anämisch - spital · pdf fileadjustedforage, diabetesmellitus, gfr, andcomorbidity....
TRANSCRIPT
A.Holbro
11.SchwyzerSymposiumfur̈InnereMedizin
October26th,2017
Schwyz,CH
Anämisch
Agenda
• Definitionof anemia• Work-up• Classification/characterization &differentialdiagnosis ofanemia• Treatment(some aspects):
- anemia of chronic disease- autoimmunehemolytic anemia
- nottransfusions ¬iron!
Anemia
• Definitionof anemia:reduced RBCmass,indicated by adecrease inhemoglobin
Adult men: Hb <130g/lAdult women*: Hb <120g/l
*Adultnon-pregnant women;WHO1986
Anemia
• Definitionof anemia:reduced RBCmass,indicated by adecrease inhemoglobin
• Symptoms:fatigue,dizziness,dyspnea,bleeding,constitutional symptoms• Clinicalfindings:pallor,tachycardia,systolic flow murmur,jaundice, splenomegaly,lymphadenopathy
Anemia
Prevalence of anemia:
Guralnik JMetal.Blood2004
Anemia of the elderly
AI:anemia of inflammation;CKD:anemia secondary to renaldisease;HemMalig:hematologic malignancy;IDA:iron-deficiency anemia;Susp MDS:suspicious for myelodysplastic syndrome;
Thal:thalassemia;UAE:unexplained anemia of the elderly
Pang WWetal.Curr Opin Hematol 2012
Adjusted for age,diabetes mellitus,GFR,and comorbidity.Culleton BFetal.Blood2006
Anemiaoftheelderly
length of hospital stay (median increase in length of stay, 8.0 days[95% CI, 4.7-11.3 days], data not shown).
Association between hemoglobin and all-cause mortality
The adjusted probability of death as a function of baselinehemoglobin for women and men is shown in Figure 2A and B,respectively. A reverse J-shaped relationship between hemoglobinand all-cause mortality is seen for both sexes, although anincreased mortality risk associated with higher hemoglobin valuesreached statistical significance in women only.
Discussion
In this community-based study of more than 17 000 older adults,anemia was common and increased with age, diabetes, andadvanced kidney disease. A significant association was foundbetween anemia and risk for all-cause hospitalization, hospitaliza-tion secondary to cardiovascular disease, and all-cause mortality.Furthermore, the association between hemoglobin and mortalitywas not linear; risk for death increased at both extremes ofhemoglobin.
Other investigators have reported adverse outcomes associatedwith anemia in select populations, including patients with conges-tive heart failure,27-29 patients with chronic kidney disease,25,26
older women with physical disabilities,4 and community-dwellingsubjects older than 85 years.3 To our knowledge, the only otherstudy to examine the association between anemia and clinicallyrelevant outcomes across a wide age range of older community-dwelling adults was the Cardiovascular Health Study.8 Of impor-tance, in a different population, our findings confirm the resultsfrom this recent report. Specifically, both studies found an in-creased mortality risk associated with anemia and a reverseJ-shaped relationship between hemoglobin and survival. AlthoughU-shaped or J-shaped relationships between hematocrit and mortal-ity have been reported in other community-based studies, includingthe Framingham Heart Study,30 the Puerto Rico Health Program,31
and the Honolulu Heart Study,32 these studies are limited by theexclusion of females31,32 and a relative paucity of older adults.30-32
The interrelations described herein with respect to kidneyfunction, anemia, and mortality are also novel. Consistent withprior reports,26,33,34 subjects at greatest risk for death had bothanemia and advanced CKD. However, to our surprise, the relativeimpact of anemia on hospitalization and mortality was greatest insubjects with normal kidney function. This is an important findingon a population level given that the majority of adults have GFRlevels more than 60 mL/min per 1.73 m2.
The sheer magnitude of the associations between anemia andclinical outcomes in this study is notable and is supported bybiologic plausibility. Hemodynamic changes associated with ane-
mia include systemic arterial vasodilatation and a resultant de-crease in systemic vascular resistance.35 Anemia also activates thesympathetic nervous system, which results in an increase in heartrate.36 Both these adaptations may aggravate myocardial isch-emia37,38 and potentially lead to altered left-ventricular (LV)structure and function.39 Alternatively, anemia may be simply aproxy for other factors including comorbidities and underlyingchronic inflammation.40 In the NHANES analysis, anemia ofchronic disease was not unexpectedly associated with elevatedC-reactive protein and rheumatoid factor.11
There are 2 major potential implications of this study. First, thepresence of anemia in patients with normal kidney function shouldbe regarded as a marker for subsequent adverse outcomes. Thesedata, combined with the Cardiovascular Health Study report,8
should be a stimulus for clinical trials to determine if the correctionof anemia in older adults impacts quality and/or duration of life.Using data from the Baltimore Longitudinal Study of Aging,Ershler et al recently suggested that, with advanced age, the regularerythropoietin compensatory mechanism associated with bloodloss or erythropoietin resistance becomes inadequate, resulting inanemia.41 This inadequate response may occur even in patientswithout measurable kidney disease,42 or in patients with occultinterstitial kidney disease and a normal GFR.43 As it is uncertainwhether treatment with erythropoietin-stimulating proteins in thesepatients would improve outcomes, controlled trials are necessarybefore this is advocated for routine clinical practice. Second, ourdata suggest that the optimal hemoglobin in older adults isapproximately 130 to 150 g/L in women and 140 to 170 g/L in men.Taking these data into consideration with the CardiovascularHealth Study report,8 one could argue that cut points for thediagnosis of anemia in the elderly should be redefined. The currentWorld Health Organization definitions for anemia are based uponstatistical distribution considerations corresponding to minus 2standard deviations below the mean in a reference nonelderlypopulation.12 Our current findings suggest the need to define
Figure 2. Association between hemoglobin and risk for all-cause mortality. (A)Women. (B) Men. Each F indicates a point estimate for this risk, and the vertical linesrepresent 95% confidence intervals around these estimates. *Adjusted for age,diabetes mellitus, GFR, and comorbidity.
Figure 1. Mortality rate (per 100 person-years) by stage of kidney function andthe presence or absence of anemia (adjusted for age and sex).
