ADH and Copeptin
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The ADH and copeptin test is a blood test in which a sample is taken from a vein to measure levels of antidiuretic hormone (ADH) and copeptin, a more stable marker released alongside ADH. It is used to help diagnose disorders of water balance, such as diabetes insipidus and other conditions affecting fluid regulation in the body.
Why get tested?
To investigate the cause of polyuria polydipsia syndrome, i.e. excessive urination and excessive drinking. Rarely this may be due to deficiency of, or lack of response to, ADH.
Diagnosis of conditions of ADH excess is usually based on clinical history and other laboratory tests, such as blood and urine osmolality as well as electrolytes.
When to get tested?
ADH or copeptin may be requested if the results of initial investigation of polyuria polydipsia syndrome are inconclusive. ADH and copeptin are usually only measured as part of stimulation testing; either the water deprivation test or the saline infusion test. ADH or copeptin analysis on a random, or unstimulated, sample is rarely required.
Sample required?
A blood sample is obtained by inserting a needle into a vein in the arm.
Test preparation needed?
Alcohol and some medications (including diuretics) can interfere with ADH and copeptin secretion, or ADH action. Talk to your doctor to identify any medications that should be discontinued before the test.
The water deprivation test and saline infusion test have specific preparation requirements. Talk to your doctor to determine what preparation is required for these tests.
What is being tested?
The ADH test measures the amount of antidiuretic hormone (ADH) in the blood. ADH, also called arginine vasopressin (AVP), is a hormone produced by the hypothalamus and stored in the posterior pituitary gland. Antidiuretic hormone helps regulate water balance in the body by controlling the amount of water the kidneys reabsorb.
The copeptin test measures the amount of copeptin in the blood. Copeptin is a polypeptide that is released as part of normal ADH production in the body. Measurement of copeptin is an effective surrogate for measurement of ADH. The advantages of testing for copeptin over ADH is that it is more stable and is easier to measure in the lab.
ADH is normally released by the posterior pituitary in response to sensors that detect increases in blood osmolality or decreases in blood volume. The kidneys react to ADH by conserving water and producing urine that is more concentrated. The retained water dilutes the blood, lowers its osmolality, and increases blood volume and pressure. If this is not sufficient to restore the water balance, then thirst is also stimulated so that the affected person will drink more water.
There are a variety of disorders, conditions, and medications that can affect either the amount of ADH released or the kidneys’ sensitivity to it. ADH deficiency and excess can cause acute and chronic symptoms that, in rare cases, may become life-threatening.
If there is too little ADH or the kidneys do not respond to ADH, then too much water is lost through the kidneys, the urine produced is more dilute than normal, and the blood becomes more concentrated. This can cause the polyuria polydipsia syndrome, i.e. excessive urination and excessive drinking. If adequate water intake is not maintained it can lead to dehydration and high blood sodium (hypernatraemia). ADH-independent causes of the polyuria polydipsia syndrome should be excluded before consideration of ADH or copeptin testing: this includes testing for diabetes mellitus and hypercalcaemia. If these tests are negative then the differential diagnosis includes central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. Central diabetes insipidus is associated with a lack of ADH production by the hypothalamus or release from the pituitary and may be due to a variety of causes, including an inherited genetic defect, head trauma, a brain tumour, or due to an infection that causes encephalitis or meningitis. The measured ADH or copeptin will be low, and will not increase in response to stimulation testing.
Nephrogenic diabetes insipidus originates in the kidney and is associated with a lack of response to ADH, causing an inability to concentrate urine. It may be inherited or caused by a variety of kidney diseases. The measured ADH or copeptin will be high. Primary polydipsia (also known as psychogenic polydipsia, i.e. compulsive water drinking) is when excessive drinking alone is the cause of the excessive urination. The measured ADH or copeptin will be low, but it should increase in response to stimulation testing. All three conditions lead to the excretion of large quantities of dilute urine.
If there is too much ADH, then water is retained, blood volume increases, and the person may experience nausea, headaches, disorientation, lethargy, and hyponatraemia. Increased concentrations of ADH and copeptin are often seen with “syndromes of inappropriate antidiuretic hormone” (SIADH). SIADH is characterised by production of too much ADH, resulting in water retention, hyponatraemia, and decreased blood osmolality. It may be due to a wide number of diseases and conditions that either stimulate excessive ADH secretion or prevent its suppression. SIADH may also be seen with cancers that produce ADH or ADH-like substances independent of the hypothalamus and pituitary glands. Regardless of the cause or source, excessive ADH causes low blood sodium and osmolality because water is retained and blood volume is increased. It is extremely unusual to measure ADH or copeptin as part of the routine clinical care of SIADH.
Common questions
Measurement of ADH or copeptin is not widely required. The investigation of polyuria polydipsia syndrome may include measurement of ADH or copeptin, usually as part of a water deprivation test or saline infusion test. Only in exceptional circumstances ADH or copeptin measurement may be required to help investigate hyponatraemia and its associated symptoms, and to identify SIADH.
