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{{Hereditary spherocytosis}}
{{Hereditary spherocytosis}}
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{{CMG}} {{AE}} {{ZAS}}


==Overview==
==Overview==
'''Hereditary spherocytosis''' is a genetically-transmitted form of [[spherocytosis]], an auto-[[hemolysis|hemolytic]] [[anemia]] characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to [[hemolysis]].
[[Hereditary spherocytosis]] is a [[Genetics|genetically]] [[Transmission (medicine)|transmitted]] form of [[hemolysis]], characterized by [[hemolytic anemia]], [[jaundice]] and [[splenomegaly]]. It was first described by Vanlair and Masius in 1871, where they described [[Chronic (medical)|chronically]] [[Icterus|icteric]] [[Patient|patients]] who had no [[bile]] in [[urine]], no evidence of [[Hepato-biliary diseases|liver disease]] and often [[splenomegaly]] and [[family history]] of [[jaundice]]. [[Hereditary spherocytosis]] is classified in 05 subtypes on the basis of underlying [[protein]] [[defect]] including; [[Ankyrin|ankyrin1]], [[Spectrin|spectrin beta chain (erythrocytic)]], [[Spectrin, alpha 1|spectrin alpha chain (erythrocytic1)]], [[band 3]] and [[protein 4.2]]. The [[Defect|defects]] in [[hereditary spherocytosis]] lie in the [[cell membrane]]. The [[cell membrane]] [[Protein|proteins]] essential for the integrity of [[cell membrane]] structure includes; [[spectrin]], [[ankyrin]], [[band 3]] and [[Protein 4.2|protein 4.1 and 4.2]], and their [[deficiency]] can produce varying degree of severity of the [[disease]]. it should be differentiated from [[Autoimmune hemolytic anemia|autoimmune hemolysis]], [[Congenital dyserythropoietic anemia|congenital dyserythropoietic anemia type II]], thermal [[injury]] and [[Hemoglobinopathy|hemoglobinopathies]]. [[Hereditary spherocytosis]] can present at any [[Ageing|age]], having a [[positive]] [[family history]] is an important [[risk factor]] for the [[disease]]. [[Mean corpuscular hemoglobin concentration|Mean corpuscular hemoglobin concentration (MCHC)]] and [[Red blood cell distribution width|erythrocyte distribution width (RDW)]] [[Test|tests]] can be used for the [[Screening (medicine)|screening]] of [[hereditary spherocytosis]]. [[Complication (medicine)|Complications]] of the [[disease]] include; [[jaundice]], [[kernicterus]], [[Gallstone disease|pigment gallstones]], [[splenomegaly]], [[hemolytic]], [[Aplastic crisis|aplastic]] and [[Megaloblastic Anemia|megaloblastic crises]]. It can present with [[Pallor|yellowing of skin]], [[fatigue]], [[irritability]], [[Dyspnea|shortness of breath]] or it can be [[asymptomatic]] altogether. [[Physical examination]] findings include [[Sclera|scleral]] [[icterus]], [[jaundice]] and [[splenomegaly]]. [[Laboratory]] [[Test|testing]] includes [[Complete blood count|CBC]], [[Mean corpuscular hemoglobin concentration|MCHC]], [[Blood film|blood smear]], [[hemolysis]] [[Test|testing]] and [[coombs test]]. There is no specific medical [[therapy]] for the [[hereditary spherocytosis]], however surveillance is needed to help detect and manage the [[Complication (medicine)|complications]]. [[Folic Acid|Folic acid]] supplementation, [[Blood transfusion|blood transfusions]] and [[erythropoietin]] may also be tried. [[Splenectomy]] is very effective in reducing the [[hemolysis]]. Partial [[Splenectomy|splenectomies]] are tried in [[Child|children]] to control [[hemolysis]] and preserve [[Spleen|splenic]] [[Function (biology)|function]] as well. Administration of [[Vaccine|vaccines]] ([[Pneumococcal vaccine|pneumococcal]], [[hemophilus influenzae]], [[Meningococcal Vaccine (patient information)|meningococcal]] and [[Influenza vaccine|influenza]]), [[Antibiotic|antibiotics]] ([[penicillin]]) and [[Folic Acid|folic acid]] should be prescribed for [[Splenectomy|postsplenectomy]] [[Patient|patients]].


==Historical Perspective==
==Historical Perspective==
* Towards the end of the nineteenth century Vanlair and Masius described the case of a young woman who developed icterus, recurrent attacks of left upper quadrant abdominal pain and [[splenomegaly]] shortly after giving birth. The [[stools]] were not light coloured, but rather deeply pigmented. The patient's mother and sister were also [[Icterus|icteric]], and the sister's [[spleen]]<nowiki/>was enlarged.
The [[hereditary spherocytosis]] was first described in 1871 by Vanlair and Masius, where they described [[Chronic (medical)|chronically]] [[Jaundice|icteric]] [[Patient|patients]] who had no [[bile]] in the [[urine]], no evidence of [[Hepato-biliary diseases|liver disease]] and often [[splenomegaly]] and [[family history]] of [[jaundice]]. It is the commonest [[Causality|cause]] of [[inherited]] [[Chronic (medical)|chronic]] [[hemolysis]] in the northern europe and north america.


