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Case Report: Severe Anemia with Anemic Heart Disease

By: Rohmantuah Trada Purba Advicer: dr. I Nyoman Suarjana, Sp.PD-KR

Department of Internist, Ulin Hospital/Unlam School of Medicine Banjarmasin, IndonesiaMei 2012

Abstract

A 36-year-old woman was admitted to Ulin Hospital on 1 Mei 2012. Shecomplained of limp, pale and skin that turn to yellow from 15 day before. She alsocomplained nausea and urin color like color of tea. She is married and not havechild yet. The patients blood pressure was 80/40 mmHg; heart rate, 100 beats per

minute; body temperature, 36,5 oC; and respiratory rate, 28 breaths per minute. Onphysical examination, the patient was somnolen, has decreased of conscious andbabbling. She also has anemic konjunctiva, icteric sclera and pale skin. In theBlood Test, she has very low value of Hemoglobin that is 1,9 g/dL. On 4 th day ofadmission in Ulin Hospital, Chest X-ray was have an appreance of cardiomegaly.In this phase patient was diagnosed with Severe Anemia with Anemic HeartDisease

Introduction

In order to make ageneralized approach to thediagnosis of anemia, the WorldHealth Organization (WHO) hasestablished a reference range fornormal blood hemoglobinconcentration, depending on age andsex.(1)According to this criterion,anemia is present if the bloodconcentration of hemoglobin falls

below 130 g/L in men or 120 g/L in

women. This rule does not apply toinfants, children and pregnantwomen, who have their own tables oflower limits of hemoglobinconcentration. The WHO criteria has

been accepted widely for diagnosisand publication, but its universalapplication has been questionedmainly because of racial differences.Beutler has proposed a lower limit ofhemoglobin (1-2 g less) in AfricanAmericans than in Caucasians. Thereference range of hemoglobinconcentration in blood may varydepending on the populationanalyzed, age, sex, environmental

conditions and food habits.

(2,3)

Age/Sex Hb Gram/dL (venous blood)

Adult male 13

Adult female 12

Adult female pregnant 11

Children 6 months to 6years

11

Children 6 to 14 years 12


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Anemia is one of the most

frequent causes of medical visitsbecause of the high incidence inchildren, young women and elderly

people, especially if malnutrition ispresent. Moreover, anemia is one ofthe leading sings in many diseases oris the first evidence of diseaseobserved in routine blood cellenumeration. Anemia is unusually

prevalent in developing countriesbecause of malnutrition, and genetic,

parasitic or infectious diseases. Theprevalence of anemia varies greatly,from 2.9% to 61%, depending on

population, age, sex, and normallimits of hemoglobin used by theauthor. (1)

Severe anemia defined as Hb< 6.0 g/dL. It has been observed thatin malaria-endemic areas, theincidence of severe anemia and age-specific rates of anemia stronglycorrelate with the intensity ofPlasmodium falciparum transmission.Beside that severe anemia iscommon in patients withmyelodysplastic syndromes andLeukimia (6,7).

Chronic severe anemia isknown to cause high-cardiac-outputheart failure (HF). Moreover, anemiais common in patients with HF, and

many recent observations haveshown that reduced hemoglobinindicates an independent risk ofhospitalization and all-causemortality in patients with HF.Anemia is frequently seen in patientswith systolic, as well as diastolic,HF. Several factors, such as hemodilution, impaired erythropoietin(Epo) secretion, chronicinflammation, and disturbed iron

metabolism, are supposed to cause

anemia in patients with HF;

however, the mechanism by whichanemia causes or facilitates HFremains largely unknown. (4)

