View source for Paroxysmal nocturnal hemoglobinuria

{{Infobox_Disease |
  Name           = {{PAGENAME}} |
  Image          = |
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  DiseasesDB     = 9688 |
  ICD10          = {{ICD10|D|59|5|d|55}} |
  ICD9           = {{ICD9|283.2}} |
  ICDO           = |
  OMIM           = 311770 |
  MedlinePlus    = |
  eMedicineSubj  = med |
  eMedicineTopic = 2696 |
  MeshID         = D006457 |
}}
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'''Paroxysmal nocturnal hemoglobinuria''' ([[PNH]]) 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 cell]]s. [[PNH]] is the only hemolytic anemia caused by an ''acquired'' intrinsic defect in the [[cell membrane]].

==History==
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).<ref>Strübing P. Paroxysmale Hämoglobinurie. ''Dtsch Med Wochenschr'' 1882;8:1-3 and 17-21.</ref><ref>[http://www.whonamedit.com/synd.cfm/2918.html Whonamedit entry]</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. ''Policlinico [Med]'' 1911;18:241-254.</ref> with further elaborations by Marchiafava in 1928<ref>Marchiafava E. Anemia emolitica con emosiderinuria perpetua. ''Policlinico [Med]'' 1928;35:105-117.</ref> and Dr Ferdinando Micheli in 1931.<ref>Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. ''G Accad Med Torino'' 1931;13:148.</ref>

==Classification==
PNH is classified:
* ''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.

It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref>  The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation').  Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected).  Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease.  The complement system is the part of the immune system that helps to destroy invading microorganisms.  The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement.  CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC.  The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.  

The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s.  They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells.  The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

==Signs and symptoms==
Quite paradoxically, the destruction of red blood cells ([[hemolysis]]) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). On-going [[hemolysis]] is a more common characteristic.

A common finding in [[PNH]] is the presence of breakdown products of [[RBC]]s ([[hemoglobin]] and [[hemosiderin]]) in the urine.

An inconsistent, but potentially life-threatening, complication of PNH is the development of clot in the veins (venous [[thrombosis]]).  These clots (thrombi) are often found in the [[hepatic vein|hepatic]] (causing [[Budd-Chiari syndrome]]), [[Portal vein|portal]] (causing [[portal vein thrombosis]]), and cerebral veins (causing [[cerebral venous thrombosis]]).

Many patients with bone marrow failure ([[aplastic anemia]]) develop [[PNH]] (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.<ref>Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."</ref> <ref>Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."</ref>

==Diagnosis==
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'' test, is performed if the sugar test is positive for hemolysis.<ref>Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibtium. ''[[N Engl J Med]]'' 1937;217:915-918.</ref>

Modern methods include [[flow cytometry]] for [[CD55]], [[CD16]] and [[CD59]] on [[white blood cells|white]] and [[red blood cells]]. <ref>Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. ''[[Blood (journal)|Blood]] 2005;106:3699-709. PMID 16051736.</ref>Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.

===MRI=== 

*Renal cortical signal intensity loss (hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma). 
*Venous thrombosis. 
*Liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis.

(Images shown below are courtesy of RadsWiki)


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==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>{{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>

===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/>

Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular 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> It binds to a subunit of the C5 convertase enzyme.  It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.  

Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis.  Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.  

Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection.  Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given.  If the patient had already received the vaccine, they may need a booster.  Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination.  Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection.  These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations.  Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards.  Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab.  

Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients.  Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count.  This is manifest clinically with a decrease in the need for transfusions.  

Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab.  This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH.  The LDH usually returns to normal or near normal within days to weeks after Eculizumab.  Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction.  The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis.  If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate.  It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis.  It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis.  

Anticoagulation is only partly effective in preventing thrombosis in PNH.  Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab.  Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady.  Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation.  Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period.  

==References==
{{reflist|2}}

==Additional Resources==
* Ross L. Titton, and Fergus V. Coakley. [http://radiology.rsnajnls.org/cgi/content/short/225/1/67 Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin.] Radiology 2002 225: 67-70.

==External links==
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
*[http://www.pnhdisease.org PNH Support Group]
*[http://www.pnhfoundation.org PNH Research and Support Foundation] 
*[http://goldminer.arrs.org/search.php?query=Paroxysmal%20nocturnal%20hemoglobinuria Goldminer: Paroxysmal nocturnal hemoglobinuria]

{{Hematology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Rare diseases]]
[[category:Genetic disorders]]

[[de:Paroxysmale nächtliche Hämoglobinurie]]
[[es:Hemoglobinuria nocturna paroxística]]
[[fr:Hémoglobinurie paroxystique nocturne]]
[[it:Emoglobinuria parossistica notturna]]
[[nl:Paroxysmale nocturnale hemoglobinurie]]
[[pl:Napadowa nocna hemoglobinuria]]
[[pt:Hemoglobinúria paroxística noturna]]
[[sr:Пароксизмална ноћна хемоглобинурија]]
[[tr:Paroksismal noktürnal hemoglobinüri]]

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