Abstract
With close to 2 billion people affected globally, anemia is a commonly seen condition worldwide. Diagnosed by a patient’s low hemoglobin, and then subsequently differentiated through red blood cell indices, a complete blood count should be performed on every patient presenting with the classic symptoms of anemia. Iron studies, as well as the corrected reticulocyte count and peripheral blood smears, can also be of use to further specify the exact type of anemia. Additionally, tests including colonoscopies, upper endoscopies and gynecologic procedures should be considered to identify the different underlying causes of the disease. The most common microcytic anemias include iron deficiency, thalassemia and anemia of inflammation. Deficiencies in folate and B12—also known as cobalamin—are the most common etiologies of macrocytic anemia. Treatment of each of these types of anemia is tailored to the individual patient based on the severity of their condition as well as the specific underlying cause. Osteopathically, anemia falls largely into the respiratory-circulatory model, as well as the metabolic-energy model, which can also be used to guide treatment. For a family physician, identifying symptoms, making accurate diagnoses and properly treating patients with anemia is of the utmost importance.
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INTRODUCTION
Anemia can be broadly defined as any condition that results in a deficiency of red blood cells (RBCs) or a decreased amount of hemoglobin, an iron-rich protein that binds oxygen. Anemia causes decreased oxygen delivery to tissues and can result in symptoms including lethargy, dyspnea, weakness and pallor. Anemia impacts approximately one-third of the world’s population.1 Estimations of the global prevalence suggest that 1.93 billion people are affected by anemia with iron deficiency being the most prominent cause, contributing to more than 60% of cases.1 Other common causes include nutritional deficiencies, such as folate and B12, and conditions that result in prolonged inflammation. Understanding this complex etiology is crucial for the diagnosis and management of anemia.
Risk factors for anemia include female sex, increased age, nutritional deficiencies, heavy menstruation and pregnancy.2 Anemia can develop by means of ineffective erythropoiesis, hemolysis and blood loss.3 Though anemia can be classified by its cause, it is typically differentiated based upon the size, shape and color of RBCs. Hemoglobin levels that fall below given thresholds in both men and women are indicative of anemia. These thresholds, established by the World Health Organization, are 12 g/dL in women and 13 g/dL in men.4,5
COMMON ETIOLOGIES
Iron deficiency anemia (IDA) is most often a result of conditions such as malabsorption, gastrointestinal bleeding and heavy menstrual periods.5,6 Folate and B12 deficiencies, which interrupt DNA synthesis, are grouped under megaloblastic anemia. B12 deficiency is common in malabsorptive states, such as malnutrition. Folate deficiency is most often seen in alcoholism, malnutrition and states of increased folate requirement, such as pregnancy. Non-megaloblastic anemias include deficiencies that are not due to a breakdown in DNA synthesis, such as liver disease and cancer.7 Anemia of inflammation (AI), previously known as anemia of chronic disease, is caused by underlying conditions which result in a decrease in RBC synthesis or an increase in RBC loss.8,9 Table 1 highlights various underlying causes of AI.
TABLE 1:
Potential causes of anemia of inflammation8–12
Infection (viral, bacterial, parasitic, fungal) |
Rheumatoid arthritis |
Systemic lupus erythematosus |
Inflammatory bowel disease |
Sarcoidosis |
Vasculitis |
Chronic kidney disease |
Chronic inflammation |
Chronic rejection post organ transplant |
Malignancy |
CLINICAL MANIFESTATIONS
Microcytic (MCV >80 fL)
General symptoms are common among all anemias and are seen due to the body’s lack of oxygenated blood resulting from reduced hemoglobin levels. These symptoms include fatigue, dizziness, lightheadedness, dyspnea, exercise intolerance, weakness, palpitations, headache and difficulty concentrating.13 Often, these symptoms appear when hemoglobin levels fall below 7.0 g/dL, though comorbidities, the duration of anemia and its underlying etiology have a significant impact as well.14 Symptoms specific to each type of anemia can be determined based on their underlying etiology as shown in Table 2.
