Anemia of Chronic Disease - Charleston APRN Conferencecharlestonaprnconference.com/Charleston...

2/15/2017

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Anemia of Chronic Disease Deborah H. Brooks MSN, ANP-BC, CNN, CNN-NP

February 23, 2017

23rd Annual Advanced Practice Registered Nurse Conference

Objectives

Identify causes of anemia

Discuss evaluation of anemia

Describe strategies to treat anemia

Disclosures None

netwellness.org

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Anemia

medicalnewstoday.com

Too few red blood cells or hemoglobin in the blood resulting in decreased capacity to carry oxygen. Anemia is not normal. Look for a cause.

Types of anemia

• Blood loss • Acute or chronic

• Destruction of blood cells • Hemolysis

• Sickle cell, thalassemia

• Toxins – venom, poison

• Mechanical destruction

• Decreased or incorrect blood cell production • Iron deficiency

• Nutrient deficits

• Medications

• Neoplasms

• Malabsorption

• Inflammation

• Infection

• Old age

50yo female Normal creatinine H/H normal, MCV/MCH low, RDW elevated Hb falling

72yo male CKD stage 4 SLE, RA, gout H/H 7.2/24

45yo female No CKD Exhausted, ice pica No bleeding source found Hb 10 despite iron replacement

60yo female SLE, TM,

hypothyroid, CKD Hb falls – 11.5 to 7.5

No bleeding

48yo male Crohn’s dz, HBV, liver transplant,

SBO Low Hb iron

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Red blood cell evaluation

• Hemoglobin (Hb) – protein in RBCs that carries oxygen

• Hematocrit (Hct) – portion of RBCs in whole blood

• Mean corpuscular volume (MCV) – average RBC cell size

• Mean corpuscular Hb (MCH) – amount of Hb in average RBCs

• Mean corpuscular Hb concentration (MCHC) – concentration of Hb in RBCs

• Reticulocyte count – newly produced immature RBCs

• Red cell width distribution (RDW) – variability in size/width of RBCs

Koury, 2014; image: www.pathologystudent.com

Current knowledge

slideshare.net

Stem to progenitor cells research

• Progenitor cells (derived from stem cells) may be the actual drivers of hematopoiesis rather than front line stem cells.

• Barcoding of DNA done in mice followed specific cell lines.

• Current: all RBC come from here

• Research: cells are generated by long lived progenitor clones

Sun et al., 2014; image: http://1.bp.blogspot.com/-k4bIJTZo9UY/TuTBCZ6hOAI/AAAAAAAAAbs/k_NaoxaYgLU/s1600/Bone_marrow_adult_Stems.png

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Anemia of chronic disease – ACD (anemia of inflammation)

2nd most common cause of anemia worldwide; iron deficiency is #1

• Infections

• Inflammation (30-60% of RA)

• Neoplasms (30-63%)

• Diabetes

• Old age (30% often due to inflammatory dz or CKD)

• Coexisting with other anemias e.g. iron deficiency

Schrier & Camaschella, 2015; Weiss, 2015

Acute ACD

• Inflammatory processes due to acute illness/injury

• Exacerbation of underlying chronic disease

• Trauma

• Surgery

• Sepsis

• Heart failure/MI

Schrier & Camaschella, 2015

Phases of inflammation

• Initiation

• Resolution

• Inflammation can persist for 10-15 yrs prior to complications e.g. DM, atherosclerosis, obesity, metabolic syndrome, RA, IBD, asthma

• Treatment can delay or reduce complications

• Current research suggests age 20-40 have more success with resolution

• Research focus on end product of omega 3 fatty acids – SPM (specialized pro-resolving mediators)which reduce/eliminate inflammation. Some people lack lipoxygenases to make the conversion.

Claria, 2017

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Hypoxia driven cycle: Erythropoiesis stimulation

Image: intranet.tdmu.edu.ua

Normal cycle for RBC production

Bloodjournal.org

Reasons for ACD (acute and chronic) Usually normochromic, normocytic, hypoproliferative, mild

• Shorter RBC life span especially with inflammation (cytokines)

• Decreased iron absorption – (hepcidin)

• Iron trapped in macrophages – (hepcidin)

• RBC precursor death – erythropoiesis can’t respond (cytokines)

• Inadequate response of erythroid cells to erythropoietin

• Decreased erythropoietin production

• Folate deficiency – folate competes with for binding sites for salicylates (used in treatment of RA), trimethoprim/sulfamethoxazole, & anticonvulsants. Folate excreted in urine.