Symptoms of ADH deficiency are often seen with one of two types of diabetes insipidus. Central diabetes insipidus is a decrease in the production of ADH by the hypothalamus or in the release of ADH from the pituitary; nephrogenic diabetes insipidus is characterised by a decrease in the kidney’s response to ADH. A water deprivation test or saline infusion test is the preferred means to diagnose diabetes insipidus and distinguish between the central and nephrogenic forms. The water deprivation test involves collection of several timed urine and blood samples for osmolality analysis during strictly controlled fluid restriction and after administration of synthetic ADH (ddAVP). The saline infusion test involves infusion of a small volume of fluid into a vein over a short time period, with collection of several timed blood samples for electrolyte, osmolality and ADH or copeptin analysis. Both procedures must be performed under close medical supervision as it can sometimes lead to severe dehydration and can pose a risk to some people with underlying diseases. The levels of ADH or copeptin obtained are used to determine if there is an appropriate ADH response to a hyperosmolar stimulus.
Symptoms of increased levels of ADH are often seen with “Syndromes of Inappropriate ADH production” or SIADH. Testing for SIADH may include blood and urine osmolality, blood and urine sodium, and tests to exclude poor renal or adrenal function. Measurement of ADH or copeptin for the diagnosis of SIADH is only required in exceptional circumstances.
Measurement of ADH or copeptin is not widely required. The investigation of polyuria polydipsia syndrome may include measurement of ADH or copeptin, usually as part of a water deprivation test or saline infusion test. Only in exceptional circumstances ADH or copeptin measurement may be required to help investigate hyponatraemia and its associated symptoms, and to identify SIADH.
ADH or copeptin test results alone are not diagnostic of a specific condition. The results are usually evaluated in conjunction with a person’s medical history, physical examination, and results of other tests. Excesses and deficiencies of ADH may be temporary or persistent, acute or chronic, and may be due to an underlying disease, an infection, an inherited condition, due to a surgery or trauma, or even due to a psychological problem that leads to excess water drinking.
Increased ADH or copeptin concentrations are often associated with SIADH and may be seen with a variety of cancers, including leukaemia, lymphoma, lung cancer, pancreatic, bladder, and brain cancer. Greatly increased concentrations of ADH or copeptin may be seen with systemic cancers that produce ADH. Moderate increases may be seen with nervous system disorders such as Guillain-Barré syndrome, multiple sclerosis, epilepsy, acute intermittent porphyria, with pulmonary disorders such as cystic fibrosis, emphysema, and tuberculosis, and in those with HIV/AIDS. Measurement of ADH or copeptin for the diagnosis of SIADH is only required in exceptional circumstances.
A low ADH or copeptin result may be seen with central diabetes insipidus, primary polydipsia, and with low serum osmolality. An increased ADH or copeptin concentration may be seen in nephrogenic diabetes insipidus, with dehydration, trauma, and surgery.
With the water deprivation test or saline infusion test, a doctor is looking at the response (in either urine osmolality or blood ADH/copeptin) to a hyperosmolar stimulus. In central diabetes insipidus, the ADH or copeptin is low and does not rise appropriately. In nephrogenic diabetes insipidus the ADH or copeptin is high from the outset. In primary polydipsia the ADH or copeptin is low, but does increase in response to hyperosmolar stimulation.
In general, the ability to concentrate urine decreases with age.
ADH secretion increases when a person is standing, at night, and with pain, stress and exercise. Secretion decreases with hypertension and when someone is lying down.
Many drugs can affect ADH levels. They include:
- Drugs that stimulate ADH release, such as: barbiturates, desipramine, histamine, morphine, nicotine, amitriptyline and carbamazepine.
- Drugs that promote ADH action, such as: acetaminophen, metformin, tolbutamide, aspirin, theophylline, and non-steroidal anti-inflammatory drugs.
- Drugs that decrease ADH or its effects, such as: ethanol, lithium, and phenytoin.
No, for most people, ADH is appropriately produced and utilised by the body to maintain water balance. The ADH or copeptin tests are not used as general screening tests and most people will never have one done.
Samples for ADH need to reach the laboratory very quickly. ADH is unstable in the withdrawn blood: the serum must be separated from the blood cells and frozen as soon as possible, therefore the test is not suitable to be ordered from a GP practice. Copeptin is very stable in withdrawn blood and could in theory be ordered from a GP practice. However it is unusual to order copeptin outside of simulation testing (water deprivation test or saline infusion test), which would always be performed in a hospital setting under medical supervision. Only a few laboratories offer ADH or copeptin analysis and so the sample may need to be sent to a reference laboratory.
Diabetes mellitus, usually referred to as diabetes, is related to either decreased insulin production or insulin resistance and causes an increase in blood glucose. Diabetes insipidus is not related to insulin or glucose, but both diabetes conditions can cause increased thirst and frequent urination.
Yes, a synthetic form of ADH can be given as a replacement to those with central diabetes insipidus. Those with nephrogenic diabetes insipidus are encouraged to drink adequate amounts of water to replace what is being lost in their urine and should talk to their doctor about possible adjustments to their diet.