3844 CULLETON et al BLOOD, 15 MAY 2006 ! VOLUME 107, NUMBER 10
For personal use only.on October 17, 2017. by guest www.bloodjournal.orgFrom
Geriatric domains impacted by anemia:
• Increased falls• Reduced strength• Reduced physical performance• Reduced mobility• Impaired activities of daily living (ADL)and instrumentalADL• Reduced cognition• Increase mortality
Anemiaoftheelderly
• History:anemia related symptoms,bleeding,constitutionalsymptoms,nutrition and alcohol,drugs,comorbidities,family history• Physical examination
Work-up
• Urgency:emergency vs.timefor complete work-up• Differentialdiagnosis and finaldiagnosis for specifictreatment• Patient-specific aspects,e.g.young vs.old• Economic issues:cost-effective work-up
Work-up - considerations
TheNewYorkTimes– 18.09.2017
Complete blood count:
• Automated cell analyzers:- Hemoglobin,RBCnumbers,hematocrit
• Automatedcellanalyzerprovideinadditiontothecellcountanumberofusefulcellindices:
- MCV,MCH,andMCHC
• Otherbloodcountabnormalities(WBC,PLT)
Work-up – initiallaboratory evaluation
MCV:mean corpuscular volume;MCH:mean corpuscular hemoglobin;MCHC:mean corpuscular hemoglobin concentration
• Reticulocytes:immatureredcellswithSubstantiareticulogranulofilamentosa (RNA).Informationregardingregenerationinthebonemarrow• Reticulocytesarebigger(MCV↑)andcontainlesshemoglobin(MCHC↓)comparedtoRBC
Work-up – initiallaboratory evaluation
EVB = Erythrozyten-Verteilungsbreite, MTV = mittleres Thrombozyten Volumen, TVB = Thrombozyten-Verteilungsbreite, MN = Mononukleäre Zellen, PMN = Polynukleäre Zellen, CHr = Hämoglobingehalt der Retikulozyten, LUC = grosse peroxidasenegative Zellen (large unstained cells),° = externe Analyse
EntnahmedatumEntnahmezeitProbeneingangsdatumProbeneingangszeitAuftragsnummer
17.02.201206:0017.02.201206:3622962123
Blutbild mit Verteilungsmuster
45/ CCU (Coronary Care Unit)
Margelist, Renée 14.07.1970 / W
844797722157193
17.02.2012 / 07:001 / 1
Labormedizin, Diagnostische HämatologiePetersgraben 4, CH-4031 Basel
Tel. 061 265 4260 Fax 061 265 4153
Patient Geb./Geschl.
Fall-Nr.Pat-Nr.
DruckdatumSeite
Arbeitsplatz ID 1305
@@NUMMER 52406 @@
Angaben im Laborbuch der Labormedizin Universitätsspital Basel sind Teil dieses Befundes (www.labormedizin-uhbs.ch)
Fachverantwortlicher: Prof. Dr. med. A. Tichelli
Analyse Resultat Referenz EinheitLeukozyten 9 59. 3.50 - 10.00 x10^9/l Erythrozyten 4 64. 4.20 - 5.40 x10^12/l Hämoglobin 151 120 - 160 g/l Hämatokrit 0 44. 0.36 - 0.46 l/l - MCV 94 0. 79.0 - 95.0 fl - MCH 32 5. 27.0 - 33.2 pg - MCHC 346 320 - 360 g/l - EVB 13 6. 11.5 - 14.5 % - hypochrome Ec 0 6. <5.0 % Thrombozyten 264 150 - 450 x10^9/l - MTV 7 8. fl - TVB 51 9. %
.Retikulozyten ‰
x10^9/l - reife % - unreife % - CHr pg
.Neutrophile 57 3. 40.0 - 74.0 %
5 495. 1.300 - 6.700 x10^9/l Lymphozyten 29 3. 19.0 - 48.0 %
2 810. 0.900 - 3.300 x10^9/l Monozyten 8 2. 3.4 - 9.0 %
0 786. + 0.120 - 0.620 x10^9/l Eosinophile 2 9. 0.0 - 7.0 %
0 278. 0 - 0.300 x10^9/l Basophile 0 7. 0.0 - 1.5 %
0 067. 0 - 0.090 x10^9/l LUC 1 6. 0.0 - 4.0 %
0 153. 0 - 0.310 x10^9/l
.PMN% 62 4. % MN% 36 4. %
Size
Hemoglobin-content
EVB = Erythrozyten-Verteilungsbreite, MTV = mittleres Thrombozyten Volumen, TVB = Thrombozyten-Verteilungsbreite, MN = Mononukleäre Zellen, PMN = Polynukleäre Zellen, CHr = Hämoglobingehalt der Retikulozyten, LUC = grosse peroxidasenegative Zellen (large unstained cells),° = externe Analyse
EntnahmedatumEntnahmezeitProbeneingangsdatumProbeneingangszeitAuftragsnummer
14.10.201100:0014.10.201109:0122896866
Blutbild mit Verteilungsmuster
64/ Zellersatzambulatorium
Pfirter, Michel 11.03.1986 / M
843693292374535
22.02.2012 / 09:151 / 1
Labormedizin, Diagnostische HämatologiePetersgraben 4, CH-4031 Basel
Tel. 061 265 4260 Fax 061 265 4153
Patient Geb./Geschl.
Fall-Nr.Pat-Nr.
DruckdatumSeite
Arbeitsplatz ID 1304Hand-Diff Centralink Y
@@NUMMER 54577 @@
Angaben im Laborbuch der Labormedizin Universitätsspital Basel sind Teil dieses Befundes (www.labormedizin-uhbs.ch)
Fachverantwortlicher: Prof. Dr. med. A. Tichelli
Analyse Resultat Referenz EinheitLeukozyten 7 07. 3.50 - 10.00 x10^9/l Erythrozyten 2 29. - 4.50 - 6.30 x10^12/l Hämoglobin 91 - 140 - 180 g/l Hämatokrit 0 25. - 0.38 - 0.52 l/l - MCV 108 6. + 79.0 - 95.0 fl - MCH 39 9. + 27.0 - 33.2 pg - MCHC 368 + 320 - 360 g/l - EVB 24 7. + 11.5 - 14.5 % - hypochrome Ec 5 1. + <5.0 % Thrombozyten 179 150 - 450 x10^9/l - MTV 6 8. fl - TVB 42 3. %
.Retikulozyten 258 + 10 - 27 ‰
591 + 40 - 140 x10^9/l - reife 63 - 80 - 96 % - unreife 37 + 4 - 17 % - CHr 40 0. + 27.0 - 33.0 pg
.Neutrophile 80 1. + 40.0 - 74.0 %
5 663. 1.300 - 6.700 x10^9/l Lymphozyten 14 1. - 19.0 - 48.0 %
0 997. 0.900 - 3.300 x10^9/l Monozyten 3 6. 3.4 - 9.0 %
0 255. 0.120 - 0.620 x10^9/l Eosinophile 1 0. 0.0 - 7.0 %
0 071. 0 - 0.300 x10^9/l Basophile 0 1. 0.0 - 1.5 %
0 007. 0 - 0.090 x10^9/l LUC 1 2. 0.0 - 4.0 %
0 085. 0 - 0.310 x10^9/l
.PMN% 83 7. % MN% 16 0. %
• CHr:contentofhemoglobininreticulocytes(≅MCH).• Earlyinformationaboutchangesinredcellindices.
Work-up – initiallaboratory evaluation
ASHImageBank
• Thebloodcountisthemostimportantanalysisinhematology/forhematologists• Automatedbloodcountvs.differential/microscopicbloodcount(smear):morphology,qualitativealterations• Cheap(26TP=1CHF/01.07.2017)!• MorphologicchangesofRBCandothercells(WBC!)