Koury, 2014; Schrier & Camaschella, 2015; Calabrese, Spivak, & Kay

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ACD: evolutionary defense against infection

• “Nutritional Immunity”- assisting innate immune defenses

• Microbes require iron for development and reproduction

• Sequestering iron reduces its availability

• Malignant cell growth may be hindered if iron is less available

• Anemia may be “collateral damage” from noninfectious chronic inflammation

Weiss, 2015

Pathways for ACD development

• Inflammatory mediators on iron regulation

• Suppression of erythropoietin

• Cytokine inhibition of erythroid progenitor cells

Weiss, 2015

Evaluation of anemia

• History & physical including onset, diet, medical history, meds

• CBC with diff and retic count and peripheral blood smear

• Renal function

• Iron studies – if suspected

• Folate/B-12 – if suspected

• Erythrocyte sedimentation rate and C-reactive protein – if indicated

• Explore other abnormalities e.g. leukopenia, thrombocytopenia as source of other disease

Koury, 2014; Price & Schrier, 2015

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Peripheral blood smears

Normal RBC – central pallor is 1/3 RBC diameter

Normochromic normocytic anemia; need CBC to diagnose anemia

images: www.studyblue.com; library.med.Utah.edu; home.kku.ac.th

Ingredients for an erythrocyte • Iron (heme) – main element of RBC

• Protein (globin) – protein portion of RBC

• Vitamin B12 (cobalamin)- needed for DNA synthesis in erythroblast nucleus to produce proteins. A cofactor for converting folate to active form.

• Folate – works with B12 for RBC synthesis

• Pyridoxine (B6) – transports B12; works with folic acid to lower homocysteine levels

• Vitamin C – glucose transporters carry C to the RBC; needed for pliability of RBC

• Nicotinic acid (B3) – needed for cellular energy metabolism; protects against ischemia

• Copper – 2 enzymes; converts ferrous to ferric for use in transferrin; aids iron uptake into RBC

• Cobalt – part of B12 for cell synthesis; interacts with hypoxia inducible factors (HIF) to increase erythropoietin production

Makama, 2014; Koury, 2014

Hypoxia-inducible factors: HIFs

• Stimulated by hypoxia which

• increases erythropoietin production

• Suppresses hepcidin which

• Increases absorption of duodenal iron

• Further research on the specifics of these pathways is continued

Weiss, 2015

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Hypothyroid • Thyroxine increases cell metabolism and O2

consumption.

• Probably causes tissue anoxia which stimulates erythropoiesis.

• Hypothyroidism leads to a mild degree of anemia.

• Slightly increased MCV (macrocytosis) possible even with normal B-12; thyroid hormone T3 reduces erythroblast size

• Anemia can be corrected by thyroxine e.g levothyroxine.

Makama, 2014; Koury, 2014

Iron deficiency: does your patient have this? • Pagophagia: craving for ice.

• Anemia may not be present yet.

• Responds almost immediately to iron therapy.

• Beeturia: bright red urine after eating beets. • Occurs normally in ~12% of the population.

• 50-80% in iron deficiency.

• Betalaine (betanin) red pigment in beets is decolorized by ferric ions.

• No iron – red urine. Disappears with iron repletion.

• Restless legs: one of the most common causes of RLS. • May have favorable response to oral iron even if the ferritin is not low.

Schrier & Mentzer, 2014

Normal iron cycle – 3-4 gms normal content

• 2gms in hemoglobin

• 400mg in proteins e.g. myoglobin

• 3-7mg plasma Fe on transferrin

• Remainder storage as ferritin or hemosiderin in liver, spleen, bone marrow • Males: 10mg/kg • Females: may be 50-70% less

>4ml/day iron loss leads to iron deficit

Singh, 2012: http://kidney2.blogspot.com/2012/01/iron-deficiency-in-ckd-role-of-hepcidin.html; Schrier & Mentzer, 2014; Koury, 2014

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Cell types

• monocytes • come from stem cells in the marrow • circulate in the blood for about 20-40 hours • migrate to the tissues to become …

• macrophages • function is phagocytosis • storage site for iron • can live for months to years

Makama, 2014; macrophage image: fineartamerica.com; monocyte image: histoly-world.com

monocyte

Macrophage infested by bacteria

Cytokines • Inflammatory markers e.g.

