Anemia of chronic disease (ACD)—or more aptly “anemia of inflammation”— is the second most common cause of anemia after iron deficiency and is associated with numerous acute or chronic conditions (eg, infection, cancer, autoimmune diseases, chronic organ rejection, and chronic kidney disease)1.
The hallmark of ACD is disturbances in iron homeostasis which result in increased uptake and retention of iron within cells of the reticuloendothelial system, with its attendant diversion of iron from the circulation and reduced availability for erythropoiesis1. More specifically, pathogens, cancer cells, or even the body’s own immune system stimulate CD3+ T cells and macrophages to produce a variety of cytokines, (eg, interferon-ɤ, TNF-α, IL-1, IL-6, and IL-10) which in turn increase iron storage within macrophages through induction of expression of ferritin, transferrin and divalent metal transporter 1.
In addition to increased macrophage storage of iron, ACD is also associated with IL-6-induced synthesis of hepcidin, a peptide secreted by the liver that decreases iron absorption from the duodenum and its release from macrophages2. TNF-α and interferon-ɤ also contribute to ACD by inhibiting the production of erythropoietin by the kidney. Finally, the life span of RBCs is adversely impacted in AKD due to their reduced deformability and increased adherence to the endothelium in inflammatory states3.
Of interest, it is often postulated that by limiting access to iron through inflammation, the body hinders the growth of pathogens by depriving them of this important mineral2.
- Weiss, G and Goodnough, L. Anemia of chronic disease. N Engl J Med 2005; 352; 1011-23. http://www.med.unc.edu/medclerk/medselect/files/anemia2.pdf
- D’Angelo, G. Role of hepcidin in the pathophysiology and diagnosis of anemia. Blood Res 2013; 48(1): 10-15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624997/pdf/br-48-10.pdf
- Straat M, van Bruggen R, de Korte D, et al. Red blood cell clearance in inflammation. Transfus Med Hemother 2012;39:353-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678279/pdf/tmh-0039-0353.pdf
Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School
High serum B12 levels, aka hypercobalaminemia (HC), is not rare among hospitalized patients with 1 study reporting “high” (813-1355 pg/ml) and “very high” (>1355 pg/ml) serum B12 levels in 13 and 7% of patients, respectively1. Common causes include excess B12 intake, solid neoplasms (particularly, hepatocellular carcinoma and metastatic neoplastic liver disease), blood disorders (eg, myelodysplastic syndrome, CML, and acute leukemias, particularly AML3), and other liver diseases, including alcohol-related diseases as well as acute and chronic hepatitis. Other inflammatory states and renal failure have also been reported2.
Paradoxically, even in the presence of HC, a functional B12 deficiency may still exist. This may be related to poor B12 delivery to cells due to its high binding by transport proteins transcobalamin I and III in HC which may in turn cause a decrease in the binding of B12 to transcobalamin II, a key player in B12 transport to tissues2. In this setting, elevated serum methylmalonic acid and homocysteine levels may be helpful.
- Arendt JFB, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS ONE 2012;9:e45979.
- Andres E, Serraj K, Zhu J. et al. The pathophysiology of elevated vitamin B12 in clinical practice. Q J Med 2013;106:505-515.
Unlike its previous 2012 guidelines that recommended overlapping hemoglobin level triggers of 7 g/dL to 8 g/dL for most inpatients, the 2016 guidelines from AABB (formerly known as the American Association of Blood Banks) assigns 2 distinct tiers of hemoglobin transfusion triggers: 7 g/DL for hemodynamically stable adults, including those in intensive care units, and 8 g/dL for patients undergoing cardiac or orthopedic surgery or with preexisting cardiovascular disease1 , often defined as history of coronary artery disease, angina, myocardial infarction, stroke, congestive heart failure, or peripheral vascular disease2,3.
These recommendations are based on an analysis of over 30 randomized trials, taking into account the potential risks of withholding transfusions, including 30-day mortality, and myocardial infarction. The new 2-tier recommendation specifically excludes those with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion-dependent anemia.