There are several potentialreasons anemia may be a riskfactorfor CVD outcomes. First, the

presence of anemia, if extended for along period, may result in ventricularremodeling and cardiac dysfunction.Chronic anemia with hemoglobin 10g/dl is known to result in increased

cardiac output that may lead to LVH.The latter is well appreciated in

patients who are anemic secondary totheir kidney disease, as well as in

patients with sickle cell disease.Second the presence of anemia mayin theory be a risk factor formyocardial ischemia. Third, reducedhemoglobin may be associated withother risk factors for CVD that werenot ascertained in this study, such asdecreased nutritional status,additional measures of lowersocioeconomic status, or increasedinflammatory status. (8)

There are physiologicreasons, however, to suspect that the

presence of chronic anemia mayresult in adverse long-termcardiovascular consequences.Chronic anemia may result in an

increased cardiac output secondaryto decreased afterload, increasedpreload and increased chronotropicand inotropic effects. Over time thismay lead to ventricular dilation andLVH. The chronic increase incardiac output may also lead toarterial remodeling of central elasticarteries such as the aorta or thecarotids. This remodeling in turnresults in arterial enlargement and

compensatory arterial intima media


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thickening, or arteriosclerosis. Thepresence of either LVH or

arteriosclerosis may be more directlyassociated with future CVD risk. (5)

The increased myocardialworkload due to hemodynamic andneurohormonal alterations observedin chronic anemia could causeadverse LV remodeling. LVhypertrophy and dilation areobserved in animal models of severeanemia and they may contribute to

poor outcomes. Whereas LV

hypertrophy is consistently found inanemic patients with CKD, it isunclear whether it is related toanemia or hypertension. Althoughthere are no data directly linking LVhypertrophy and anemia in HF, a 1-g/dl increase in Hgb over the courseof 24 weeks was associated with a4.1-g/m2 decrease in LV mass in theRENAISSANCE (RandomizedEtanercept North American Strategyto Study Antagonism of Cytokines)trial. (9)

When faced withhemodynamic load burden, heartcompensated with Frank-Starlingmechanisms to increase cross-bridgeformation, increase muscle mass toface the additional burden, and use ofneurohormonal mechanisms toincrease contractility. In accordance

with the law of LaPlace that the loadon all parts of the heart muscle =(pressure x radius) / (2 x wallthickness), then persistent pressureload on the heart muscle that settledin a long time, such as hypertensionand aortic stenosis, will causesmuscle fibers to grow thicker andincreases muscle mass. Parallelarranged sarcomeres causes dilationof myocyte and result in the form of

concentric hypertrophy remodeling

(increase ratio of wall thickness /size of the room). Because systolic

stress (load end) is a majordeterminant of the pumping

performance, so normalization ofsystolic stress to maintain a normalejection fraction is required.(10)

Increased wall stress andstrain is generate stimulation signalcausing transcription of mRNA toincrease muscle protein. Thesenuclear reactions produce protectionto cardiac muscle against excessive

pressure wall to minimize oxygenconsumption.(10)

Biomechanical stress such ashypertension and chronic pressureload enable signal hypertrophy andapoptosis in parallel. At the sametime, also led to induction of

biomechanical stress-related ligandson gp130 as kardiotropin 1. Thiscytokine bound to receptors thatcontain gp130-LIF (leukemiainhibitory factor) heterodimer,resulting in activation of gp130

pathway that inhibits the action ofthe apoptosis pathway. Withoutgp130, cardiac myocytes respond to

biomechanical stress shifted towardapoptosis, resulting in loss offunctional myocytes and theincidence of heart failure.The resultof biomechanical stress depends on

the balance between these twoopposing signaling transductionpathways. (10)

The regulation of cell growthmediators that including cytokines,growth hormone (GH) and insulin-like growth factor 1 (IGF-1), also

plays an important role in influencegrowth and composition of the heartmuscle. These mediators are alsoinvolved in a regression that caused

the transition from compensated left


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ventricular hypertrophy types ofstructural changes towards severe

heart muscle leading to heart failure.mRNA IGF-1 is increased byangiotensin II heart throughhemodynamic and non hemodynamicmechanisms and regulate cardiacstructural changes that occur inhypertension. There has beenevidence of a direct effect of GH in

the ventricular response to a numberof physiological and pathological

stimuli that increase cardiac load.GH / IGF-1 pathway may also helpexplain the relationship betweenobesity, increased blood pressure, thedevelopment of hypertrophy of theleft ventricle, and the metabolicsyndrome.(1)

