Mean Corpuscular Volume

Etiology

Clinicians can discern definitive diagnoses regarding the type of anemia—microcytic, normocytic, and macrocytic—based on MCV values.

Microcytic anemia is characterized by erythrocytes that are smaller than normal and notably smaller than leukocytes. On a complete blood count (CBC), the MCV measure is below 80 fL, while a normal MCV ranges between 80 and 100 fL. This type of anemia is commonly associated with conditions such as chronic iron deficiency anemia (IDA), sideroblastic anemia, and thalassemias, although it can also occur in other conditions. Microcytic cells may exhibit a larger area of central pallor, particularly in the context of IDA and anemia of chronic disease (ACD).

Macrocytic anemia is characterized by an increased average red blood cell volume compared to normal levels, with an MCV measurement exceeding 100 fL on a CBC. Megaloblastic anemia is further categorized as megaloblastic, characterized by impaired DNA synthesis, or non-megaloblastic, where DNA synthesis remains normal. Megaloblastic anemia is commonly caused by deficiencies in folate (also known as folic acid or vitamin B9), cobalamin/vitamin B12, or orotic aciduria—an autosomal recessive disorder that hinders the conversion of orotic acid to uridine monophosphate (UMP). On the other hand, non-megaloblastic anemia can result from hepatic insufficiency, chronic alcoholism, or a rare congenital disease known as Diamond-Blackfan anemia.

Normocytic anemia has a low hemoglobin and hematocrit range, but MCV is in the normal range of 80 to 100 fL. This type of anemia can be subclassified as hemolytic or non-hemolytic forms. Normocytic hemolytic anemia can occur intravascularly and extravascularly due to various underlying causes. Other laboratory values on the CBC will further indicate the type of anemia, aiding in diagnosis. Non-hemolytic normocytic anemias may present in conditions such as early ACD, early IDA, aplastic anemia, microangiopathic hemolytic anemias, and certain plasmodial infections.

Epidemiology

The MCV gradually increases with age,[1] following 2 linear subsets—patients aged 1 to 25 and 26 to 88. In the demographic of individuals aged 40 to 80, females typically display lower MCV values compared to males. The demographics affected by various types of anemias vary depending on the MCV value and underlying etiologies. Microcytic anemia has epidemiological variations in its underlying causes, with IDA being the most common cause of microcytic anemia. IDA frequently occurs in premenopausal, menstruating women due to menorrhagia and chronic blood loss without adequate iron supplementation. However, for men and post-menopausal women aged 50 and older, the primary concern is colorectal cancer until ruled out, necessitating prompt colonoscopy evaluation.

ACD is the second most common type of anemia worldwide.[2] This type of anemia primarily affects patients with chronic inflammatory conditions, leading to disruptions in iron homeostasis.[3] The demographics range between men and women of all age ranges. ACD can occur across demographics, affecting both men and women of all age groups, and is associated with a wide range of underlying conditions, including diabetes, rheumatologic diseases, and malignancies. Sideroblastic anemia can either be congenital or acquired, with potential causes such as lead exposure, myelodysplastic disorders, myeloproliferative neoplasms, vitamin B6 deficiency, isoniazid use, chronic alcoholism, or copper deficiency. The presence of ringed sideroblasts can aid clinicians in narrowing down the diagnosis, particularly towards myelodysplastic disorders or myeloproliferative neoplasms, by investigating spliceosome mutations.

Myelodysplastic disorders affect approximately 10,000 individuals annually, predominantly affecting adult males aged 65 and older.[4][5] Myeloproliferative diseases include acquired and familial types of the disease. Thalassemia is categorized into β and α types, each varying in severity and distribution. α-thalassemia is more prevalent in African, Southern Chinese, Malaysian, and Thai populations, whereas β-thalassemia is prominent in African and Mediterranean populations. Both types are congenital conditions.[6][7]

Macrocytic anemia is common, with a prevalence ranging from 1.7% to 3.6%.[8] Folate and vitamin B12 deficiencies can affect diverse demographics globally due to dietary imbalances; however, vitamin B12 deficiency is more common in individuals with vegan diets due to its primary source in animal products. Moreover, vitamin B12 deficiency can also occur in malabsorptive diseases, Diphyllobothrium latum infection, pernicious anemia, and gastrectomy. Organic acidemias affect approximately 1 in 784 live births in the United Kingdom.[9]

Hepatic insufficiency demonstrates demographic variability, with chronic alcoholism showing a prevalence range of 20% to 36%.[10] Diamond-Blackfan anemia is a congenital condition that typically manifests within the first year of life, with an estimated prevalence ranging from 1 per 100,000 to 1 per 200,000 live births, affecting diverse races and ethnicities.[11] However, the epidemiology of normocytic anemia varies widely across all ethnicities, ages, and genders due to its numerous causes, many of which are acquired.