==Classification==
==Classification==
* Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
The [[hereditary spherocytosis]] classified into 05 subtypes on the basis of underlying [[Protein|protein defect]] including; [[Ankyrin|ankyrin 1]], [[Spectrin|spectrin beta chain (erythrocytic)]], [[Spectrin, alpha 1|spectrin alpha chain (erythrocytic 1)]], [[band 3]] and [[protein 4.2]]. It is also classified on the basis of [[clinical]] severity into mild, moderate and severe subtypes.


==Pathophysiology==
==Pathophysiology==
There is intrinsic defects in erythrocyte membrane proteins that result in [[Red blood cell|RBC]] [[cytoskeleton]] instability. Loss of erythrocyte surface area leads to the spherical shape of RBCs (spherocytes), which are culled rapidly from the circulation by the [[spleen]]. [[Hemolysis]] mainly confined to the spleen and, therefore, is extravascular. Splenomegaly commonly develops.
The [[Defect|defects]] in [[hereditary spherocytosis]] lie in the [[cell membrane]]. The [[Protein|proteins]] essential for integrity of [[cell membrane]] structure lie immediately under the [[lipid bilayer]], horizental [[Spectrin|alpha & beta spectrin molecules]] form [[Heterodimeric|heterodimers]] with linkage to vertical elements including [[ankyrin]], [[Protein|proteins]] 4.1 & 4.2 and [[band 3]] ([[transmembrane protein]]). The shorter the [[lifespan]] of [[Red blood cell|red blood cells]], the worse the [[clinical]] effects. [[Spectrin]] [[protein]] is a [[tetramer]] composed of alpha & beta [[Dimer|dimers]], its [[deficiency]] is most frequently seen in [[hereditary spherocytosis]]. [[Spectrin]] [[deficiency]] can result from impaired [[synthesis]] of [[spectrin]] or from [[qualitative]] or [[quantitative]] [[Defect|defects]] in other [[Protein|proteins]] that integrate [[Protein|proteins]] into [[Red blood cell|red blood cells]]. [[Ankyrin]] is the principal [[binding site]] for [[spectrin]] on [[Red blood cell|red blood]] [[cell membrane]], its [[deficiency]] leading to decreased incorporation of [[spectrin]], leading to proportional decrease in [[spectrin]] content as well despite normal [[synthesis]] of [[spectrin]]. [[Band 3]] [[deficiency]] is seen in 10-20% of [[Patient|patients]] with mild to moderate [[Autosomal dominant inheritance|autosomal dominant]] [[hereditary spherocytosis]] and is considerably greater in older [[Red blood cell|red blood cells]]. [[Protein 4.2|Protein 4.2 (Pallidin)]] [[deficiency]] leads to abnormal [[red blood cell]] [[morphology]] including [[Spherocytosis|spherocytes]], elliptocytes or sphero-ovalocytes, it is relatively common in japan. [[Red blood cell]] [[antibodies]] may also have a [[Pathogenesis|pathogenic]] role in [[red blood cell]] [[Opsonin|opsonization]] and removal by [[spleen]].
 
The following four abnormalities in RBC membrane proteins have been identified in HS:
* [[Spectrin]] deficiency alone
* Combined [[spectrin]] and [[ankyrin]] deficiency
* [[Band 3|Band 3 deficiency]]
* [[Protein 4.2]] defects


==Causes==
==Causes==
* [[Hereditary spherocytosis|HS]] is caused by a variety of [[mutations]] that lead to defects in [[Red blood cells|red blood cell (RBC)]] membrane proteins. HS usually is transmitted as an [[autosomal dominant]] trait, and the identification of the disorder in multiple [[Generation|generations]] of affected families is the rule. [[Homozygosity]] for this dominantly transmitted [[Hereditary spherocytosis|HS]] [[gene]] has not been identified, which suggests that the [[homozygous]] state is incompatible with life.
[[Hereditary spherocytosis]] is caused by a variety of [[Genetics|genetic]] [[Mutation|mutations]]. The 05 [[Gene|genes]] associated with [[hereditary spherocytosis]] include; [[Spectrin, alpha 1|alpha spectrin (SPTA1)]], [[Spectrin|beta spectrin (SPTB)]], [[Ankyrin|ankyrin (ANK1)]], [[band 3]] ([[SLC4A11|SLC4A1]]) and [[protein 4.2]] (EPB42). [[Mutation|Mutations]] in one or more of these [[Gene|genes]] can cause [[Cell membrane|membrane]] [[protein]] [[deficiency]] leading to [[hereditary spherocytosis]].


