Anemia of chronic disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

The word “hematology,” which appears to have been first used in this country in 1811, is older than might be expected, for in 1743, Thomas Schwencke (1694-1768) wrote Hamatologia, sive Sanguinis Historia, Experimentis passim superstructa etc. Hagae Comitum. Hematology, like bacteriology, has developed as the result of laboratory methods and the applications of physics and chemistry.Inflammatory cytokines induce increased amounts of hepcidin by the liver. Hepcidin blocks ferroportin from releasing iron from the body stores. Inflammatory cytokines also decrease ferroportin expression and stops erythropoiesis by increasing bone marrow erythropoietin resistance. Apart from iron sequestration, white blood cells production is promoted by inflammatory cytokines. Bone marrow stem cellsproduce both red blood cells and white blood cells cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This may also have a role in inhibition of erythropoiesis ,even when erythropoietin levels are normal, and aside from the effects of hepcidin. Conditions that can lead to anemia of chronic disease include autoimmune disorders, such as Crohn’s disease, systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis, Cancer including lymphoma and Hodgkin’s disease, chronic kidney disease, liver cirrhosis, long-term infections, such as bacterial endocarditis, osteomyelitis (bone infection), HIV/AIDS, hepatitis B or hepatitis C, less production of erythropoietin (EPO) by kidneys, resistance of bone marrow to EPO., decreased half life of red blood cells, hospitalized for severe acute infections, trauma, or other conditions that cause inflammation and aging process may cause inflammation and anemia. The primary goal in the treatment of anemia of chronic disease it to treat the disease itself. Supplemental iron is recommended, as needed, to keep the transferrin saturation of above 20 percent and a serum ferritin level of above100 ng/mL. Intravenous iron is more effective than oral supplementaion. Stable patients can be administered synthetically prepared erythropoiesis-stimulating agent such as erythropoietin. It is important to give oral iron supplementation to all the patients receiving erythropoietin or darbepoetin, in order to maintain a transferrin saturation more than 20 percent and a serum ferritin more than 100 ng/mL. In case of severe disease, blood transfusion is recommended.

The word “hematology,” which appears to have been first used in this country in 1811, is older than might be expected, for in 1743, Thomas Schwencke (1694-1768) wrote Hamatologia, sive Sanguinis Historia, Experimentis passim superstructa etc. Hagae Comitum. Hematology, like bacteriology, has developed as the result of laboratory methods and the applications of physics and chemistry.

There is no established classification of anemia of chronic disease.

Inflammatory cytokines induce increased amounts of hepcidin by the liver. Hepcidin blocks ferroportin from releasing iron from the body stores. Inflammatory cytokines also decrease ferroportin expression and stops erythropoiesis by increasing bone marrow erythropoietin resistance. Apart from iron sequestration, white blood cells production is promoted by inflammatory cytokines. Bone marrow stem cellsproduce both red blood cells and white blood cells cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This may also have a role in inhibition of erythropoiesis ,even when erythropoietin levels are normal, and aside from the effects of hepcidin.

Conditions that can lead to anemia of chronic disease include autoimmune disorders, such as Crohn’s disease, systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis, Cancer including lymphoma and Hodgkin’s disease, chronic kidney disease, liver cirrhosis, long-term infections, such as bacterial endocarditis, osteomyelitis (bone infection), HIV/AIDS, hepatitis B or hepatitis C, less production of erythropoietin (EPO) by kidneys, resistance of bone marrow to EPO., decreased half life of red blood cells, hospitalized for severe acute infections, trauma, or other conditions that cause inflammation and aging process may cause inflammation and anemia.

The most important differential is whether the patient has ACD alone or ACD with ongoing iron deficiency anemia (ACD/IDA). The following parameters will distinguish the two: Soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also. Percentage of hypochromic red cells and reticulocyte hemoglobin may help.

30 to 60 percent of patients in rheumatoid arthritis patients have anemia. More than 30 of cancer patients have anemia. The rate reached 63 percent. In elderly patients, about one third of the cases of anemia are ACD.

Risk factors for anemia of chronic disease include autoimmune disorders, chronic infection, trauma, major surgery, malignancy, HIV infection, rheumatologic disorders, inflammatory bowel disease, castleman disease, heart failure, older adults, renal insufficiency and chronic obstructive pulmonary disease.

There is insufficient evidence to recommend routine screening for anemia of chronic disease. Age-appropriate health screening and evaluations directed at any patient symptoms can be done to find out the underlying cause of ACD.

