Familial erythrocytosis: Description, Causes and Risk Factors:
Erythrocytosis is a rare red cell disorder that can arise from diverse molecular origins. It is characterized by an elevated hematocrit and hemoglobin level. There is no accompanying increase in the number of white cells or platelets. Both sporadic and familial forms exist and age of presentation is highly variable. Individuals with erythrocytosis exhibit a wide range of serum Epo (erythropoietin) levels and this reflects the heterogeneity of this disorder.
Erythrocytosis can be further classified as either primary or secondary depending on whether the defect is intrinsic or extrinsic to the erythroid progenitor cells. In primary erythrocytosis the serum Epo level is subnormal and the erythroid progenitors are hypersensitive to Epo, which suggests the defect lies in the Epo-induced signaling pathway. Secondary erythrocytosis is associated with inappropriately normal or raised serum Epo levels indicating a defect in the control of Epo synthesis by the oxygen-sensing pathway. Both reflect our current understanding of how red blood cell mass is regulated.
Familial erythrocytosis is an inherited condition characterized by an increased number of red blood cells (erythrocytes). The primary function of these cells is to carry oxygen from the lungs to tissues and organs throughout the body. Signs and symptoms of familial erythrocytosis can include headaches, dizziness, nosebleeds, and shortness of breath. The excess red blood cells also increase the risk of developing abnormal blood clots that can block the flow of blood through arteries and veins. If these clots restrict blood flow to essential organs and tissues (particularly the heart, lungs, or brain), they can cause life-threatening complications such as a heart attack or stroke. However, many people with familial erythrocytosis experience only mild signs and symptoms or never have any problems related to their extra red blood cells.
Familial erythrocytosis can result from mutations in the EPOR, VHL, EGLN1, or EPAS1 gene. Researchers define four types of familial erythrocytosis, ECYT1 through ECYT4, based on which of these genes is altered.
The EPOR gene provides instructions for making a protein known as the erythropoietin receptor, which is found on the surface of certain blood-forming cells in the bone marrow. Erythropoietin is a hormone that directs the production of new red blood cells. Erythropoietin fits into the receptor like a key into a lock, triggering signaling pathways that lead to the formation of red blood cells. Mutations in the EPOR gene cause the erythropoietin receptor to be turned on for an abnormally long time after attaching to erythropoietin. The overactive receptor signals the production of red blood cells even when they are not needed, which results in an excess of these cells in the bloodstream. When familial erythrocytosis is caused by mutations in the EPOR gene, it is known as ECYT1.
The proteins produced from the VHL, EGLN1, and EPAS1 genes are also involved in red blood cell production; they each play a role in regulating erythropoietin. The protein produced from the EPAS1 gene is one component of a protein complex called hypoxia-inducible factor (HIF). When oxygen levels are lower than normal (hypoxia), HIF activates genes that help the body adapt, including the gene that provides instructions for making erythropoietin. Erythropoietin stimulates the production of more red blood cells to carry oxygen to organs and tissues. The proteins produced from the VHL and EGLN1 genes indirectly regulate erythropoietin by controlling the amount of available HIF. Mutations in any of these three genes can disrupt the regulation of red blood cell formation, leading to an overproduction of these cells. When familial erythrocytosis results from VHL gene mutations it is known as ECYT2; when the condition is caused by EGLN1 gene mutations it is called ECYT3; and when the condition results from EPAS1 gene mutations it is known as ECYT4.
Researchers have also described non-familial (acquired) forms of erythrocytosis. Causes of acquired erythrocytosis include long-term exposure to high altitude, chronic lung or heart disease, episodes in which breathing slows or stops for short periods during sleep (sleep apnea), and certain types of tumors. Another form of acquired erythrocytosis, called polycythemia vera, results from somatic (non-inherited) mutations in other genes involved in red blood cell production. In some cases, the cause of erythrocytosis is unknown.
Whatever the cause of erythrocytosis, symptoms may not be apparent in the early stages and the condition may be discovered from routine blood tests. Vague symptoms such as tiredness
may be present and sometimes sweating, itching, dizziness and headaches may be experienced. For people who have polycythemia vera, there is an increased risk of blood clots occurring and in some cases the first sign of the condition may be a thrombosis, or clot, inside a blood vessel, causing a problem such as a stroke or heart attack.
Stage I diagnosis:
Full blood count/?lm.
- Arterial oxygen saturation.
- Ferritin level.
- Renal and liver function tests.
- Abdominal ultrasound.
- Serum erythropoietin level.
- Chest X-ray.
Stage II diagnosis:
Bone marrow aspirate/trephine.
- BFU-E culture.
- Oxygen dissociation curve (p50).
- Sleep study.
- Lung function tests.
- Erythropoietin receptor gene analysis.
- VHL analysis.
The treatment of erythrocytosis depends on the cause. Secondary forms of the condition require treatment of the underlying disorder, and the outlook will depend on how successful this is. In the case of a long-term lung disease, giving oxygen may help reduce the levels of erythropoietin and decrease red blood cell numbers.
For the primary condition, if the rare blood disease polycythemia vera is the cause, the outlook is poor without treatment. There is a high risk of a fatal stroke or heart attack occurring within 18 months. With treatment, the outlook improves to give an estimated Life expectancy of around 20 years.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.