==Differentiating {{PAGENAME}} from Other Diseases==
==Differentiating {{PAGENAME}} from Other Diseases==
The differential diagnosis of HS includes a number of other hemolytic anemias with spherocytes on the peripheral blood smear.
[[Hereditary spherocytosis]] usually presents with [[hemolysis]], therefore should be [[Differentiate|differentiated]] from other [[Disease|diseases]] including; [[Autoimmune hemolytic anemia|autoimmune hemolysis]], thermal [[injury]], [[Clostridia|clostridial]] [[Sepsis|septicemia]], [[Wilson's disease|wilson disease]], [[Hemoglobinopathy|hemoglobinopathies]], [[hereditary stomatocytosis]], [[Congenital dyserythropoietic anemia|congenital dyserythropoietic anemia type II]], [[Infant|infantile]] [[Pyknosis|pyknocytosis]] and [[Hemolytic disease of the newborn|hemolytic disease of fetus and newborn (HDFN)]].
# Infantile pyknocytosis,  
# Congenital dyserythropoietic anemia (CDA)
# [[Autoimmune hemolytic anemia|Autoimmune hemolytic anemias]]:
# Other inherited hemolytic anemias: hereditary elliptocytosis (HE) and elliptocytosis variants (eg, Southeast Asian ovalocytosis [SAO], hereditary pyropoikilocytosis [HPP], hereditary stomatocytosis (HSt), and hereditary xerocytosis (HX). RBC enzyme disorders include glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase (PK) deficiency, and other rarer metabolic disorders.
# Hemolytic disease of the fetus and newborn (HDFN):


==Epidemiology and Demographics==
==Epidemiology and Demographics==
* HS is seen in all populations but appears to be especially common in people of northern European ancestry.
[[Hereditary spherocytosis]] can present at any [[Ageing|age]] with any presentation from [[hydrops fetalis]] [[Uterus|inutero]] through [[diagnosis]] in the ninth decade of [[life]], and is reported worldwide in all [[Race|racial]] and [[Ethnic group|ethnic groups]]. It is most [[Common-cause and special-cause|common]] [[inherited]] [[anemia]] in northern european ancestry and north america. The reported [[incidence]] is 1 in 2000 [[Birth|births]]. Approximately 25% of all [[hereditary spherocytosis]] is [[autosomal recessive]]. It is most often [[Diagnosis|diagnosed]] in childhood or early [[Adult|adulthood]].
 
* In the United States, the incidence of the disorder is approximately one case in 5000 people.
* In northern European, HS affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent).


==Risk Factors==
==Risk Factors==
* The risk factors for this condition have not yet been properly identified.
There are no clearly identified [[Risk factor|risk factors]] for the [[hereditary spherocytosis]], but having a positive [[family history]] is an important [[risk factor]] for the [[disease]].
* However, having a family member with this condition can increase your susceptibility to this disease. The condition is also most common in individuals of North European origin although it has been found to arise in people of all races.


==Screening==
==Screening==
* It is also important to test newborns of affected parents for HS, as affected newborns may have severe hyperbilirubinemia and anemia. This may be done by a clinician with expertise in hemolytic anemias or by a genetic counselor. It is possible for an individual with no hemolysis, no spherocytes on the blood smear, and a normal reticulocyte count to be a carrier of HS, which may be relevant in certain families.
The combination of two [[Test|tests]]; [[Mean corpuscular hemoglobin concentration|mean corpuscular hemoglobin concentration (MCHC)]] and [[Red blood cell distribution width|erythrocyte distribution width]] are an excellent [[Screening (medicine)|screening tests]] for [[hereditary spherocytosis]]. For [[Young adult|young]] [[Patient|patients]] with the [[disease]], a full [[family history]], [[Complete blood count|complete blood count (CBC)]], [[Reticulocyte|reticulocyte count]] and [[Physical examination|examination]] of [[Blood film|peripheral blood smear]] on each parent and sibling is required to determine whether the [[Spherocytosis|spherocytic]] [[mutation]] is [[Autosomal dominant|dominant]] or [[Autosomal recessive|recessive]]. For individuals of childbearing [[Ageing|age]] with [[hereditary spherocytosis]], review of [[Family|familial]] [[mutation]] and its mode of [[Transmission (medicine)|transmission]] is useful for discussions of likelihood of [[disease]] in [[Child|children]].