Work-up – initiallaboratory evaluation
MorphologicchangesofRBCandothercells(WBC!):
Work-up – initiallaboratory evaluation
Summary:
Work-up – initiallaboratory evaluation
Parameter Information Classification
Hemoglobin Definition& severity* Slight: >100g/lModerate:70-100g/lSevere:>70g/l
RBCparameters MCV,MCH,MCHC Micro-/Normo-/MacrocyticHypo-/Normochromic
Reticulocytes ↓ /↑ AregenerativeRegenerative
WBCincl.DifferentialPLT
Isolated anemia vs.combined disorders
[...]
Morphology Specific vs.non-specific [...]
*Differentclassifications
Guidedbyclinicalsuspicion:
• Metabolicprofile(creatinine,liverenzymes,bilirubin,CRP,LDH)• Ironstatus• HPLC,Hb electrophoresis,genetics• VitaminB12andfolate• Hämolysis:DAT• Erythropoietin
Work-up – further steps
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Erslev AJ.NEJM1991;Adamson JW.Blood1968
Work-up – further steps
Blooddonors
Patients with anemia
Whentorefertothehematologist?
• Refractoryanemia• Additionalbloodcountabnormalities(bicytopenia/pancytopenia;unexplainedleukocytosis/thrombocytosis)• Pathologicbloodsmear(redcellabnormalities,dysplasia,blasts,…)
Work-up – further steps
Generalcomments:
• Dependingonthepatient(e.g.youngvs.old)• Dynamics(e.g.acutevs.chronicbleeding)• Causativevs.supportive(transfusions)
Treatment
Characterization of anemia
• Clinicalapproach:- acute vs.chronic- acquired vs.inborn
• Kinetic approach (reticulocytes):- regenerative- aregenerative
• Morphological approach (MCV):- microcytic- normocytic- macrocytic
MCV
Microcytic anemia Normocytic anemia Macrocytic anemia
MCV<80fl MCV>100fl
- Irondeficiency- Hemoglobinopathy- Anemia of chronicdisease +/- irondeficiency
- Bleeding*- Hemolysis*- Anemia of chronicdisease- Anemia inCKD- Bone marrow failure/infiltration
(- Reticulocytosis*)- Vit.B12 deficiency- Folate deficiency- Liver disease- Hypothyroidism- Alcohol abuse- Dyslipidemia- MDS- Drugs
Thecut-offvaluesforthissubclassification donotcorrespondtothereferencevaluesofMCV.CKD:chronic kidney disease;MDS:Myelodysplastic syndrome
Classification of anemia
- Cold agglutinins- Oldblood
- Copper deficiency- LeadIntoxication- Sideroblastic anemia
MCV
Microcytic anemia Normocytic anemia Macrocytic anemia
MCV<80fl MCV>100fl
- Irondeficiency- Hemoglobinopathy- Anemia of chronicdisease +/- irondeficiency
- Bleeding*- Hemolysis*- Anemia of chronicdisease- Anemia inCKD- Bone marrow failure/infiltration
(- Reticulocytosis*)- Vit.B12 deficiency- Folate deficiency- Liver disease- Hypothyroidism- Alcohol abuse- Dyslipidemia- MDS- Drugs
Thecut-offvaluesforthissubclassification donotcorrespondtothereferencevaluesofMCV.CKD:chronic kidney disease;MDS:Myelodysplastic syndrome
Classification of anemia
- Cold agglutinins- Oldblood
- Copper deficiency- LeadIntoxication- Sideroblastic anemia
Microcytic anemia
DeLoughery TGNEJM2014
Microcytic Anemia
n engl j med 371;14 nejm.org october 2, 2014 1325
an alternative messenger RNA (mRNA) splice site, leading to a marked reduction in protein synthesis. People who are heterozygous for hemoglobin E have microcytosis with target cells, and those who are homozygous have only mild anemia. However, children with one copy each of the β-thalassemia gene and the hemoglobin E gene will have a se-vere phenotype, resulting in a transfusion-depen-dent anemia.
A nemi a of Infl a mm ation
Inflammatory states are often accompanied by microcytic anemia. The cause of this anemia is twofold.2 First, renal production of erythropoietin is suppressed by inflammatory cytokines, resulting in decreased red-cell production. Second, lack of iron availability for developing red cells can lead to microcytosis. The lack of iron is largely due to the protein hepcidin,3 an acute-phase reactant that leads to both reduced iron absorption and re-duced release of iron from body stores. The pro-tein ferroportin mediates cellular efflux of iron. Hepcidin binds to and down-regulates ferropor-tin, thereby blocking iron absorbed by enterocytes from entering the circulation and also preventing the release of iron from its body stores to develop-ing red cells (Fig. 2).
Iron Deficienc y
The most common anemia is iron-deficiency ane-mia. Besides playing a crucial role as an oxygen carrier in the heme group of hemoglobin, iron is found in many key proteins in the cells, such as cytochromes and myoglobin, so it is not unexpect-ed that a lack of iron has effects other than ane-mia. Three studies have focused on nonanemic iron deficiency leading to fatigue. Two studies showed that oral iron supplementation reduces fatigue, with no significant change in hemoglobin levels, in women with a ferritin level of less than 50 ng per milliliter,4,5 and a third study showed a lessening of fatigue with parenteral iron admin-istration in women with a ferritin level of 15 ng per milliliter or less or an iron saturation of 20% or less.6
Owing to obligate iron loss through menses, women are at greater risk for iron deficiency than men. Iron loss in all women averages 1 to 3 mg per day, and dietary intake is often inadequate to maintain a positive iron balance.7,8 A 1967 study showed that 25% of healthy, college-age women had no bone marrow iron stores and that another 33% had low stores.9 Pregnancy adds to demands for iron, with requirements increasing to 6 mg per day by the end of pregnancy.10
Iron
Protoporphyrin
Heme
Iron deficiencyAnemia of inflammation
Sideroblastic anemia
Thalassemia
Globin
Hemoglobin
1
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Microcytic Anemia
Figure 1. Disorders Characterized by Microcytosis.
Red cells become microcytic because of a lack of hemoglobin. This can result from a lack of iron (deficiency or in-flammation), defects in heme synthesis (sideroblastic anemias), or defects in the production of hemoglobin protein (thalassemia).
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Ironcycle
n engl j med 372;19 nejm.org May 7, 20151834
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
low in girls and young women and higher — similar to levels in men — in postmenopausal women; fluctuations in hepcidin levels have a
strong direct correlation with serum levels of ferritin.19,20 In iron deficiency, the transcription of hepcidin is suppressed. This adaptive mecha-
Figure 1. The Iron Cycle — Mechanisms of Adaptation to Iron Deficiency.
