Chronic Anemia


Article Author:
Madhu Badireddy


Article Editor:
Krishna Baradhi


Editors In Chief:
Jasleen Jhajj
Cliff Caudill
Evan Kaufman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/22/2019 12:28:09 PM

Introduction

The word Anemia derives from an ancient Greek word anaimia meaning “lack of blood.”

Anemia, like a fever, is not a diagnosis but a presentation of an underlying disease. Multiple diseases can present as anemia due to various mechanisms.

Anemia affects a significant number of people worldwide (more so in the developing world) resulting in a considerable increase in the cost of medical care.

Anemia can be defined as a reduction in hemoglobin (less than 13.5 g/dL in men; less than 12.0 g/dL in women) or hematocrit (less than 41.0% in men; less than 36.0% in women) or red blood cell (RBC) count. The terms hemoglobin and hematocrit are more commonly used than RBC count in day-to-day clinical practice. There are different lower limits of normal range based on ethnicity, gender,  and age.  

Anemia causes decreased oxygen-carrying capacity of the blood leading to tissue hypoxia.

Grading of anemia according to the National Cancer Institute is as follows:

  1. Mild: Hemoglobin 10.0 g/dL to lower limit of normal
  2. Moderate: Hemoglobin 8.0 to 10.0 g/dL
  3. Severe: Hemoglobin 6.5 to 7.9 g/dL[1]
  4. Life-threatening: Hemoglobin < 6.5 g/dL

Anemia classified into acute anemia and chronic anemia. Acute anemia is predominantly due to acute blood loss or acute hemolysis. Chronic anemia is more common and is secondary to multiple causes.

Etiology

Etiology of chronic anemia based on mean corpuscular volume (MCV is the average size of RBC).

 Microcytic Anemia (MCV less than 80 femtoliters [fL])

  • Iron deficiency anemia: Most common cause of anemia
  • Thalassemia
  • Anemia of chronic disease
  • Sideroblastic anemia

 Macrocytic Anemia (MCV greater than 100 fL)

  • Vitamin B12 and folic acid deficiency
  • Alcoholism and liver disease
  • Myelodysplastic syndromes
  • Drug-induced
  • Hypothyroidism

 Normocytic Anemia (MCV 80 to 100 fL)

  • Bone marrow suppression (aplastic anemia and myelophthisic anemia)
  • Anemia of chronic disease 

Some conditions can present in more than 1 classification. For example, early iron deficiency can be normocytic. Anemia of chronic disease is mostly normocytic but can be microcytic too. Hemolytic anemia[2] can cause either macrocytic or normocytic anemia.

Epidemiology

Iron deficiency anemia is the most common type of anemia, affecting approximately 8% to 9% of the world’s population.

Anemia is more prevalent in:

  • Developing countries from malnutrition and lack of proper medical care
  • Women due to pregnancy and menstrual bleeding [3]
  • African Americans due to sickle cell disease and G6PD deficiency
  • Older adults due to multiple comorbidities like chronic kidney disease (CKD), malignancy, medications, among others[4]

Pathophysiology

Erythropoiesis

RBC is produced in bone marrow with the help of nutrients (iron, B12, folic acid), cytokines, erythroid-specific GF and EPO (erythropoietin, produced by kidneys). Once RBCs are released into the blood, they have a lifespan of about 110 to 120 days. Approximately 1% of RBCs are removed every day from the circulation. Under normal conditions, there is a balance between the number RBC released into circulation by bone marrow to the number removed from circulation. Imbalance of production and release by bone marrow to loss of RBC leads to anemia as below.

Decreased Red Blood Cell Production

  • Lack of nutrients (malnutrition and malabsorption)
  • Bone marrow problems (suppression and lack of RBC precursors)
  • Lack of hormones (CKD, hypothyroidism)
  • Ineffective erythropoiesis (defective RBC production)

Increased Red Blood Cell Destruction (Hemolytic Anemia)

Inherited hemolytic anemia

  • Sickle cell anemia
  • Thalassemia
  • Hereditary spherocytosis and elliptocytosis
  • G6PD deficiency
  • Pyruvate kinase deficiency

Acquired hemolytic anemia

  • Immune hemolytic anemia
  • Mechanical hemolytic anemia
  • Paroxysmal nocturnal hemoglobinuria

Blood Loss

  • Gastrointestinal
  • Menstrual cycles (menorrhagia)
  • Surgery
  • Trauma

Some conditions can cause anemia by over one mechanism (2 or even all the 3 mechanisms).

Anemia of chronic disease is a common form of anemia seen in hospitalized patients caused by long-standing diseases, infections, inflammations, and malignancies. These chronic conditions cause increased production of hepcidin[5] by the liver. Hepcidin binds to its receptor ferroportin and decreases intestinal iron absorption and decreases the release of iron from liver and macrophages leading to decreased availability of iron for erythropoiesis. Other mechanisms that contribute to anemia are by inflammatory cytokines that increase red cell destruction, suppress proliferation of erythroid precursors and by inhibiting release of erythropoietin from kidneys.