Potentially life-threatening complications include congestive heart failure, Angina, arrhythmia, myocardial infarction and high-output heart failure. If left untreated, anemia of chronic disease usually manifests as congestive heart failure, angina, arrhythmia, myocardial infarction and high-output heart failure.The anemia will improve when the disease that is causing it is successfully treated.

There is no single diagnostic study of choice for test that will reliably make the diagnosis of ACD

Past medical history could include Autoimmune disorders, chronic infection, Trauma, major surgery, Malignancy, HIV infection, rheumatologic disorders, Inflammatory bowel disease, Castleman disease, Heart failure, older adults, Renal insufficiency and Chronic obstructive pulmonary disease.

Symptoms would be of the underlying disease rather than the anemia itself.

Mild normocytic and normochromic anemia with a hemoglobin concentration of 10 to 11 g/dL. Less than 25 percent of the cases have microcytic and hypochromic anemia with a mean corpuscular volume (MCV) less than 70 fL. Normal or low mean corpuscular hemoglobin (MHC) similar to the MCV, and normal to increased red cell distribution width (RDW). No significant changes in the mean corpuscular hemoglobin concentration (MCHC). 20 percent of cases have severe anemia, with a hemoglobin concentration <8 g/dL. Absolute reticulocyte count is frequently low (<25,000/microL). There could be an elevation in cytokines (eg, IL-6, interferon-gamma) and acute phase reactants (eg, fibrinogen, erythrocyte sedimentation rate, C-reactive protein, ferritin, haptoglobin, factor VIII)

An ECG may show left ventricular hypertrophy (LVH) in anemia of chronic disease.

Chest x-rays are often used to rule out infection in anemia patients.

Ultrasound can detect an enlarged spleen or may demonstrate the cause of anemia such as uterine fibroids.

CT provides detailed images of internal organs,and lymph nodes. It can help identify an enlarged spleen or lymph node abnormalities associated with certain types of anemia, and is useful for detecting cause of bleeding such as gastrointestinal malignancies that may be causing anemia in patients who cannot undergo colonoscopy or endoscopy

MRI is effective at imaging bone and bone marrow disorder . It also can help assess iron concentration in various organs such as heart and liver, particularly in patients with multiple blood transfusions and concern for iron overload.

There are no other imaging findings associated with anemia of chronic disease.

There are no other imaging findings associated with anemia of chronic disease.

The primary goal in the treatment of anemia of chronic disease it to treat the disease itself. Supplemental iron is recommended, as needed, to keep the transferrin saturation of above 20 percent and a serum ferritin level of above100 ng/mL. Intravenous iron is more effective than oral supplementaion. Stable patients can be administered synthetically prepared erythropoiesis-stimulating agent such as erythropoietin. It is important to give oral iron supplementation to all the patients receiving erythropoietin or darbepoetin, in order to maintain a transferrin saturation more than 20 percent and a serum ferritin more than 100 ng/mL. In case of severe disease, blood transfusion is recommended. If the case is underlying malignancy, chemotherapy or radiotherapy may transiently exacerbate anemia due to mylesuppressive effects, however in the long term, it leads to improvement. If the cause is inflammatory disorder, such as rheumatoid arthritis the management of the disease with a disease-modifying antirheumatic drug (DMARD) improves the anemia significantly.

Surgical intervention is not recommended for the management of anemia of chronic disease.

There are no established measures for the primary prevention of anemia of chronic disease.

There are no established measures for the secondary prevention of anemia of chronic disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

The word “hematology,” which appears to have been first used in this country in 1811, is older than might be expected, for in 1743, Thomas Schwencke (1694-1768) wrote Hamatologia, sive Sanguinis Historia, Experimentis passim superstructa etc. Hagae Comitum. Hematology, like bacteriology, has developed as the result of laboratory methods and the applications of physics and chemistry.

The word “hematology,” which appears to have been first used in this country in 1811, is older than might be expected, for in 1743, Thomas Schwencke (1694-1768) wrote Hamatologia, sive Sanguinis Historia, Experimentis passim superstructa etc. Hagae Comitum. Hematology, like bacteriology, has developed as the result of laboratory methods and the applications of physics and chemistry. There is a resemblance between the evolution of surgery and that of haematology; in the case of the surgeon’s craft the advent of anmesthesia in the middle of the last century greatly facilitated the performance of operations, but eventual success was deferred until Lister’s teaching was accepted and practised. The invention of magnifying lenses arid microscopes which, with their progressive improvements, especially the compound achromatic form of microscope invented by G. D. Amici (1786-1863) of Modena a hundred years ago, was the first step in making it possible to see the solid constituents of the blood, long preceded any real knowledge of haematology. It is wonderful what Antonj van Leeuwenhoek (1632-1723) of Delft saw even with his own lenses.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

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There is no established classification of anemia of chronic disease.

