Approach to Anemia: An Interactive Discussion

Mark M. Udden, MDChief, Benign HematologyBaylor College of Medicine

DisclosuresI didnt do it.

You didnt see me.

You have no evidence.

Consultant for NovartisCo-Investigator for sameFree meals from Injectafer

people

Bart Simpson

Objectives: Develop an Approach

to evaluation of microcytic anemia anemia

to evaluation of microcytic anemia

to evaluation of iron deficiency

to anemia of chronic disorders

to anemia of renal disease

After the Hx and PE:

Peripheral Blood Smear Reticulocyte Count

Patient 1

A 25-year-old woman presents with weakness, fatigue, and pallor. She reports that she has had heavy periods for most of her adult life and that she has three children, the youngest of which is 10 months old.Her CBC shows a Hct of 28 %, with an MCV of 72 fL, and a platelet count of 540,000. The WBC is normal.

Iron Deficiency Anemia History

BleedingPicaRestless LegsSubtle neurologic dysfunctionDysphagia

Physical ExamPainless stomatitisSpoon nailsBlue Sclera?Telangiectasia

Peripheral Blood Smear in Fe Deficeincy

Peripheral Blood Smear in Fe Deficeincy

Forms of Pica Reported in Association with Iron Deficiency

Pagophagia Ice Geophagia Clay, dirt Amylophagia Starch Geomelophagia Potatoes Gooberphagia Peanuts

Unnamed Forms of Pica

Ash Baking Powder Card Board Paper Venetian Blind Dust Wood, Toothpicks

Nail Changes in Fe Deficiency

Spooning!

Plummer Vincent: Esophageal Web

Iron Studies in Fe Deficiency

Low SI, high TIBC; low % sat Low ferritin How high can the ferritin be? Two other causes of a low ferritin

HypothyroidismVitamin C deficiency

Causes of Iron Deficiency Nutritional

infants women of child

bearing years Blood loss

uterine (menorrhagia, fibroids)

vWF disease GI bleeding

Helicobacter pylori

IBD HHT

Trauma Frequent blood

donation

Malabsorption Gastric bypass postgastrectomy sprue

Loss as hemosiderin valve hemolysis PNH

Pulmonary hemosiderosis

Unusual causes of iron deficiency

PresenterPresentation NotesWhen you can liver forever, what do you live for?

Bella Lugosi on the left and Bella Swan played by Kristen Stewart.Film buffs know Bella Lugosi. See the movie Ed Wood (Johnny Depp), a biopic about the worst movie director of all time. Martin Landau is a wonderful Bella Lugosi in that movie.

http://www.imdb.com/media/rm2266076160/tt1099212http://www.imdb.com/media/rm2266076160/tt1099212

More Vampires

PresenterPresentation NotesMaila Nurmi (Vampira) and Martin Landau (as Bella Lugosi in the movie Ed Wood).

Treatment of Iron Deficiency

Use cheap FeSO4, 325 mg TID Keep away from Children Ascorbic acid may help absorption

Follow Hematocrit, ferritin

Iron Refractory Iron Deficiency Anemia (IRIDA)

Endoscopic evaluation often fails to identify a cause of iron deficiency anemia Capsule studies have been informative AVM in the elderly arent always detected

Some patients will not respond to oral iron even if complianttoo much iron is being lost Menstrual loses IBD, HHT, Cancer

Patient has something else: Thalassemia

Poor Mans Iron Absorption Test

Patient Fasts Overnight AM baseline serum iron Give 100 mg of elemental iron PO as liquid

FeSO4 Draw serum iron at one and two hours Typical basal iron is

IRIDA

Celiac Disease Anti TTG (tissue transglutaminase)

Autoimmune gastritis Achlorhydria, anti Parietal cell and Intrinsic

factor antibodies and PA H. Pylori

Relationship to autoimmune gastritis Hereditary IRIDArara avis

PresenterPresentation NotesTTG ab are IGA and may not be present in IgA deficient individuals, Anti endomysial abs, seronegative mild celiac disease HLA DQ2/DQ8Exlude ACD with CRPChronic renal failure PPI, GI bleeding due to drugs

IV Iron

IBD HHT Menorrhagia Pregnancy Roux en Y

Sleeves/stapling ? Ordinary iron deficiency and intolerance to

oral iron

Patient 2

A 40 year old man presents after having been told that he was anemic after routine tests for an insurance physical exam. He has no history of bleeding and has enjoyed good health. He is a runner who puts in 20 miles per week and has done a marathon in the last year. He believes that his mother was anemic. His CBC: HCT 32 with MCV of 70 fL. WBC and platelet count are normal.