CKD [6]is one of the common causes of anemia of chronic disease. The incidence of anemia increases with progression of CKD, especially from stage III to stage IV and stage V. Erythropoietin is an important hormone needed for erythropoiesis. Anemia causes tissue hypoxia which, in turn, stimulates erythropoietin production by kidneys. Kidneys produce about 90% of the total erythropoietin, and as CKD progress, its response to hypoxia decreases causing low erythropoietin levels leading to anemia. CKD can also cause anemia from hemolysis.

History and Physical

Symptoms and signs of chronic anemia are mostly due to decreased tissue oxygenation from the reduction of the oxygen-carrying capacity of the blood. Symptoms are worse when anemia is severe, with a rapid decrease in hemoglobin/HCT and with increased oxygen demands states like exercise.

Common presenting symptoms include:

  • Weakness, fatigue
  • Dizziness, Near syncope, Syncope
  • Exertional dyspnea (exercise intolerance)
  • Chest pain and palpitations
  • Anorexia
  • Cognitive impairment in elderly

A detailed history should include medical history, home medications, alcohol use, and family history. Ethnicity and country of origin are also helpful.

Important examination findings include:

  • Pallor
  • Jaundice
  • Tachycardia
  • Tachypnea
  • Orthostatic hypotension and
  • Other findings relevant to underlying etiology

Evaluation

Initial Work-Up

  • Complete blood count: Hemoglobin, HCT, MCV, reticulocyte count index
  • Comprehensive metabolic panel: Renal and liver function tests
  • Iron studies which include serum iron, TIBC (total iron binding capacity) and ferritin
  • Serum vitamin B12, folic acid, and thyroid-stimulating hormone (TSH)
  • Stool for occult blood

 Differentiation of Microcytic Anemias Based on Iron Studies

  • Iron deficiency anemia: Low serum iron, high TIBC, and low ferritin.
  • Anemia of chronic disease: Low serum iron, low TIBC, and high ferritin.
  • Sideroblastic anemia: High serum iron, normal TIBC, and high ferritin.
  • Thalassemia: Normal serum iron, normal TIBC and normal ferritin.

Peripheral smear, hemoglobin electrophoresis, and bone marrow examination if needed. Further testing would include esophagogastroduodenoscopy (EGD) and colonoscopy if gastrointestinal (GI) bleeding is suspected and imaging studies if malignancy suspected.

Treatment / Management

Chronic anemia is managed predominantly in outpatient settings. They need hospitalization if:

  • Patient is symptomatic
  • Significant drop in hemoglobin/HCT
  • Transfusion needed
  • Extensive investigations needed

If hemoglobin is less than 7 g/dL or if a patent is symptomatic, transfusion of packed red blood cells (PRBC) is indicated.

Transfusions should be done with caution in patients with volume overload status like end-stage renal disease (on hemodialysis) and congestive heart failure (CHF).

Other treatments include treating underlying conditions as below.

  • Iron deficiency anemia: Intravenous (IV) iron versus oral iron
  • Vitamin B12 and folic acid deficiency with B12 and folic acid supplementation
  • Treating underlying bone marrow disorders
  • EPO injections in chronic kidney disease patients
  • Synthroid in patients with hypothyroidism
  • Avoiding any culprit medications
  • Treatment of GI causes of blood loss (PPI for gastritis and PUD)
  • Regulation of menstrual cycles in patients with menorrhagia

Prognosis

Prognosis of anemia varies based on the cause of anemia. Other factors contributing to the prognosis include:

  1. Age of the patient
  2. Severity of anemia
  3. Duration of anemia
  4. Comorbidities
  5. Access to medical care
  6. Diet

Elderly patients have a poor prognosis due to their advanced age, malnutrition, duration, and multiple comorbidities they tend to have as they age. Patients in the developing world also have a poor prognosis due to malnutrition and lack of access to or delayed medical care.

Hemoglobin less than 6.5 is life-threatening and can cause death.

Complications

Untreated anemia can be life-threatening and can even cause death.

Anemia results in decreased oxygen carrying capacity of the blood. In the short term, a body can compensate with an increase in heart rate and respiratory rate. If left untreated, anemia can cause multi-organ failure. This can include high output heart failure, angina, arrhythmias, cognitive impairment, and renal failure, among others.

In pregnant women, untreated anemia can cause premature birth and low birth weight.

Consultations

  1. Gastroenterology if GI bleeding suspected
  2. Nephrology in patients with chronic kidney disease
  3. Hematology if bone marrow disease or hemolysis suspected
  4. Obstetrics and Gynecology (OB/GYN) for menorrhagia

Deterrence and Patient Education

Anemia is a condition with decreased oxygen-carrying capacity of the blood. Anemia is very common and caused by different conditions ranging from simple nutritional deficiencies (iron, vitamin B12, and folic acid) to blood loss to other complicated causes. 

Anemia is a common medical condition and easily diagnosed with a simple blood work CBC. Treatment can be simple like nutritional supplements (iron, vitamin B12, and folic acid) to blood transfusion to treating complex underlying conditions.