interleukins IL-1 and IL-6, tumor necrosis factor TNf from activated monocytes

• Bone marrow less responsive to erythropoietin

• RBC precursors destroyed

• May down regulate erythropoietin in renal cells

• May down regulate ferritin and transferrin receptors

Schrier & Camaschella, 2015; image Nov 2013: http://nature-in-human-health.com/proinflammatory-cytokines-part-13.html#more-2950; IL-6 wikipedia; IL-1 www.lookfordiagnosis.com

TNF - Tumor necrosis factor

IL-6 IL-1 beta

Hepcidin • Peptide from the liver

• Controls iron absorption from the intestines via the iron transport protein ferroportin

• High hepcidin = low iron absorption (acute phase reactant in response to IL-6)

• Blocks iron release from storage in the macrophages

• Kidney is main route of hepcidin excretion

• Hepcidin levels are not available for clinical use

Schrier & Camaschella, 2015; Singh, 2012: http://kidney2.blogspot.com/2012/01/iron-deficiency-in-ckd-role-of-hepcidin.html;

Ganz, T. (2003) Blood www.bloodjournal.org

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Hepcidin blockage of iron transfer

J Clin Invest (2005). Of mice and men: the iron age. Vaulant, Lou, Viatte, Kahn, 115(8), 2079-82, doi:10.1172/JCI25642

Functional iron deficiency

• Iron stores are adequate but not available

• High ferritin suggests iron trapped in macrophages and low iron and low transferrin suggests a deficiency in ability to recycle iron.

• Low ferritin(<30ng) indicates absolute iron deficiency; look for blood loss.

• ACD may actually suppress erythropoietin production.

• Reticulocyte hemoglobin gives an indication of available functional iron in the past 3-4 days. It may be a more sensitive indicator of functional iron deficiency in ACD. Can be ordered as part of hematology panel.

Calabrese, Spivak, & Kay; Schrier & Mentzer, 2014; Weiss, 2015

Zinc • If insufficient iron is available, zinc substitutes in the heme and

forms zinc protoporphyrin (ZPP). • ZPP can be measured.

• Its presence indicates a lack of iron but not a reason for the lack.

• ZPP is also present in elevated lead levels and can be useful in monitoring response to lead treatment. Not a good screening test for mild lead toxicity.

• Copper and zinc are absorbed at the same intestinal site. • Consider Cu deficit with anemia e.g. bypass surgery, poor absorption.

• Poor iron utilization with Cu deficit.

• Zn takes precedence in absorption if doses are >50mg/day.

• Levels can be measured.

Schrier & Mentzer, 2014

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ACD & Inflammatory Bowel Disease

• Primary defect: iron deficiency

• IL-6 is prime inflammatory marker

• Hepcidin blocks ferroportin which transfers iron across endocyte membrane into the circulation

• This blocks absorption of iron from food or storage RES or macrophages

• Be alert for folate and B-12 deficits too due to malabsorption

Goldberg, 2013; Basseri et al., 2013

Case study: Crohn disease w/ additional risks

• 48 yo male

• PMH: Crohn’s disease, hepatitis B, ETOH abuse, liver transplant

• Recent hospitalization for small bowel obstruction

• Meds include tacrolimus

• Allergies: infliximab and numerous others

• Labs: Hemoglobin 10, iron 21, ferritin 14

• Considerations for treatment- • B12/Folate ok?

• Crohn’s disease monitored and controlled?

• Iron replacement ok? What form is best – oral or IV?

Case study: Acute ACD - vasculitis

• 53 yo male

• HTN, DM, microscopic polyangiitis

• Baseline creatinine 1.3-1.5 for 7 years; AKI with vasculitis

• Baseline Hb 11-12 w/ chronic low indices and elevated RDW; 7-8 with AKI

• Folate/B12/TSH normal

• Tired – no illnesses, no bleeding

• Medications hx – rituximab, dapsone, omeprazole, azathioprine

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Risks and treatment

• Underlying microcytic anemia with low indices • Diabetes

• Acute illness with vasculitis and AKI • Cytokine production

• Blood loss

• Erythropoietin suppression

• Required blood transfusions, apheresis, acute HD, immunosuppressive therapy, iron supplementation and erythropoiesis therapy

ACD and SLE/transverse myelitis

• 60 yo female

• PMH: transverse myelitis, SLE, CKD sCr 2, hypothyroidism

• Hospitalized with dehydration and recurrent pneumonia; developed acute kidney injury sCr 4

• Hemoglobin dropped from 11.5 baseline to 7.5

• Rehydrated, transfused, diuretic readjusted

• ACD risks • SLE flare or TM exacerbation? Cellcept continued • Pneumonia symptomatic of underlying immunoglobulin deficiency? No • Bleeding? No source – transfused 2 units

Successful return to baseline kidney function.