The mechanisms of adaptation to iron deficiency are centered on the suppression of the hepatic hormone hepcidin and the tissue hypoxia that develops consequent to anemia. The production of erythropoietin (EPO) by the kidney increases in response to enhanced levels of hypoxia-inducible factor 2α (HIF-2α). As a consequence of the stimula-tion of erythropoietin, erythropoiesis is increased and hypochromic microcytic red cells are produced owing to the low availability of iron. Senescent red cells are destroyed by macrophages, and their iron is recycled. The increase in erythropoiesis suppresses the production of hepcidin. In mice, this function is mediated by erythroferrone (ERFE), which is secreted by the erythroblasts21 to maintain adequate iron absorption and efficiency in erythropoiesis. HIF-2α increases the expression of the duodenal divalent metal transporter 1 (DMT1)22 on the apical surface of enterocytes to increase the transfer of dietary iron from the lumen to enterocytes. Hepcidin levels are depressed in response to a reduction in the physiologic signals that maintain its production (e.g., increases in levels of iron-bound transferrin and in the iron content of the liver),2,18 to the increased activity of the inhibitor transmembrane protease, serine 6 (TMPRSS6),23 to the reduction in levels of the activator bone morphogenetic protein 6 (BMP6), and to increased in-hibition from erythropoietin-stimulated erythropoiesis. Ferroportin (FPN), which is no longer being degraded because of the low levels of hepcidin, exports the available iron across the enterocyte basal membrane and from macrophage stores17 to the circulation. Once stores are exhausted, levels of circulating iron decrease, even if absorption from the lumen is increased. Reduced levels of iron in the liver trigger increases in the synthesis of the iron carrier transferrin (referred to as apotransferrin when not bound to iron), further decreasing levels of iron-bound transferrin, the ligand of the transferrin receptor. Consequently, the uptake of iron from transferrin receptors by all cells and organs (e.g., skeletal muscles and the heart) is reduced.
Hepatocyte
Enterocyte
FPN
FPN
DMT1
Heart
Skeletalmuscle
↓Fe↓Fe
+
↑HIF-2α
↑HIF-2α
EPO
↓Fe
↓Fe
↑Fe
Fe
Fe
↑Fe
↑TMPRSS6
ERFE?
Erythropoiesis
Erythroblasts
Spleenmacrophage
Kidney
Red cells
BMP6BMP6
Fe
Hepcidin
ERFE?
HepcidinHepcidin
TMPRSS6
↓HepcidinHepcidinHepcidinHepcidin
↓Fe
↓Fe
↓FeApotransferrin
Fe
↓Fe
ApotransferrinApotransferrin
Allorgans
↓organsorgans
↓FeFe ↓↓↓↓↓↓↓↓
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Camaschella CNEJM2015
Differentialdiagnosis
Irondeficiency anemia Thalassemia minor
RBC: <4.0x1012/l >5.0x1012/l
Hemoglobin: <100g/l > 110g/l
MCV: ↓ ↓
MCHC: ↓ normal
Morphology:
MCV
Microcytic anemia Normocytic anemia Macrocytic anemia
MCV<80fl MCV>100fl
- Irondeficiency- Hemoglobinopathy- Anemia of chronicdisease +/- irondeficiency
- Bleeding*- Hemolysis*- Anemia of chronicdisease- Anemia inCKD- Bone marrow failure/infiltration
(- Reticulocytosis*)- Vit.B12 deficiency- Folate deficiency- Liver disease- Hypothyroidism- Alcohol abuse- Dyslipidemia- MDS- Drugs
Thecut-offvaluesforthissubclassification donotcorrespondtothereferencevaluesofMCV.CKD:chronic kidney disease;MDS:Myelodysplastic syndrome
Classification of anemia
- Cold agglutinins- Oldblood
- Copper deficiency- LeadIntoxication- Sideroblastic anemia
Anemia of chronic disease
Chronic diseases leading to anemia:
• Infections (acute and chronic)• Cancer• Autoimmunediseases (SLE,RA,vasculitis,inflammatorybowel disease)• Malnutrition• Criticalill patients• Heartfailure• Others [...]
Anemia of chronic disease=anemia of inflammationCullis JOBJH2011
DeLoughery TGNEJM2014
Microcytic Anemia
n engl j med 371;14 nejm.org october 2, 2014 1327
Normal State Anemia of Inflammation
Gut lumen
Gut lumen
Enterocyte
Blood vessel
Hepatocytes
Transferrin Transferrin
Enterocyte
Ferroportin
Ferroportin
Ferroportin
Internalization and degradation
Ferroportin
Enterocyte cytoplasm
Enterocyte cytoplasm
Enterocyte cytoplasm
Hepatocyte cytoplasm
Hepatocyte cytoplasm
Hepcidin blocks iron absorption by preventing release of iron from enterocyte
Iron is absorbed into the blood and binds to transferrin
Iron is transferred to developing red cells
Excess iron is stored in the liver
Excess iron is stored in the liver
Stored iron is transported to
developing red cells
Release of iron from the liver is impaired
Desaturated transferrin supplies less iron to developing red cells
Absorption of iron into the blood is impaired
Fe2+
Fe2+
Fe2+Fe2+
Fe2+
Fe2+
Fe2+
Lysosome
DMT1
Hepcidin blocks ironrelease from hepatocyte
Internalization and degradation
Lysosome
2
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Anemia of chronic disease
Anemia of chronic disease
gulation of another transport protein, divalent metal trans-
porter-1 (DMT-1) rather than ferroportin (Brasse-Lagnel et al,
2011; Burpee et al, 2011). The combined effect is to restrict
iron availability for erythropoiesis, sometimes referred to as a
state of ‘functional iron deficiency’, and to result in iron
accumulation in tissue macrophages (Fig 1). Hepcidin over-
expression in transgenic mice reproduces many of the features
of ACD (Roy et al, 2007), and hepcidin levels are raised in a
variety of inflammatory disorders (Ganz et al, 2008; Sharma
et al, 2008; Busbridge et al, 2009; Demirag et al, 2009; de Mast
et al, 2009; Hohaus et al, 2010). Once bound to ferroportin,
the ligand-receptor complex is internalized and degraded, and
cellular iron export ceases (Nemeth et al, 2004b).
Regulation of hepcidin production occurs through recogni-
tion of iron levels and erythropoietic activity. Thus iron excess
stimulates hepcidin production, leading to reduced iron
absorption and switching off iron release from tissue stores.
Conversely, in iron deficiency, hepcidin production is
suppressed, enabling increased iron absorption and release of
storage iron: similar changes occur when erythroid activity
increases. In inflammatory conditions, hepcidin production is
increased, and IL-6 has been shown to be a potent inducer of
hepcidin via signal transducer and activator of transcription-3
(STAT-3) signalling (Nemeth et al, 2004a; Wrighting &
Andrews, 2006). There is also evidence of a role for other
inflammatory cytokines, including IL-1 (Lee et al, 2005), and
bone morphogenetic proteins (BMPs) 2, 4, 6 and 9 (Truksa
et al, 2006). Parallel processes can be seen in malignant
conditions. For example, in patients with Hodgkin lymphoma,
hepcidin levels were closely correlated with levels of IL-6,
rather than other cytokines (Hohaus et al, 2010) whereas a
recent study suggests that BMP-2, rather than IL-6, is the key
inducer of hepcidin in patients with multiple myeloma:
hepcidin levels in patients with myeloma inversely correlate
with haemoglobin levels, and anti-BMP-2 antibodies blocked
the hepcidin-inducing activity of sera from patients with
myeloma more consistently than anti-IL-6 antibodies (Maes
et al, 2010).
