Paroxysmal nocturnal hemoglobinuria 513180 220742621 2008-06-21T10:43:56Z DOI bot 6652755 Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Infobox_Disease | Name = {{PAGENAME}} | Image = | Caption = | DiseasesDB = 9688 | ICD10 = {{ICD10|D|59|5|d|55}} | ICD9 = {{ICD9|283.2}} | ICDO = | OMIM = 311770 | MedlinePlus = | eMedicineSubj = med | eMedicineTopic = 2696 | MeshID = D006457 | }} '''Paroxysmal nocturnal hemoglobinuria''' (PNH), sometimes referred to as '''Marchiafava-Micheli syndrome''', is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced [[hemolytic anemia]] (anemia due to destruction of [[red blood cell]]s in the bloodstream), red [[urine]] (due to the appearance of [[hemoglobin]] in the urine) and [[thrombosis]]. PNH is the only hemolytic anemia 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"). Treatment is usually supportive ([[blood transfusion]] for anemia, [[anticoagulant|anticoagulation]] for thrombosis), although the [[monoclonal antibody]] [[eculizumab]] (Soliris) is being used to treat some cases.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699}} {{PMC|1895106}}</ref> ==Signs and symptoms== Most people with "primary PNH" have red urine at some point in their disease course. Many of them continue to have low-grade breakdown of red blood cells, leading to anemia. Typical symptoms of anemia are [[tiredness]], [[shortness of breath]] and [[palpitations]]. On laboratory examination of the urine, breakdown products of red blood cells ([[hemoglobin]] and [[hemosiderin]]) may be identified.<ref name=parker2005/> A small proportion of patients report abdominal pain, [[dysphagia]] (difficulty swallowing) and [[odynophagia]] (pain during swallowing), as well as [[erectile dysfunction]] in men - this occurs mainly when the breakdown of red blood cells is rapid.<ref name=parker2005/> Forty percent of patients develop [[thrombosis]] (a blood clot) at some point in their illness. This is the main cause of severe complications and death in PNH. 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 mesenteric vein|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.<ref name=parker2005/> ==Diagnosis== [[Blood test]]s in PNH show changes consistent with [[hemolytic anemia]]: low [[hemoglobin]], raised [[lactate dehydrogenase]], raised [[reticulocyte]]s (immature red cells released by the [[bone marrow]] to replace the destroyed cells), raised [[bilirubin]] (a breakdown product of hemoglobin) and decreased levels of [[haptoglobin]]. The [[direct antiglobulin test]] (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by [[antibody|antibodies]].<ref name=parker2005/> A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called ''Ham's acid hemolysis'' (after Dr Thomas Ham, who described the test in 1937) test, is performed if the sugar test is positive for hemolysis.<ref>{{cite journal|author=Ham TH|title=Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium|journal=N Engl J Med|year=1937|volume=217|pages=915–918}}</ref> More sensitive modern methods include [[flow cytometry]] for [[CD55]] and [[CD59]] on [[white blood cells|white]] and [[red blood cells]]. Dependent on the presence of these molecules on the cell surface, they are 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 higher the number of type III cells, the higher the risk of hemolysis and thrombosis.<ref name=parker2005/> ==Classification== PNH is classified by the context under which it is diagnosed:<ref name=parker2005/> * ''Classic PNH''. Evidence of PNH in the absence of another bone marrow disorder. * ''PNH in the setting of another specified bone marrow disorder''. * ''Subclinical PNH''. PNH abnormalities on flow cytometry without signs of hemolysis. ==Pathophysiology== All cells have proteins attached to their membranes and they 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.<ref name=parker2005/> An enzyme called {{Gene|PIGA}} (phosphatidylinositol glycan A) is needed to make a cell membrane anchor for proteins called [[glycosylphosphatidylinositol|GPI]] (glycosylphosphatidylinositol). 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. If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the "GPI anchor". 