TABLE 2:
UNIQUE SYMPTOMS/SIGNS | SPECIAL CONSIDERATIONS | |
IDA | Pica Restless leg syndrome | Symptoms can occur prior to a change in the patient’s hemoglobin level. |
Brittle integument | ||
Cheilosis | ||
Spooning of the fingernails | ||
B12 | Loss of proprioception Loss of vibratory senses Areflexia | Gait abnormalities can be in the form of sensory ataxia that manifests as a positive romberg sign. |
Irritability | ||
Acute psychosis | ||
Gait abnormalities | ||
Folate | None | None |
DIAGNOSTIC WORKUP
The initial workup of anemia is commonly done through the evaluation of hemoglobin concentration. A hemoglobin value indicative of anemia can only diagnose anemia and cannot determine the exact cause. Once established, the mean corpuscular volume (MCV) is assessed, which categorizes the anemia as microcytic (<80 fL), normocytic (80–100 fL) or macrocytic (>100 fL), which then allows for a more tailored evaluation.21
Microcytic
Once the anemia has been determined to be microcytic, iron studies—which include serum iron, ferritin, total iron binding capacity (TIBC) and transferrin saturation (TSAT)—are conducted. Figure 1 outlines the lab values that are used to further differentiate the 3 common causes of microcytic anemia.
FIGURE 1:
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Ferritin levels, which serve as a measure of iron stores, below 45 µg/mL and above 100 µg/L are associated with IDA and AI, respectively.9 Traditionally, a threshold of under 15 µg/mL can diagnose IDA, but a concentration of less than 45 µg/mL has a higher sensitivity with only a mild decrease in specificity.22 The upregulation of ferritin, noted in AI, is due to ferritin being an acute-phase protein whose secretion is promoted by inflammatory mediators.9,23 However, the inflammatory cytokines of AI reduce the levels of transferrin. The functional capacity of transferrin to bind iron is represented by the TIBC. The transferrin saturation, which is calculated by dividing serum iron by the TIBC, will be low in both IDA and AI.18,24
If all iron studies are normal, then thalassemia should be part of the differential diagnosis. Thalassemia can be further differentiated by hemoglobin electrophoresis. The Mentzer index, which is calculated by dividing the MCV by the RBC count, helps differentiate thalassemia from IDA. A Mentzer index value of <13 is indicative of thalassemia.23,25
FIGURE 2:
See PDF version.
Normocytic
When the MCV is within 80–100 fL, the corrected reticulocyte count (CRC)—also known as the reticulocyte index—and peripheral blood smear are then evaluated to find the root cause of the anemia. Typically, normocytic anemia is further subdivided by the CRC, which is derived from the reticulocyte count. The CRC adjusts for the degree of anemia and better reflects the state of erythropoiesis.18,28 A decreased CRC is indicative of an inadequate bone marrow response to the anemia.28 Though AI can be found in microcytic anemia, it is commonly the cause of normocytic anemia with a decreased or normal CRC.9,13,18,29 Alternatively, an elevated CRC implies increased RBC turnover due to blood loss or hemolysis.23 Hemolysis is supported with labs of increased indirect bilirubin, decreased haptoglobin and increased lactate dehydrogenase, and hemolysis can be further subdivided into congenital or acquired by a Coombs test. To determine the etiology of the hemolysis, a peripheral blood smear should be completed.24 Figure 2 illustrates the lab evaluation for normocytic anemia.
Macrocytic
Macrocytic anemia is subdivided into megaloblastic and non- megaloblastic anemias based on a peripheral blood smear. Hypersegmented neutrophils and macro-ovalocytes will be found with megaloblastic anemia, while morphological abnormalities are not present with non-megaloblastic anemia.18,24 Serum homocysteine and methylmalonic acid levels can be obtained to further differentiate between folate or B12 deficiencies. Only homocysteine levels will be increased with folate deficiency, whereas both homocysteine and methylmalonic acid will be elevated in B12 deficiency.18 Figure 3 highlights the workup for macrocytosis.
FIGURE 3:
See PDF version.
