Anemia of chronic disease differential diagnosis

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

Overview

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.

Differential Diagnosis

Concomitant iron deficiency

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

●Percentage of hypochromic red cells and reticulocyte hemoglobin may help

●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

Myelodysplastic syndromes

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

Sideroblastic anemias

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

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

Endocrine disorders

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

Miscellaneous

IDA, thalassemia, sideroblastic anemias, and the sideroblastic variants of the myelodysplastic syndrome

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	−	Menorrhagia GI loss GI surgery Pregnancy	Koilonychia Pica	Glossitis Cheilosis Dysphagia	−	−	Hypochromic	Microcytic	↑	Nl or ↓	Nl	Nl	↓	↑	↑	↓	↓↓↓	Central pallor
Iron deficiency anemia (early phase)	−	Pica Glossitis Cheilosis	Fatigue Headache	Koilonychia Conjunctival pallor Dry skin	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↑	↑	↓	↓	Pencil cells Elliptocytosis Hypochromasia
Lead poisoning	−	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	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	−	Rheumatoid arthritis SLE Neoplasm Chronic kidney disease	Headache Shortness of breath	−	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	↑	↓	Nl	↓	↑	−	NA
Thalassemia	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	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	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	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	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	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	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	−	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	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	−	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	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	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	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	Autosomal recessive Deficiency of enzyme UMPS	Episodic vomiting Rhabdomyolysis	Coma Gastrointestinal manifestation	Neurological manifestation	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Fanconi anemia	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	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	−	Associated with Malaria Babesia	Fever	Fever Signs of shock Headache	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	−	−	−	Trophozoite Maltese crosses
Chronic kidney disease	−	Pericarditis Encephalopathy Rectal incontinence Decreased libido Restless leg syndrome	Polyuria Hematuria Edema	Hypertension	−	−	Normochromic	Normocytic	↑	Nl/↑	Nl	↑	↓	−	↓	↑	↓	Nl
Liver disease	−	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	−	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

References

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