ACD and rheumatoid arthritis

• IL-6 causes elevated hepcidin levels and blocks iron availability

• IL-6 increases plasma volume (diluted Hb)

• Inhibition of IL-6 (e.g. tocilizumab or infliximab) increases iron availability

• Divide ferritin by 3; if < 20 iron deficiency is probably present

• ~1/3 have SCr >2 with CKD so ESA therapy is helpful

• Anemia often occurs later in the disease and is more common in women

Calabrese, Spivak, & Kay; Poggiali et al., 2014; Schrier & Mentzer, 2014

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Case study: contributing factors

• 50yo female

• Diabetes

• HTN

• Lumbar radiculopathy

• Rheumatoid arthritis – nonerosive

• GERD

• Iron deficiency

• Polysubstance abuse (cig, crack, marijuana)

eGFR >59ml

Hb ↓ 6.5 – 12

MCV ↓ 55-77

MCH ↓ 16-24

MCHC ↓ 26-29

RDW ↑ 21-15

Iron ↓ 11-18

Ferritin ↓ 3.6-3

Sat % ↓ 2-5

HbA1C ↑ 6-13

Rheum factor ↑

48

Blood for $

Treatment plan - Replace iron - PO not

tolerated; insurance requested precert; 4units Hb 3.5

- Minimize pill burden - Combine appointments - Substance abuse therapy

(current is smoking cessation)

Normal endoscopy

Case study: lupus nephritis

• 72 yo male

• PMH: CKD stage 4, lupus nephritis per biopsy, rheumatoid arthritis, gout, hypothyroid

• Several RBC transfusions and IV iron infusions

• Medications – mycophenolate, hydroxychloroquine, levothyroxine, losartan, colchicine

• Darbepoetin 150mcg every 2-4 weeks

• Considerations: B12/folate deficiency; thyroid function

Hb 7.1 ↓

Hct 24 ↓

MCV 102 ↑

MCH 30

MCHC 29.5 ↓

RDW 15.8 ↑

Ferritin 116

Iron 86

% sat 39

creatinine 4.2

eGFR 13

Overcoming ACD: research areas

• Hepcidin lowering agents • Mouse and monkey models

• Early clinical trials with healthy human volunteers

• Activation of hypoxia-mediated pathways to reduce hepcidin

• Erythropoietin therapy research to inhibit cytokine formation

• Monoclonal antibodies e.g. tocilizumab binds to IL-6 receptors and reduces inflammation

• Vitamin D

Poggiali et al. 2014; Weiss, 2015

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Vitamin D and Hepcidin suppression

• Vitamin D is an inducer of antimicrobial proteins (e.g. cathelicidin CAMP)

• Hepcidin is an iron-regulatory protein in monocytes and hepatocytes

• Vitamin D (25D) seen to suppress hepcidin by 34% for 72hr in study

• Hepcidin suppression increases iron availability

Suppression of Iron-reg hepcidin… vitamin D Bacchetta et al 2014, JASN 25(3) 564-72; Poggiali et al., 2014; Weiss, 2015

Iron overload: research • Hereditary hemochromatosis and B-thalassemia both have iron

overload from hepcidin deficiency

• Hepcidin agonists – too expensive to reproduce hepcidin

• Hepcidin has short ½ life

• Mini-hepcidin in the animal lab have decreased iron load in serum & liver

• Synthetic hepcidin antagonist research options

• Anti hepcidin antibodies are being investigated

Preza et al., 2011; Poggiali et al. 2014

Peripheral blood smears

images: www.studyblue.com; library.med.Utah.edu; home.kku.ac.th

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Thalassemia • Inherited blood disorder; either the alpha (α) or beta (β) globin are

missing or mutated and cause a hemoglobin abnormality • Heterozygous are silent carrier w/ low normal Hb or slightly low Hb and MCV

• Homozygous have mild microcytic anemia

• Thalassemia trait found in 30% African Americans • This ethnic group has slightly lower Hb even without thalassemia, iron

deficiency, sickle cell traits/disease

• Thalassemia trait also found in persons from Mediterranean, Africa, Middle East, China, and Southeast Asia

• Alert - B12/folate macrocytosis may be masked

• Iron stores and RBC count usually normal

Price & Schrier, 2015; Schrier, 2014

Case study: multifactorial causes of anemia

• 45yo African American female

• Symptoms: Significant fatigue, ice pica (pagophagia)

• PMH: anemia during pregnancy, DM2, hypertension, hyperlipidemia, sleep apnea

• Pertinent negatives: no overt blood loss, normal colonoscopy, no menorrhagia, no kidney disease

• Oral iron had not repleted her and caused GI upset

• Given several IV iron infusions over 2 years with return of symptoms

Case study (cont)

• Hematology evaluation

• Pertinent lab findings: • Decreased - Hb 10.2, MCV 74, MCH 24, ferritin 10.

