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2/15/2017
1
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
2/15/2017
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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
2/15/2017
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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
2/15/2017
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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
2/15/2017
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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
2/15/2017
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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
2/15/2017
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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