Introduction

Classifying anemia as regenerative or nonregenerative is useful because it provides information about the mechanism of disease.

The CBC hallmark of nonregenerative anemias is absence of reticulocytosis - the lack of an appropriate compensatory response to anemia - which usually indicates that erythropoiesis is being inhibited in some way. Nonregenerative anemias typically develop slowly because erythrocytes already in circulation have a long life span.

There are many potential underlying causes of nonregenerative anemia, as discussed further below.

Mechanisms of Disease

Anemia of Inflammation

The most common form of nonregenerative anemia is anemia of inflammation (aka anemia of chronic disease).

It has long been recognized that patients with infectious or inflammatory disease often develop anemia, and that this phenomenon is associated with functional iron deficiency. Of course, iron is an essential constituent of hemoglobin. Anemia of inflammation may be a side-effect of an evolutionary immunologic adaptation to limit microbial access to iron.

In contrast to absolute iron deficiency anemia (see below), anemia of inflammation is usually normocytic and normochromic.

Recent years have seen breakthroughs in the understanding of molecular mechanisms of anemia of inflammation, including new insights into the relationship between innate immunity and iron regulation. Many of the new insights involve the hormone and acute phase protein, hepcidin, now generally accepted as the key mediator of anemia of inflammation. Some facts about hepcidin:

 Synthesized mainly in the liver.

 First recognized for its direct antimicrobial effects.

 Bioactive form is a highly conserved 25-amino acid peptide.

 Expression increases with inflammation or iron overload, and decreases with anemia or hypoxia.

Hepcidin exerts its effects by binding to the iron efflux protein, ferroportin, and inducing its internalization and degradation. This interaction inhibits absorption of dietary iron and inhibits release of storage iron, thus resulting functional iron deficiency.

Inflammation can also contribute to anemia via other mechanisms. For example, inflammation has been shown to cause decreased erythrocyte survival in some species; some studies have implicated inflammatory cytokines as inhibitors of erythropoiesis via direct toxic effects on erythroid precursors, decreased expression of hematopoietic factors, or decreased expression of erythropoitin receptors; and some investigators have suggested that oxidants produced by activated neutrophils cause altered erythrocyte surface antigenicity, in turn lead to accelerated immunological destruction of erythrocytes.

Absolute Iron Deficiency

True iron deficiency (aka absolute iron deficiency) has long been recognized as a cause of anemia. Iron deficiency in domestic animals occurs most commonly because of chronic external hemorrhage, and thus loss of iron-rich hemoglobin.

Iron deficiency anemia can be regenerative or nonregenerative. The classic hematologic picture with iron deficiency is microcytic (subnormal MCV), hypochromic (subnormal MCHC) anemia. Microcytosis typically develops before hypochromasia.

Other Mechanisms of Nonregenerative Anemia

Chronic Renal Failure

Nonregenerative anemia is an expected complication of chronic renal failure (CRF), and is recognized to contribute to overall morbidity. Decreased production of erythropoietin (Epo) is generally accepted to be the major cause of anemia in patients with CRF is. However, impaired renal function can cause decreased urinary excretion of hepcidin, and the role of this mechanism as a cause of anemia is an area of active study. Other contributing factors recognized in people include inflammation, hemorrhage, iron deficiency, decreased RBC survival due to metabolic insult or mechanical damage, and the anti-proliferative effects of uremic toxins.

Neoplasia

Recognized causes of anemia in animals with cancer include both disease- and treatment-related factors. The deleterious effects of anemia on quality of life in veterinary patients with cancer have received little attention and needs further investigation. Disease-related mechanisms of anemia include hemorrhage, hemolysis, and decreased or ineffective erythropoiesis.

Endocrinopathies

Some endocrine diseases that are well characterized in veterinary medicine - including hypothyroidism, diabetes mellitus, and hypoadrenocorticism - may be associated with anemia. The mechanisms are probably multifactorial, but anemia develops primarily as a result of decreased erythropoiesis.

Nonregenerative IMHA & Other Forms of Ineffective Erythropoiesis

Some forms of IMHA - diagnosed by excluding other conditions and by response to immunosuppressive therapy - are nonregenerative. Often, nonregenerative IMHA is associated with ineffective hematopoiesis, a condition in which blood cells are being produced at normal or increased levels, but are destroyed before they enter the circulation. Another cause of ineffective hematopoiesis is myelodysplastic syndrome, a neoplastic condition characterized by bone marrow hyperplasia, peripheral cytopenias, and abnormal blood cell morphology.

Liver Disease

Anemia secondary to liver disease is most likely in cases of chronic liver disease or portosystemic shunts. Proposed mechanisms include anemia of inflammation, abnormal nutrient metabolism, and defective iron handling. PSS dogs are often microcytic, even if they are not anemic.

Infection of Erythropoietic Cells

Some viruses - notably FeLV and equine infectious anemia virus - can infect hematopoietic precursors. Multiple mechanisms probably contribute to anemia in affected animals, including direct suppression of early-stage erythropoietic cells, anemia inflammation, and immune-mediated hemolysis.

Toxic Insult to the Bone Marrow

Toxic injury to the bone marrow is likely to result in pancytopenia. Examples include anti-cancer therapy and hyperestrogenism.

Space-Occupying Disease in the Bone Marrow

Replacement of hematopoietic tissue by abnormal tissue (myelophthisis) is likely to result in pancytopenia. Examples include fibrosis and neoplasia.

Other Rare Conditions

 Other nutritional deficiencies - such as copper deficiency, folate deficiency, or cobalamin deficiency.

 Inherited conditions - such as congenital dyserythropoiesis in English springer spaniels and polled Herefords.

References

1.  Fry MM. Anemia of inflammatory, neoplastic, renal, and endocrine diseases. In: Weiss DJ, Wardrop KJ, eds. Schalm's Veterinary Hematology. 6th ed. Ames: Wiley Blackwell; 2010:246–250.

2.  Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425–33.

3.  Grimes CN, Giori L, Fry MM. Role of hepcidin in iron metabolism and potential clinical applications. Vet Clin North Am Sm Anim Pract. 2012;42(1):85–96.