Pathophysiology

Microcytic Anemia

Microcytosis can result from a deficiency in a hemoglobin component, leading to noticeably smaller cells on a peripheral blood smear. Hemoglobin is composed of heme and globin molecules. For instance, the ferrochelatase enzyme plays a role in heme synthesis by incorporating iron into the protoporphyrin ring structure to form the heme molecule.[12] As a result, the lack of iron from chronic IDA can make the protoporphyrin rings in the heme molecules defective.

ACD is due to an evolutionary response aimed at safeguarding iron from bacteria that utilize it for growth. Bacterial infections trigger inflammation, leading to elevated levels of acute-phase reactants such as hepcidin, which sequesters iron in macrophages and reduces iron absorption in the gastrointestinal tract. This effect is similar to the presentation of IDA.[8] In cases of IDA, ACD, or sideroblastic anemia secondary to lead poisoning, impaired synthesis of heme and hemoglobin results in significantly smaller erythrocytes. Thalassemias, characterized by mutations in the α- or β-globin chains, also disrupt hemoglobin synthesis, leading to microcytic erythrocytes in these hemoglobinopathies.

Macrocytic Anemia

Macrocytic anemia can be categorized as either megaloblastic or non-megaloblastic anemia. During pyrimidine synthesis, folate undergoes hydrogenation to tetrahydrofolate and contributes a carbon group. Vitamin B12, also known as cobalamin, acts as a cofactor for the enzyme responsible for transferring the carbon group from tetrahydrofolate. Deficiencies in either folate or vitamin B12 enzymes disrupt the proper division of erythrocytes to their normal size. Consequently, erythrocytes cease dividing due to deficient pyrimidines, resulting in enlarged cells.

Sunitinib, a chemotherapy agent, is known to elevate MCV levels without affecting B12 or folate levels.[13] This tyrosine kinase inhibitor targets multiple intracellular signaling pathways, including the stem cell growth receptor (ckit) pathway, leading to ckit inhibition and subsequently increased MCV. Non-megaloblastic anemia affects macrocytes differently. Liver disease can hinder lipid production, potentially compromising the integrity of erythrocyte phospholipid bilayers due to liver failure.[14] Moreover, chronic alcoholism leading to alcoholic cirrhosis may impair folate absorption, exacerbating the development of macrocytic anemia.[15]

Normocytic Anemia

Normocytic anemia commonly arises due to either intravascular or extravascular hemolysis. However, another cause of normocytic anemia is aplastic anemia, which involves the destruction of myeloid stem cells responsible for producing erythrocytes.

Histopathology

The MCV findings are typically followed by a peripheral blood smear examination. This smear helps determine the size of erythrocytes relative to leukocytes. Microcytes are smaller and often exhibit a larger central area of pallor compared to normal erythrocytes, especially in cases of IDA or ACD. Depending on the underlying cause of microcytosis, microcytic erythrocytes may also display features such as target cells and anisopoikilocytosis in thalassemia, or basophilic stippling, characteristic of lead poisoning. Sideroblasts, on the other hand, are observed exclusively in bone marrow aspirates.

Megaloblastic macrocytosis refers to enlarged erythrocytes that are comparable in size to leukocytes. This condition is often associated with hypersegmented polymorphonuclear neutrophils due to disruptions in DNA and RNA synthesis. However, individuals with liver failure may exhibit acanthocytes or spur cells, along with macro-ovalocytes, stemming from lipid dysfunction from hepatic insufficiency.

Various histopathological findings may be observed in normocytic anemia resulting from hemolysis. These include sickled cells in sickle cell anemia, spherocytes in conditions like hereditary spherocytosis and autoimmune hemolytic anemia, Heinz bodies, Howell-Jolly bodies, degmacytes, and schistocytes. The specific presentations depend on the intrinsic or extrinsic factors contributing to normocytic anemia.