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
[[Hereditary spherocytosis]] can present at any [[Ageing|age]] with any severity, ranging from [[hydrops fetalis]] [[Uterus|in utero]] through [[diagnosis]] in the ninth decade of [[life]], with variable [[clinical]] [[Course (medicine)|course]] depending upon the severity of [[disease]]. Majority of affected individuals have mild or moderate [[hemolysis]] and known [[family history]], making the [[diagnosis]] and treatment relatively easy. [[Complication (medicine)|Complications]] include; [[jaundice]], [[kernicterus]], [[Gallstones|pigment gallstones]], [[Hemolysis|hemolytic]], [[Aplastic anemia|aplastic]] and [[Megaloblastic anemia|megaloblastic crises]], [[splenomegaly]] and [[leukemia]]. The [[prognosis]] is usually good with early [[diagnosis]], regular followup and management. [[Patient|Patients]] with mild [[disease]] may develop [[Symptom|symptoms]] only with environmental [[Trigger|triggers]]. Many [[Patient|patients]] who undergo [[splenectomy]] are able to maintain normal [[Hemoglobin|hemoglobin levels]], however [[Patient|patients]] with severe [[hereditary spherocytosis]] may remain [[Anemia|anemic]] [[Splenectomy|postsplenectomy]] and require regular [[Blood transfusion|blood transfusions]]. [[Splenectomy|Postsplenectomy]] [[Patient|patients]] are at increased risk of [[life]] threatening [[Infection|infections]] ([[sepsis]]), therefore require [[Vaccination|vaccinations]] and [[Antibiotic|antibiotics]].
* '''Disease severity and age of presentation''' — [[Hereditary spherocytosis|HS]] can present at any age and with any severity, with case reports describing a range of presentations, from [[hydrops fetalis]] in utero through diagnosis in the ninth decade of life.  
 
* The majority of affected individuals have mild or moderate hemolysis or [[hemolytic anemia]] and a known family history, making diagnosis and treatment relatively straightforward. Individuals with significant severe hemolysis may develop additional complications such as [[jaundice]]/[[hyperbilirubinemia]], [[folate deficiency]], or [[splenomegaly]].
 
===Complications===
Common complications of [[hemolysis]] include [[neonatal jaundice]], [[splenomegaly]], and pigment gallstones.
* '''[[Neonatal jaundice]]''' — [[Hereditary spherocytosis|HS]] may present in the neonatal period with [[jaundice]] and hyperbilirubinemia, and the serum [[bilirubin]] level may not peak until several days after birth. Some experts have proposed that [[Hereditary spherocytosis|HS]] is underdiagnosed as a cause of [[neonatal jaundice]]. A requirement for [[phototherapy]] and/or [[exchange transfusion]] during this period is common.
* '''[[Splenomegaly]]''' — [[Splenomegaly]] is rare in neonates, but can often be seen in older children and adults with [[Hereditary spherocytosis|HS]]. Early reports of family studies found palpable spleens in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear.
* '''Pigment gallstones''' — Pigment (bilirubin) [[gallstones]] are common in individuals with [[Hereditary spherocytosis|HS]] and may be the presenting finding in adults. [[Gallstones]] are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe [[hemolysis]]. [[Gallstones]] appear to be more common in individuals with [[Gilbert syndrome]].


===Prognosis===
*Overall, the long-term outlook for people with [[hereditary spherocytosis]] (HS) is usually good with treatment. However, it may depend on the severity of the condition in each person.
*People with very mild [[Hereditary spherocytosis|HS]] may not have any signs or symptoms unless an environmental "trigger" causes symptom onset. In many cases, no specific therapy is needed other than monitoring for  and watching for signs and symptoms.[8] Moderately and severely affected people are likely to benefit from splenectomy.<ref name="pmid220550202">{{cite journal| author=Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ, General Haematology Task Force of the British Committee for Standards in Haematology| title=Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update. | journal=Br J Haematol | year= 2012 | volume= 156 | issue= 1 | pages= 37-49 | pmid=22055020 | doi=10.1111/j.1365-2141.2011.08921.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22055020  }}</ref>
*Most people who undergo [[splenectomy]] are able to maintain a normal [[hemoglobin]] level.[4] However, people with severe [[Hereditary spherocytosis|HS]] may remain anemic post-splenectomy, and may need [[blood transfusions]] during an infection.<ref name="pmid22055020">{{cite journal| author=Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ, General Haematology Task Force of the British Committee for Standards in Haematology| title=Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update. | journal=Br J Haematol | year= 2012 | volume= 156 | issue= 1 | pages= 37-49 | pmid=22055020 | doi=10.1111/j.1365-2141.2011.08921.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22055020  }}</ref>
==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
The [[diagnosis]] of [[hereditary spherocytosis]] can be based on [[physical examination]], [[Complete blood count|complete blood count (CBC)]], [[Reticulocyte|reticulocyte count]], [[medical history]] and specific [[Test|tests]] including eosin-5-maleimide binding (EMA) [[test]] and acidified glycerol lysis time (AGLT) [[test]]. The [[diagnosis]] can be made at any [[Ageing|age]]. EMA binding [[test]] has high [[Sensitivity (tests)|sensitivity]] and [[Specificity (tests)|specificity]] for the [[hereditary spherocytosis]]. Other [[Test|tests]] include; osmotic fragility (OF) [[test]], pink [[test]] and ektacytometry. [[Gel electrophoresis]] analysis of [[Red blood cell|erythrocyte]] [[Membrane|membranes]] is the method of choice for [[diagnosis]] of atypical [[Disease|cases]].