The guidelines also emphasize that good clinical practice dictates considering not only the hemoglobin level but the overall clinical context when considering blood transfusion in patients. These factors include alternative therapies to transfusion, rate of decline in hemoglobin level, intravascular volume status, dyspnea, exercise tolerance, light-headedness, chest pain considered of cardiac origin, hypotension, tachycardia unresponsive to fluid challenge, and patient preferences. In addition, standard practice should be to initiate a transfusion with 1 unit of blood rather than 2 units1.
- Carson JL, Guyatt G, Heddle NW. Clinical practice guidelines from the AABB red blood cell transfusion thresholds and storage. JAMA. Doi:10.1001/jama.2016.9185. Published online October 12, 2016.
- Carson JL, Duff A, Poses RM, et al. Effect of anemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055-60.
- Carson JL, Siever F, Cook DR, et al. Liberal versus restrictive blood transfusion strategy: 3-year survial and cause of death results from the FOCUS randomized controlled trial. Lancet 2015;385:1183-1189.
HS syndrome is characterized by aortic stenosis and GI angiodysplasia1. The pathophysiology of this syndrome involves not only increased number of angiodysplasias but higher risk of bleeding from them. The physiological link between angiodysplasia and aortic stenosis is unclear but hypo-oxygenation of intestinal mucosa, possibly related to cholesterol emboli with resultant vasodilatation, has been hypothesized among many others2. Bleeding from angiodysplasias appears related to the high shear stress across the stenotic aortic valve, leading to acquired von Willebrand’s disease (Type 2AvWF disease) and coagulopathy2.
Cessation of bleeding following SAVR or TAVR with gradual disappearance of angiodysplasia has been reported, in some cases despite long-term anticoagulant therapy3,4. GIB may cease in 95% of cases following AVR vs 5% in cases undergoing laparotomy with or without bowel resection. In patients who have undergone SAVR, aortic valve restenosis usually leads to the recurrence of GI bleeding which resolves after redo surgery.
- Heyde EC. Gastrointestinal bleeding in aortic stenosis. N Engl J Med 1958;259:196.
- Kapila A, Chhabra L, Khanna A. Valvular aortic stenosis causing angiodysplasia and acquired von Willebrand’s disease: Heyde’s syndrome. BMJ Case Rep 2014 doi:10.1136/bcr-2013-201890.
- Abi-akar R, El-rassi I, Karam N et al. Treatment of Heyde’s syndrome by aortic valve replacement. Curr Cardiol Rev 2011; 7:47–49.
- Pyxaras, SA, Santangelo S. Perkan A et al. Reversal of angiodysplasia-derived anemia after transcatheter aortic valve implantation. J Cardiol Cases 2012; 5: e128–e131.
Contributed by Biqi Zhang, medical student, Harvard Medical School
Pica refers to the compulsive craving and persistent consumption of substances not fit as food such as ice (pagophagia) and soil (geophagia). Several reports have implicated iron deficiency as a cause of pica, with resolution of symptoms following treatment of iron deficiency (1). In a recent study involving blood donors , pica (particularly pagophagia) was nearly 3 times as likely among donors with iron deficiency compared to iron-replete donors (11% vs 4%, respectively, P<0.0001). In the same study, donors with pica reported a marked reduction in their pica by day 5-8 of iron therapy.
It has been suggested that cerebral tissue function may be adversely impacted by a deficiency in Fe-containing enzymes (e.g. cytochrome c reductase) resulting in behavioral disorders, such as hyperactivity and pica (2). Of interest, cats can be induced to swallow inedible objects when certain points in the hypothalamic area high in iron content are stimulated (3).
- Bryant BJ, Yau YY, Arceo SM, et al. Ascertainment of iron deficiency and depletion in blood donors through screening questions for pica and restless legs syndrome. Transfusion 2013;53:1637-1644.
- Osman YM, Wali YA, Osman OM. Craving for ice and iron-deficiency anemia: a case series from Oman. Pediatric Hematol Oncol 2005; 22:127-131.
- Von Bonsdorff B. Pica: a hypothesis.. British J Haematol 1977;35:476-477.
Contributed by S.J. Lee, Medical Student, Harvard Medical School, Boston, MA