That the erythropoietic and inflammatory pathways regu-
lating hepcidin production may be separate was suggested by a
study by Theurl et al (2009): using a rat model of ACD, they
demonstrated that animals with ACD rendered iron-deficient
by phlebotomy had lower hepcidin levels than animals with
ACD alone. Similar findings were noted in patients with ACD/
IDA when compared to individuals with ACD, and the former
were able to absorb dietary iron and mobilize iron from
macrophage stores. This is an important observation if
hepcidin levels are to be incorporated into the diagnostic
pathway for patients with ACD.
Reduced EPO production
Under normal physiological conditions, levels of EPO are
inversely correlated with haemoglobin levels and tissue
oxygenation, but in chronic inflammatory conditions the
EPO response is blunted, leading to inadequate levels of EPO
Table I. Diseases associated with ACD.
Associated diseases
Infections
Viral
Bacterial
Parasitic
Fungal
Malignancies
Haematological
Solid tumours
Autoimmune
Rheumatoid arthritis
Systemic lupus erythematosus and related conditions
Vasculitis
Sarcoidosis
Inflammatory bowel disease
Renal
Chronic renal failure
Cardiac
Chronic heart failure
HypoxiaIncreased erythropoietic demand
Inflammationvia IL-6, BMP-2, -4, -6 and -9
–
+
Hepcidin
Liver
Transferrin
Macrophages
Duodenum
–
–Iron
20–30 mg/d
Iron1–2 mg/d
Bonemarrow
Erythrocytes
EPO +
Kidney
IL-1TNF-IFN-–
–
–
Iron overload +
Fig 1. Effects of inflammation on erythropoiesis and iron metabolism. Key: + = stimulatory effect; ) = inhibitory effect; for other abbreviations seetext.
Review
290 ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 289–300
Cullis JOBJH2011
Anemia of chronic disease
• Typically mildto moderateanemia (80-110g/l)• Usually normocytic,normochromic• Hyporegenerative(low reticulocytes)• Morphologically no specific findings• Inadequate Erythropoietin levels
Differentialdiagnosis
Camaschella CHematology AmSoc Hematol Educ Program 2015
Laboratory diagnosis of iron deficiency and irondeficiency anemia: iron parametersSerum ferritin !30ng/mL is the most sensitive and specific test toidentify isolated iron deficiency,26 as it reflects low stores (Table 2).In the progression of the deficiency, because of low iron andincreased transferrin synthesis, transferrin saturation (or thesaturated iron binding capacity) drops !16%, di-ferric transfer-rin, the ligand of transferrin receptor, is reduced and iron supplyto the bone marrow becomes insufficient. At this point serumferritin is usually !12 ng/mL.4 In parallel, soluble transferrinreceptor is shed in the circulation by the proprotein convertasesubtilisin/kexin 7 (PCSK7), which cleaves the receptor whenunbound to its ligand.27
Both transferrin saturation and serum ferritin are consensuallydecreased in iron deficiency anemia. Transferrin saturation may alsobe decreased in the anemia of chronic inflammation, but ferritinlevels are increased, reflecting macrophage iron sequestration. Inaddition, transferrin and soluble transferrin receptor are not in-creased in inflammation. Although the distinction of iron defi-ciency anemia from anemia of chronic disease is straightforward,there is no clear-cut test that diagnoses iron deficiency anemia inthe setting of inflammation (Table 2). Low transferrin saturationis one criterion with ferritin levels empirically set at !100ng/mL28 or higher (!300 ng/mL) as in chronic kidney disease orin heart failure.14 Other proposed tests, such as the levels ofserum soluble transferrin receptor (increased in iron deficiencyand normal/low in inflammation) or the ratio between solubletransferrin receptor and log ferritin levels,28 are uncommonlyused in clinical practice.
Perl’s iron staining of bone marrow smears allows visualization ofthe absence of iron in both macrophages and erythroblasts in irondeficiency; the presence of iron in macrophages but not in erythro-blasts occurs in anemia of chronic inflammation. Once the goldstandard for the diagnosis of iron deficiency, Perl’s staining is rarelyassessed because it is qualitative and requires performance of aninvasive procedure.4 In general the combination of tests rather thana single test helps to ascertain the correct diagnosis (Table 2).
In IRIDA, a discrepancy is often observed with extremely lowtransferrin saturation levels and normal/borderline low serumferritin levels. Iron parameters differentiate IRIDA from othermicrocytic anemias,29 and a normal C-reactive protein level fromanemia of inflammation. Measuring serum hepcidin might be usefulin IRIDA, because levels are abnormally high (or normal butinappropriately high)30 considering the iron deficiency. At present,hepcidin assays are used for research but are not widely availablefor diagnostic purposes.
Laboratory tests: erythrocyte traitsLow mean corpuscular volume and mean corpuscular hemoglo-bin are typical of iron deficiency anemia. Red cell distributionwidth (RDW), a measure of variation of red cell volume isincreased, especially in the initial phases of iron deficiency whennewly produced small hypochromic red cells coexist with normalones. The RDW is also increased after iron therapy that induces theproduction of better hemoglobinized cells in the context of the arrayof hypochromic microcytic ones. RDWs, as well as erythrocyteindexes, are not affected in anemia of chronic inflammation. Thedifferential diagnosis of microcytic anemia has been recentlyreviewed.29
Decreased reticulocyte hemoglobin content, a parameter that mea-sures the functional iron available for erythropoiesis over theprevious 3-4 days, is an early sign of iron-restricted erythropoiesis,(eg, after treatment with ESA). On the other side its increase is ameasure of an early (2-4 days after treatment start) responsefollowing intravenous iron therapy. The percentage of hypochromicred cells is less useful because it is not as early a sign as thereticulocyte hemoglobin content.26
Lack of iron affects the last step of heme synthesis leading toaccumulation of protoporphyin IX and incorporation of zinc insteadof iron in the protoporphyin ring. Increased red cell zinc protopor-phyrins may be used as a screening test for iron deficiency.However, protoporphyrins may increase also in the rare sideroblas-tic anemias due to defects of enzymes in the heme syntheticpathway.
Table 2. Laboratory tests to evaluate the iron status
Irondeficiency
Functional irondeficiency
Iron deficiencyanemia IRIDA
Anemia ofchronic disease
Iron deficiency andanemia of chronic disease
Normal values(adult subjects)
Currently used testsSerum iron 2 N/2 2 2 2 2 10-30 !Mol/LTSAT, % "16 N/2 !16 !10 N/2 N/2 "16!45Serum ferritin, !g/L !30 N !12 Variable "100 !100 20-200 (F)
40-300 (M)Hb g/dL N N 2 2 2 2 "12 (F) "13 (M)MCV, fl N N !80 22 N/2 2 80-95MCH, pg N N !27 22 N/2 2 27-34
Other testssTFR 1 1 1 1 N/1 Variable †sTFR/log ferritin NA NA "2* NA !1* "2*ZPP N 1 1 1 1 1 †Serum hepcidin 2 2 22 N/1 1 N/1 †CHr pg !25 !29 2 2 2 2 31.2#1.6BM iron staining $ # % $ $$$ $ #
N indicates normal; TSAT, transferrin saturation; F, females; M, males; Hb, hemoglobin; ZPP, Zn Protoporphyrin; CHr, reticulocyte Hb content; BM, bone marrow; MCV, meancorpuscular volume; MCH, mean corpuscular hemoglobin; and sTFR, soluble transferrin receptor.* According to Weiss and Goodnough.28
† Normal values are according to the method used.Adapted from Camaschella.14
10 American Society of Hematology
Differentialdiagnosis
several reasons for attempting to correct the anaemia present.