Case Report

A 36-year-old woman was

admitted to Ulin Hospital on 1 Mei2012. She complained of limp, paleand skin that turn to yellow from 15day before. She also complainednausea and urin color like color oftea. She is married and not havechild yet. According to her family,she was have complain like this 10years ago and diagnosed withHepatitis.

Her blood pressure was 80/40mmHg; heart rate, 100 beats perminute; body temperature, 36,5 oC;and respiratory rate, 28 breaths perminute. On physical examination, the

patient was somnolen, has decreasedof conscious and babbling. She alsohas anemic konjunctiva, icteric scleraand pale skin. She was diagnosedthen with Anemia Gravis e.cHemolitic Anemia and differential

diagnose Hepatitis B.On 1st day admission on UlinHospital, laboratotium finding forthis patient is : Hb = 1.9 g/dL,Leukosit=6500/uL, Eritrosit :670.000/uL, Hematokrit 5 vol%.

She has very low value ofHemoglobin. On day 1st day ofhospitalization, she still had mentalstatus changes, which includedsomnolen and hard to talk with

others. She sent to the ward after get

2 kolf PRC transfusion and she is

getting better at respiration and herconsciousness. In the ward physicalexamination has found an anemickonjunctiva and pale skin especiallyin palmar. This clinical findingssuggested that patient still hasanemia even after treated inemergency care.

1st day of admission she wasgiven IVFD NaCl 20 dpm, Lamesoninjection 12 gr vial/12 hour,Ranitidin injection 50 mg/12hour, 2kolf PRC transfusion/day and O2 3lpm. On day 4rd Bone marrowAspiration has been do to patient andthe result is MDS. On day 4th,Coombs test, Thorax rontgen andEKG have been do to patient and theresult is Coomb test:negative, Thoraxrontgen and EKG suggested thatthere are left ventricular hyperthropy

so in day 4th

patient diagnosed withAnemia Gravis with Anemic HeartDisease.On day 2nd until day 9th ofadminission her blood pressure, heartrate, respiratory and bodytemperature rate were in normallevel. Her complain of limp and hardmove is decrease.

She was discharged 9 daysafter admission with skin still pale,

limp body and other anemic sign .


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The doctor planned to give IVFDNaCl 20 dpm, Lameson injection 12

gr vial/12 hour, Ranitidin injection

50 mg/12hour, PRC transfusion untilpatient Hb > 10 and Kemotherapy

for her MDS.

Discussion

On admission at the UlinHospital, the patient come with somesevere anemic sign such as pale andicteric skin, limp, somnolen andanemic conjunctiva. Her Hemoglobin value is 1,9 gr/dLindicated that this patient has aanemia gravis (Hb < 6 gr/dL)

resulting a decrease in the oxygen-carrying capacity of the blood. Asthe oxygen content is diminished inanemia, the anemic patient canmaintain the overall supply ofoxygen to the tissues only byincreasing cardiac output and thatcompensation reducing the cardiacreserve. If the coronary blood flowfails to deliver sufficient oxygen theheart muscle becomes relativelyhypoxic, and there will be a fall incardiac output and a reduction insystemic blood flow.