There is no established classification of anemia of chronic disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[3]

Inflammatory cytokines induce increased amounts of hepcidin by the liver. Hepcidin blocks ferroportin from releasing iron from the body stores. Inflammatory cytokines also decrease ferroportin expression and stops erythropoiesis by increasing bone marrow erythropoietin resistance. Apart from iron sequestration, white blood cells production is promoted by inflammatory cytokines. Bone marrow stem cells produce both red blood cells and white blood cells cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This may also have a role in inhibition of erythropoiesis, even when erythropoietin levels are normal, and aside from the effects of hepcidin.

• Inflammatory cytokines induce increased amounts of hepcidin by the liver. Hepcidin blocks ferroportin from releasing iron from the body stores.^[1][2][3]
• Inflammatory cytokines also decrease ferroportin expression and stops erythropoiesis by increasing bone marrow erythropoietin resistance.^[4][5]
• Apart from iron sequestration, white blood cells production is promoted by inflammatory cytokines. Bone marrow stem cells produce both red blood cells and white blood cells cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This may also have a role in inhibition of erythropoiesis , even when erythropoietin levels are normal, and aside from the effects of hepcidin.^[6][7]
• However, the combined effects of all the process are likely be in favor as it will allow the body to keep iron away from bacteria while the body boost the immune cell production.^[5][8]
• Sometimes, HIV infection and chronic kidney disease can lead to inflammation that can ultimately produce cytokines that can cause anemia of chronic disease.

Activated monocytes release cytokines like the interleukins (eg, IL-1 and IL-6) and tumor necrosis factor (TNF-alpha). These cytokines activate a cascade of reactions leading to the secretion of interferon (IFN)-beta and IFN-gamma by T lymphocytes leading to increased resistance of bone marrow to EPO.^[9][10]

Hepcidin is directly involved in iron metabolism and a component of the innate immune response to acute infection. It decreases the absorption of iron from small intestine, from placenta and from macrophages as well, secondary to its effect on internalization and degradation of the iron export protein ferroportin.^{[11][12][13][14]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Shyam Patel [2]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[3]

Conditions that can lead to anemia of chronic disease include autoimmune disorders, cancer, chronic kidney disease liver cirrhosis, long-term infections, HIV/AIDS, hepatitis B or hepatitis C, less production of erythropoietin (EPO) by kidneys, resistance of bone marrow to EPO, decreased half life of red blood cells, hospitalization for severe acute infections, trauma, or other conditions that cause inflammation.

Conditions that can lead to anemia of chronic disease include:^[1][2][3][4]

• Autoimmune disorders, such as Crohn’s disease, systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis
• Cancer, including non-Hodgkin lymphoma and Hodgkin disease
• Chronic kidney disease^[5]
• Liver cirrhosis
• Long-term infections, such as bacterial endocarditis, osteomyelitis (bone infection), HIV/AIDS, hepatitis B or hepatitis C
• Inability to properly store and use iron normally
• Less production of erythropoietin (EPO) by kidneys
• Resistance of bone marrow to EPO
• Decreased half life of red blood cells
• Hospitalization for severe acute infections, trauma, or other conditions that cause inflammation
• Aging, which can contribute to inflammation and anemia
• Sarcoidosis
• Vasculitis and other rheumatologic disease^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Shyam Patel [2]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[3]

The most important differential is whether the patient has ACD alone or ACD with ongoing iron deficiency anemia (ACD/IDA). The following parameters will distinguish the two: Soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also. Percentage of hypochromic red cells and reticulocyte hemoglobin may help.