===History and Symptoms===
==History and Symptoms==
* As in any other chronic hemolytic states, the signs and symptoms of [[Hereditary spherocytosis|hereditary spherocytosis (HS]]) include mild [[pallor]], intermittent [[jaundice]], and [[splenomegaly]]. However, signs and symptoms are highly variable. [[Anemia]] or [[hyperbilirubinemia]] may be of such magnitude as to require [[exchange transfusion]] in the neonatal period. The disorder also may escape clinical recognition altogether. [[Anemia]] usually is mild to moderate, but is sometimes very severe and sometimes not present.
The [[hereditary spherocytosis]] is a [[Family|familial]] [[Hemolysis|hemolytic]] [[Disorder (medicine)|disorder]] with increased [[Heterogeneous|heterogeneity]]. [[Clinical]] features range from [[asymptomatic]] to [[fulminant]] [[hemolytic anemia]]. [[History and Physical examination|History]] and [[Symptom|symptoms]] of [[hereditary spherocytosis]] include; [[Jaundice|yellowing of skin]], [[fatigue]], [[irritability]], [[weakness]], [[Dyspnea|shortness of breath]], [[anemia]], [[hemolysis]], [[thrombocytopenia]] and [[hyperbilirubinemia]]. [[Gallstones|Pigment gallstones]] may be found in young [[Child|children]], but [[incidence]] of [[Gallstone disease|gallstones]] increases markedly with [[Ageing|age]], however [[jaundice]] is more prominent in [[newborns]].
* Symptoms of hereditary spherocytosis include:
** Yellowing of the skin and eyes (jaundice)
** [[Pallor|Pale coloring (pallor)]]
** [[Fatigue]]
** Irritability
** [[Shortness of breath]]
** [[Weakness]]


===Physical Examination===
==Physical Examination==
* [[Splenomegaly]] is the rule in [[Hereditary spherocytosis|HS]]. Palpable [[Spleen|spleens]] have been detected in more than 75% of affected subjects. The [[liver]] is normal in size and function.
The [[physical examination]] findings in [[hereditary spherocytosis]] include; [[Sclera|scleral]] [[icterus]], [[jaundice]], [[splenomegaly]]. [[Right upper quadrant abdominal pain resident survival guide|Right upper quadrant abdominal pain]] may be elicited if [[gallbladder]] [[disease]] is present.


* Other important clues are [[jaundice]] and upper right abdominal pain indicative of [[gallbladder disease]]. This is especially important if the patient has a family history of [[Gallbladder disease|gallbladder disease.]]
==Laboratory Findings==
* Any patient who presents with profound and sudden [[anemia]] and [[reticulocytopenia]] with the aforementioned physical findings also should have [[Hereditary spherocytosis|HS]] in the differential diagnosis.
The initial [[laboratory]] [[Test|testing]] for [[hereditary spherocytosis]] include; [[Complete blood count|complete blood count (CBC)]], [[Mean corpuscular hemoglobin concentration|mean corpuscular hemoglobin concentration (MCHC)]], [[Blood film|blood smear review]], [[hemolysis]] [[Test|testing]] and [[Coombs test|coombs testing]]. All individuals suspected of having [[hereditary spherocytosis]] based on [[family history]], [[neonatal]] [[jaundice]] or other findings should have a [[Complete blood count|complete blood count (CBC)]], [[reticulocyte count]] and [[Red blood cell|RBC]] indices done. Confirmatory [[Test|tests]] for [[hereditary spherocytosis]] includes EMA binding test, osmotic fragility test, glycerol lysis test, cryohemolysis and [[Cell membrane|plasma membrane]] [[electrophoresis]].