Hyperanemia is a severe formof anemia, in which the hematocrit is

below 10%. Critical condition ofpatient reported in this case, requiredaggressive treatment in order toavoid fatal consequences of anemiaand hypovolemia. In this case,

management is aimed at preventingtissue hypoxia by maintaining anadequate circulating volume of redcells. this requires a multidisciplinaryapproach including control of therelevant physiological parameters,maintenance of tissue perfusion,temperature control and bloodcomponent or pharmacologicaltreatment to support coagulation. (11)

The effects of anemia must

be separated from hypovolemia,

although both can impede tissueoxygen delivery. Oxygen delivery inhealthy adults is maintained evenwith hemoglobin levels as low as 6-7g/dl. But with Hb value 1,9 this

patient will need an O2 treatment toincrease tissue perfusion. So this

patient get O2 treatment 3 lpm in

emergency care. (11)Transfusion is necessary to

minimize symptoms and risksassociated with symptomatic chronicanemia when hemoglobin is below 6g/dl. This patient get repeatedly PRCtransfusions 2 kolf/ day to increase

physiological parameters that causedby this severe anemia, maintenanceof tissue perfusion and bloodcomponent. This patient get givenIVFD NaCl 20 dpm. The purpose offluid resuscitation is to delay or

prevent the chain of events that leadsto irreversible shock caused bysevere anemia. (11)

This patient has sign ofhemolytic anemia that she complainher skin turn to yellow and in

physical examination we get anicteric sclera so patient get a

methylprednisolon therapy inLameson injection 12 gr vial/ 12hour. Immunosuppressive therapywith corticosteroids is the first linetherapy of warm type AIHA (AutoImmune Hemolytic Anemia) and aresponse is seen in approximately80% of cases. But in day 4th Coombtest is done and the result is negativeso in purpose to get a cause ofanemia BMA is done in 4th day and

the result of BMA is Myelodisplasia


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Syndrome. Because this BMA result,planning for this patient is

kemotherapy but patient wasdischarge before she getkemotherapy. (12)

In the Antero-Posteriorthorax rontgen on 4th day, there are acardiomegaly in this patient. Withoutany history of etiology or risk factorof cardiomegaly such ashypertension, heart disease or thyroiddisorders, the cause of thiscardiomegaly is expected from

severe anemia. The lack or theinsufficient presence of Red BloodCells (RBCs) in the blood may behighly responsible for causingcardiomegaly. This exerts pressureon the heart to beat at a fast pace soas to compensate for the loss ofadequate oxygen to the tissues. Butthis has the unfortunate consequenceof enlarging the heart and this iscausing cardiomegaly. (13)

Severe anemia defined as Hb< 6.0 g/dL and this patient Hb value

in 1st day of admission is 1,9g/dL.With this low value of Hb, oxygen

will not delivered normally. Theresult is tissue and end organ willhave a hipoperfusionand will give afeedback to increase perfusion. Insevere anemia, low Hgb reducessystemic vascular resistance (SVR)as the result of decreases in bloodviscosity and enhanced nitric oxide-mediated vasodilation. Low SVRreduces blood pressure (BP) andcauses baroreceptor-mediated

neurohormonal activation , identicalto that seen in low output HF . Theincreased sympathetic and renninangiotensin activity decreases RBFand glomerular filtration rate,resulting in salt and water retention

by the kidneys and expansion of theextracellular and plasma volumes.The combined effect of volumeexpansion and vasodilation increasesthe cardiac output which may help toincrease oxygen transport. (9)


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When faced withhemodynamic load burden, heart

compensated with Frank-Starlingmechanisms to increase cross-bridgeformation, increase muscle mass toface the additional burden, and use ofneurohormonal mechanisms toincrease contractility. In accordancewith the law of LaPlace that the loadon all parts of the heart muscle =(pressure x radius) / (2 x wallthickness), then persistent pressureload on the heart muscle that settled

in a long time, such as hypertensionand aortic stenosis, will causesmuscle fibers to grow thicker andincreases muscle mass. Parallelarranged sarcomeres causes dilationof myocyte and result in the form ofconcentric hypertrophy remodeling(increase ratio of wall thickness /size of the room). Because systolicstress (load end) is a majordeterminant of the pumping

performance, so normalization ofsystolic stress to maintain a normalejection fraction is required.(10)