TREATMENT
Treatment of anemia is guided by the underlying cause. Oral iron therapy is typically prescribed for patients diagnosed with nutritional IDA. Ferrous salts are the standard first line oral iron therapy because of their high bioavailability, cost effectiveness, and accessibility.5,30,31 Among the ferrous iron compounds, their side effects, bioavailability and efficacy are similar though their elemental iron content varies as shown in Table 3. The recommended daily dose of elemental iron for IDA patients is 150–200 mg.18 It is recommended to avoid consumption of inhibitors of iron absorption such as whole grains, legumes, tea, coffee, red wine, hot chocolate, as well as proton pump inhibitors and antacids.5,30 Common side effects with iron supplementation include metallic taste, epigastric pain, nausea, vomiting, constipation and dark stools.16,21
TABLE 3
Oral iron therapy for iron deficiency anemia 5,30,31
ORAL IRON FORMULATION | DOSE PER TABLET | ELEMENTAL IRON PER TABLET | SPECIAL CONSIDERATIONS |
Heme Iron Polypeptide | 398 mg | 11 mg | Can be taken with food |
Acidic environment not required for absorption | |||
Ferrous Gluconate | 240 mg 325 mg | 27 mg 38 mg | Best absorbed on empty stomach |
Ferrous Sulfate | 325 mg | 65 mg | Best absorbed on empty stomach |
Ferrous Fumarate | 325 mg | 106 mg | Best absorbed on empty stomach |
Polysaccharide Iron Complex | 150 mg | 150 mg | Can be taken with food |
Acidic environment not required for absorption |
In 2019, the FDA approved ACCRUFeR®, a new oral iron therapy for adults with IDA. This ferric maltol based compound represents a comparably efficacious and well-tolerated alternative for those who experience treatment-limiting intolerance issues such as nausea, abdominal discomfort, and constipation.32,33 Other advancements in the treatment of IDA include Injectafer®, a ferric carboxymaltose based compound that offers an alternative parenteral option for treating patients who are refractory to or cannot tolerate conventional oral iron therapy.34
Treatment options for B12 deficiency anemia include supplementation with either 1 mg intramuscular (IM) injections or 1–2 mg oral formulations19. Dosing schedule and duration depend on the patient’s symptomatic state as well as the underlying cause of the deficiency. If the patient’s underlying cause is reversible and the patient is without severe neurologic symptoms, then dosing 3 times per week is warranted.19 In cases with severe neurologic deficits, the frequency of dosing should increase to every other day.19 For patients with a reversible condition, such as a nutritional insufficiency, supplementation should be discontinued following a resolution of symptoms or a correction of deficiency, whichever occurs first.19 If the cause of deficiency is irreversible, such as malabsorption, then the treatment continues indefinitely.19 Oral supplementation is non-inferior to IM injections throughout the first 8 weeks of treatment. After 8 weeks, IM injections were found to be superior.35
Folate deficiency anemia is generally treated with oral folate supplementation due to the underlying cause of the deficiency typically being a lack of dietary intake. Folic acid, the oral supplement for folate replacement, is dosed up to 5 mg per day. The duration of treatment continues until resolution of the anemic state or until the underlying cause of the deficiency is addressed. If the cause of the deficiency is irreversible, such as a malabsorptive state, then treatment continues indefinitely.11,14
AI and macrocytic non-megaloblastic anemias are treated by controlling the underlying cause of disease or by removing the offending agent. Referral to hematology may be considered in some circumstances.
OTHER STUDIES
Given that anemia is a disease of multiple potential etiologies, numerous evaluative techniques can be performed to find the root cause for each patient. Determining the underlying cause, such as folate, B12 or iron deficiencies, or malabsorption is key to coordinating treatment. Beyond those already mentioned, other studies should be considered to evaluate the various causes. Since IDA can be due to blood loss, either gross or occult, further work-up should include evaluations of the gastrointestinal tract with both colonoscopy and upper endoscopy.36 If neither evaluation identifies the cause, small bowel investigation is warranted. In women, heavy menstrual bleeding is a common cause of IDA.37 Pelvic ultrasonography, saline infusion ultrasonography and hysteroscopy can be used to screen for common causes of heavy menstrual bleeding, such as endometrial polyps, intracavitary lesions or adnexal lesions.38
OSTEOPATHIC CONSIDERATIONS
Anemia primarily involves the metabolic-energy and respiratory- circulatory osteopathic models. This model aims to restore optimal function of metabolic processes while replenishing energy loss and fatigue due to ineffective metabolism.39 Including more leafy green vegetables, for example, can help prevent recurrence of iron- deficiency anemia. There have been numerous studies conducted investigating the relationship between veganism, Mediterranean diets, and anemia.40,41 Veganism is frequently associated with the development of mineral deficiencies, and it is even recommended that vegans should also receive B12 supplements regularly.42
The respiratory-circulatory model aims to restore vascular, gaseous and lymphatic movement.39 It is understood that nutrition and blood flow create an environment that can facilitate or impede organ function.19 The circulation absorbs nutrients from our diets and is distributed systemically. An anemic state can markedly disturb this circuit.
A significant consequence of anemia is fatigue. The CV4 technique increases parasympathetic activity and decreases sympathetic activity. For this technique, with the patient supine, the physician cradles the occipital bone laterally while easing the cranium into extension. This results in a decrease in sleep latency, thus improving fatigue.43
Occipitoatlantal decompression is another technique used to increase parasympathetic activity.44 For this treatment, with the patient supine, the physician’s fingers balance the patient’s head at the occipital condyles. The physician then applies a superior tractional force, decompressing the condylar region.45
CONCLUSION
Anemia continues to affect a widespread population around the world. While various treatments have been instituted, investigation remains both about the origins of the disease and its pathophysiology. Due to its multifaceted etiologies, anemia remains elusive in terms of its root causation in many patients. Continued studies of micronutrients could be analyzed to further manage this disease state. Increasing awareness of appropriate nutrition and lifestyle habits will help to alleviate the burden of anemia.
