Inadequate delivery of oxygen to the tissue is sensed by a heme protein in the kidney, and erythropoietin production in the kidney is increased. Erythropoietin stimulates erythropoiesis, resulting in enhanced red blood cell production and increased tissue oxygen delivery.

During adult life, approximately 90% of erythropoietin production occurs in the kidney, and 10% occurs in the liver. Disorders of either the kidney or the liver can result in an inappropriate increase in erythropoietin production.

Tissue Hypoxia

What circumstances or types of disorders might result in tissue hypoxia?

• Life at high altitude. The partial pressure of oxygen at which hemoglobin is 50% saturated is normally 27 mm Hg. An increase in the concentration of 2,3-bisphosphoglycerate shifts the curve to the right, enhancing oxygen release in the tissues.

  Oxygen hemoglobin dissociation curve

  
  Click on the image to see the 2,3 BPG effect.

  Adaptation to life at high altitude includes an increase in the respiratory rate and the cardiac output, and an increase in the level of 2,3-bisphosphoglycerate, to facilitate oxygen unloading from hemoglobin to the tissues. Six to 24 hours after ascent to high altitude, erythropoietin levels increase, resulting in reticulocytosis and subsequently an increase in the hematocrit.

• High-affinity hemoglobin. The partial pressure of oxygen at which hemoglobin is 50% saturated is normally 27 mm Hg. In patients with a high affinity hemoglobin, the curve is shifted to the left, impairing oxygen unloading in the tissues.

  Oxygen hemoglobin dissociation curve

  
  Click on the image to see the high-affinity hemoglobin effect.

  High affinity hemoglobin results from specific single amino acid mutations in either the a chain or the ß chain of globin that interferes with the conformational change that hemoglobin normally undergoes during oxygen loading and unloading.

  Impeded conformational change: High affinity hemoglobin impedes oxygen release to the tissues, resulting in tissue hypoxia, increased erythropoietin production, and erythrocytosis. High affinity hemoglobin is usually familial, and is inherited in an autosomal dominant manner. Records of prior complete blood counts document life-long erythrocytosis. When the diagnosis of high affinity hemoglobin is contemplated, the P₅₀ (the partial pressure of oxygen at which hemoglobin is 50% saturated) should be measured and will be found to be reduced.

  

  Hemoglobin electrophoresis is not a useful test in the evaluation of high affinity hemoglobin, as many of the mutations are electrophoretically silent. Erythrocytosis in these patients is a physiologic adaptation to tissue hypoxia, and no treatment is needed.

• Tissue hypoxia caused by cardiopulmonary disease. Polycythemia caused by cardiopulmonary disease is due to failure to adequately load oxygen onto hemoglobin in the lungs. Patients with cyanotic congenital heart disease (for example, Eisenmenger's complex, cyanotic congenital heart disease, tetralogy of Fallot) may have significant polycythemia, with hematocrit values of 60-75%. Hyperviscosity symptoms including headache, dizziness, fatigue, and decreased mental acuity are common. Phlebotomy to a hematocrit of less than 65% may improve symptoms due to hyperviscosity and can improve exercise tolerance.

  Severe chronic obstructive pulmonary disease can occasionally be associated with polycythemia. Hypoxemia plus a smoking-induced elevation in the carboxyhemoglobin concentration may contribute to the development of polycythemia.

• Obesity-hypoventilation Syndrome
  Patients with obesity-hypoventilation syndrome are usually morbidly obese (body mass index of 40 kg/m2) and have daytime hypersomnolence and cor pulmonale. These patients have central hypoventilation due to a blunted respiratory response to hypoxemia and hypercapnea. The chronic hypoxemia may result in erythrocytosis.

  
  Thomas Nast drawing from The Pickwick Papers

  Note: Obesity-hypoventilation syndrome is also known as Pickwickian syndrome based on Charles Dickens' astute description of the obese coachboy in The Pickwick Papers.
• Obstructive Sleep apnea
  Obstructive sleep apnea is due to episodic upper airway collapse during sleep, which obstructs air movement and results in intermittent nocturnal hypoxemia. The partner may describe loud snoring, followed by periods of silence lasting up to 1 minute, followed by gasping sounds. Patients with obstructive sleep apnea often have excessive daytime sleepiness, and may have mild polycythemia. It has been estimated that up to 4% of middle-aged men, and 2% of middle-aged women, may have sleep apnea syndrome. The diagnosis can be established by nocturnal polysomnography.
• High carboxyhemoglobin level
  Carbon monoxide binds to hemoglobin with an affinity more than 200-fold higher than that of oxygen, and thus decreases the amount of hemoglobin available for oxygen transport. Carbon monoxide binding also increases the affinity of hemoglobin for oxygen, thus shifting the oxygen-hemoglobin dissociation curve to the left and impeding oxygen unloading in the tissues.

  Oxygen hemoglobin dissociation curve
  
  Click on the image to see carboxyhemoglobin effect.

  Chronic carbon monoxide exposure from smoking or from occupational exposure to automobile exhaust in poorly ventilated areas can result in mild erythrocytosis. The half-life of carboxyhemoglobin is approximately 4 hours, so the carboxyhemoglobin level should be measured at the end of the day, to accurately reflect the patient's smoking habits or occupational exposure. Treatment consists of smoking cessation or changes in the work environment.