Firstly, anaemia may be deleterious in itself, with effects on the
cardiovascular system needed to maintain tissue oxygen
supply. Secondly, anaemia may be associated with a poorer
prognosis in many chronic disease states (Caro et al, 2001;
Nissenson et al, 2003), although whether anaemia plays a
causative role in determining prognosis is open to debate.
Thirdly, treatment may improve the quality of life for patients
living with chronic conditions (Moreno et al, 2000; Littlewood
et al, 2001).
Treatment of the underlying inflammatory or malignant
process associated with ACD will often result in improvement
in the degree of anaemia, examples being the use of corticos-
teroids in polymyalgia rheumatica, the use of TNF-a inhibitors
in rheumatoid arthritis or inflammatory bowel disease (IBD)
(Moreland et al, 1997; Doyle et al, 2009; Bergamaschi et al,
2010), and the use of antiretroviral drugs in human immu-
nodeficiency virus (HIV) infection (Semba et al, 2001). Indeed
the severity of the anaemia will frequently mirror the activity of
the chronic condition causing it, for example in rheumatoid
arthritis (Vreugdenhil et al, 1990b). However, treatment of the
underlying condition may not always be possible, for example
in patients with incurable cancers or chronic renal or cardiac
failure and alternative strategies may be necessary. Correction
of as many contributory factors as possible is also desirable, for
example correction of nutritional deficiencies (Vreugdenhil
et al, 1990a).
Blood transfusion
Blood transfusion is widely available in the developed world
and is a simple means of treating patients with moderate to
severe anaemia, but blood remains a precious and expensive
resource, and transfusion therapy carries long-term risks of
viral transmission, iron overload and alloimmunization.
Transfusion should therefore be reserved for patients with
severe or life-threatening anaemia in the context of ACD, and
is not an appropriate treatment for patients with this form of
chronic anaemia (Cavill et al, 2006).
Erythropoiesis-stimulating agents
The rationale for the use of erythropoiesis-stimulating agents
(ESA) in ACD is based on the blunted EPO response seen in
ACD, with lower serum levels of EPO detected than would be
expected for the observed degree of anaemia, together with the
reduced sensitivity of erythroid progenitors to endogenous
EPO seen in ACD. In addition, there is limited data to suggest
that administration of EPO may reverse cytokine-mediated
inhibition of erythropoiesis (Means & Krantz, 1991). Recom-
binant human EPO (rHuEPO) and its derivatives are widely
used in patients with chronic renal failure, patients with cancer
undergoing chemotherapy and patients infected with HIV on
myelosuppressive anti-retroviral medication. Several different
rHuEPOs are currently available or in development: epoetin-a
Haemoglobin <130 g/l inmales or 120 g/l in females
Biochemical or other evidence of inflammation
Transferrin saturation <16%
Exclude other causes of anaemia
Ferritin reduced and MCH <27 pg
Ferritin normal Ferritinnormal/increased
sTFR/log ferritin ratio
raised OR hepcidinnormal
sTFR/log ferritin ratio
low OR hepcidin raised
IDA ACD/IDA ACD
Fig 2. Possible algorithm for the differential diagnosis of IDA, ACD and ACD/IDA (modified fromWeiss & Goodnough, 2005, with permission fromthe Massachusetts Medical Society! 2005). IDA, iron deficiency anaemia; ACD, anaemia of chronic disease; MCH, mean cell haemoglobin; sTFR,serum transferrin receptor.
Review
ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 289–300 293
Cullis JOBJH2011
Treatment- Anemia of chronic disease
• Therapeutic measures notalways necessary since frequentlymildanaemia• Treatmentof the underlying disease• Intravenous (lower dose!)iron supplementation (TSAT<20%)• Erythropoiesis-stimulating agents (ESA)– notalwaysapproved!
Example:Venofer®200mgi.v. 1-2xweekly over 3–4weeksEprex® 10’000Es.c.or i.v. 1xweekly
or20'000Es.c.or i.v. every 2weeks
Fernàndez-Gaxiola ACetal.TheCochrane Collaboration 2011
MCV
Microcytic anemia Normocytic anemia Macrocytic anemia
MCV<80fl MCV>100fl
- Irondeficiency- Hemoglobinopathy- Anemia of chronicdisease +/- irondeficiency
- Bleeding*- Hemolysis*- Anemia of chronicdisease- Anemia inCKD- Bone marrow failure/infiltration
(- Reticulocytosis*)- Vit.B12 deficiency- Folate deficiency- Liver disease- Hypothyroidism- Alcohol abuse- Dyslipidemia- MDS- Drugs
Thecut-offvaluesforthissubclassification donotcorrespondtothereferencevaluesofMCV.CKD:chronic kidney disease;MDS:Myelodysplastic syndrome
Classification of anemia
- Cold agglutinins- Oldblood
- Copper deficiency- LeadIntoxication- Sideroblastic anemia
Hemolysis:shortened red blood cell (RBC)survival• Classification(s)of hemolysis:
- congenital vs.acquired- intravascular vs.extravascular- immunevs.non-immune
• Immunehemolysis:- autoimmune(AIHA)- alloimmune (TR)- drugs (DIHA)
Hemolysis
Autoimmunehemolytic anemia
• (normocytic)Anemia (and reticulocytosis)?• Hemolysis?i.e.bilirubin ,LDH,haptoglobin ¯,
(hemoglobinemia,hemoglobinuria,urinary hemosiderin)• Autoimmune:DAT(usually)+
• And:don‘t forget the blood smear (...)!