Increased wall stress andstrain is generate stimulation signal

causing transcription of mRNA toincrease muscle protein. These

nuclear reactions produce protectionto cardiac muscle against excessive

pressure wall to minimize oxygenconsumption.(10)

Biomechanical stress such ashypertension and chronic pressureload enable signal hypertrophy andapoptosis in parallel. At the sametime, also led to induction of

biomechanical stress-related ligandson gp130 as kardiotropin 1. This

cytokine bound to receptors thatcontain gp130-LIF (leukemiainhibitory factor) heterodimer,resulting in activation of gp130

pathway that inhibits the action ofthe apoptosis pathway. Withoutgp130, cardiac myocytes respond to

biomechanical stress shifted towardapoptosis, resulting in loss offunctional myocytes and theincidence of heart failure.The resultof biomechanical stress depends onthe balance between these twoopposing signaling transduction

pathways.(10)


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The regulation of cell growthmediators that including cytokines,

growth hormone (GH) and insulin-like growth factor 1 (IGF-1), also

plays an important role in influencegrowth and composition of the heartmuscle. These mediators are alsoinvolved in a regression that causedthe transition from compensated leftventricular hypertrophy types ofstructural changes towards severeheart muscle leading to heart failure.mRNA IGF-1 is increased by

angiotensin II heart throughhemodynamic and non hemodynamicmechanisms and regulate cardiacstructural changes that occur inhypertension. There has beenevidence of a direct effect of GH inthe ventricular response to a numberof physiological and pathologicalstimuli that increase cardiac load.GH / IGF-1 pathway may also helpexplain the relationship betweenobesity, increased blood pressure, thedevelopment of hyper-trophy of the left ventricle, and themetabolic syndrome.(10)

The treatment of patientswith anemic heart disease conditionsincluding causative therapy andsymptomatic therapy. In this patientclinician has planning to give akemotherapy as a causative therapy

for her MDS because that MDS thatmake a conditions of severe anemiain this patient. Until the recent past,treatment for MDS was limited to

best supportive care (growthfactors and transfusion support)for the majority of patients andallogeneic stem cell transplant forthe small minority of patientseligible for the procedure. Of thesetreatments, only transplant offered

an approach that changed the

natural history of the disease andoffered a cure. More recently, newer

agents, such as azacitidine anddecitabine, have been FDA approvedto treat MDS based on their impacton the natural history of diseasethrough decreasing the rate oftransformation from MDS to AML.(14)

Cyclosporine and ATG wereamong the first immunomodulatoryagents used in the treatment ofMDS and showed partial success in

producing transfusionindependence. Early studies ofthalidomides effectiveness in

patients with MDS reported 31%hematologic responses after twelveweeks of therapy. Subsequentstudies revealed response ratesfrom minimal to nearly 50% with

partial success inducing transfusionindependence seen in a subset of

patients . Unfortunately, the sideeffect profile of hypotension,neuropathy, constipation, anddrowsiness makes the drug poorlytolerated, especially in elderly

patients . Consequently, based onthe clinical activity of thalidomide,newer analogues have beendeveloped to try to minimize sideeffects. Lenalidomide is the onlycurrently clinically available

thalidomide analogue for treatmentof patients with MDS. It is reportedto share many of the samemechanisms of action withthalidomide; however, lenalidomidehas not shown the same effect onendothelial cell proliferation. (14)

Anemia in cancer patients isfrequent but often underestimated.Anemia affects the health-relatedquality of life and impacts prognosis

and outcome of therapy. Treatment


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options include the administration ofhematopoietic growth factors and red

blood cell transfusions. Bloodtransfusions result in rapid but oftentransient improvement of anemia.Administration of epoetin ordarbepoetin alfa increaseshemoglobin levels, decreases bloodtransfusions, and improves quality oflife in patients with cancer.Presently, trials investigate whethertreatment of anemic cancer patients

with erythropoietin impacts onoutcome of chemo- and/or

radiotherapy and on overall survival.Oncologists must be aware of theclinical relevance of anemia andoffer adequate treatment options totheir patients. Supportive treatmentof anemic cancer patients presentinganemia-related symptoms should be

performed to reduce symptoms incancer patients and optimizeoutcome to anticancer therapy. (15)