• Elevated - RDW 16, soluble transferrin receptor 7 (1.9-4.4 n’l)

• Soluble transferrin receptor (sTfR) – elevates with iron deficiency and is not an acute phase reactor (from bone marrow erythroid precursors – indicates erythropoietic activity so not specific for iron deficiency)

• Alpha-globin gene analysis – one alpha globin gene is deleted; patient is a silent alpha thalassemia carrier. Mild microcytosis is common.

• Additional diagnoses: iron deficiency and ACD/inflammation

Schrier & Mentzer, 2014

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α-thalassemia

images: virtual.medic.wordpress.com ; http://ukts.org/about-thalassaemia/thalassaemia-types/carrier/genetic.html

Hypochromic, microcytic anemia with thalassemia

Our patient is missing a single alpha globin chain; is a silent carrier

Older adults: those >65 years • WHO Hb criteria: <13-14g/dL for men; <12.3g/dL for women

• Older person proposed: 12.7-13.2g/dL men; 11.5-12.2g/dL women

• ~10-25% older adults are anemic

• Lower level needs evaluation – may have underlying process & ↑ morbidity/mortality (more frailty, depression)

• Ferritin levels increase with age; “normal” may mask deficiency.

• Decreased ferritin with normal/low anemia can have gi blood loss.

• Thalassemia trait; what is their anemia history

• Estimated world population – by 2030 8.4 billion people, 216 million >80 with 49 million being anemic

Price & Schrier, 2015

Case study: 86 yo female

• HTN, GERD, OA, CKD 3b

• Depressed, confused

• Hb 9 – falls to 7

• Iron stores normal

• Meds: amlodipine, ethacrynic acid, famotidine, calcium/vit D, darbepoetin

• Labs: n’l MCV, MCH, MCHC

• Hb falls to 6, requires blood

• N’l iron stores, neg hemocult

• Declines further w/u

• B-12/folate obtained: B12 low; given cyanocobalamin replacement.

• One month later B-12 n’l, Hb 10.5, confusion cleared.

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Risk factors for B-12 or folate deficiency

Age >65 year old

Medications e.g. proton pump inhibitors, H2 blockers, metformin

Lack of intrinsic factor (IF) – underdiagnosed and more common in > age

Gastritis, gastrectomy, ileal disease, IBD

Inadequate diet – vegans/vegetarians (B-12 is only in animal products)

HIV – nutrition, diarrhea, ileal dysfunction (B12 <125pmol/L poorer survival)

Megablastic changes (> MCV/MCH) may not be present especially if GI blood loss is present

Schrier 2014; Koury, 2014

B-12 vs. folate

B-12

• Huge stores so it takes years for deficiency to appear

• Can cause permanent neurologic damage (<vibratory sense, + Romberg – can’t stand with feet together)

folate

• Small stores so deficiency occurs in 4-5 months

• Most common cause is diet or ETOH (animal products/leafy veg)

• Symptoms are r/t anemia not neurological

Case study: age & risks • 81 yo male

• PMH: CKD, CAD, aortic valve replacement, HTN, peptic ulcer disease, DM, hypothyroid, gout, stasis leg ulcer, melanoma 50 years ago

• Multiple meds

• Had IV iron 6 months ago; c/o tired and cold. Labs unchanged

Pt range pre and post IV iron

New info

Hb 9.4-9.6 +kappa

Hct 29-30 +lambda

Ferritin 10-14 2gm proteinuria

% sat 25-29

creatinine 2.4-3.2

Elevated kappa and lambda light chains can be found in severe kidney disease, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, and amyloidosis.