Diagnosing aplastic anemia necessitates a bone marrow aspirate, which typically appears dry due to the absence of cells or may contain multiple white adipocytes lacking erythrocytes, leukocytes, or progenitor cells.

History and Physical

Mean Corpuscular Volume Below 80 fL

IDA presents with conjunctival pallor, fatigue, cold intolerance, cold distal extremities, koilonychia, occasionally pica, glossitis, dry, cracked lips, and cheilosis. Patients with IDA often report a history of chronic blood loss, chronic inflammation, exposure to lead paint, or a family history of thalassemia. In contrast, ACD presents with disease-causing chronic inflammation, such as arthritis in rheumatoid arthritis or malignancy. Also, these patients may remain asymptomatic. A family history of cancer, autoimmune disease, or rheumatologic conditions can provide valuable diagnostic clues in such cases.

Furthermore, thalassemias can present with characteristic "chipmunk" facies resulting from bone marrow expansion and extramedullary hematopoiesis. Upon physical examination, this process may also lead to hepatomegaly and splenomegaly, while x-rays can reveal additional skeletal deformities. Thalassemia patients typically have a family history of the condition, often inherited from one or both parents.

Individuals with lead exposure are frequently exposed to lead paints, notably children in older homes where lead-based paints are common. Adults with lead exposure may report occupational exposures such as mining, pipefitting, auto repair work, and ceramic glazing. Lead poisoning can present with characteristic lead lines on the gums and metaphyses of long bones, along with symptoms such as abdominal pain, peripheral neuropathy (most commonly affecting the fibular and radial nerves), and fatigue. In severe cases, children can develop encephalopathy.

Sideroblastic anemia can occur as a result of lead poisoning or chronic alcohol use, serving as the underlying etiology in some cases. Studies have shown a correlation between a low (pre-surgical) MCV and advanced stages (III or IV) of endometriosis.[16] These lower indices are believed to reflect dysregulated iron metabolism. 

Mean Corpuscular Volume Above 100 fL

Patients with vitamin B12 deficiency may present with various symptoms, including:

• A strict vegan lifestyle without supplementation
• Short bowel syndrome with a history of small bowel resection
• Pernicious anemia characterized by nausea, increased flatulence, diarrhea, weight loss, and anorexia
• Malabsorptive symptoms such as steatorrhea, foul-smelling stools, diarrhea, weakness, and/or weight loss

Vitamin B12 deficiency typically develops over several years due to hepatic storage lasting approximately 3 to 6 years. Consequently, when symptoms do appear, they often involve the nervous system, as fatty acid synthesis is important for myelin sheath formation.

Patients with MCV above 100 fL often exhibit signs of subacute combined degeneration, including cerebellar ataxia, bilateral hemiplegia, decreased vibration, and discriminative touch sensations. Folate deficiency may manifest with glossitis as a prominent symptom but typically lacks other specific symptoms. However, pregnant individuals with folate deficiency are at risk of fetal neural tube defects such as spina bifida occulta, especially if they do not use supplemental vitamins during pregnancy. Chronic alcoholism can contribute to folate deficiency, adding to the risk in such cases. Orotic aciduria typically presents early in life and is characterized by failure to thrive and delayed development, particularly in patients with a family history of the condition. Non-megaloblastic anemias often stem from underlying causes such as hepatic insufficiency, which can also be associated with chronic alcoholism, a prevalent contributing factor in these cases.

In addition, patients can report symptoms of jaundice, fatigue, spider angiomas, palmar erythema, ascites, peripheral edema, and easy bleeding and bruising. Diamond-Blackfan anemia presents in the first year of life and is characterized by facial and hand malformations, growth retardation, and predisposition to malignancies.[17] An elevated MCV, along with an increased mean corpuscular hemoglobin (MCH) but not MCH concentration (MCHC), is associated with long-term cardiovascular events and elevated homocysteine levels—a proatherogenic risk factor.[18] An increased MCV is also associated with acute coronary syndrome and post-stroke depression, with a significant correlation observed between high MCV values and increased 30-day mortality from intracranial hemorrhage.[19]

MCV is crucial in assessing esophageal cancer.[20][21] Studies have shown that patients with locally advanced esophageal squamous cell carcinoma and an elevated MCV experience poor recurrence-free survival and overall survival rates. In this context, MCV establishes a harbinger of responsiveness for neoadjuvant chemotherapy. Furthermore, research findings support the idea that an increased MCV may indicate the presence of esophageal cancer. 