Conclusion

A 36-year-old woman wasadmitted to Ulin Hospital on 1 Mei2012. She complained of limp, paleand skin that turn to yellow from 15day before. She also complainednausea and urin color like color oftea. Her Hb value is 1,9 g/dL. InChest X-ray there are an appreanceof cardiomegaly. This patient wasdiagnosed as Severe Anemia with

Anemic Heart Disease. This patientswith anemic heart disease conditionshas treated with causative therapyand symptomatic therapy such as

blood transfussion for her anemia,Methylprednisolon for her hemolyticanemia, fluid resuscitation and

planning for kemotherapy for herMDS.

References

1. Jose A, Maria S, Martn G.Classifcation of anemia forgastroenterologists. World JGastroenterol 2009 October 7;15(37): 4627-4637.

2. Beutler E, Waalen J. The

definition of anemia: what is thelower limit of normal of theblood hemoglobin concentration. Blood. 2006;107:17471750.

3. Patel KV, Harris TB, FaulhaberM, Angleman SB, Connelly S,Bauer DC, Kuller LH, NewmanAB, Guralnik JM. Racialvariation in the relationship ofanemia with mortality andmobility disability among older

adults. Blood. 2007;109:46634670.

4. Yoshiro N, Takeshi T, Mika Met al. Adaptive response of theheart to long-term anemiainduced by iron deficiency. AmJ Physiol Heart Circ Physiol2009 :296: 585593.

5. Metivier F, Marchais SJ, GuerinAP, Pannier B, London GM.Pathophysiology of anaemia:focus on the heart and bloodvessels. Nephrol Dial Transplant2000;15 Suppl 3:1418.


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6. Kwadwo A et al. Severe anemiain young children after high and

low malaria transmissionseasons in the kassena-nankanadistrict of northern Ghana. Am.J. Trop. Med. Hyg. 2000: 62(6):670674

7. Esther N, Carina S, Adam S. Areview of anemia as acardiovascular risk factor in

patients with myelodysplasticsyndromes. Am J Blood Res2011;1(2):160-166.

8. Mark J et al. Anemia as a RiskFactor for CardiovascularDisease in the AtherosclerosisRisk in Communities (ARIC)Study.JACC 2002: Vol. 40: 2733.

9. Inder S. Anemia and ChronicHeart Failure: Implications andTreatment Options. Journal ofthe American College ofCardiology 2008: vol 52: 501511

10. Sanjaya W, Soerianata S.Peranan faktor faktor hemodinamik dan nonhemodinamik dalam mekanisme

patogenik hipertrofi ventrikel

kiri. Cermin Dunia Kedokteran2004 :143 : 15-18

11. Dankovi A, ubo A. Severeanemia: a case report. Journal ofHealth Sciences 2011: 1 (2):110-114.

12. Yaral N, Fgn T, Kara A,Duru F. Successful managementof severe chronic autoimmunehemolytic anemia with low dosecyclosporine and prednisone inan infant. The Turkish Journalof Pediatrics 2003; 45: 335-337.

13. http://www.primehealthchannel.com/cardiomegaly-definition-symptoms-causes-diagnosis-and-treatment.html. DiaksesTanggal 23 mei 2012.

14. Warlick E, Smith B.Myelodysplastic Syndromes:Review of Pathophysiology andCurrent Novel TreatmentApproaches. Current CancerDrug Targets, 2007, 7, 541-558.

15. Gudrun M I, Heinz L.Supportive treatment for anemiccancer patients. Wien MedWochenschr 2004. 154(9) 10 :226-234
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