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Case study: is it EPO deficiency? Pt range

Hb ↓ 6.6-7 √

Hct ↓ 22.3-22.7 √

MCV 94-87

MCH 26-27.8

MCHC 29.6-31.7

RDW ↑ 15.5-14.8 √

Retic count (21-171K) 42

Retic % (0.5-2.8) 1.8

Retic Hb (30.5-33.9)↓ 27.6 √

EPO (2.6-18.5) 9.2

Iron 88-134

Ferritin 311-384

% sat 46-66

Creatinine ↑ 2.3-1.6 √

• 62 yo female

• PMH: SLE, lupus nephritis per biopsy, proteinuria, hypothyroid, gout

• Meds: allopurinol, mycophenolate, hydroxychloroquine, losartan, spironolactone, levothyroxine, etc

• Hospitalized with AKI (diarrhea, dehydration)

• Anemia contributors • Decline in kidney function (3b to 4) • SLE & gout – no active flares • Action plan is to start Epo • Monitor labs and check thyroid function

• If Hb doesn’t respond repeat iron studies and retic Hb

Erythropoietin levels

• Normal is 4-24 mlU/ml with 8-10 the usual range (follow your lab guide).

• If Hb <10.5 begin to observe elevated EPO levels

• Levels increase in iron deficiency

• EPO regulated by cytokine production, oxygen in tissues, & iron availability

• In older patients EPO levels may rise with age • possibly r/t need to maintain erythropoiesis • response to hypoxia • hypoplastic bone marrow

Calabrese, Spivak, & Kay; Price & Schrier, 2015

Summary

• Anemia always needs to be investigated

• Anemia is often multifactorial

• Anemia not responding to therapy - look for additional cause

• New onset anemia – assess for health changes and cause

• Approach is global but treatment needs to be individualized

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References • Basseri et al. (2013). Hepcidin is a key mediator of anemia of inflammation in Crohn’s disease.

Journal of Crohn’s and Colitis, 7, e286-e291. http://dx.dot.org/10.1016/j.crohns.2012.10.013

• Calabrese, L., Spivak, J. & Kay, J. (). Anemia in patients with rheumatoid arthritis. Current challenges in rheumatoid arthritis. Retrieved http://www.medpagetoday.com/pdf/MEVH06/pages.cfm?section=09-liverintropart2.html

• Claria, J., (2017). Inflammatory origins of chronic disease: novel clinical insights for effective management. Healthcare Institute for Clinic Nutrition. https://reachmd.com/programs

• Goldberg, N. D. (2013). Iron deficiency anemia in patients with inflammatory bowel disease. Clinical and Experimental Gastroenterology, 6, pp 61-70.

• Koury, M.J. (2014). Abnormal erythropoiesis and the pathophysiology of chronic anemia. Blood Review, 28, pp. 49-66. http://dx.doi.org/10.1016/j.blre.2014.01.002

• Makama, F. T. (2014). General considerations in hematology: blood formation in erythropoiesis and leukocyte formation. http://hubpages.com/education/General-Considerations-In-Hematology-Blood-Formation-In-Erythropoiesis

References

• Poggiali, E., De Amicis, M. M., & Motta, I. (2014). Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. European Journal of Internal Medicine, 25, PP 12-17. http://dx.doi.org/10.1016/j.ejim.2013.07.011

• Preza, G. C., Ruchala, P., Pinon, R., Ramos, E., Qiao, B., Peralta, M. A., Sharma, S., Waring, A., Ganz, T. & Nemeth, E. (2011). Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest, 121(12), pp. 4880–4888. doi: 10.1172/JCI57693

• Price, E.A. & Schrier, S.L. (2015). Anemia in the older adult. Retrieved from www.uptodate.com

• Schrier, S. & Camaschella, C. (2015). Anemia of chronic disease/inflammation. Retrieved from www.uptodate.com

• Schrier, S. & Mentzer, W. (2014). Causes & diagnosis of iron deficiency anemia in adults. Retrieved from www.uptodate.com

References

• Schrier, S. (2015). Approach to the adult patient with anemia. Retrieved from www.uptodate.com

• Schrier, S. (2014). Etiology and clinical manifestations of vitamin B12 and folate deficiency. Retrieved from www.uptodate.com

• Sun, J., Ramos, A., Chapman, B., Johnnidis, J., Le, L., Ho, Y., Klein, A., Hofmann, O., & Camargo, F. (2014). Clonal dynamics of native haematopoiesis. Nature, 514(7522). pp 322-327. doi:10.1038/nature13824

• Weiss, G. (2015). Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Seminars in Hematology, 52(4), pp 313-320. doi.org/10.1053/j.seminhematol.2015.07.004