===Laboratory Findings===
== Imaging Findings ==
'''Initial testing'''
There are [[chest X-ray]], [[CT scan]] or [[MRI]] findings associated with [[hereditary spherocytosis]].
* '''CBC and RBC indices''' – All individuals with suspected [[Hereditary spherocytosis|HS]] based on [[family history]], [[neonatal jaundice]], or other findings should have a [[Complete blood count|complete blood count (CBC)]] with [[reticulocyte count]] and [[Red blood cell|red blood cell (RBC)]] indices. The [[Mean corpuscular hemoglobin concentration|mean corpuscular hemoglobin concentration (MCHC)]] is often the most useful parameter for assessing [[spherocytosis]]; an MCHC ≥36 g/dL is consistent with [[Spherocyte|spherocytes]]. A low [[Mean corpuscular volume|mean corpuscular volume (MCV)]] is also helpful in some cases, especially in [[neonates]], but variable degrees of [[reticulocytosis]] make the [[MCV]] less useful in older children and adults.
* '''[[Blood smear]] review''' – All individuals with suspected [[Hereditary spherocytosis|HS]] should have a [[blood smear]] reviewed by an experienced individual. In a [[peripheral blood smear]], the abnormally small [[Red blood cell|red blood cells]] lacking the central pallor i.e. spherocytes are seen. Other abnormal [[RBC]] shapes, and the degree of polychromatophilia, which reflects [[reticulocytosis]].
* '''[[Coombs test|Coombs testing]]''' – If [[hemolysis]] is present, Coombs testing (also called direct antiglobulin testing [DAT]) is usually done to eliminate the possibility of immune-mediated hemolysis, which may be due to [[Hemolytic disease of newborn|hemolytic disease of the fetus and newborn (HDFN)]] in neonates or [[Autoimmune hemolytic anemia|autoimmune hemolytic anemia (AIHA)]] in older children and adults. The results of testing may also be useful to the [[transfusion]] service if [[transfusion]] is indicated. [[Coombs test|Coombs testing]] in [[Hereditary spherocytosis|HS]] is negative.
'''Confirmatory tests'''
* '''EMA binding'''  ●'''Osmotic fragility''' '''●Glycerol lysis''' ●'''Cryohemolysis'''


===Imaging Findings===
==Other Diagnostic Studies:==
 
There are no other diagnostic studies associated with [[hereditary spherocytosis]].
===Other Diagnostic Studies===


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
* As with most inherited hemolytic anemias, treatment is directed at preventing or minimizing complications of chronic hemolysis and anemia. There are no specific treatments directed at the underlying red blood cell (RBC) membrane defect.
There is no specific medical [[therapy]] for the [[hereditary spherocytosis]], as the [[diagnosis]] is made, surveillance is needed to help detect and manage any [[Complication (medicine)|complications]]. A routine annual review is usually sufficient to detect any [[Complication (medicine)|complications]]. [[Folic Acid|Folic acid]] supplementation is not always required, but is used as a routine for [[Child|children]] with severe [[hemolysis]] and in [[pregnancy]] regardless of severity of [[disease]]. [[Blood transfusion]] may also be required in severely affected [[Infant|infants]] and may be needed during [[aplastic crisis]] or [[pregnancy]]. However, [[Erythropoietin|erythropoietin (EPO)]] may be helpful in reducing the need for [[Blood transfusion|transfusion]] in some [[Infant|infants]].
 
* If a neonate is suspected of having HS (eg, based on positive family history and neonatal jaundice), treatment can be initiated for HS without awaiting diagnostic confirmation. This may include therapy for hyperbilirubinemia and, in severe cases, transfusion or even exchange transfusion [83
* The goals of pharmacotherapy for hereditary spherocytosis are to reduce morbidity and prevent complications. Folic acid supplementation is indicated to prevent megaloblastic crisis.


===Surgery===
===Surgery===
* Generally, the treatment of HS involves presplenectomy care, splenectomy, and management of postsplenectomy complications.
Generally, the treatment of [[hereditary spherocytosis]] involves presplenectomy care, [[splenectomy]] and management of postsplenectomy [[Complication (medicine)|complications]]. [[Splenectomy]] is very effective in reducing [[hemolysis]], leading to significant prolongation of [[red blood cell]] [[lifespan]]. Partial [[Splenectomy|splenectomies]] can be used in [[Pediatrics|pediatric]] [[Patient|patients]] as it controls [[hemolysis]] and preserves [[Spleen|splenic]] [[Function (biology)|function]]. [[Patient|Patients]] having concomitant [[Gallstone disease|gallstones]] are likely to benefit from combined [[splenectomy]] and [[cholecystectomy]] in terms of [[life expectancy]]. Post [[splenectomy]] [[Complication (medicine)|complications]] may include; [[Infection|infections]] & [[sepsis]] caused by [[encapsulated organisms]] ([[streptococcus pneumoniae]], [[neisseria meningitidis]], [[Haemophilus influenzae|haemophilus influenza]]), [[Deep vein thrombosis|deep venous thrombosis (DVT)]], [[Pulmonary embolism|pulmonary emboli]] and [[portal vein thrombosis]].
* In pediatric cases, splenectomy ideally should not be performed until a child is older than 6 years because of the increased incidence of postsplenectomy infections with encapsulated organisms such as ''S pneumoniae'' and ''H influenzae'' in young children.
* Partial splenectomies are increasingly used in pediatric patients, as this approach appears to both control hemolysis and preserve splenic function.


