경희대학교 의과대학·의학전문대학원

철 결핍성 빈혈

경희의대 종양혈액내과 조경삼

Erythropoiesis

• RBC production • Hemoglobin =

heme + globin

• Heme = a porphyrin ring + an iron atom

Iron

• Critical element of cell function • Free iron : highly toxic

– Transferrin, ferritin, hemosiderin

• Carry O2 : hemoglobin, myoglobin

• Iron containing enzyme : cytochrome system in mitochodria

• Iron deficiency :

– Decreased Hb synthesis : anemia, hypoxia

Body iron distribution

Iron content (mg) Male(80 kg) Female(60 kg) Hemoglobin 2,500 1,700 Myoglobin/enzyme 500 300 Transferrin iron 3 3 Iron stores 600 – 1,000 0 - 300

Iron cycle

• Gain : absorption – diet, medicine

• Loss : the loss of epithelial cells from the skin,

gut, and genitourinary tract blood loss (via

gastrointestinal bleeding, menses, or other forms of bleeding) and

• Male : 1 mg/d ; Female : 1.4 mg/d • RBC : 1 mg/mL

• Daily 0.8 – 1% destruction • Fe turnover : 16 – 20 mg/day

Iron absorption

• Proximal small intestine

• Stomach : acidic content

• Gut cell : DMT-1(divalent metal transporter-1) ferritin

---ferroportin (negatively controlled by hepcidin)

• Erythroid hyperplasia : low hepcidin

Hepcidin

• The central regulator of iron absorption, plasma iron levels, and iron distribution

• Hepatocyte, macrophage, adipocyte

• Inhibit iron flows into plasma from macrophage, duodenal enterocyte, hepatocyte

• Bind to the ferroportin (major entryway for iron into plasma) and causing its degradation

• Hepcidin production is regulated by iron and erythropoietic activity

• hepcidin levels are elevated in a range of

inflammatory disease including rheumatologic

diseases, inflammatory bowel disease, a variety of infections, critical illness, and malignancies

Nutritional Iron

• 6 mg/ 1,000 calories • Red meat • M : 6 mg – 15% absorption • F : 11 mg – 12% • Iron deficiency :

– meat-containing diet iron : 20% absorption – Vegetarian diet iron : 5 – 10%

Food iron absorption

• Compare to ferrous sulfate

• Iron in vegetables : 1/20

• Egg iron : 1/8

• Liver iron : 1/2

Increased iron

requirement

• Infant

• Children

• Adolescent

• Pregnancy : last trimesters : 5-6mg • Increased erythropoiesis

Anemia classification

• Etiologic

– Excessive destruction or loss

• Blood loss : acute, chronic

• Hemolysis – Inadequate production • Nutritional • Marrow failure • Others • Morhologic – Macrocytic : • megaloblastic • nonmegaloblastic – Normochromic normocytic – Hypochromic microcytic

normocytic normochromic

hypochromic microcytic

Iron deficiency anemia

• One of the most prevalent forms of malnutrition

• Globally 50% of anemia • 841,000 deaths annually

• Africa and part of Asia : 71% • North America : 1.4%

Stages of iron deficiency

• Negative iron balance : blood

loss(10-20mL/day), pregnancy, rapid growth spurt, inadequate dietay iron

• Iron-deficient erythropoiesis : microcytic cells, hypochromic

reticulocytes

Absolute iron deficiency

Dietary (growth/development) Women’s health

Pregnancy/breast feeding Menstrual blood losses Chronic blood loss

Blood donation

Nonsteroidal anti-inflammatory drugs (NSAIDs) Gastrointestinal neoplasms

Gastrointestinal parasites (developing countries) Decreased iron absorption

Celiac disease

Helicobacter pylori infection Autoimmune atrophic gastritis

Functional iron deficiency

Iron-sequestration syndromes

Anemia of chronic disease/inflammation Autoimmune diseases

Infections Malignancies

Chronic kidney disease Hepcidin-producing adenomas

Iron refractory iron deficiency anemia (IRIDA) Copper deficiency

Molecular defects in iron transport, recycling, and utilization

Divalent metal transporter 1 (DMT1) mutations Hypotransferrinemia

Ferroportin disease Aceruloplasminemia

Hereditary sideroblastic anemias (ALAS2 mutations) Heme oxygenase deficiency

Clinical presentation of

iron deficiency

• Signs of anemia

– Fatigue – Pallor

– Reduced exercise capacity

• Cheilosis

Laboratory iron studies

• Serum iron(SI) / Total iron-binding capacity(TIBC) :

50-150/300-360 µg/dL (N) • Serum ferritin : < 15 µg/L

• Bone Marrow iron stores : stainable iron, sideroblast, ringed sideroblast (MDS)

