Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease in which the bone marrow produces abnormal blood cells, including red blood cells. Such red blood cells are too easily broken, and the hemoglobin inside them is released. The disease is sometimes characterized by nighttime attacks (nocturnal paroxysms) on red blood cells, when the cells break down and spill hemoglobin into the urine (hemoglobinuria). The result is reddish-brown urine upon rising in the morning.
Description
Also known as Marchiafava-Micheli syndrome, PNH was first identified in 1882. PNH is caused by a change (mutation) in a gene that prevents it from making a fat required by the three types of blood cells: red blood cells, white blood cells, and platelets.
When the fat (glycosylphosphatidylinositol, or GPI) is missing from the outside walls of blood cells, proteins cannot stick to the cells and the cells cannot function normally. In healthy red blood cells, GPI binds proteins that protect the cells from chemical attack. In healthy white blood cells, GPI may attach to proteins that help the cells fight infections. In healthy platelets, GPI helps control the platelets clotting mechanism.
Not only are all types of blood cells abnormal in PNH, but the numbers of blood cells are decreased. The decrease in red blood cells, coupled with their destruction, causes anemia in people affected with PNH.
The severity of PNH varies greatly from individual to individual. In some affected people, blood in the urine is barely detectable; others lose so much blood that they require repeated transfusions to stay alive. In severe cases, abnormal platelets may cause abnormal clotting, and about one-third of people with PNH die from clots in the veins of the liver, stomach, or brain.
Genetic profile
Mutations in any of 10 different genes can affect the production of GPI. Only one gene, however, is always altered in PNH. This is the PIG-A gene, located on the X chromosome. Females have two X chromosomes (only one is active) and males have one X chromosome.
People are not born with an altered PIG-A gene, probably because such an abnormality would be lethal to an unborn child. Rather, changes occur in the PIG-A gene sometime after birth, resulting in PNH. PNH is thus an acquired genetic disease, not an inherited disease.
Demographics
PNH is a rare disease. In a million people, only about two to six cases of PNH will be diagnosed. PNH is most common in adults between the ages of 30 and 50, although it has been identified in infants less than one year old and people as old as 82. The disease is slightly more common in females than in males (the ratio is 1.2-to-1). Researchers have not reported that the disease is more common in one population than others, although Asians are much less likely to have clotting problems than are Caucasians.
Signs and symptoms
Only about one-quarter of people with PNH have the telltale sign, reddish-brown urine, for which the disease is named. Other symptoms vary greatly among affected individuals. All those affected, however, have some degree of red cell breakdown that results in more or less severe anemia.
Contributing to anemia in people with PNH is the decreased production of red blood cells in the center of the bones (bone marrow). When the needed fat, GPI, is missing, the bone marrow fails to produce functioning red blood cells, white blood cells, and platelets, and the numbers of these blood cells drop dangerously low. This condition is called bone marrow failure.
Those affected with PNH may have frequent infections because their white blood cells are decreased in number and the cells that circulate in the blood are abnormal. Individuals with PNH may have stomach pain because abnormal platelets can cause clotting in liver and
stomach veins. Headaches may result when clots form in veins that pass through the brain.
Diagnosis
PNH and other types of blood diseases are usually diagnosed by examining a sample of bone marrow cells or tissue under a microscope for abnormalities. Doctors obtain the sample by performing a bone marrow aspiration or biopsy on the individual. In PNH, the bone marrow usually looks empty because so few blood cells are being produced.
Two tests that are more specific to PNH require the affected person's blood. The Ham test, developed in 1938, has long been the standard laboratory test for confirming PNH. The test determines whether an individual's red blood cells break down when attacked by certain chemicals. The Ham test is very sensitive and identifies minuscule levels of abnormal red blood cells, but it also identifies individuals with another disease of the red blood cells, congenital dyserythropoietic anemia. A second laboratory test, the sugar water test, works on principles similar to the Ham test. Although the sugar water test is less sensitive to low levels of abnormal red blood cells than the Ham test, it is positive only when the person has PNH.
The most sensitive and specific laboratory test for PNH is flow cytometry. In this test, the individual's blood cells are treated with a chemical that normally binds to proteins on the cell wall. The size of the treated cells is measured to determine if the chemical is attached to the cell. In people with PNH, there are no proteins on the cell wall so the chemical does not bind and the cells appear smaller than normal cells.
Treatment and management
PNH can be treated with a bone marrow transplant, a procedure in which the diseased bone marrow is destroyed and replaced with healthy bone marrow. The operation can be risky, however, so bone marrow transplants are most often performed on children. The operation is most successful if the healthy bone marrow is donated by an identical twin of the affected child, but bone marrow from other family members can sometimes be used.
If a suitable bone marrow donor cannot be found or if the affected person is not strong enough to withstand a bone marrow transplant, PNH can be managed by supportive treatment. Those affected may take drugs to prevent clots from forming and to prevent red blood cells from breaking down. If the number of blood cells falls dangerously low, affected individuals may receive multiple transfusions of blood cells or may be given drugs. When a person has lost a lot of red blood cells, doctors may prescribe iron supplements to help build up the blood again.
Gene therapy is an experimental treatment for PNH. In gene therapy, the normal PIG-A gene is inserted into the affected person's cells, where it takes the place of the abnormal gene and begins making the missing fat. The effectiveness of gene therapy for PNH has not yet been proven in humans.
Prognosis
After an affected individual has been diagnosed with PNH, he or she usually lives for another 10 to 20 years. About 25% of people with PNH live more than 25 years after first being diagnosed. In a few people (about 15%), the disease disappears altogether and the person recovers spontaneously.
Most people who die from PNH do so because of abnormal clotting. About 10% of these individuals develop and eventually die from another disease involving red blood cells, aplastic anemia. About 5% of people with PNH develop a disease involving abnormal white blood cells, acute myelogenous leukemia.
BOOKS
Rosse, Wendell F. "Paroxysmal Nocturnal Hemoglobinuria." In Hematology: Basic Principles and Practice 3rd ed. Ed. Ronald Hoffman, et al., 331–342. New York: Churchill Livingstone, 2000.
PERIODICALS
Hillmen, Peter, and Stephen J. Richards. "Implications of Recent Insights into the Pathophysiology of Paroxysmal Nocturnal Haemoglobinuria." British Journal of Haematology 108 (2000): 470–79.
Nishimura, Jun-ichi, et al. "Paroxysmal Nocturnal Hemoglobinuria: An Acquired Genetic Disease." American Journal of Hematology 62 (1999): 175–82.
ORGANIZATIONS
Anemia Institute for Research and Education. 151 Bloor St. West, Suite 600, Toronto, ONT M5S 1S4. Canada (877) 99-ANEMIA. <http://www.anemiainstitute.net>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
