A 67-Year-Old Woman With a Diabetic Foot Ulcer and Significant Anemia

AUTHOR:
Ronald N. Rubin, MD^1,2—Series Editor

AFFILIATIONS:
¹Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
²Department of Medicine, Temple University Hospital, Philadelphia, Pennsylvania

CITATION:
Rubin RN. A 67-year-old woman with a diabetic foot ulcer and significant anemia. Consultant. 2020;60(11):20-22. doi:10.25270/con.2020.11.00003

DISCLOSURES:
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad St, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

A 67-year-old woman is seen in the office a week after a long hospital admission for a variety of diabetes-related complications. She has had diabetes for 30 years, and her management has progressed from dietary changes to a variety of oral antidiabetes agents to, in recent years, injected insulin regimens.

About a month ago, she was admitted for further attempts to better manage her glycemic control and to address a nonhealing ulcer on her left heel. Evaluation revealed a deep ulceration of the left heel, with a probe appearing to touch bone. Plain radiographs and magnetic resonance imaging scans confirmed significant osteomyelitis of the left calcaneus. Interestingly and not surprisingly, there was minimal tenderness to the area, which was anesthetic to touch or pain on physical examination.

Two weeks ago, she underwent surgical debridement of the area. Culture results of a surgical specimen showed mixed aerobic and anaerobic organisms, and broad-spectrum antibiotics were initiated and are currently being continued at home with the assistance of a visiting nurse. During the hospital admission, consistent concerns demonstrated on blood studies were hyperglycemia, an elevated creatinine level of about 3 mg/dL, and persistent anemia, with a hemoglobin level initially measured at 8.0 g/dL and ranging between 7 and 8 g/dL, except for a briefly higher value after perioperative blood transfusion.

A battery of outpatient laboratory studies performed a day prior to the current clinic visit revealed the following values: blood glucose, 180 mg/dL; creatinine, 2.9 mg/dL; serum iron, 84 µg/dL; total iron binding capacity (TIBC), 200 µg/dL; serum ferritin, 84 ng/mL; and erythrocyte sedimentation rate (ESR), 92 mm/h. A complete blood cell count showed a hemoglobin level of 7.5 g/dL and a mean corpuscular volume of 79 µm³ with normal white blood cell (WBC) and platelet counts.

On physical examination, the patient was pale and ill-appearing but not in pain. Her major concern was fatigue essentially all the time, with moderate dyspnea with any exertion. Her blood pressure was 110/70 mm Hg, and her chest was essentially clear to auscultation. There was no lower extremity edema in her right foot, whereas the left foot was bandaged due to the presence of the surgically debrided heel ulcer.

Answer: C, administer an EPO preparation in pharmacologic dosage.

The presented patient has significant anemia, with a hemoglobin level of 7.5 g/dL, without obvious hematologic cause. Her ferritin and vitamin B₁₂ levels are normal, even elevated, and her haptoglobin level—the most sensitive routinely available hemolysis test—is also normal, excluding deficiencies in these as etiologies of her nontrivial anemia.

Of note, the entire clinical background is dominated by a serious and long-term infection, namely osteomyelitis in the bones of her feet. In fact, it is the osteomyelitis that is the true if “indirect” cause of her anemia, and this is a classic presentation of anemia of inflammation, previously and still often referred to as anemia of chronic disease. As will hopefully become apparent, the former nomenclature is now the appropriate one, given that we have learned so much about how the inflammatory process can create this anemia.

In overview, anemia of inflammation is a mild to moderately severe anemia (hemoglobin of 7-11 g/dL) that is associated with and caused by a serious, chronic systemic inflammatory process. The inflammatory process can be triggered by infections (eg, chronic osteomyelitis, tuberculosis (TB), HIV, empyema), autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus), or neoplasms (eg, Hodgkin disease, other lymphomas, lung and ovarian carcinoma).¹ In fact, our patient’s case illustrates that the trigger of the systemic inflammatory response—the heel osteomyelitis—often dominates the patient’s presentation and overall findings, with the anemia being an almost “incidental” finding, even when quite significant. The systemic inflammatory reaction then triggers biochemical changes that result in (1) decreased production of red blood cells (RBCs), (2) diminished bone marrow sensitivity to endogenous EPO, (3) bone marrow reprogramming away from RBC production and toward WBC production, and (4) a mild decrease in RBC survival.² A core mechanism of these changes is disorder of iron distribution in the body, demonstrable by low serum iron levels (hypoferremia) yet preserved iron stores, with often increased serum ferritin levels and bone marrow/ reticuloendothelial system (RES) iron staining such that there is plentiful iron in the body, but it is “trapped” and unavailable for RBC production.

In recent years, the pathophysiology and biochemistry of anemia of inflammation has been elegantly elucidated. Inflammation triggers recruitment and enhanced activity of inflammatory cells, which within hours start producing the inflammatory cytokines interleukins 1 and 6, interferon, and tumor necrosis factor, which are the effectors of the iron trapping, restricted erythropoiesis, and diminished RBC survival.^1,2

As previously alluded to, anemia of inflammation is basically a disorder of iron distribution with disordered iron homeostasis, and the keystone protein involved is the hepatically synthesized hepcidin. Hepcidin is the controller of the ferroportin “iron gates” found on the iron-absorbing gastrointestinal (GI) tract enterocytes, in macrophages, and in hepatocytes. When these gates are open, iron can be absorbed by the GI tract cells into plasma and released from RES storage by the macrophages and hepatocytes into plasma. Thus, the iron required for RBC production is plentiful, and erythropoiesis thrives. When these gates are closed, iron becomes unavailable despite there being adequate iron in the body. Hepcidin is the latchkey to all the ferroportin gates—when hepcidin is elevated, they are locked/latched shut, and the normal distribution processes described above stop.² Physiologically, when plasma and storage iron levels are low, the liver makes less hepcidin, which results in opening the ferroportin gates, with increased iron absorption resulting. When storage and plasma iron levels are high, there is more hepcidin synthesis, which closes the gates. Inflammation can and does override the normal physiology and causes greatly increased hepcidin synthesis, regardless of plasma/storage iron levels, with the major effector inflammatory cytokines being shown to directly do this. Serum hepcidin levels may increase 10-fold in sepsis situations.²

