individual variation.

As with AVP release, there are also specific physiological situations in which the relationship between plasma osmolality and thirst breaks down.

- The act of drinking: reduces osmotically stimulated thirst.

- Extracellular volume depletion: this stimulates thirst through volume-sensitive cardiac afferents and the generation of circulating and intra-cerebral A-II, a powerful dipsogen.

- Pregnancy, the luteal phase of the menstrual cycle and super ovulation syndrome: these states reduce the osmolar threshold for thirst.

- Aging: both thirst appreciation and fluid intake can be blunted in the elderly.

The act of drinking reduces thirst perception before any change in plasma osmolality.

This effect is produced through three mechanisms: oropharyngeal sensory afferents; gastro-intestinal stretch-sensitive afferents; and peripheral osmoreceptors in the hepatic portal vein. As with AVP release, hypovolemia resets the relationship between plasma osmolality and thirst. A-II is one of the key mediators of this physiological response. Peripheral A-II generation can act on central osmoreceptors, to increase both thirst and AVP release. An independent, intra-cerebral A-II system is activated in parallel. A-II is a powerful central dipsogen.

Clinical problems secondary to defects in the hypothalamo-posterior pituitary axis

Defects in the production or action of AVP manifest as clinical problems in maintaining plasma sodium concentration and fluid balance, reflecting the key role of the hormone in these processes. A further group of related clinical conditions reflect primary defects in thirst. In some cases, the two may coincide, reflecting the close anatomical and functional relationship of both processes.

Diabetes Insipidus

Classification

Diabetes insipidus (DI) is characterized by production of dilute urine in excess of >50 ml/kg/24 hours in adults. DI arises through one of four mechanisms:

- Deficiency of AVP: central diabetes insipidus (CDI), also called Arginine Vasopressin Deficiency

- Inappropriate, excessive water drinking: primary polydipsia

- Renal resistance to the antidiuretic action of AVP: nephrogenic diabetes insipidus (NDI), also called Arginine Vasopressin Resistance

- Increased vasopressinase expression in pregnancy: gestational diabetes insipidus

Figure showing different forms of hypotonic polyurea

Central Diabetes Insipidus (CDI) (Arginine Vasopressin Deficiency)

CDI (also known as neurogenic or cranial DI) is the result of partial or complete lack of osmoregulated AVP secretion. Plasma AVP concentrations are inappropriately low with respect to prevailing plasma osmolalities. Presentation with CDI implies destruction or loss of function of more than 80% of vasopresinergic magnocellular neurons. Though persistent polyuria can lead to dehydration, most patients can maintain water balance through appropriate polydipsia if given free access to water.

Hypothalamic tumors (e.g., craniopharyngioma) or pituitary metastases (e.g., breast or bronchus) can present with CDI. However, primary pituitary tumors rarely cause CDI. In childhood, craniopharyngioma and germinoma/teratoma are a relatively common cause.

When obvious causes are not present, most cases of CDI will be "idiopathic". However, the possibility of an autoimmune process should be considered, as many idiopathic cases are considered to be autoimmune in origin. A well-recognized cause of autoimmune CDI is lymphocytic infundibulohypophysitis.

Primary Polydipsia (PP)

PP is a polyuric syndrome secondary to excess fluid intake. PP can be associated with organic structural brain lesions, e.g. sarcoidosis of the hypothalamus and craniopharyngioma. It can also be produced by drugs that cause a dry mouth or by any peripheral disorder causing an elevation of renin and/or angiotensin. However, mostly there is no identifiable pathologic etiology; in this circumstance the disorder is often associated with psychiatric syndromes. It also seems to be increasingly prevalent in health conscious people who voluntarily change their drinking habits with the aim to improve their well-being, in which case it is often called habitual polydipsia.

Nephrogenic Diabetes Insipidus (NDI)

NDI is due to renal resistance to the antidiuretic effects of AVP. Genetic variants of NDI usually present in infancy. In these forms, NDI can occur as a result of mutations in the V2 receptor and mutations of the aquaporin 2 water channels.

The development of NDI in an adult is less likely to reflect a genetic cause. Among causes of acquired NDI are hypokalemia, hypercalcemia, and release of bilateral urinary tract obstruction associated with downregulation of aquaporin 2 and decreased function of vasopressin. NDI secondary to lithium is characterized by dysregulated AQP2 expression and trafficking along the whole collecting duct as well as dysregulated expression of the amiloride-sensitive epithelial sodium channel (ENaC) in the cortical collecting duct.

Gestational Diabetes Insipidus

In normal pregnancy, physiologic adaptations include expansion of blood volume and decreased plasma osmolality and serum sodium. Thirst and increased fluid intake are commonly reported in pregnancy, but in some patients the increased thirst is driven by marked polyuria, which may point to the presence of diabetes insipidus. Two types of transient diabetes insipidus must be differentiated in pregnancy, both caused by the placental enzyme cysteine aminopeptidase, named oxytocinase, which enzymatically degrades oxytocin. Because of the close structural homology between AVP and oxytocin, this enzyme also metabolizes AVP. In the first type of pregnancy-associated DI, the activity of oxytocinase is abnormally elevated. This syndrome has been referred to as vasopressin resistant diabetes insipidus of pregnancy and has been reported to be associated with preeclampsia, acute fatty liver, and coagulopathies.

Figure showing the algorithm for the differential diagnosis for the diabetes insipidus.

In establishing the underlying mechanisms of central DI, once the diagnosis is confirmed, imaging of the hypothalamus, pituitary and surrounding structures with MRI is essential. If no mass lesion is identified, imaging should be repeated after 6-12 months so that slow growing germ cell tumors are not missed. Idiopathic and familial central DI are often associated with loss of the normal hyper-intense signal of the posterior pituitary on T1-weighted images. Signal intensity is correlated strongly with AVP content of the gland. 

Evidence of anterior pituitary dysfunction should be looked for in central DI, though it is relatively uncommon in the adult population. Interestingly, evidence of organ-specific autoimmune disease is relatively common in adult patients with isolated central DI, consistent with an autoimmune basis for the condition.