The most important differential is whether the patient has ACD alone or ACD with ongoing iron deficiency anemia (ACD/IDA). The following parameters will distinguish the two:

●Soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also present^[1]

●Percentage of hypochromic red cells and reticulocyte hemoglobin may help^[2][3]

●Bone marrow examination in n difficult cases the diagnosis can often be established by bone marrow examination. Findings in the most common disorders include:

• ACD: Normal to increased iron in bone marrow macrophages while erythroid precursors may show decreased to absent iron
• Iron deficiency: No stainable iron in macrophages and erythroid precursors

Single or multi-lineage dysplastic changes with or without increased number of sideroblasts, including ring forms, are commonly seen in patients with myelodysplasia

Presence of ring sideroblasts on bone marrow examination

●Serum erythropoietin (EPO) levels lower in ACD than in patients with IDA and comparable degrees of anemia^[4]

●Oral iron supplementation for four to six weeks may help in the differentiation between ACD and ACD/IDA

Hyperthyroidism, hypothyroidism, panhypopituitarism, and primary and secondary hyperparathyroidism may also present with a normocytic, normochromic hypoproliferative anemia.

IDA, thalassemia, sideroblastic anemias, and the sideroblastic variants of the myelodysplastic syndrome^[5]

Anemia must be differentiated based on different laboratory findings including mean cell volume (MCV), reticulocytosis, and hemolysis.

To review the differential diagnosis of anemia, see below table.

To review the differential diagnosis of microcytic anemia, click here.

To review the differential diagnosis of normocytic anemia, click here.

To review the differential diagnosis of macrocytic anemia, click here.

To review the differential diagnosis of hypochromic anemia, click here.

To review the differential diagnosis of normochromic anemia, click here.

To review the differential diagnosis of anisochromic anemia, click here.

To review the differential diagnosis of hemolytic anemia, click here.

To review the differential diagnosis of anemia with intrinsic hemolysis, click here.

To review the differential diagnosis of anemia with extrinsic hemolysis, click here.

To review the differential diagnosis of anemia with low reticulocytosis, click here.

To review the differential diagnosis of anemia with normal reticulocytosis, click here.

To review the differential diagnosis of anemia with high reticulocytosis, click here.

