Description

The syndrome of inappropriate antidiuretic hormone production (SIADH) is a condition

in which the body develops an excess of water and a decrease in sodium (salt)
concentration, as a result of improper chemical signals. Patients with SIADH may
become severely ill, or may have no symptoms at all.

A syndrome is a collection of symptoms and physical signs that together follow a pattern.
SIADH is one of theparaneoplastic syndromes, in which a cancer leads to widespread ill
effects due to more than just the direct presence of tumor.

Normal Physiology

The body normally maintains very tight control over its total amount of water and its
concentration of sodium. Many organs including the kidneys, heart, and the adrenal,
thyroid, and pituitary glands participate in this regulation. One important contribution is
the release of a chemical substance, or hormone, by the pituitary gland into
thebloodstream. This chemical substance, called antidiuretic hormone (ADH), is also
known as arginine vasopressin, orAVP.

The pituitary releases ADH into the bloodstream when receptors in various organs detect
that the body has too little water or too high a concentration of salt. ADH then affects the
way the kidneys control water and salt balance. ADH causes the kidneys to decrease their
output of urine. The body thus saves water by undergoing antidiuresis, that is,
not excreting urine.

Simultaneously, the concentration of sodium in the body serum decreases. This decrease
results from a second effect of ADH on the kidneys. When the kidneys retain extra water,
the existing concentration of sodium in the body decreases slightly as a result of dilution.
These functions are all part of the body's extremely precise control over water and salt
balance in health.

Abnormal Physiology in Siadh

Certain disease states can upset the delicate balance of water and salt in the body. If there
is too much ADH in the body, or if the kidneys overreact to the ADH they receive, the
body retains excess water and the serum sodium concentration becomes diluted and falls
to abnormal levels. The patient with SIADH develops symptoms based on the degree of
abnormality in the serum sodium concentration and the speed with which this
concentration falls.

Normal serum sodium concentration is 135-145 mEq/L (milliEquivalents of sodium per

liter of body fluid). When the sodium concentration is 125–135 mEq/L the patient may
have mild nausea, loss of appetite, fatigue, headache, or still remain free of symptoms. As
the sodium level drops below 120 mEq/L, the patient experiences greater weakness,
confusion, sleepiness, vomiting, and weight gain. As the sodium concentration
approaches 110 mEq/L, the patient may suffer seizures, coma, and death.

Causes

SIADH has many known causes, some of which particularly relate to cancer or its
treatment. These causes include specific types of cancer, drugs used to treat cancer itself,
drugs used to treat the effects of cancer, and conditions that arise as a consequence of
cancer or its treatment.

Specific Types of Cancer

SIADH results from numerous different types of cancer. The malignancies known to
cause SIADH include:

• Lung cancer, small cell type

• Gastrointestinal cancers (pancreatic cancer, exocrine; duodenal or stomach
cancer)
• Genitourinary cancer (bladder cancer, prostate cancer, ovarian cancer)
• Lymphoma, including Hodgkin's disease
• Head and neck cancers (oral cancers, laryngeal cancer, nasopharyngeal cancer)
• Thymoma
• Brain and central nervous system tumors
• Breast cancer
• Melanoma

Certain cancers produce and secrete ADH themselves. This production occurs without
regard for the needs of the body. Thus, the kidneys receive repeated signals to save water,
even when the body already has a marked excess of fluid. Of all the types of cancer that
produce ADH themselves, small-cell lung cancer is by far the most common. Small-cell
cancer of the lung is the cause in 75% of cases of SIADH caused directly by a tumor. In
some cases, the appearance of SIADH may be the first indication that a cancer exists.

Also, primary or metastatic tumors in the brain may lead to SIADH. SIADH here results
from an increase inintracranial pressure (pressure within the head), or from other effects
of intracranial disease on the brain.Increased intracranial pressure commonly causes
various parts of the brain to work improperly.

Drugs Used to Treat Cancer Itself

A variety of drugs used in cancer treatment may lead to SIADH. The mechanism of this
effect may be that the drug causes the abnormal release of ADH, or that the drug makes
existing ADH work in a stronger fashion than usual.Chemotherapy drugs that cause
SIADH include:
 • Vincristine, vinblastine, vinorelbine and other vinca alkaloids (Oncovin, Velban,
Navelbine)
• Cyclophosphamide, ifosfamide, melphalan and other nitrogen mustards (Cytoxan,
Ifex, Alkeran)
• Cisplatin (Platinol-AQ)
• Levamisole (Ergamisol)

Drugs Used to Treat the Effects of Cancer

SIADH may occur as a reaction to drugs used to treat effects of cancer such as
pain, depression, or seizures. SIADH also may result from general anesthesia.

• Narcotic pain medications (morphine, Oramorph SR, fentanyl, Duragesic)

• Tricyclic antidepressants (amitriptyline, Elavil)
• Carbamazepine (Tegretol)
• General anesthetics

Conditions That Arise As a Consequence of Cancer

SIADH may result from some of the debilitating consequences of cancer. For example, a
person with cancer who is weak or unsteady will have a tendency to fall and hit the head.
Skull fracture and other types of head injury may damage the brain or increase the
intracranial pressure, and thus lead to SIADH.

Also, cancer patients who are weak, malnourished, receiving chemotherapy, or spending
excessive time in bed have an increased risk of pneumonia and other infections.
Infections including pneumonia, meningitis, and tuberculosiscan cause SIADH.

Treatments

The treatment of SIADH involves relief of the urgent symptoms and correction of the
underlying problem. For immediate improvement, all patients with SIADH require sharp
restriction of their daily water intake. As little as two cups of liquid, about 500 ml, may
be the daily limit for some patients. In cases where the sodium concentration is already
dangerously low, doctors may cautiously give an intravenous infusion of fluid with a high
concentration of sodium (hypertonic saline solution). However, this treatment carries
some risk of damaging the brain. Physicians may also use a medicine such
as furosemide (Lasix) that promotes water excretion (diuresis). Another
drug,demeclocycline, blocks the action of ADH in the kidney.

The most definitive way to relieve SIADH is to address the underlying problem itself.
Thus, if a tumor produces abnormal ADH, then surgery, radiation therapy, or
chemotherapy may help by reducing tumor size. If SIADH results from use of a drug,
then the patient must discontinue the medicine. Finally, doctors try to identify and treat
any other correctable cause, such as an infection.
Prognosis

The prognosis of SIADH depends largely on its cause. Until recently, many physicians
believed that the appearance of SIADH indicated a poor prognosis for cancer. However,
more recent reports contradict this idea. The patient's ability to observe severe restriction
of fluid intake may determine the degree of ongoing symptoms. SIADH usually improves
after stopping a drug or curing an infection when that is the cause. When cancer is the
direct cause of SIADH, one hopes for similar improvement of SIADH from treatments
that reduce the amount of cancer in the body.