In fact, it is postulated that the iron trapping induced by the systemic inflammatory response is one of nature’s first antibiotics, so to speak—historical but elegant animal experiments and more current human observational studies have demonstrated significant antimicrobial effects, particularly on gram-negative organisms, resulting from the hypoferremia of circulating plasma iron induced by inflammation.^3,4 It seems that the organisms require generous amounts of iron more than we do.

The core principles of diagnosis of anemia of inflammation include (1) a mild to moderate anemia (hemoglobin of 7-11 g/dL); (2) the presence of a bona fide serious inflammation or infection that often dominates the clinical picture; (3) elevated inflammatory markers such as ESR and C-reactive protein (CRP) level, often dramatically so; (4) a low plasma iron level and TIBC and a high ferritin level.^1,2

Of note, bone marrow iron staining, once routinely used to exclude iron deficiency, is now rarely if ever indicated. And noninflammatory “chronic diseases” such as most cases of congestive heart failure, diabetes without infection, and such do not cause the anemia of inflammation process and changes. Thus, the author much favors the term “anemia of inflammation” rather than “anemia of chronic disease” for this entity.

Therapy for anemia of inflammation is to effectively treat the underlying cause as is practical— for example, antibiotics for chronic infections, corticosteroids and immune suppression for autoimmune disease, and antineoplastic regimens where effective for neoplasm. Response and improvement of anemia can be as rapid as 2 weeks in autoimmune causation but takes much longer (1-2 months) in chronic infections such as TB.¹ When this approach is not feasible, or when patients are significantly symptomatic from anemia, consider EPO compounds in generous dosages to overcome the cytokine-induced EPO resistance. However, EPO should be avoided in the presence of documented serious ongoing infection until the infection is under control and in solid tumors, since there is some evidence that such tumors may have EPO growth receptors on them.¹ A wide variety of novel agents directed at hepcidin and the effector cytokines themselves are in clinical trials and may be safe and effective adjuncts to therapy in anemia of inflammation situations.^5,6

In the case of the patient presented above, the findings were consistent with anemia of inflammation, and the ferritin level actually was far above normal, essentially excluding iron deficiency as a cause, making Answers A and D inappropriate here. The clinical facts of the case suggested chronic osteomyelitis more so than rheumatoid arthritis, making steroids (Answer B) a poor choice, and even more so in a person with diabetes. The best answer offered is Answer C, the use of an EPO preparation once antibiotics are in place, since chronic osteomyelitis can require weeks or more before resolution, and EPO can raise the hemoglobin level and provide symptomatic relief in the meantime.

PATIENT FOLLOW-UP

A variety of imaging studies essentially confirmed that the diabetic ulcer had involved the tarsal bones, and that chronic osteomyelitis was present. A course of long-term antibiotics was initiated, and within several days, the low-grade fevers had improved. EPO was initiated, and after 4 weeks, her hemoglobin level had risen to 9.8 g/dL, with marked improvement in energy, fatigue, and exertional dyspnea. The ESR was still elevated at 67 mm/h but was improving from the time of presentation. Ongoing monthly evaluations regarding the osteomyelitis and potential requirement for amputation were put in place.

TAKE-HOME MESSAGE

“Anemia of chronic disease” is now more properly termed “anemia of inflammation” and is a moderately severe anemia that occurs in association with serious infections and inflammatory and neoplastic conditions. The common and causative pathophysiologic mechanism is the initiation of a severe inflammatory reaction, which results in release of inflammatory cytokines (ie, interleukins 1 and 6, tumor necrosis factor, and interferon). From a hematologic standpoint, these cytokines most importantly cause a marked increase in hepcidin synthesis by the liver. Hepcidin is the key regulator of iron homeostasis, and increased hepcidin results in a profound disorder of iron distribution with hypoferremia due to diminished GI tract absorption and macrophage storage iron-trapping. Additional disturbed pathophysiology includes decreased RBC production in marrow and decreased RBC survival. All of these result in anemia. Characteristic findings are normocytic anemia evolving to mildly microcytic anemia, a low serum iron level and TIBC, but normal to increased ferritin levels. Most often but not universally, the causative illness (eg, autoimmune condition, severe infection, cancer) will dominate the clinical scenario. The optimal treatment is to resolve the causative disease when possible, after which the associated anemia resolves within weeks to months. In certain situations, such as when the anemia becomes severe and/or symptomatic, transfusions (temporary) or a course of EPO may be helpful.

REFERENCES:

1. Ganz T. Anemia of inflammation. N Engl J Med. 2019;381(12):1148-1157. doi:10.1056/NEJMra1804281
2. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783-788. doi:10.1182/blood-2003-03-0672
3. Stefanova D, Raychev A, Arezes J, et al. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood. 2017;130(3):245-257. doi:10.1182/blood-2017-03-772715
4. Stefanova D, Raychev A, Deville J, et al. Hepcidin protects against lethal Escherichia coli sepsis in mice inoculated with isolates from septic patients. Infect Immun. 2018;86(7):e00253-18. doi:10.1128/IAI.00253-18
5. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001-1010. doi:10.1056/NEJMoa1813599
6. Kaplan J. Roxadustat and anemia of chronic kidney disease. N Engl J Med. 2019;381(11):1070-1072. doi:10.1056/NEJMe1908978