Disease	Genetics	Clinical manifestation					Lab findings
		History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Iron studies					Specific finding on blood smear
													Serum iron	Serum Tfr level	Transferrin or TIBC	Ferritin	Transferrin saturation
Iron deficiency anemia[6]	−	Menorrhagia GI loss GI surgery Pregnancy	Koilonychia Pica	Glossitis Cheilosis Dysphagia	−	−	Hypochromic	Microcytic	↑	Nl or ↓	Nl	Nl	↓	↑	↑	↓	↓↓↓	Central pallor
Iron deficiency anemia (early phase)[7]	−	Pica Glossitis Cheilosis	Fatigue Headache	Koilonychia Conjunctival pallor Dry skin	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↑	↑	↓	↓	Pencil cells Elliptocytosis Hypochromasia
Lead poisoning[8]	−	House painted with chipped paint	Burtonian lines Basophilic stippling Wrist drop Foot drop	Wrist drop Foot drop Burtonian lines	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	Nl	Nl to ↓	Nl	Nl	Nl to ↓	−	RBCs retain aggregates of rRNA Basophilic stippling
Sideroblastic anemia[9]	Defect in ALA synthase gene Autosomal dominant Autosomal recessive X-linked	Alcohol abuse Isoniazid use Chloramphenicol use Idiopathic	Seborrheic dermatitis Glossy Tongue Tingling	Patient present with symptoms of Vitamin B6, copper deficiency symptoms	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	Nl	↑	Nl	Nl to ↓	↑	−	Ringed sideroblasts
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Anemia of chronic disease[10]	−	Rheumatoid arthritis SLE Neoplasm Chronic kidney disease	Headache Shortness of breath	−	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	↑	↓	Nl	↓	↑	−	NA
Thalassemia[11]	α-thalassemia α– globin gene deletions Cis deletions Trans deletions β-thalassemia Point mutation in splice sites and promoter sequences	Associated with parvovirus B19	α-thalassemia Hydrops fetalis β-thalassemia Skeletal deformities Chipmunk facies	Hepatomegaly Splenomegaly	−	−	Hypochromic	Microcytic	Nl	Thalassemia trait: Nl or ↓ Thalassemia Syndromes: ↑	Nl	Nl	Nl to ↑	Nl	Nl	↑	Nl to ↑	Target cells Anisopoikilocytosis
G6PD deficiency[12]	Defect in G6PD enzyme X-Linked recessive	History of using Sulfa drugs Antimalarials Fava Beans Infections	Back pain Hemoglobinuria	Back pain	+	Intrinsic	Normochromic	Normocytic	↑	↑ but usually causes resolution within 4-7 days	↓	↓	Nl to ↑	Nl	↑	↑	↑	RBC with Heinz bodies Bite cells Blister cells
Pyruvate kinase deficiency[13]	Mutation in the PKLR and PKM gene Autosomal recessive	Gallstones	Hydrops fetalis Neonatal hyperbilirubinemia Iron overload Perinatal complications	Skin ulcers Splenomegaly	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↑	Nl	Nl	↑	−	Prickle cells Polychromatophilic erythrocytes
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Sickle cell anemia[14]	HbS point mutation causes a single amino acid replacement in β chain	High altitude Low Oxygen Acidosis African-American race Parvovirus B19 infection	Painful crisis Dactylitis Priapism Acute chest syndrome Avascular Necrosis Stroke Autosplenectomy Salmonella osteomyelitis	Dactylitis Priapism	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl or moderately ↑	Nl	Nl	Nl or moderately ↑	↓	Nl	Increased erythropoiesis Howell-Jolly bodies Anisocytosis
HbC disease[15]	Glutamic acid–to-lysine mutation in β-globin	Gallstone	Joint pains Increased risk of infections	Splenomegaly Cholelithiasis Avascular necrosis of the femoral head	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	Nl	↓	−	Hemoglobin crystals inside RBCs Target cells
Paroxysmal nocturnal hemoglobinuria[16][17]	PIGA gene mutations Impaired synthesis of GPI anchor for decay-accelerating factor	Associated with aplastic anemia Thrombosis	Fatigue Chest pain Dyspnea on exertion Headache	Chronic hemolysis Hepatomegaly Ascites Papilledema Skin nodules	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	↑	↓	−	NA
Hereditary spherocytosis[18]	Mutations in Ankyrin, Band 3, Protein 4.2, and spectrin	Associated with parvovirus B19 Cholelithiasis Megaloblastic crisis	Aplastic crisis	Splenomegaly	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	↑	Nl	−	Small, round RBCs with less surface area and no central pallor
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Microangiopathic hemolytic anemia[19][20]	−	Associated with DIC TTP HUS SLE HELLP syndrome Hypertensive emergency	Purpura Confusion Aphasia Diplopia	Numbness of an arm or hand Jaundice Pale conjunctiva	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	↑	−	Helmet cells
Macroangiopathic hemolytic anemia[21]	Autoimmune	Associated with Prosthetic heart valves Aortic stenosis	Pallor Fatigue	Signs of anemia Complications of hemolysis Decreased vascular volume	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	−	−	Spherocytes or schistocytes
Autoimmune hemolytic anemia[22]	−	Associated with: SLE CLL Mycoplasma pneumonia	Painful blue fingers and toes on exposure to cold temperature Chest pain Chills Dizziness Tachycardia Headache Fatigue	Painful, blue fingers and toes with cold weather	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	−	−	RBC agglutination
Aplastic anemia[23]	Constitutive expression of Tbet Mutations in the perforin gene Mutations in SAP gene	Exposure to Radiation Drugs like Benzene, chloramphenicol, alkylating agents Viral infections like EBV, HIV, Hepatitis Fanconi anemia Idiopathic like Immune mediated, primary stem cell defect	Symptoms based on underlying condition	Short stature Cafe-au-lait spots Thumb defects Radial defects	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↓	Nl	↑	↓	Pancytopenia Fatty infiltration
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Folate deficiency[24]	Impaired DNA synthesis	Alcohol consumption History of using drugs like methotrexate, trimethoprim, and phenytoin Low socioeconomic groups with poor nutrition Older people Pregnant and lactating women	No neurological symptoms vs B12 deficiency Odynophagia Angular stomatitis	Glossitis Signs of heart failure Anencephaly and spina bifida	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	RBC macrocytosis Hypersegmented neutrophils Pancytopenia in severe cases
Vitamin B12 deficiency[25]	Impaired DNA synthesis	Pernicious anemia Crohn’s disease Gastrectomy Veganism Diphyllobothrium latum infection	Psychosis Insomnia Depression Cognitive slowing Restless leg syndrome	Neurological deficit Myelopathy Memory loss with reduced attention span Nystagmus Positive romberg sign Positive Lhermitte’s sign	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Senile neutrophil Anisocytosis Ovalocytes
Orotic aciduria[26]	Autosomal recessive Deficiency of enzyme UMPS	Episodic vomiting Rhabdomyolysis	Coma Gastrointestinal manifestation	Neurological manifestation	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Fanconi anemia[27]	Autosomal recessive X-linked recessive	History of anemia at age 16	Hypopigmentation Cafe-au-lait patches Radial ray anomaly	Significant for bilateral short thumbs	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Nl appearing WBC, RBC and Platelets But the number is greatly reduced
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Diamond-Blackfan anemia[28]	Mutations in: RPL5 RPL11 RPL35A RPS7 RPS10 RPS17 RPS19 RPS24 RPS26	Associated with myelodysplastic syndrome Increased risk of AML	Pale skin Sleepiness Heart murmurs	Triphalangeal thumbs Short stature Microcephaly Hypertelorism Ptosis Micrognathia	−	−	Anisochromic	Macrocytic	Nl	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Infections[29]	−	Associated with Malaria Babesia	Fever	Fever Signs of shock Headache	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	−	−	−	Trophozoite Maltese crosses
Chronic kidney disease[30]	−	Pericarditis Encephalopathy Rectal incontinence Decreased libido Restless leg syndrome	Polyuria Hematuria Edema	Hypertension	−	−	Normochromic	Normocytic	↑	Nl/↑	Nl	↑	↓	−	↓	↑	↓	Nl
Liver disease[31]	−	Hepatitis Binge drinking Gall bladder disease	Jaundice Abdominal pain Itchy skin	Ascites Right upper quadrant pain Hepatomegaly Swelling in the legs Ankle swelling	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Round macrocytes Target macrocytes
Alcoholism[32]	−	History of increased alcohol intake Folic acid deficiency	Memory impairment Nausea Sweating	Truncal obesity Asterixis Encephalopathy Spider angiomas Hematemesis Gynecomastia	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Oval macrocytes Hypersegmented neutrophils
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Shyam Patel [2]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[3]