Mean Corpuscular Volume Between 80 and 100 fL

Both intrinsic and extrinsic hemolytic normocytic anemias can present with similar symptoms. Patients often experience darkened urine due to increased urobilinogen levels. In cases of intravascular hemolysis caused by microangiopathic hemolytic anemias or paroxysmal nocturnal hemoglobinuria (PNH), hemoglobin and hemosiderin may also be detected in the urine.

The etiology of many of these diseases is spontaneous, but specific triggers or associations, as mentioned below, can provide diagnostic clues.

• Malaria may be suspected in patients who have recently traveled to endemic areas, participated in recent camping activities, or had Ixodes tick bites suggestive of babesiosis.

• Consumption of undercooked ground beef can raise suspicion for hemolytic uremic syndrome (HUS).

• Systemic lupus erythematosus (SLE).

• In cases of SLE, symptoms such as foamy urine (indicative of proteinuria), along with epistaxis and hypertension in pregnant women beyond 20 weeks gestation, may indicate HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome.

Aplastic anemia, characterized by pancytopenia, can present with pallor, purpura, petechiae, an increased risk of mucosal bleeding and infections, and fatigue secondary to pancytopenia. 

Evaluation

A CBC, which includes hemoglobin, hematocrit, and MCV, is essential for determining the type of anemia. The specific diagnostic approach for microcytic anemia depends on the patient's presentation. For instance, if a menstruating woman presents with an MCV below 80 fL and exhibits symptoms of menorrhagia, further investigations such as a Von Willebrand factor assay and/or thyroid panel may be necessary to ascertain the underlying cause related to menstrual history.

On the contrary, in the case of microcytic anemia in individuals aged 50 or older, a colonoscopy is typically recommended to investigate whether the iron deficiency originates from colonic polyps or neoplasms. Additional diagnostic steps may include a urea breath test and an upper endoscopy to assess for Helicobacter pylori infection, especially if the patient reports symptoms suggestive of gastritis-type pain.

When managing ACD with an unknown cause, several diagnostic tests are necessary. These include assessments for rheumatoid factor, anti-double-stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-myeloperoxidase antibodies, as well as a urine spot test to evaluate renal function through measures such as glomerular filtration rate, creatinine, and blood urea nitrogen levels. Screening for HLA-B27 and various rheumatologic antibodies is also crucial. Consideration may be given to malignancy screening using imaging modalities such as computed tomography (CT) scans or chest x-rays.

A blood lead level test is the gold standard diagnostic tool if lead poisoning is suspected. However, a bone marrow biopsy becomes necessary if other causes of sideroblastic anemia are possible. A detailed medical history is vital in identifying the underlying etiology, potentially avoiding the need for a bone marrow biopsy. Suspected β-thalassemia cases can be further evaluated through hemoglobin electrophoresis to determine the proportions of hemoglobin A versus A2. For α-thalassemia, genetic analysis offers superior diagnostic accuracy. 

Peripheral blood smear and urine analysis help distinguish between intravascular and extravascular hemolysis in normocytic anemia. The presence of schistocytes and hemoglobin in urine suggests microangiopathic hemolytic anemia. However, the absence of schistocytes in the peripheral blood smear and the absence of hemoglobin in the urine despite suspected hemolysis warrant further investigation. Detection of spherocytes in the peripheral blood smear prompts a direct Coombs test to differentiate autoimmune hemolytic anemia from splenic sequestration in hereditary spherocytosis, aiding diagnosis.

Renal analysis has found an inverse relationship between MCV and bone marrow density in patients on dialysis.[22] This was observed with hemodialysis but not peritoneal dialysis. Reticulocyte mean corpuscular volume (MCVr), representing larger and younger cells, is typically elevated compared to mature red blood cells.[23] Monitoring MCVr can be instrumental in tracking recovery from various conditions, ranging from iron deficiency (microcytosis) to megaloblastic anemia, providing valuable clinical insights.