• Red cell protoporhyrin levels : > 100 µg/dL

• Soluble transferrin receptor (sTfR) : 4-9 µg/L (N) • Percent hypochromic red cell (% Hypo)

Differential Diagnosis

Hypochromic microcytic

anemia

– Thalassemia

– Anemia of chronic inflammation – Myelodysplastic syndrome

Treatment of

iron-deficiency anemia

• Diet : heme iron • RBC transfusion • Oral iron therapy

• Parenteral iron therapy

– Iron dextran

– Sodium ferric gluconate – Iron sucrose

Amount of iron needed

Ganzoni’s fomula :

BW(kg) X 2.3 X (15 – pt’s Hb, g/dL) + 500 or 1,000 mg (for stores)

Parenteral iron therapy

• Unable to tolerate oral iron

• Absorbtion defect

• Whose need are relatively acute • Epo therapy

• Iron dextran : severe side effect Sodium ferric gluconate

Iron sucrose

Iron prep. ( 본원 )

• Ferrous sulfate

– Feroba-You : 256 mg (80 mg) / tab

• Iron acetyl-transferrin hydroglycerin – Bolgre Soln : 2 mL (40 mg) / 15 mL

• Iron protein succinylate

– Hemo-Q : 800 mg (40 mg) / 15 mL • Ferric chloride

1st Case 25 세 , 여자 ; 주소 : 창백한 피부 • P.I. : 서서히 시작된 운동시 호흡곤란 , 불규칙한 월경 , 채식 위 주로 식사 • CBC : RBC : 3,200,000/uL, Hb : 7.4 g/dL, Hct : 23% MCV : 72 fL(81-99), MCH : 23.1pg/cell(27-31), MCHC : 32.1 g/dL(33-37) WBC : 8,500/uL, Platelet : 485,000/uL

• Peripheral blood smear : Hypochromic, microcytic, anisocytosis (++), pikilocytosis (+)

• Chemistry : serum Fe : 26 ug/dL, TIBC : 460 ug/dL Ferritin : 15 ng/mL

Normocytic normochromic

Hypochromic microcytic

진단

• Hypochromic, microcytic anemia

– Fe deficience – Inflammation – Thalassemia – Sideroblastic • Fe deficiency anemia – Causes

• 2nd Case : 40 세 , 여자 ; 주소 : 운동시 호흡곤란 P.I. : 서서히 진행 , 창백한 피부 , 잘 부러지는 손톱 , 규칙적이나 양이 많은 월경 • 3rd Case : 58 세 , 여자 ; 주소 : 창백한 피부 P.I. : 서서히 진행되는 운동시 호흡곤란 , 채식위주로 식사 PMH : 5 년전 위암으로 위절제술 , 7 년전 폐 경 • 4th Case : 50 세 , 남자 ; 주소 : 운동시 호흡곤란 P.I. : 서서히 진행 , 식사는 규칙적이고 균형 잡힘 , 특별한 약물 복용 없음 •

진단

• 1st case : blood loss (mense), diet (+),

demend (?)

• 2nd case: blood loss (mense), diet (?),

demend (-): gynecological problem

• 3rd case : blood loss (-), diet (+),

demend (-) : absorption (gastrectomy)

• 4th case : blood loss (?), diet (-),

Treatments of Cases

• 1st Case :

• 2nd Case :

• 3rd Case :

만성 질환 빈혈

경희의대 종양혈액내과 조경삼

만성 질환에 수반된 빈혈

(Anemia of Chronic Disorders,ACD)

• 철결핍 빈혈 다음으로 가장 흔한 빈혈이다 . • 기저질환이 호전되어야 빈혈도 호전된다 . • 임상적으로 빈혈의 증상에 기저질환의 다양한 증 상들이 겹쳐서 나타난다 . • 빈혈의 심한 정도는 대개 기저질환의 정도와 비례한다 . • 만성질환 외의 빈혈을 악화시키는 요인이 있 는지 확인이 필요하다 .