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 ([[clone (cell biology)|clone]])will also have the defect.<ref name=parker2005/> Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the [[complement system]]. The complement system is part of the [[immune system]] and helps to destroy invading microorganisms. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins which carry out this function are [[CD55]] and [[CD59]].<ref name=parker2005/> The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of [[platelet]]s due to binding by [[complement]], or possibly due to low [[nitric oxide]] levels.<ref name=parker2005/> 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.<ref name=parker2005/> 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]].<ref>{{cite journal |author=Rother RP, Bell L, Hillmen P, Gladwin MT |title=The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease |journal=JAMA |volume=293 |issue=13 |pages=1653–62 |year=2005 |month=April |pmid=15811985 |doi=10.1001/jama.293.13.1653 |url=http://jama.ama-assn.org/cgi/content/full/293/13/1653}}</ref> ==Treatment== ===Long-term=== PNH is a chronic condition. In patients who have 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).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref> 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.<ref name=parker2005/> ===Acute attacks=== 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.<ref name=parker2005/> A new [[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.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> ==Screening== Screening for PNH is performed every year in people with previous aplastic anemia, and may be performed in people with myelodysplastic syndrome of the "refractory anemia" type.<ref name=parker2005/> ==Epidemiology== 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.<ref name=parker2005/> 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).<ref name=parker2005/> ==History== The first description of paroxysmal hemoglobinuria was by the [[Germany|German]] physician Paul Strübing ([[Greifswald]], 1852-1915) in 1882.<ref>{{cite journal|author=Strübing P|title=Paroxysmale Hämoglobinurie|language=German|journal=Dtsch Med Wochenschr|year=1882|volume=8|pages=1–3 and 17–21}}</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>{{cite journal|author=Marchiafava E, Nazari A|title=Nuovo contributo allo studio degli itteri cronici emolitici|language=Italian|journal=Policlinico [Med] | year=1911|volume=18|pages=241–254}}</ref> with further elaborations by Marchiafava in 1928<ref>{{cite journal|author=Marchiafava E|title=Anemia emolitica con emosiderinuria perpetua|language=Italian|journal=Policlinico [Med] |year= 1928|volume=35|pages=105–117}}</ref> and Dr Ferdinando Micheli in 1931.<ref>{{cite journal|author=Micheli F|title=Uno caso di anemia emolitica con emosiderinuria perpetua|language=Italian|journal=G Accad Med Torino|year=1931|volume=13|pages=148}}</ref><ref>{{Whonamedit|synd|2918|Strübing-Marchiafava-Micheli syndrome}}</ref> The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or ''haemoglobinuria paroxysmalis nocturia'' in Latin) in 1928.<ref>{{cite journal| author=Enneking J | title=Eine neue form intermittierender haemoglobinurie (Haemoglobinuria paroxysmalis nocturia) | language=German | journal=Klin Wochensch | year=1928| volume=7 | pages=2045 | doi=10.1007/BF01846778}}</ref> ==References== {{reflist|2}} ==External links== *[http://www.aamds.org Aplastic Anemia & MDS International Foundation] *[http://www.pnhfoundation.org PNH Research and Support Foundation] *[http://www.pnhdisease.org PNH Support Group] {{Hematology}} [[Category:Hematology]] [[Category:Rare diseases]] [[category:Genetic disorders]] [[ca:Hemoglobinúria paroxística nocturna]] [[de:Paroxysmale nächtliche Hämoglobinurie]] [[es:Hemoglobinuria nocturna paroxística]] [[fr:Hémoglobinurie paroxystique nocturne]] [[it:Emoglobinuria parossistica notturna]] [[nl:Paroxysmale nocturnale hemoglobinurie]] [[ja:発作性夜間血色素尿症]] [[pl:Napadowa nocna hemoglobinuria]] [[pt:Hemoglobinúria paroxística noturna]] [[sr:Пароксизмална ноћна хемоглобинурија]]