In cases of macrocytic anemia, a thorough history and physical examination are pivotal in identifying potential causes such as chronic alcoholism, liver failure, malabsorptive disorders, or dietary deficiencies such as veganism without proper vitamin supplementation. Notably, it is crucial to assess both vitamin B12 and folate levels, considering that folate supplementation can mask underlying vitamin B12 deficiency. Suspected orotic aciduria necessitates urine analysis to detect orotic acid and ammonia levels. The ammonia test can differentiate a deficiency in ornithine transcarbamylase versus orotic aciduria. Due to the rarity of Diamond-Blackfan anemia, a detailed history, physical examination, and CBC are typically sufficient for diagnosis. However, due to associated predispositions, clinicians may opt for follow-up CT scans to screen for potential malignancies.[17] 

Treatment / Management

Microcytic Anemia

Treatment for microcytic anemia due to IDA typically involves iron supplementation for premenopausal women. In some cases, women may also receive treatment with oral contraceptive pills to regulate menstrual cycles and reduce menstrual flow or levothyroxine if the cause is secondary to hypothyroidism.

Macrocytic Anemia

Treatments for macrocytic anemia vary depending on the underlying causes. For vitamin B12 and folate deficiencies, supplementation with folate and vitamin B12 is the standard therapeutic approach. Individuals who consume alcohol are advised to discontinue alcohol consumption and are often supplemented with folate. Patients diagnosed with orotic aciduria typically require supplementation with UMP to bypass the deficient enzyme and restore normal function.[24]

Normocytic Anemia 

Treatment for patients with PNH typically involves the use of eculizumab, which can effectively reduce hemolysis and prevent complications such as portal hypertension resulting from venous thromboses.[25] Blood transfusions may be necessary in severe anemia cases to restore hemoglobin levels. Patients with bone marrow failure may undergo hematopoietic stem cell transplantation as a potential treatment option. For individuals with macroangiopathic hemolytic anemia secondary to conditions such as prosthetic heart valves or aortic stenosis, surgical interventions such as valve repair or replacement may be considered. Those experiencing intravascular hemolysis due to malaria or babesiosis require treatment with appropriate anti-malarial or babesiosis medications to manage the underlying infection effectively.(B3)

Microangiopathic hemolytic anemia can arise from various conditions such as thrombotic thrombocytopenic purpura (TTP), HUS, SLE, hypertensive emergency, and HELLP syndrome. TTP is treated with plasmapheresis and corticosteroids. HUS is treated with plasmapheresis, which is similar to TTP. SLE is treated with prednisone to decrease flares, hydroxychloroquine, mycophenolate mofetil, and tumor necrosis factor (TNF)-α inhibitors. HELLP syndrome is treated with anti-hypertensives such as labetalol or hydralazine, magnesium sulfate to prevent convulsions, corticosteroids to further develop the baby’s lung development before delivery, and blood transfusion if required due to thrombocytopenia.

Treatment for hereditary spherocytosis includes folate supplementation, blood transfusions if hemoglobin falls below 7 g/dL, and erythropoietin administration for infants up to 9 months old. Vaccination against encapsulated bacteria is recommended as a final step before splenectomy. Autoimmune hemolytic anemia can be managed initially with glucocorticoids and then with cytotoxic drugs such as rituximab if the condition is refractory.[26] Aplastic anemia treatment involves identifying and removing any causative agents if possible. Hematopoietic stem cell transplants are commonly used for its management.[27]

Treatment for ACD commonly involves anti-inflammatories, corticosteroids, and TNF-α inhibitors unless malignancy is the underlying cause, in which case, the malignancy requires a standard treatment protocol. Lead poisoning is managed with chelation therapy using dimercaprol, EDTA, and succimer for children. Copper deficiency requires copper supplementation. Patients taking isoniazid and are vitamin B6-deficient should receive vitamin B6 supplementation and/or discontinue isoniazid. Immediate cessation of chronic alcohol intake is necessary. Thalassemias are managed differently depending on severity; most cases do not require medication or transfusions, but therapy for β-thalassemia may include chronic blood transfusions.

Other types of thalassemia typically remain asymptomatic and do not necessitate treatment. Iron supplementation is contraindicated, especially in patients receiving chronic transfusions, due to concerns about acquired hemochromatosis. If H pylori infection is suspected, a urea breath test is necessary. An upper endoscopy can also be performed for biopsy and to assess severity, particularly because this bacterium is associated with premalignant conditions.