• Fatigue,lower backor flankpain,pallor,dyspnea,tachycardia,dark urine,jaundice,hepatosplenomegaly
Packman CH.Transfus Med Hemother 2015;HillQAetal.BJH2016
AIHA- Clinicalfindings and diagnosis
Direct antiglobulin test (DAT)=Coombs Test
• Direct antiglobulin test (DAT):– Detection of RBCbound antibodies
• Indirect antiglobulin test (IAT):– Detection of antibodies inpatient’s serum/plasma
Patient‘s RBC Anti IgG/C3d Agglutination
Classification of AIHA
• Warmautoimmunehemolytic anemia (WAIHA;70%):- primary (idiopathic)- secondary
• Cold autoimmunehemolytic anemia (CAIHA;15%):- cold agglutinin disease (CAS:primary/secondary)- paroxysmalcold hemoglobinuria(primary/secondary)*
• Mixed(primary/secondary)• Drug-induced autoimmunehemolytic anemia (12%)
(drug history!)• [Paroxysmalnocturnal hemoglobinuria (PNH)]
*Donath-Landsteinersyndrome
Packman CH.BloodRev 2008;TransfusionTherapy:ClinicalPrinciples and Practice,3rdedition,Bethesda,AABBPress,2011
Adapted from TransfusionTherapy:ClinicalPrinciples and Practice,3rdedition,Bethesda,MD:AABBPress,2011and Gehrs BCetal.AmJHematol 2002
WAIHA CAS Mixed PCH
Autoantibody(Antigen)
IgG(Rh,others)
IgM(I/i,others) IgG &IgM Biphasic IgG*
(P)
Clinic Extravascular Intravascular Combined Intravascular
DAT IgG +/- C3(IgG1,IgG3) C3alone IgG +C3 C3alone
*Donath-Landsteinerantibody
Differentialdiagnosis
• Folinic acid substitution• Transfusions:
- Donotwithhold transfusions incritical cases!- Physician‘s decision (and responsibility),closemonitoring- Selection of RBC,depending onurgency:
1.O,RhDneg.,Kneg.2.ABO,R(C/c,D,E/e)and Kcompatible3.Compatible RBCafterexclusion ofalloantibodies (adsorption,extendedRBCphenotyping,genotyping,...)
PetzLD.Br JHaematol 2004;Kalfa TA.Hematology AmSoc Hematol Educ Program.2016
AIHA– Therapy wAIHA
• Treat the underlying disease insecondary AIHA!• Remarks:
1.Weak evidence2.No accepted therapy response criteria
• First-line:corticosteroids (prednisolone 1mg/kg/d)• Second-line:rituximab (off-label)or splenectomy• Others:IVIG,danazol,cyclophosphamide,azathioprine,mycophenolate mofetil,cyclosporine,bortezomib• Erythropoietin (?)• Generallynotindicated:plasma exchange,whole bloodexchange transfusion,HSCT
Crowther Metal.Blood2011;LechnerKetal.Blood2010;ZanellaAetal.Haematologica 2014;Barcellini Wetal.Blood2012;Dierickx Detal.Blood2015;Ratnasingam Setal.BloodAdv.2016;Sys Jetal.BloodRev.2017
AIHA– Therapy wAIHA
• Avoidance of cold temperatures• Warmtransfusions (if needed)and infusions (weakevidence!)• Indications for treatment:symptomatic anemia,transfusiondependence,disabling circulatory symptoms• Steroids/splenectomy are noteffective• Rituximab (+/- fludarabine)• Plasmaexchange (ASFA2013:2C/II)• Eculizumab• Treatmentof underlying disease (e.g.lymphoma)
Swiecicki PLetal.Blood2013;Berentsen S.Br JHaematol 2011;SchwartzJetal.JClin Apher 2016;Berentsen Setal.Blood2004;Berentsen Setal.Blood2010;RothAetal.Blood2009
AIHA– Therapy cAIHA
MCV
Microcytic anemia Normocytic anemia Macrocytic anemia
MCV<80fl MCV>100fl
- Irondeficiency- Hemoglobinopathy- Anemia of chronicdisease +/- irondeficiency
- Bleeding*- Hemolysis*- Anemia of chronicdisease- Anemia inCKD- Bone marrow failure/infiltration
(- Reticulocytosis*)- Vit.B12 deficiency- Folate deficiency- Liver disease- Hypothyroidism- Alcohol abuse- Dyslipidemia- MDS- Drugs
Thecut-offvaluesforthissubclassification donotcorrespondtothereferencevaluesofMCV.CKD:chronic kidney disease;MDS:Myelodysplastic syndrome
Classification of anemia
- Cold agglutinins- Oldblood
- Copper deficiency- LeadIntoxication- Sideroblastic anemia
Kaferle Jetal.AmPhamPhysician 2009
Macrocytic anemia
Macrocytosis
204 American Family Physician www.aafp.org/afp Volume 79, Number 3 February 1, 2009
deficiencies, and could be used to clarify the cause of megaloblastic anemia, although this is not yet standard clinical practice.8
Nonmegaloblastic processes develop from multiple mechanisms and have not been fully outlined. Mac-rocytosis can occur when there is increased RBC pro-duction secondary to peripheral blood cell destruction (i.e., hemolysis) or loss (i.e., hemorrhage), leading to a reticulocytosis. Reticulocytes are incompletely pro-cessed RBCs and, therefore, are slightly larger than the average RBC. The mechanisms by which the other dis-eases listed in Table 11,3-5 cause macrocytosis have not been fully explained.
Diagnostic StrategyOnce macrocytosis is identified, the history and physical examination help narrow the differential diagnosis. The
presence of anemia, the degree of elevation of the mean corpuscular volume, and the patient’s overall health guide how aggressively the work-up progresses. At least some amount of investigation is warranted if the diag-nosis is not readily apparent or if the patient is anemic (defined by the World Health Organization as a hemo-globin level less than 13 g per dL [130 g per L] in men and less than 12 g per dL [120 g per L] in women).9
The algorithm outlined in Figure 3 suggests a work-up for macrocytosis. Physicians should begin by ordering a peripheral smear, a reticulocyte count, and a vitamin B12 serum level for all patients with macrocytosis. It may be necessary to specifically order a reticulocyte index in some laboratories, which assesses if there is an adequate bone marrow response. Hemorrhage or hemolysis is the most likely cause if the reticulocyte count is elevated, but anemia recovery also causes an elevation in the
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Clinical recommendationEvidence rating References
Obtain a vitamin B12 level for every patient with an elevated mean corpuscular volume. C 1, 3-5, 19Evaluate peripheral smear for megaloblastosis and perform a reticulocyte count in patients with
suspected macrocytosis.C 1, 3-5, 19
Order methylmalonic acid and homocysteine levels if vitamin B12 level is borderline low (i.e., 100 to 400 pg per mL [74 to 295 pmol per L]).
C 8
Oral vitamin B12 may be as effective as intramuscular therapy for vitamin B12 deficiency. B 21Obtain red blood cell folate level if other etiologies are not found (serum folate levels may be misleading). C 25, 26
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.
Table 1. Prevalence of Major Causes of Macrocytosis in Studied Populations
Etiology
Study population
Hospitalized patients in New York City 3 (%)
Outpatients in Finland 1 (%)
Finnish persons older than 75 years 4 (%)
Finnish and American patients 5 (%)
Alcohol 26 65 15 36B12 and/or folate deficiency 6 9 28 21Medications 37* 3 2 11Hypothyroidism — 1 12 5Bone marrow dysplasias 6 1 5 5Liver disease (nonalcoholic) 6 — 2 6Reticulocytosis 8 — — 7Miscellaneous 3 21 13 7Not established 7 — 22 12
NOTE: Etiologies listed from most to least common.
*—13 percent from zidovudine (Retrovir).
Information from references 1 and 3 through 5.
