Chuvash Polycythemia- Causes, Symptoms, Diagnosis, Complications and Management

Introduction:

Chuvash polycythemia is a hereditary condition different from polycythemia vera, which was first recognized in the year 1970 by Russian hematologist Lydia Andreevna Polyakova. She found out that this condition is different from polycythemia vera and is an inherited condition. This condition affects around 100 people in the Chuvash Republic of the Russian Federation. Though this condition is endemic to the Chuvash population, this mutation can occur worldwide and originates from an ancient event.

What Is Polycythemia?

Polycythemiais a condition that results in an increased level of circulating red blood cells in the bloodstream. Individuals with polycythemia have an increase in hematocrit, hemoglobin, or red blood cell count above normal limits. Red blood cell production takes place in the bone marrow.

What Is Chuvash Polycythemia?

Chuvash polycythemia is an inherited condition caused by a specific mutation in the VHL (von Hippel-Lindau) gene that results in the substitution of R200W amino acid, leading to increased levels of hypoxia-inducible factor (HIF)-1 and HIF-2 resulting in hypoxic response even when the oxygen levels are normal. This condition results in increased concentrations of erythropoietin, the hormone that regulates the production of red blood cells (RBC), causing polycythemia.

In this Chuvash polycythemia, the patients respond to normal oxygen levels as if they are in a hypoxic environment and produce more red blood cells than required.

What Are the Clinical Features of Chuvash Polycythemia?

The clinical features of Chuvash polycythemia are:

• Abnormality of blood and blood-forming tissues.

• Abnormality of the endocrine system.

• Abnormality of the cardiovascular system.

• Abnormality of the integument.

• Constitutional symptom.

• Abnormality of the nervous system.

• Growth abnormality.

• Neoplasm.

What Are the Symptoms of Chuvash Polycythemia?

Chuvash polycythemia can be identified by getting a routine blood test. On examination of the blood tests, there will be elevated hemoglobin and hematocrit levels. Initially, there will be no symptoms, or they may report headaches.

Chuvash polycythemia is also marked by:

• Vertigo.

• Dizziness.

• Leg varices.

• Increased systolic pulmonary artery pressure.

• Hemorrhage.

• Aberrant iron metabolism.

• Thrombosis that does not correlate with hematocrit elevation.

• Vertebral and hepatic hemangiomas.

• Lower white blood count and reduced platelet count.

• Major bleeding episodes.

How Does Chuvash Polycythemia Develop?

Chuvash polycythemia is an inherited autosomal recessive condition. Several studies showed that the disease was caused by a specific mutation in the VHL (von-Hippel-Lindau) gene, resulting in the substitution of R200W amino acid. This condition leads to increased hypoxia-inducible factors (HIF)-1 and HIF-2 and upregulation of the hypoxic response even when the oxygen levels are normal. This results in an increased concentration of erythropoietin, the hormone that regulates red blood cell production.

What Is the Role of Von-Hippel-Lindau (VHL) In Chuvash Polycythemia?

Von-Hippel-Lindau (VHL) is a gene that is involved in the hypoxia-sensing pathway. Hypoxia-inducible factor (HIF)-1 and HIF-2 are the transcription factors that help regulate the body’s response to hypoxia. The VHL protein spots the alpha subunits of HIF-1 and HIF-2 for destruction when normal oxygen levels. These alpha subunits are constantly produced, and under normal oxygen levels, they get degraded by the process that is initiated by the VHL protein.

When these cells are exposed to hypoxia, these HIF subunits are no longer degraded by the process that is initiated by the VHL protein. Instead, they survive and combine with a constitutive beta HIF subunit and cause altered regulation of many different genes. Whereas in the case of Chuvash polycythemia, the mutation in the VHL gene causes impaired recognition of the alpha subunits of HIFs, causing impaired degradation of the cells under normoxic conditions.

Typically when there are increased levels of HIFs, it can lead to an upregulation of the body’s hypoxic response even when the oxygen levels are normal.

How Is Pregnancy Managed With Chuvash Polycythemia?

The management of pregnant women with Chuvash polycythemia consists of therapy of low-dose Aspirin and phlebotomies to maintain hematocrit less than 50 percent while monitoring iron stores to avoid severe deficiency detrimental to the fetus. Though the initial fetal growth was normal, the pregnancy was complicated by preterm birth due to chorioamnionitis. The placenta shows no signs of thrombotic events.

What Are the Complications of Chuvash Polycythemia?

As the patient enters adulthood, there is a marked increase in mortality. The mortality curve is known to diverge by the age of 25 years. A study found that only around 29 % of patients with Chuvash polycythemia survived by the age of 65 compared to normal individuals born in the same place.

There is a significant increase in stroke and other thrombotic events in patients with Chuvash polycythemia. There was also an increase in the bleeding events, and some of the strokes were hemorrhagic.

The other complications include pulmonary hypertension and hemangiomas.

How Is Chuvash Polycythemia Diagnosed?

Chuvash polycythemia is diagnosed by a combination of medical history, physical examination, including blood pressure and body weight, and laboratory tests of the peripheral blood. Blood samples are collected and stored at -70 degrees Celsius.

How Is Chuvash Polycythemia Treated or Managed?

The ideal management of Chuvash polycythemia is not known. Doctors use phlebotomy similar to how they operate in treating polycythemia vera. Still, there are not many studies to prove how effective phlebotomy is in decreasing complications or mortality. One major issue is that frequent phlebotomy procedures can result in iron deficiency. So, it is still not known if phlebotomy is appropriate for treating Chuvash polycythemia.

The other forms of treatment include Aspirin and Busulfan.

Why Is There an Increase in Mortality Rate in Patients With Chuvash Polycythemia?

The common cause of death among patients with Chuvash polycythemia is cerebral vascular events. There was also an increase in death from peripheral thrombosis in patients with Chuvash polycythemia.

What Are All Areas Still Under Research In the Case of Chuvash Polycythemia?

Certain patients with Chuvash polycythemia report pulmonary and metabolic complications. It is still not completely elucidated why patients with Chuvash polycythemia have decreased glucose concentrations and reduced hemoglobin A1c levels, reflecting the average glucose levels.

Conclusion:

The hypoxic response affects the other aspects of the body’s metabolism, immune response, and endocrine pathways. Further research is needed in the case of Chuvash polycythemia and its associated coagulation pathways to help prevent at-risk patients from developing complications. The development of potential therapeutic agents can help assess patients with Chuvash polycythemia.