Iron-sequestration syndromes

Anemia of chronic disease/inflammation Autoimmune diseases

Infections Malignancies

Chronic kidney disease Hepcidin-producing adenomas

Iron refractory iron deficiency anemia (IRIDA) Copper deficiency

Molecular defects in iron transport, recycling, and utilization

Divalent metal transporter 1 (DMT1) mutations Hypotransferrinemia

Ferroportin disease Aceruloplasminemia

Hereditary sideroblastic anemias (ALAS2 mutations) Heme oxygenase deficiency

Anemia of Chronic

Disorders

• Anemia of Chronic Inflammation • Anemia of Uremia

• Anemia due to Endocrine Failure • Anemia of Liver Disease

Anemia of Chronic Inflammation

• (1) 감염 : 세균심내막염 , 골수염 , 폐농양 , 결핵 , 신우신 염 ( 급성염증 시 1-2 일에 혈색소 2-3g/dL 감소 가능 , 용혈도 관여 ) • (2) 교원성 질환 : 류마티스관절염 ,SLE, 혈관염 (temporalarteritis), sarcoidosis,

regional enteritis, tissue injury

• (3) 종양 :HodgkinDisease, 폐암 , 유방암 , 등

( 철결핍 , 골수침윤 , 엽산결핍 , 용혈빈혈 , 약제 , 방사선요법 등에 의한 빈혈 감별 필요 )

임상소견 ( 혈액 소견

)

• 대개 증상 없음 . • 노령에는 증상 나타날 수 있음 .( 심혈관증상 ) • Reti. index 2.0 이하 . • 질환의 기간과 중증도에 비례 • (1) 경도 또는 중등도 ( 혈색소치 9-11g/dL), normocytic or slightly microcytic

• (2) 골수소견 : 정상 적혈구 성숙 , 철아구 감소 , 대 식구 내 철 증가

• (3)Reti. 감소 , 혈청철 감소 , transferrin 치 감소 , transferrin saturation : 15-20%, ferritin 은 증가 또는 정상

병태생리

•Ironreutilization 장애로 iron 이

RES 에 sequestration(hepcidin

이 관여

)

•적혈구 수명의 감소 (modest)

•골수의 Epo 반응 감소 , 골수 억제

진단

• Unequivocal diagnosisis often difficult

• Diagnosis of exclusion (infiltration by tumor, fibrosis, or infection, MDS)

• Dx with reticulocyte, Fe, TIBC, serum ferritin, in systemic illness

• R/O nutritional def, hemolysis, sequestration. BM usually not helpful

• DDx of IDA (serum ferritin?, serum transferrin receptor?)

치료

• 철분제재 , 엽산 , 비타민 B12 등의 투여에 반 응 하지 않으나 , 수혈이 필요한 경우는 드뭄 . • 빈혈이 예상보다 심한 경우는 실혈 , 약제에 의한 골수저하 등의 요인이 있는지 조사 . • 만성 출혈로 철결핍 겹친 경우는 철제제 치료에 반응 .

• 적응증이 되는 경우 low serum EPO 면 rEPO 사용

Anemia of Uremia

• 대개 azotemia 의 정도에 비례한다 . ( 급성신부전은 비례하지 않는 다 .)

• (BUN > 36mg/dL,Cr3-5mg/dL 면 Hb7g/dL 정도 )

• Polycystic kidney, HUS 때는 적혈구조혈 증가 , 당뇨병에서는 감소

• 정상적혈구 정상색소 빈혈이다 .

• 신장에서 erythropoietin 이 적절히 분비가 되지 않아 빈혈이 발생한 다 .

• 일부 ineffective erythropoiesis, 용혈 , aluminium salt 등이 빈혈의 기전으로 작용한다 .

• 치료 : 신기능의 회복 ( 혈액투석 , 신이식 ), erythropoietin(rhEpo) • 출혈 ( 위장관 , 혈액투석 ), 엽산결핍 ( 혈액투석 , 영양부족 ) 등 다른

Anemia of Hypometabolism:

산소요구량 감소에 의한 적혈구조혈 감소

• Anemia due to Endocrine Failure

– hypothyroidism, Addison'sdisease, hypogonadism, panhypopituitarism, hyperparathyroidism

– Addison'sdisease 치료시 plama volume 감소가 교정되면서 잠시 혈색소

치는 감소하기도 한다.

• Anemia of Liver Disease

– Cholesterol 증가 : Burrcell, stomatocyte – RBC 수명 단축 , 골수 보상 활동 저하

– alcohol: 골수에 독성 , 엽산결핍 , 철결핍 ( 위장관 출혈 , 식이 부족 )

• Anemia of Protein Deprivation:

– volume depletion 으로 masking 가능

• 치료 :

– 수혈 : 증상에 따라 결정 . CV or pulm disease, elderly ,risk of transfusion – Erythropoietin(EPO) w/o iron: 4-6 주에 Hb10-12g/dL 도달 .

– Decreased response: infection, iron del[etion, Al toxicity, hyperparathyroidism

결론

• 복합적인 기전이 관여 • 경도 내지는 중등도의 빈혈 • 추가적인 요인의 유무 확인 필요 • 원인 질환의 치료가 1 차적인 목표 • 교정될 수 있는 추가적 요인에 대한 치료 • 환자의 삶의 질 고려