Paroxysmal nocturnal hemoglobinuria overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]
Overview
Paroxysmal nocturnal hemoglobinuria is a rare, acquired, potentially life-threatening disease of the blood characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane.
Historical Perspective
Paroxysmal nocturnal hemoglobinuria was first described by the European physicians in the 19th century. The hypothesis of hemolysis of red blood cells due to the increased plasma acidity in the night time was described by Dr. Strübing in 1815. From 1911 to 1950, more studies were conducted in order to establish the full description of PNH.
Classification
Paroxysmal nocturnal hemoglobinuria may be classified according to the diagnosis results into three subtypes. The subtypes of PNH include classic PNH, secondary PNH, or subclinical PNH.
Pathophysiology
Paroxysmal nocturnal hemoglobinuria is believed to be caused by a genetic mutation and complement mediated hemolysis. A mutation in PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the GPI anchor synthesis. The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes. Other genetic mutation may also cause PNH like TET2, SUZ12, U2AF1, and JAK2. The anemia in PNH is due to complement mediated hemolysis of RBCs which are defective in the CD59//CD55 markers which are important in inactivating the complement system and protecting the RBCs. Paroxysmal nocturnal hemoglobinuria may be associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.
Causes
Common causes of paroxysmal nocturnal hemoglobinuria include a somatic mutation in the PIGA gene. Other causes include mutations in genes of TET2, SUZ12, U2AF1, and JAK2.
Differentiating Paroxysmal Nocturnal Hemoglobinuria from Other Diseases
Paroxysmal nocturnal hemoglobinuria must be differentiated from other causes of anemia which include iron deficiency anemia, thalassemia, anemia of chronic disease, lead poisoning, and blood loss.
Epidemiology and Demographics
The incidence of paroxysmal nocturnal hemoglobinuria is approximately 0.13 per 100,000 individuals worldwide. Paroxysmal nocturnal hemoglobinuria commonly affects adults. However, some cases of PNH in the childhood have been reported.
Risk Factors
There are no established risk factors for paroxysmal nocturnal hemoglobinuria. However, PNH is usually associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.
Screening
According to the American society of hematology, screening for paroxysmal nocturnal hemolglobinuria is recommended among patients with hemoglobinuria, cytopenia, suspected myelodysplasia, negative direct coombs test intravascular hemolytic anemia, refractory anemia, and aplastic anemia with no apparent sign of intravascular hemolysis.
Natural History, Complications, and Prognosis
If left untreated, patients with paroxysmal nocturnal hemoglobinuria may progress to develop thrombosis which is a main cause of death in PNH. Common complications include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis. Prognosis of paroxysmal nocturnal hemoglobinuria is good as long as anti-complemant therapy eculizumab is taken regularly.
Diagnosis
Diagnostic Study of Choice
Diagnosis of paroxysmal nocturnal hemoglobinuria has a minimal essential diagnostic criteria. The diagnostic test of choice is flow cytometry. The flow cytometry is used in order to reveal the GPI deficient RBCs.
History and Symptoms
Common symptoms of paroxysmal nocturnal hemoglobinuria include fatigue, dyspnea, headaches, abdominal pain, dysphagia and chest pain. Less common symptoms may include necrotic skin lesions.
Physical Examination
Patients with paroxysmal nocturnal hemoglobinuria usually appear tired. Physical examination of patients with PNH is usually remarkable for fever, skin pallor, skin ecchymosesand skin nodules. Physical examination may show abdominal distension if PNH is associated with budd chiari syndrome.
Laboratory Findings
Laboratory findings consistent with the diagnosis of paroxysmal nocturnal hemoglobinuria include low hemoglobin level, low RBCs count, and negative coombs test. Flow cytometry is the diagnostic test of choice where it shows GPI deficient RBCs.
Electrocardiogram
There are no ECG findings associated with paroxysmal nocturnal hemoglobinuria.
X-ray
There are no x-ray findings associated with paroxysmal nocturnal hemoglobinuria.
CT scan
There are no CT scan findings associated with paroxysmal nocturnal hemoglobinuria. However, a CT scan may be helpful in the diagnosis of complications of PNH, which include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis.
MRI
There are no MRI findings associated with PNH. However, MRI may be helpful in the diagnosis of complications of PNH which include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis.
Other Imaging Findings
There are no other imaging findings associated with PNH.
Other Diagnostic Studies
There are no other diagnostic studies associated with PNH.
Treatment
Medical Therapy
The mainstay of treatment for paroxysmal nocturnal hemoglobinuria is medical therapy. Treatment includes anticomplement therapy which includes Eculizumab which acts on reducing the hemolysis and possible complications of PNH. Other treatment regimens include hematopoietic cell transplantation and treatment of the anemia.
Surgery
Surgical intervention is not recommended for the management of paroxysmal nocturnal hemoglobinuria.
Primary Prevention
There are no established measures for the primary prevention of paroxysmal nocturnal hemoglobinuria.
Secondary Prevention
There are no established measures for the secondary prevention of paroxysmal nocturnal hemoglobinuria.