It is very important to follow up with the doctor and sometimes with a specialist to treat anemia because untreated anemia can be life-threatening and may even cause death.

Pearls and Other Issues

  1. Anemia is the most common hematological disease and is one of the most common conditions seen in the clinical practice.
  2. Iron deficiency anemia is the most common cause of anemia while anemia of chronic disease is most common anemia in hospitalized patients.
  3. Anemia is not a diagnosis but a presentation of underlying diseases. Work up for the cause of anemia can unmask many of the underlying diseases thereby helping to treat patients early and appropriately.
  4. Most of the anemias are easy to treat and thereby improve a person's productivity. 
  5. Comprehensive history taking and physical examination are very important in diagnosing anemia.
  6. If early workup is unrevealing, appropriate consultation by a specialist is important for further workup and treatment.
  7. Encouraging patients to eat a healthy and balanced diet is important to prevent anemia from nutritional deficiencies. 
  8. Women of childbearing age are at increased risk of anemia due to pregnancies and menstrual bleeding and need close monitoring.

Enhancing Healthcare Team Outcomes

Chronic anemia is a very common condition seen in day-to-day clinical practice and managed in outpatient settings. Anemia management can range from simple to complex based on the underlying condition causing it. Most of the time patient's primary care physician needs help with a specialist based on underlying condition either a gastroenterologist or a hematologist or a nephrologist or a gynecologist. It is very important to have good interprofessional communication and care coordination for the management of anemia appropriately and promptly. This would help both in correcting anemia and treating underlying conditions.


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Chronic Anemia - Questions

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In treating a patient with the anemia of chronic disease, which of the following is the most important treatment?



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Which of the following is correct about anemia of chronic illness?



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Which choice does not differentiate iron deficiency from anemia of chronic disease (ACD)?



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Fatty change with "tigroid" appearance in the myocardium is characteristic of:



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How does one differentiate iron deficiency anemia (IDA) and anemia of chronic disease (ACD) based on iron studies?



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A 45-year-old female with a past medical history significant for chronic anemia from menorrhagia and hypothyroidism comes to the clinic complaining of weakness and exertional dyspnea for the past few weeks but denies any worsening of her menstrual bleeding. She recently had routine labs done for this follow-up appointment. Her hemoglobin was 8.0g/dL with MCV of 78fl and TSH of 2.45mIU/mL. Her vitals reveals BP of 126/78mmHg and heart rate of 105 beats per min. Which of the following is true regarding the need for blood transfusion in this patient



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A 36-year-old female with a past medical history significant for menorrhagia from uterine fibroids presents to her primary care provider's office with exertional dyspnea and extreme weakness. She eats a balanced diet. Examination reveals conjunctival pallor, and the rest of the examination is normal. Laboratory tests reveal a hemoglobin of 7.2 grams/dL, mean corpuscular volume (MCV) 70, and normal liver functions tests. Iron studies reveal a serum iron of 50 micrograms/dL (normal is 60 to 170 mcg/dL), total iron binding capacity (TIBC) of 500 micrograms/dL (normal is 240 to 450 mcg/dL), and ferritin of 8 nanograms/ml (normal is 12 to 300 ng/ml). What type of anemia does the patient have, and what is the most likely cause?



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A 48-year-old African American male with a past medical history significant for asthma and hypertension presents to the emergency department with a 5-day history of progressively worsening weakness, fatigue, anorexia, and exertional dyspnea. He was recently treated for a urinary tract infection with a 1-week course of nitrofurantoin. Examination reveals conjunctival pallor and tachycardia. Labs reveal a hemoglobin of 7.9 grams/dL, mean corpuscular volume (MCV) of 108 fL, and total bilirubin of 5.5 mg/dL. A peripheral smear reveals bite cells. What is the most likely cause of anemia in this patient?



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Chronic Anemia - References

References

Tas F,Eralp Y,Basaran M,Sakar B,Alici S,Argon A,Bulutlar G,Camlica H,Aydiner A,Topuz E, Anemia in oncology practice: relation to diseases and their therapies. American journal of clinical oncology. 2002 Aug     [PubMed]
Válka J,Čermák J, Differential diagnosis of anemia. Vnitrni lekarstvi. 2018 Summer     [PubMed]
Kunireddy N,Jacob R,Khan SA,Yadagiri B,Sai Baba KSS,Rajendra Vara Prasad I,Mohan IK, Hepcidin and Ferritin: Important Mediators in Inflammation Associated Anemia in Systemic Lupus Erythematosus Patients. Indian journal of clinical biochemistry : IJCB. 2018 Oct     [PubMed]
Lanier JB,Park JJ,Callahan RC, Anemia in Older Adults. American family physician. 2018 Oct 1     [PubMed]
Baradwan S,Alyousef A,Turkistani A, Associations between iron deficiency anemia and clinical features among pregnant women: a prospective cohort study. Journal of blood medicine. 2018     [PubMed]
Anand S,Thomas B,Remuzzi G,Riella M,Nahas ME,Naicker S,Dirks J, Kidney Disease null. 2017 Nov 17     [PubMed]

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