REFERENCES
Kassebaum NJ, GBD 2013 Anemia Collaborators. The global burden of anemia. Hematol Oncol Clin North Am. 2016;30(2):247–308. doi:10.1016/ j.hoc.2015.11.002
Chaparro CM, Suchdev PS. Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries. Ann N Y Acad Sci. 2019;1450(1):15–31. doi:10.1111/nyas.14092
World Health Organization. Nutritional anaemias: Tools for effective prevention and control. Geneva: World Health Organization; 2017. https://www.who.int/publications/i/item/9789241513067?sequence=1. Published November 13, 2017. Accessed July 1, 2021.
World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Geneva: World Health Organization; 2011. https://www.who.int/iris/bitstream/handle/10665/85839/WHO_NMH_NHD_MNM_11.1_eng.pdf. Accessed June 2, 2021.
Ning S, Zeller MP. Management of iron deficiency. Hematology Am Soc Hematol Educ Program. 2019;2019(1):315–322. doi:10.1182/ hematology.2019000034
Carlos AM, Souza BMB de, Souza RAV de, et al. Causes of microcytic anaemia and evaluation of conventional laboratory parameters in the differentiation of erythrocytic microcytosis in blood donor candidates. Hematology Am Soc Hematol Educ Program. 2018;23(9):705–711. doi:10.1080/10245332.2018.1446703
Moore CA, Adil A. Macrocytic Anemia. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed July 15, 2021.
Madu AJ, Ughasoro MD. Anaemia of Chronic Disease: An In-Depth Review. Med Princ Pract. 2017;26(1):1–9. doi:10.1159/000452104
Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40–50. doi:10.1182/blood-2018-06-856500
Hardang IM, Lilleholt K, Hagve T-A. [Anemia of chronic disease]. Tidsskr Nor Laegeforen. 2017;137(17). doi:10.4045/tidsskr.16.1128
Socha DS, DeSouza SI, Flagg A, Sekeres M, Rogers HJ. Severe megaloblastic anemia: Vitamin deficiency and other causes. Cleve Clin J Med. 2020;87(3):153–164. doi:10.3949/ccjm.87a.19072
Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2018;2018(1):382–389. doi:10.1182/ asheducation-2018.1.382
Yilmaz G, Shaikh H. Normochromic Normocytic Anemia. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed July 2, 2021.
Green MD, PhD R, Mitra MD AD. Megaloblastic Anemia. Med Clin North Am. 2017;101(2). https://www.clinicalkey.com/#!/content/playContent/ 1-s2.0-S0025712516373643?scrollTo=%23hl0000550. Accessed July 2, 2021.
Kolukisa M, Soysal P, Gületkin TÖ, Karatoprak C, Bilgen HR, Gürsoy AE. Restless Leg Syndrome/Willis-Ekbom disease in women with iron deficiency anemia. Ideggyogy Sz. 2016;69(9-10):356–360. doi:10.18071/ isz.69.0356
Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol. 2016;91(1):31–38. doi:10.1002/ajh.24201
Uchida T, Kawati Y. Pagophagia in iron deficiency anemia. Rinsho Ketsueki. 2014;55(4):436–439.
Powell DJ, Achebe MO. Anemia for the primary care physician. Prim Care. 2016;43(4):527–542. doi:10.1016/j.pop.2016.07.006
Langan RC, Goodbred AJ. Vitamin B12 deficiency: Recognition and management. Am Fam Physician. 2017;96(6):384–389.
Qudsiya Z, De Jesus O. Subacute combined degeneration of the spinal cord. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed July 2, 2021.
Lanier JB, Park JJ, Callahan RC. Anemia in older adults. Am Fam Physician. 2018;98(7):437–442.
Ko CW, Siddique SM, Patel A, et al. AGA clinical practice guidelines on the gastrointestinal evaluation of iron deficiency anemia. Gastroenterology. 2020;159(3):1085–1094. doi:10.1053/j.gastro.2020.06.046
Jansen V. Diagnosis of anemia-A synoptic overview and practical approach. Transfus Apher Sci. 2019;58(4):375–385. doi:10.1016/j. transci.2019.06.012
Newhall DA, Oliver R, Lugthart S. Anaemia: A disease or symptom. Neth J Med. 2020;78(3):104–110.
Wang M. Iron deficiency and other types of anemia in infants and children. Am Fam Physician. 2016;93(4):270–278.