===Prevention===
==Prevention==
In general, once the diagnosis and baseline severity of HS in a child are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (such as intercurrent infection and pallor, or an increase in jaundice). A routine annual review is usually sufficient together with an open door policy for potential complications such as parvovirus infection, or abdominal pain, which may trigger investigation for gallstones.
There is no primary prevention available for the [[hereditary spherocytosis]], however administration of [[Vaccine|vaccines]] including [[Pneumococcal vaccine|pneumococcal]], [[Haemophilus influenzae|hemophilus influenzae]], [[Neisseria meningitidis|meningococcal]] and [[Influenza vaccine|influenza]] should be given two to three weeks before [[splenectomy]]. [[Folic Acid|Folic acid]] supplementation as well as oral [[penicillin]] is also suggested for postsplenectomy [[Patient|patients]] untill reaching [[Adult|adulthood]].


===References===
===References===

Latest revision as of 01:10, 11 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]

Overview

Hereditary spherocytosis is a genetically transmitted form of hemolysis, characterized by hemolytic anemia, jaundice and splenomegaly. It was first described by Vanlair and Masius in 1871, where they described chronically icteric patients who had no bile in urine, no evidence of liver disease and often splenomegaly and family history of jaundice. Hereditary spherocytosis is classified in 05 subtypes on the basis of underlying protein defect including; ankyrin1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic1), band 3 and protein 4.2. The defects in hereditary spherocytosis lie in the cell membrane. The cell membrane proteins essential for the integrity of cell membrane structure includes; spectrin, ankyrin, band 3 and protein 4.1 and 4.2, and their deficiency can produce varying degree of severity of the disease. it should be differentiated from autoimmune hemolysis, congenital dyserythropoietic anemia type II, thermal injury and hemoglobinopathies. Hereditary spherocytosis can present at any age, having a positive family history is an important risk factor for the disease. Mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width (RDW) tests can be used for the screening of hereditary spherocytosis. Complications of the disease include; jaundice, kernicterus, pigment gallstones, splenomegaly, hemolytic, aplastic and megaloblastic crises. It can present with yellowing of skin, fatigue, irritability, shortness of breath or it can be asymptomatic altogether. Physical examination findings include scleral icterus, jaundice and splenomegaly. Laboratory testing includes CBC, MCHC, blood smear, hemolysis testing and coombs test. There is no specific medical therapy for the hereditary spherocytosis, however surveillance is needed to help detect and manage the complications. Folic acid supplementation, blood transfusions and erythropoietin may also be tried. Splenectomy is very effective in reducing the hemolysis. Partial splenectomies are tried in children to control hemolysis and preserve splenic function as well. Administration of vaccines (pneumococcal, hemophilus influenzae, meningococcal and influenza), antibiotics (penicillin) and folic acid should be prescribed for postsplenectomy patients.

Historical Perspective

The hereditary spherocytosis was first described in 1871 by Vanlair and Masius, where they described chronically icteric patients who had no bile in the urine, no evidence of liver disease and often splenomegaly and family history of jaundice. It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.

Classification

The hereditary spherocytosis classified into 05 subtypes on the basis of underlying protein defect including; ankyrin 1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic 1), band 3 and protein 4.2. It is also classified on the basis of clinical severity into mild, moderate and severe subtypes.

Pathophysiology

The defects in hereditary spherocytosis lie in the cell membrane. The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizental alpha & beta spectrin molecules form heterodimers with linkage to vertical elements including ankyrin, proteins 4.1 & 4.2 and band 3 (transmembrane protein). The shorter the lifespan of red blood cells, the worse the clinical effects. Spectrin protein is a tetramer composed of alpha & beta dimers, its deficiency is most frequently seen in hereditary spherocytosis. Spectrin deficiency can result from impaired synthesis of spectrin or from qualitative or quantitative defects in other proteins that integrate proteins into red blood cells. Ankyrin is the principal binding site for spectrin on red blood cell membrane, its deficiency leading to decreased incorporation of spectrin, leading to proportional decrease in spectrin content as well despite normal synthesis of spectrin. Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis and is considerably greater in older red blood cells. Protein 4.2 (Pallidin) deficiency leads to abnormal red blood cell morphology including spherocytes, elliptocytes or sphero-ovalocytes, it is relatively common in japan. Red blood cell antibodies may also have a pathogenic role in red blood cell opsonization and removal by spleen.

Causes

Hereditary spherocytosis is caused by a variety of genetic mutations. The 05 genes associated with hereditary spherocytosis include; alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band 3 (SLC4A1) and protein 4.2 (EPB42). Mutations in one or more of these genes can cause membrane protein deficiency leading to hereditary spherocytosis.

Differentiating Hereditary spherocytosis overview from Other Diseases

Hereditary spherocytosis usually presents with hemolysis, therefore should be differentiated from other diseases including; autoimmune hemolysis, thermal injury, clostridial septicemia, wilson disease, hemoglobinopathies, hereditary stomatocytosis, congenital dyserythropoietic anemia type II, infantile pyknocytosis and hemolytic disease of fetus and newborn (HDFN).