Differential Diagnosis

The differential diagnoses for microcytic, normocytic, and macrocytic anemias based on MCV findings in a CBC are outlined below. Differential diagnoses for MCV below 80 fL include IDA, ACD, sideroblastic anemia, H pylori infection, and thalassemias. IDA can also present with various differential diagnoses such as menorrhagia, colorectal adenocarcinoma, bleeding colonic polyp, bleeding peptic ulcer disease, H pylori infection, hematemesis, chronic epistaxis, duodenal malabsorption, or resection.

ACD presents with a range of differential diagnoses, including malignancy, rheumatologic conditions such as SLE and rheumatoid arthritis, autoimmune diseases such as primary biliary cirrhosis or multiple sclerosis, chronic kidney disease, and chronic infection. Differential diagnoses for sideroblastic anemia, leading to microcytic anemia, include chronic alcoholism, vitamin B6 deficiency, isoniazid use, myelodysplastic disorder, lead poisoning, copper deficiency, and congenital sideroblastic anemia. The main types of thalassemia include α1, α2, α3/hemoglobin H disease, α4 (fatal), β-thalassemia minor and major, and HbS/β-thalassemia heterozygote. 

Differential diagnoses of MCV above 100 include megaloblastic anemia and non-megaloblastic anemia. Causes of megaloblastic anemia include folate deficiency caused by chronic alcoholism, barbiturate use, phenytoin use, sulfasalazine use, methotrexate use, triamterene use, trimethoprim/sulfamethoxazole use, pyrimethamine use, and duodenal or jejunal malabsorption or resection. Differential diagnoses for vitamin B12 deficiency would include Crohn disease ileitis, short bowel syndrome, strict vegan diet without supplementation, D latum infection, chronic metformin use, pernicious anemia, atrophic gastritis, orotic aciduria, Diamond-Blackfan anemia. 

Non-megaloblastic differential diagnoses include conditions leading to hepatic insufficiency or cirrhosis secondary to chronic alcoholism, fulminant hepatitis secondary to drug toxicity, α-1-antitrypsin disease, galactosemia, Wilson disease, chronic hepatitis B viral infection, chronic hepatitis C infection, hemochromatosis, autoimmune hepatitis, amyloidosis, chronic decompensated right heart failure, and parasitic infections such as Schistosoma haematobium.

Differential diagnoses of MCV between 80 and 100 fL include conditions that can lead to intravascular hemolytic anemia, extravascular hemolytic anemia, and aplastic anemia. Intravascular hemolytic anemia may arise from conditions such as PNH and micro/macroangiopathic hemolytic anemia due to TTP, HUS, HELLP syndrome, disseminated intravascular coagulation, aortic stenosis, and defective prosthetic cardiac valve. On the other hand, extravascular hemolytic anemia can be caused by disorders including hereditary spherocytosis, sickle cell anemia, glucose 6-phosphate dehydrogenase (G6PD) deficiency, infections such as malaria and babesiosis, and autoimmune hemolytic anemia.

Some differential diagnoses for autoimmune hemolytic anemia causes include chronic lymphocytic leukemia, SLE, and hematopoietic stem cell transplant. Furthermore, differential diagnoses for aplastic anemia would include Fanconi anemia, PNH, radiation exposure, drug toxicities such as chloramphenicol, sulfonamides, benzene exposure, viral infections such as parvovirus B19 (especially in immunocompromised patients), HIV, Epstein-Barr virus, hairy cell leukemia, and myelodysplastic disorders. 

Pertinent Studies and Ongoing Trials

Outside of anemia, MCV and red blood cell distribution are thought to determine the risk of cardiovascular events after surgery and/or blood transfusions. Patients with macrocytic or microcytic anemia have a higher risk after surgery or blood transfusion than those with normocytic anemia. These values may help prevent cardiovascular events due to closer monitoring after these procedures.[28] Additionally, MCV can determine the risk of restenosis after stent placement into the coronary arteries. Microcytic erythrocytes were associated with restenosis of the coronary arteries with stent more than macrocytosis or normocytic erythrocytes.[3]

Prognosis

The prognosis may vary with changes in MCV. IDA has a good prognosis with iron supplementation. However, if iron deficiency is secondary to chronic blood loss from malignancy, the prognosis is poor and often fatal. The prognosis of ACD varies due to the underlying etiology. Chronic inflammation secondary to malignancy can have a poorer prognosis than a rheumatologic disease controlled by medication. However, sideroblastic anemia is relatively mild and easily treated with supplementation or withdrawal from the causal agent.