Approximately 30-60% of patients with rheumatoid arthritis also have anemia. More than 30% of cancer patients have anemia. In elderly patients, about one third of the cases of anemia are ACD.

• Approximately 30-60% of patients with rheumatoid arthritis also have anemia^[1]
• More than 30% of cancer patients have anemia. Some estimates suggests that 63% of cancer patients have anemia^[2].
• In elderly patients, about one third of the cases of anemia are ACD
• The incidence of anemia of chronic disease increases with age and affects 77% of people in whom an alternative etiology of anemia cannot be identified

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Risk factors for anemia of chronic disease include autoimmune disorders, chronic infection, trauma, major surgery, malignancy, HIV infection, rheumatologic disorders, inflammatory bowel disease, castleman disease, heart failure, older adults, renal insufficiency and chronic obstructive pulmonary disease.

Risk factors for anemia of chronic disease include:^{[1][2][3][4][5]}

• Autoimmune disorders
• Chronic infection
• Trauma
• Major surgery
• Malignancy
• HIV infection
• Rheumatologic disorders
• Inflammatory bowel disease
• Castleman disease
• Heart failure
• Older adults
• Renal insufficiency
• Chronic obstructive pulmonary disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

There is insufficient evidence to recommend routine screening for anemia of chronic disease. Age-appropriate health screening and evaluations directed at any patient symptoms can be done to find out the underlying cause of ACD.

There is insufficient evidence to recommend routine screening for anemia of chronic disease. Age-appropriate health screening and evaluations directed at any patient symptoms can be done to find out the underlying cause of ACD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Potentially life-threatening complications include congestive heart failure, Angina, arrhythmia, myocardial infarction and high-output heart failure. If left untreated, anemia of chronic disease usually manifests as congestive heart failure, angina, arrhythmia, myocardial infarction and high-output heart failure.The anemia will improve when the disease that is causing it is successfully treated.

If left untreated, anemia of chronic disease usually manifests as congestive heart failure, angina, arrhythmia, myocardial infarction and high-output heart failure.

• Congestive heart failure Angina
• Arrhythmia Myocardial infarction

• High-output heart failure

Decreased oxygen delivery^[1]

• Exertional dyspnea Dyspnea at rest
• Fatigue Hyperdynamic signs like bounding pulses, palpitations, and a roaring pulsatile sound in the ears
• Lethargy, confusion

Hypovolemia

• Easy fatigability Lassitude
• Muscle cramps Postural dizziness
• Lethargy Syncope

• Persistent hypotension Shock, and death
• Exacerbation of thrombocytopenic bleeding ^[2]

• A correlation has been observed between severe anemia and increased bleeding risk

The anemia will improve when the disease that is causing it is successfully treated.

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