Alpha Thalassemia

Diagnosis of exclusion Normal iron studies Normal Hb electrophoresis Common in Black Americans Hypochromic microcytic anemia

(mild) Normal RDW

New Methylene Blue Stain in Hemoglobin H disease

Alpha ThalassemiasPOPULATION GENOTYPE CLINCAL

PRESENTATIONAfrican 0+/++ Silent

0+/0+ ThalassemiaMinor

Asia, Near East 00/++ ThalassemiaMinor

00/0+ Hemoglobin H

00/00 Hydrops Fetalis

POPULATION

GENOTYPE

CLINCAL PRESENTATION

African

0+/++

Silent

0+/0+

Thalassemia Minor

Asia, Near East

00/++

Thalassemia Minor

00/0+

Hemoglobin H

00/00

Hydrops Fetalis

Beta Thalassemia Minor

Seen in all groups, common in Mediterranean

Hypo/micro, fine basophilic stippling, targeting, normal RDW

May have minimally enlarged spleen Normal iron studies, Hb electrophoresis:

A2> 3.5 %; F variably increased Genetic Counseling

Thalassemic Hemoglobinopathies

Hemoglobin E traitHigh frequency in SE Asia

Viet NamCambodia

Microcytic E-Beta thalassemia

Thalassemia major Thalassemia intermedia

Patient 3

A 55-year-old woman presents with a long history of rheumatoid arthritis. For the past two weeks she has had a flare with pain in the hands. Her Hematocrit is 30 %, her MCV is 83 fL, and the WBC and platelet counts are normal. On exam she has swollen tender MCP joints.

IL-6 up regulates production of hepcidin in the liverHepciden interacts with iron transporter ferroportin 1 which is then internalized and destroyediron not able to get out of macrophages

Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023

Pathophysiological Mechanisms Underlying Anemia of Chronic Disease

PresenterPresentation NotesFigure 1. Pathophysiological Mechanisms Underlying Anemia of Chronic Disease.

In Panel A, the invasion of microorganisms, the emergence of malignant cells, or autoimmune dysregulation leads to activation of T cells (CD3+) and monocytes. These cells induce immune effector mechanisms, thereby producing cytokines such as interferon-{gamma} (from T cells) and tumor necrosis factor {alpha} (TNF-{alpha}), interleukin-1, interleukin-6, and interleukin-10 (from monocytes or macrophages). In Panel B, interleukin-6 and lipopolysaccharide stimulate the hepatic expression of the acute-phase protein hepcidin, which inhibits duodenal absorption of iron. In Panel C, interferon-{gamma}, lipopolysaccharide, or both increase the expression of divalent metal transporter 1 on macrophages and stimulate the uptake of ferrous iron (Fe2+). The antiinflammatory cytokine interleukin-10 up-regulates transferrin receptor expression and increases transferrin-receptor-mediated uptake of transferrin-bound iron into monocytes. In addition, activated macrophages phagocytose and degrade senescent erythrocytes for the recycling of iron, a process that is further induced by TNF-{alpha} through damaging of erythrocyte membranes and stimulation of phagocytosis. Interferon-{gamma} and lipopolysaccharide down-regulate the expression of the macrophage iron transporter ferroportin 1, thus inhibiting iron export from macrophages, a process that is also affected by hepcidin. At the same time, TNF-{alpha}, interleukin-1, interleukin-6, and interleukin-10 induce ferritin expression and stimulate the storage and retention of iron within macrophages. In summary, these mechanisms lead to a decreased iron concentration in the circulation and thus to a limited availability of iron for erythroid cells. In Panel D, TNF-{alpha} and interferon-{gamma} inhibit the production of erythropoietin in the kidney. In Panel E, TNF-{alpha}, interferon-{gamma}, and interleukin-1 directly inhibit the differentiation and proliferation of erythroid progenitor cells. In addition, the limited availability of iron and the decreased biologic activity of erythropoietin lead to inhibition of erythropoiesis and the development of anemia. Plus signs represent stimulation, and minus signs inhibition.