Kaferle Jetal.AmPhamPhysician 2009
Macrocytic anemiaMacrocytosis
206 American Family Physician www.aafp.org/afp Volume 79, Number 3 February 1, 2009
bowel-related symptoms (including diarrhea), or a his-tory of bowel surgery for weight loss. Findings on physi-cal examination may include neurologic signs such as ataxia, decreased proprioception, and vibratory sensa-tion. Patients may also have poor dentition or nonspe-cific oral stomatitis or glossitis.
Because pregnant women take folic acid routinely in prenatal vitamins, macrocytic anemia is much less com-mon during pregnancy. Consider nitrous oxide abuse in at-risk populations, because nitrous oxide inacti-vates vitamin B12 through oxidation.13 Other uncom-mon causes include Diphyllobothrium latum (i.e., fish tapeworm) infection or inherited disorders of cobalamin metabolism, including Imerslund syndrome (a congenital
vitamin B12 malabsorption associated with proteinuria).20 Only 10 percent of persons with vitamin B12 deficiency are actually anemic.19
The normal range for serum measures of vitamin B12 varies among laboratories. If the vitamin B12 level is borderline low (i.e., 100 to 400 pg per mL [74 to 295 pmol per L]), methylmalonic acid and homocysteine levels should be ordered and, if elevated, may provide evidence of B12 deficiency.8 The Schilling test (i.e., mea-suring enteral absorption of vitamin B12) is not widely available at this time.
Oral therapy appears to be as effective as intramuscu-lar therapy for the treatment of vitamin B12 deficiency.21 Relapse of pernicious anemia occurs at a mean interval
Evaluation of Macrocytic Anemia
Figure 3. Algorithm for the evaluation of macrocytic anemia. (RBC = red blood cell; MMA = methylmalonic acid.)
Mean corpuscular volume > 100 fL; order peripheral smear, vitamin B12 level, and reticulocyte count
Is peripheral blood smear abnormal?
No (no megalobastic features) Yes (megalobastic features)
Reticulocyte count > 2 percent?
Yes
Suspect hemolysis and work-up for hemolytic anemia
No
Review vitamin B12 level
Consider alcohol-related, drug-related, thyroid-related, and liver disease pathologies, and consider checking liver function tests and thyroid-stimulating hormone levels
Vitamin B12 level is < 100 pg per mL (74 pmol per L)
Vitamin B12 level is > 400 pg per mL; order RBC folate level
Consider further evaluation with bone marrow biopsy
Vitamin B12 deficiency
Treat with folic acid
MMA and homo-cysteine levels are elevated
MMA and homo-cysteine levels are normal
MMA level is normal and homocysteine level is elevated
MMA level is elevated and homocysteine level is normal
Treat with oral vitamin B12
Vitamin B12 level is 100 to 400 pg per mL (295 pmol per L)
Check MMA and homocysteine levels RBC folate
level is normalRBC folate level is low
Consider further evaluation with bone marrow biopsy
Folic acid deficiency
Folic acid &VitaminB12
Hesdorffer CSetal.NEJM2015
n engl j med 373;17 nejm.org October 22, 20151656
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
intestinal absorption of vitamin B12 is an altera-tion in the intestinal pH. Since vitamin B12 is a weak acid, its absorption is decreased in an al-kaline environment. Phenytoin in solution has a very high pH (approximately 12), and an elevated
gastric pH has been noted in persons who have been receiving long-standing phenytoin therapy. This may partially explain why antacids such as histamine2-receptor antagonists (H2 blockers) and proton-pump inhibitors may, on rare occa-
— Vitamin B12
STOMACH
ILEUM
TERMINAL ILEUM
ILEALCELL
GALLBLADDER
DUODENUM
JEJEJE U
NUM
PANCREAS
— Intrinsic factor
Absorption
— Transcobalamin II
— Cubilin
— Folic acid
Folic acid
Vitamin B12
Intrinsicfactor
Transcobalamin I
Transcobalamin II
Cubilin
— Transcobalamin I
Vitamin B
Intrinsic
Cubilin
Transcobalamin I
MESENTERICVESSEL
Transcobalamin II
Vitamin B12–Intrinsic-factorcomplex
The New England Journal of Medicine Downloaded from nejm.org by ANDREAS HOLBRO on October 22, 2015. For personal use only. No other uses without permission.
Copyright © 2015 Massachusetts Medical Society. All rights reserved.
VitaminB12deficiency
Stabler SPNEJM2013
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 368;2 nejm.org january 10, 2013152
BrainAltered mental statusCognitive defects“Megaloblastic madness”: depression, mania, irritability, paranoia, delusions, lability
Optic atrophy, anosmia, loss of taste, glossitis
Infertility
Bone marrowHypercellular, increased erythroid precursorsOpen, immature nuclear chromatinDyssynchrony between maturation of cytoplasm and nucleiGiant bands, metamyelocytesKaryorrhexis, dysplasiaAbnormal results on flow cytometry and cytogenetic analysis
Spinal cordMyelopathySpongy degeneration
ParesthesiasLoss of proprioception: vibration, position, ataxic gait, limb weakness; spasticity (hyperreflexia); positive Romberg sign; Lhermitte’s sign; segmental cutaneous sensory level
Autonomic nervous systemPostural hypotensionIncontinenceImpotence
Peripheral nervous systemCutaneous sensory lossHyporeflexiaSymmetric weaknessParesthesias
Abnormalities in infants and childrenDevelopmental delay or regression, permanent disabilityDoes not smileFeeding difficultiesHypotonia, lethargy, comaHyperirritability, convulsions, tremors, myoclonusMicrocephalyChoreoathetoid movements
Peripheral bloodMacrocytic red cells, macroovalocytesAnisocytosis, fragmented formsHypersegmented neutrophils, 1% with six lobes or 5% with 5 lobesLeukopenia, possible immature white cellsThrombocytopeniaPancytopeniaElevated lactate dehydrogenase level (extremes possible)Elevated indirect bilirubin and aspartate aminotransferase levelsDecreased haptoglobin levelElevated levels of methylmalonic acid, homocysteine, or both
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Copyright © 2013 Massachusetts Medical Society. All rights reserved.
MCV
Microcytic anemia Normocytic anemia Macrocytic anemia
MCV<80fl MCV>100fl
- Irondeficiency- Hemoglobinopathy- Anemia of chronicdisease +/- irondeficiency
- Bleeding*- Hemolysis*- Anemia of chronicdisease- Anemia inCKD- Bone marrow failure/infiltration
(- Reticulocytosis*)- Vit.B12 deficiency- Folate deficiency- Liver disease- Hypothyroidism- Alcohol abuse- Dyslipidemia- MDS- Drugs
Thecut-offvaluesforthissubclassification donotcorrespondtothereferencevaluesofMCV.CKD:chronic kidney disease;MDS:Myelodysplastic syndrome
Classification of anemia
- Cold agglutinins- Oldblood
- Copper deficiency- LeadIntoxication- Sideroblastic anemia
Conclusions
• Definitionof anemia• Anemia is never „normal“• Work-up of anemia &when to refer to the specialist• Classification &differentialdiagnosis according to MCV• Treatmentaccording to underlying disease/definitediagnosis
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