Vieth JT, Lane DR. Anemia. Hematol Oncol Clin North Am. 2017;31(6):1045–1060. doi:10.1016/j.hoc.2017.08.008
Buttarello M. Laboratory diagnosis of anemia: Are the old and new red cell parameters useful in classification and treatment, how? Int J Lab Hematol. 2016;38 Suppl 1:123–132. doi:10.1111/ijlh.12500
Brandow AM. Pallor and Anemia. In: Nelson Pediatric Symptom-Based Diagnosis. Elsevier; 2018:661–681.e2. doi:10.1016/B978-0-323-39956-2.00037-6
Turner J, Parsi M, Badireddy M. Anemia. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed July 2, 2021.
Stoffel NU, von Siebenthal HK, Moretti D, Zimmermann MB. Oral iron supplementation in iron-deficient women: How much and how often? Mol Aspects Med. 2020;75:100865. doi:10.1016/j.mam.2020.100865
Girelli D, Ugolini S, Busti F, Marchi G, Castagna A. Modern iron replacement therapy: clinical and pathophysiological insights. Int J Hematol. 2018;107(1):16–30. doi:10.1007/s12185-017-2373-3
Schmidt C, Allen S, Kopyt N, Pergola P. Iron replacement therapy with oral ferric maltol: Review of the evidence and expert opinion. J Clin Med. 2021;10(19). doi:10.3390/jcm10194448
Pergola PE, Fishbane S, Ganz T. Novel oral iron therapies for iron deficiency anemia in chronic kidney disease. Adv Chronic Kidney Dis. 2019;26(4):272–291. doi:10.1053/j.ackd.2019.05.002
Lichtenstein GR, Onken JE. Improved hemoglobin response with ferric carboxymaltose in patients with gastrointestinal-related iron-deficiency anemia versus oral iron. Dig Dis Sci. 2018;63(11):3009–3019. doi:10.1007/s10620-018-5204-3
Sanz-Cuesta T, Escortell-Mayor E, Cura-Gonzalez I, et al. Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: A pragmatic, randomised, non-inferiority clinical trial (OB12). BMJ Open. 2020;10(8):e033687. doi:10.1136/ bmjopen-2019-033687
Hempel EV, Bollard ER. The evidence-based evaluation of iron deficiency anemia. Med Clin North Am. 2016;100(5):1065–1075. doi:10.1016/ j.mcna.2016.04.015
Mansour D, Hofmann A, Gemzell-Danielsson K. A review of clinical guidelines on the management of iron deficiency and iron-deficiency anemia in women with heavy menstrual bleeding. Adv Ther. 2021;38(1):201–225. doi:10.1007/s12325-020-01564-y
Sriprasert I, Pakrashi T, Kimble T, Archer DF. Heavy menstrual bleeding diagnosis and medical management. Contracept Reprod Med. 2017;2:20. doi:10.1186/s40834-017-0047-4
Seffinger MA. Foundations of Osteopathic Medicine. 4th ed. Wolters Kluwer; 2018.
Bachmeyer C, Bourguiba R, Gkalea V, Papageorgiou L. Vegan diet as a neglected cause of severe megaloblastic anemia and psychosis. Am J Med. 2019;132(12):e850–e851. doi:10.1016/j.amjmed.2019.06.025
Yaskolka Meir A, Tsaban G, Zelicha H, et al. A green-Mediterranean diet, supplemented with Mankai duckweed, preserves iron-homeostasis in humans and is efficient in reversal of anemia in rats. J Nutr. 2019;149(6):1004–1011. doi:10.1093/jn/nxy321
Larpin C, Wozniak H, Genton L, Serratrice J. Vegetarian and vegan diets and their impact on health. Rev Med Suisse. 2019;15(667):1849–1853.
Żurowska A, Malak R, Kołcz-Trzęsicka A, Samborski W, Paprocka- Borowicz M. Compression of the fourth ventricle using a craniosacral osteopathic technique: A systematic review of the clinical evidence. Evid Based Complement Alternat Med. 2017;2017:2974962. doi:10.1155/2017/2974962
Roberts B, Makar AE, Canaan R, Pazdernik V, Kondrashova T. Effect of occipitoatlantal decompression on cerebral blood flow dynamics as evaluated by Doppler ultrasonography. J Osteopath Med. 2021;121(2):171–179. doi:10.1515/jom-2020-0100
Nicholas AS. Chapter 18: Osteopathic Cranial Manipulative Medicine. In: Atlas of Osteopathic Techniques. 3rd ed. Wolters Kluwer; 2016.