Epidemiology and Demographics

Hereditary spherocytosis can present at any age with any presentation from hydrops fetalis inutero through diagnosis in the ninth decade of life, and is reported worldwide in all racial and ethnic groups. It is most common inherited anemia in northern european ancestry and north america. The reported incidence is 1 in 2000 births. Approximately 25% of all hereditary spherocytosis is autosomal recessive. It is most often diagnosed in childhood or early adulthood.

Risk Factors

There are no clearly identified risk factors for the hereditary spherocytosis, but having a positive family history is an important risk factor for the disease.

Screening

The combination of two tests; mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width are an excellent screening tests for hereditary spherocytosis. For young patients with the disease, a full family history, complete blood count (CBC), reticulocyte count and examination of peripheral blood smear on each parent and sibling is required to determine whether the spherocytic mutation is dominant or recessive. For individuals of childbearing age with hereditary spherocytosis, review of familial mutation and its mode of transmission is useful for discussions of likelihood of disease in children.

Natural History, Complications, and Prognosis

Hereditary spherocytosis can present at any age with any severity, ranging from hydrops fetalis in utero through diagnosis in the ninth decade of life, with variable clinical course depending upon the severity of disease. Majority of affected individuals have mild or moderate hemolysis and known family history, making the diagnosis and treatment relatively easy. Complications include; jaundice, kernicterus, pigment gallstones, hemolytic, aplastic and megaloblastic crises, splenomegaly and leukemia. The prognosis is usually good with early diagnosis, regular followup and management. Patients with mild disease may develop symptoms only with environmental triggers. Many patients who undergo splenectomy are able to maintain normal hemoglobin levels, however patients with severe hereditary spherocytosis may remain anemic postsplenectomy and require regular blood transfusions. Postsplenectomy patients are at increased risk of life threatening infections (sepsis), therefore require vaccinations and antibiotics.

Diagnosis

The diagnosis of hereditary spherocytosis can be based on physical examination, complete blood count (CBC), reticulocyte count, medical history and specific tests including eosin-5-maleimide binding (EMA) test and acidified glycerol lysis time (AGLT) test. The diagnosis can be made at any age. EMA binding test has high sensitivity and specificity for the hereditary spherocytosis. Other tests include; osmotic fragility (OF) test, pink test and ektacytometry. Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

History and Symptoms

The hereditary spherocytosis is a familial hemolytic disorder with increased heterogeneity. Clinical features range from asymptomatic to fulminant hemolytic anemia. History and symptoms of hereditary spherocytosis include; yellowing of skin, fatigue, irritability, weakness, shortness of breath, anemia, hemolysis, thrombocytopenia and hyperbilirubinemia. Pigment gallstones may be found in young children, but incidence of gallstones increases markedly with age, however jaundice is more prominent in newborns.

Physical Examination

The physical examination findings in hereditary spherocytosis include; scleral icterus, jaundice, splenomegaly. Right upper quadrant abdominal pain may be elicited if gallbladder disease is present.

Laboratory Findings

The initial laboratory testing for hereditary spherocytosis include; complete blood count (CBC), mean corpuscular hemoglobin concentration (MCHC), blood smear review, hemolysis testing and coombs testing. All individuals suspected of having hereditary spherocytosis based on family history, neonatal jaundice or other findings should have a complete blood count (CBC), reticulocyte count and RBC indices done. Confirmatory tests for hereditary spherocytosis includes EMA binding test, osmotic fragility test, glycerol lysis test, cryohemolysis and plasma membrane electrophoresis.

Imaging Findings

There are chest X-ray, CT scan or MRI findings associated with hereditary spherocytosis.

Other Diagnostic Studies:

There are no other diagnostic studies associated with hereditary spherocytosis.

Treatment

Medical Therapy

There is no specific medical therapy for the hereditary spherocytosis, as the diagnosis is made, surveillance is needed to help detect and manage any complications. A routine annual review is usually sufficient to detect any complications. Folic acid supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy regardless of severity of disease. Blood transfusion may also be required in severely affected infants and may be needed during aplastic crisis or pregnancy. However, erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.

Surgery

Generally, the treatment of hereditary spherocytosis involves presplenectomy care, splenectomy and management of postsplenectomy complications. Splenectomy is very effective in reducing hemolysis, leading to significant prolongation of red blood cell lifespan. Partial splenectomies can be used in pediatric patients as it controls hemolysis and preserves splenic function. Patients having concomitant gallstones are likely to benefit from combined splenectomy and cholecystectomy in terms of life expectancy. Post splenectomy complications may include; infections & sepsis caused by encapsulated organisms (streptococcus pneumoniae, neisseria meningitidis, haemophilus influenza), deep venous thrombosis (DVT), pulmonary emboli and portal vein thrombosis.

Prevention

There is no primary prevention available for the hereditary spherocytosis, however administration of vaccines including pneumococcal, hemophilus influenzae, meningococcal and influenza should be given two to three weeks before splenectomy. Folic acid supplementation as well as oral penicillin is also suggested for postsplenectomy patients untill reaching adulthood.

References

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