Paroxysmal nocturnal hemoglobinuria
|Paroxysmal nocturnal hemoglobinuria|
|Classification and external resources|
Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, generally acquired, life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia (anemia due to destruction of red blood cells in the bloodstream), red urine (due to the appearance of hemoglobin in the urine) and thrombosis. After diagnosis and with only supportive measures, 35% of patients will be dead within 5 years.
PNH is the only hemolytic anemia which is most often caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to absence of protective proteins on the membrane). It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority (26%) have the telltale red urine in the morning.
Allogeneic bone marrow transplantation is the only curative therapy, but has significant rates of both mortality and ongoing morbidity.
Signs and symptoms
When first discovered, PNH patients were noted to have dark colored urine which occurred episodically, and most often in the morning. Further understanding and research into the disease has shown that this is in fact a chronic condition which is progressive with episodes where signs, symptoms and laboratory values worsen.
Most people with "primary PNH" have red urine at some point in their disease course, but they may often have PNH for a considerable time before this. Many of them continue to have low-grade breakdown of red blood cells, which leads to a release of the contents of red blood cells, LDH, hemoglobin and L-arginase. The signs and symptoms are due to this hemolysis.
Free hemoglobin is both directly toxic when not quickly bound to haptoglobin in several different ways.
1) Scavenging of free nitric oxide. Nitric oxide is a potent antithrombotic (by preventing activation of platelets) as well as smooth muscle relaxant. Removing nitric oxide can cause a variety of symptoms, from abdominal pain, dysphagia (difficulty swallowing) and odynophagia (pain during swallowing), as well as erectile dysfunction, as is demonstrated by published data from the PNH registry
2) Damage to end organs due to deposition of iron. This is especially true in the kidneys where chronic inflammation leads to a worsening of kidney function which if treated early is reversible.
The destruction of red blood cells can often lead to anemia. Typical symptoms of anemia are tiredness, shortness of breath, and palpitations, but the tiredness in PNH is not merely due to the reduction in hemoglobin, and is also due to nitric oxide depletion and the cytokine storm.
The most clinically significant finding thrombosis (a blood clot) which is responsible for 40% to almost 70% of mortality, and patients with PNH have a massively increased risk of thrombosis compared to the general population - 62 times. These may develop in common sites (deep vein thrombosis of the leg veins and resultant pulmonary embolism when these clots break off and enter the lungs), but, in PNH, blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia), and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in PNH. In some cases a blood clot might be the first clinical manifestation of PNH but can be overlooked if the thrombus is in a common site.
Damage to kidneys is chronic and multifactorial, due to reduced perfusion, chronic inflammation due to hemosiderosis and microthrombi. This damage leads to mortality in 8% to 18% of patients.
Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no iron deficiency present. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies.
Historically, the sucrose lysis test, in which a patient's red blood cells are placed in low-ionic-strength solution and observed for hemolysis, was used for screening. If this was positive, the Ham's acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation.
Today, the gold standard is flow cytometry for CD55 and CD59 on white and red blood cells. Based on the levels of these cell proteins, erythrocytes may be classified as type I, II, or III PNH cells. Type I cells have normal levels of CD55 and CD59; type II have reduced levels; and type III have absent levels. The fluorescein-labeled proaerolysin (FLAER) test is being used more frequently to diagnose PNH. FLAER binds selectively to the glycophosphatidylinositol anchor and is more accurate in demonstrating a deficit than simply for CD59 or CD55.
PNH is classified by the context under which it is diagnosed:
- Classic PNH. Evidence of PNH in the absence of another bone marrow disorder.
- PNH in the setting of another specified bone marrow disorder such as Aplastic Anemia and mylodylastic syndrome (MDS)
- Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.
All cells have proteins attached to their membranes that are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. PNH occurs as a result of a defect in one of these mechanisms.
There are several enzymes that are needed to make glycosylphosphatidylinositol (GPI), a molecule that anchors proteins to the cell membrane. The most common enzyme that is defective in PNH is phosphatidylinositol glycan A (PIGA). The gene that codes for PIGA is located on the X chromosome, which means that only one active copy of the gene for PIGA is present in each cell (initially, females have two copies, but one is silenced through X-inactivation). There has recently been a case report of a patient with a PIGT mutation, which led to inherited PNH
If a mutation occurs in this gene then PIGA may be defective, which leads to the GPI anchor not being expressed on the cell membrane. When this mutation occurs in a bone marrow stem cell (which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect.
Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins. Although red blood cells, white blood cells and platelets are targeted by compliment, red blood cells are particularly vulnerable to lysis.
The complement system is part of the innate immune system and has a variety of functions, from destroying invading microorganisms by opsonisation to direct destabilization by the Membrane Attack Complex. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins that carry out this function are decay-accelerating factor (DAF) (CD55), which disrupts formation of C3 convertase, and protectin (CD59), which binds the membrane attack complex and prevents C9 from binding to the cell.
The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells. There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure.
PNH is a chronic condition. In patients with only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with warfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).
Episodes of thrombosis are treated as they would in other patients, but, given that PNH is a persisting underlying cause, it is likely that treatment with warfarin or similar drugs needs to be continued long-term after an episode of thrombosis.
A monoclonal antibody, eculizumab, protects blood cells against immune destruction by inhibiting the complement system. It has been shown to reduce the need for blood transfusion in patients with significant hemolysis. Sufferers from New Zealand in January 2013 called on the government's medicine buying agency Pharmac to fund the purchase of eculizumab. New Zealand is the only country in the OECD not to fund it.
There is disagreement as to whether steroids (such as prednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia, this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.:
There are several groups where screening for PNH should be undertaken. These include: Patients with unexplained thrombosis who<refThrombosis in paroxysmal nocturnal hemoglobinuria Anita Hill, Richard Kelly and Peter Hillmen, Blood, 2013></ref> 1. are young 2. The thrombosis occurs in an unusual site e.g. intra-abdominal veins, cerebral veins, dermal veins 3. have any evidence of hemolysis (i.e. a raised LDH) 4. have any cytopenia
Have aplastic Anemia and should be screened annually. Have mylodysplastic Syndrome Unexplained Hemolytic Anemia Unexplained cytopenia
PNH is rare, with an annual rate of 1-2 cases per million. Many cases develop in people who have previously been diagnosed with aplastic anemia or myelodysplastic syndrome. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia.
25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively).
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (Greifswald, 1852–1915) in 1882. A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911, with further elaborations by Marchiafava in 1928 and Dr Ferdinando Micheli in 1931. The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturna in Latin) in 1928.
- PNH from mutations of another PIG gene Lucio Luzzatto Blood 2013
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