Furthermore, thalassemias have varying prognoses. Hemoglobin Bart syndrome, or α-thalassemia major, is fatal, causing hydrops fetalis, and has a poor prognosis in utero. β-thalassemia major has improved outcomes with increasing iron chelation treatment and chronic blood transfusions, allowing patients to live reasonably normal lives. However, the outlook is still poor due to the early mortality of these patients from restrictive diseases secondary to acquired hemochromatosis. Patients with other α- and β-thalassemia forms generally live normal lives without significant complications and have excellent prognoses.

Megaloblastic anemias secondary to folate and cobalamin deficiencies tend to have good prognoses with proper supplementation therapy. However, vitamin B12 deficiency with severe subacute combined degeneration can be fatal and has a poor prognosis. This condition is preventable with appropriate supplementation via vitamins, food intake, or injections. Folate deficiency has a good prognosis in patients who are not pregnant. However, the prognosis for neonates with folate-deficient mothers is poor, depending on the etiology of the neural tube defect. Patients with spina bifida occulta have a good prognosis and are often unaware of their condition. However, patients with rachischisis have a poor prognosis and may not survive in utero.

Patients with orotic aciduria and Diamond-Blackfan anemia can have a good prognosis depending on chronic supplementation. If these patients are non-compliant with supplementation, their anemias can have a poor prognosis and can become severe and fatal. Non-megaloblastic anemias tend to have poor prognoses. Patients with chronic alcoholism have many vitamin deficiencies ranging from folate to thiamine. These deficiencies can cause neurological issues, cerebellar damage, and hepatic insufficiency. Hepatic insufficiency and cirrhosis also have a poor prognosis, depending on their severity. Many of these patients suffer from portal hypertension and esophageal varices with the risk of rupture and hemorrhage. They can, in turn, develop hepatorenal syndrome and become encephalopathic, which can lead to their demise. A preoperative high and low MCV is a poor prognostic factor.[29] Studies revealed that the worst prognostic effect was in stage III. 

Normocytic anemias tend to have poorer prognoses due to their chronic hemolysis and deteriorating conditions. With newer treatments, intravascular hemolysis, such as PNH, has an improved prognosis. However, without treatment, the patient can develop pancytopenia and suffer from aplastic anemia, which can be fatal. If treated, the prognoses of microangiopathic hemolytic anemias are generally positive; however, patients must adhere to their treatments. Extravascular hemolytic diseases, such as sickle cell anemia, have a poor prognosis and a life expectancy ranging from age 30 to 40. These patients may experience chronic vaso-occlusive crises, which can be fatal. 

Complications

The lack of treatment and increased mortality are common complications for anemias with varying MCV. Patients with IDA without supplementation can develop high-output heart failure. Lead poisoning can also be fatal without chelation therapy and removal of the causal agent. Untreated diseases such as SLE can lead to renal insufficiency, which is the most common cause of death in these patients. Patients with β-thalassemia major are prone to complications from treatment, such as acquired hemochromatosis. Without chronic chelation therapy, these patients are at risk of death from iron intoxication and restrictive pericarditis due to iron deposition in the pericardium. 

Folate deficiency can lead to complications in pregnant patients, causing neural tube defects in the developing fetus. Vitamin B12 deficiency can result in subacute combined degeneration of the nervous system. Unfortunately, without appropriate supplementation, conditions such as orotic aciduria and Diamond-Blackfan anemia can be fatal.

Patients with hepatic insufficiency or cirrhosis face a spectrum of complications, including hyperammonemia, ascites, portal hypertension, cardiomegaly, esophageal varices with a risk of rupture and hemorrhage, internal hemorrhoids, hepatorenal syndrome, and hepatic encephalopathy. Chronic alcoholism can also contribute to these complications due to alcoholic cirrhosis, along with the development of Wernicke-Korsakoff syndrome resulting from thiamine deficiency.

Normocytic anemia can lead to various complications such as hemoglobinuria, hematuria, syncope, petechial rashes, high fevers, and even death. Timely and effective treatment is crucial in mitigating these potential complications and improving overall patient outcomes.