Anemia of Chronic Disorders

Hypo/micro or normochromic anemiaLow serum iron (< 60 ug/dL) and

TIBC, Low % saturation Ferritin (>50 ng/mL) Normal RDW Bone marrow shows adequate iron

stores, but no incorporation into precursors

Conditions Associated with Anemia of Chronic Disorders

Acute or Chronic Infection 32 Inflammatory Disease 5 Malignant Disease 17 Renal Insufficiency 14 Other 22

Other In ACD

ETOH liver disease (5) CHF (5) DVT (3) COPD/no apparent infection (2) Myocardial Ischemia (2) Multiple Diagnoses (2) Brittle DM (1) Hypothyroidism (1)

Patient 4

60 year old woman with history of DM for 18 years. Has early retinopathy. Urine study shows microalbuminuria.

Hb is 10.5, MCV is 88 fl, reticulocyte count 1.2 %

GFR estimated is 65 ml/min Iron studies are normal, B12 and folate

are normal

Heme Work Up

Peripheral blood smear normal Thyroid Function Tests normal SPEP and kappa/lambda are

normal Erythropoietin level ordered Testosterone level ordered when

patient is a man

Anemia and DM

Anemia is a common complication of DM and correlates with renal failure

Rate of anemia is higher in patients with Diabetic nephropathy than in non diabetic renal disease with similar levels of renal impairment.

Failure to increase EPO in response to decrease in Hb due to damage to the tubulointerstium.

Patient 5

A 65-year-old black man, a retired minister, presents with anemia. He is diabetic but has done well on a diet. He is referred to you for evaluation of mild anemia: Hct 28 %, MCV 110, and folate, B12, and iron studies are normal. His physical exam is unremarkable, he has no splenomegaly.

Sideroblastic Anemia

Dual Population of RBCs Pseudo Pelger Huet WBC in

Myelodysplastic Increased serum iron, and increased %

Sat High Ferritin Presence of Ringed Sideroblasts TX: Pyridoxine, Transfusions

Differential Diagnosis of Sideroblastic Anemia

Hereditary X-linked Autosomal Recessive Mitochondrial

Pearsons Pancreatic Syndrome Abcb7 deficiency and ataxia

ALA synthase deficiency Acquired

Myelodysplasia V617F JAK2 mutation: Sideroblastic anemia and thrombocytosis Toxins: Alcohol, Lead Drugs: INH, PZA, cycloserine, chloramphenicol Copper Deficiency, Zinc overload, Hypothermia

Causes of Microcytic Anemia

Iron Deficiency Thalassemia Minor Anemia of Chronic Disease Sideroblastic Anemia

IRON STUDIESTEST IRON

DEFICIENCYACD

SERUM IRON LOW LOW

TIBC HIGH LOW

% SAT LOW LOW

FERRITIN 50

TEST

IRON DEFICIENCY

ACD

SERUM IRON

LOW

LOW

TIBC

HIGH

LOW

% SAT

LOW

LOW

FERRITIN

50

Use of Ferritin Alone

5070 ng/ml ACD A rule of thumb: If hemoglobin is 10 or

less and ferritin is less than 50there is a component of iron deficiency.

Rudyard Kipling

Gold is for the mistress, silver for the maid.Copper for the craftsman cunning at his trade.Good! said the Baron, sitting in his hall.But IronCold Ironis master of them all.

PresenterPresentation NotesTime cover in 1926 Canadian Engineers are given an iron ring as part of their graduation ceremony devised by RK

Approach to Anemia: An Interactive DiscussionDisclosuresObjectives: Develop an ApproachAfter the Hx and PE:Patient 1Iron Deficiency AnemiaPeripheral Blood Smear in Fe DeficeincyPeripheral Blood Smear in Fe DeficeincyForms of Pica Reported in Association with Iron DeficiencyUnnamed Forms of PicaSlide Number 11Slide Number 12Slide Number 13Iron Studies in Fe DeficiencyCauses of Iron DeficiencySlide Number 16More VampiresTreatment of Iron DeficiencyIron Refractory Iron Deficiency Anemia (IRIDA)Poor Mans Iron Absorption TestIRIDAIV IronPatient 2Slide Number 24Slide Number 25Alpha ThalassemiaSlide Number 27Alpha ThalassemiasBeta Thalassemia MinorThalassemic HemoglobinopathiesPatient 3Slide Number 32Slide Number 33Anemia of Chronic DisordersConditions Associated with Anemia of Chronic DisordersOther In ACDPatient 4Heme Work UpAnemia and DMPatient 5Slide Number 41Slide Number 42Sideroblastic AnemiaDifferential Diagnosis of Sideroblastic AnemiaSlide Number 45Slide Number 46Slide Number 47Causes of Microcytic AnemiaIRON STUDIESSlide Number 50Use of Ferritin Alone Rudyard Kipling