Anemia Due to Endocrine Disorders

Article written and reviewed by Dr Luca Moretti

Anemia due to endocrine disorders is a frequent hematologic manifestation of numerous chronic hormonal disorders (see general overview). Although it is often a mild, hypoproliferative anemia associated with endocrine dysfunction, endocrine anemia is characterized by distinctive pathogenetic mechanisms involving regulation of red blood cell production, iron metabolism and survival of circulating red blood cells. Recognizing this form of anemia is essential because correction of the underlying hormonal abnormality may lead to complete resolution of the anemic condition.

Epidemiology and clinical settings

Endocrine disorders are an underestimated but relatively frequent underlying cause of chronic anemia in both adults and children. Prevalence and phenotype vary according to the hormone involved, the duration of the deficiency, the patient's age and the presence of other associated conditions. Endocrine disorders most often associated with anemia include:

• Hypothyroidism (primary or central): anemia is a frequent association, but prevalence varies widely among populations and according to the severity and duration of thyroid dysfunction and concomitant deficiencies; the phenotype is often normocytic, with possible microcytic or macrocytic forms when other causes coexist.
• Chronic adrenal insufficiency: cortisol deficiency may result in hypoproliferative normocytic anemia, which often goes unrecognized.
• Hypopituitarism: combined deficiency of pituitary hormones (GH, ACTH, TSH, gonadotropins) produces a complex and variable anemic picture.
• Diabetes mellitus: anemia occurs mainly in advanced forms, in the presence of chronic nephropathy and systemic inflammation.
• Hypogonadism, especially in men: androgen deficiency reduces erythropoietic stimulation.

In pediatric settings and in older adults, manifestations may be particularly subtle and require targeted investigations.

Pathophysiology and molecular mechanisms

Anemia due to endocrine disorders involves several mechanisms, often coexisting and interacting:

• Reduced erythropoietin (EPO) synthesis: many hormones directly or indirectly regulate renal EPO production. Hypothyroidism, hypopituitarism and hypogonadism reduce erythropoietic stimulation, producing a hypoproliferative pattern.
• Altered iron metabolism: iron deficiency, inflammation, kidney disease or blood loss may coexist with the endocrine disorder and alter ferritin and transferrin saturation; there is no demonstrated general mechanism of reduced iron absorption caused by deficiency of thyroid hormones or glucocorticoids.
• Associated mechanisms: concomitant kidney disease, inflammation, hemolysis or nutritional deficiencies may reduce red blood cell survival, but they do not represent a uniform mechanism of hypothyroidism or adrenal insufficiency.
• Influence on the bone marrow microenvironment: GH, androgens and other hormones promote erythroid progenitor proliferation, globin synthesis and cell differentiation. Their deficiency reduces proliferative and differentiative support to the erythroid lineage.
• Associated complications: in patients with diabetes, nephropathy, chronic inflammation and vascular abnormalities aggravate the red blood cell deficit, with features overlapping those of anemia in chronic kidney disease.

In autoimmune endocrine disorders, the anemic picture may be aggravated by systemic inflammatory processes and polyautoimmunity (Schmidt syndrome, autoimmune polyglandular syndromes type I and II).

Clinical characteristics and phenotypic variability

Anemia due to endocrine disorders tends to develop slowly, with symptoms that are often insidious and subtle and attributed to the underlying disease. Typical symptoms are:

• Asthenia, drowsiness, easy fatigability
• Pallor of the skin and mucous membranes, reduced ability to concentrate
• Sometimes exertional dyspnea, palpitations, irritability
• In severe cases, signs of tissue hypoxia and neurocognitive changes

In hypothyroidism, anemia may be associated with myxedema, bradycardia, skin changes and dyslipidemia, whereas in hypogonadism asthenia, sarcopenia and osteoporosis are typical. In adrenal insufficiency, hyponatremia, hypotension and adrenal crises may coexist.
In children and adolescents, the underlying endocrine disease may cause delayed growth and pubertal abnormalities; anemia may contribute to asthenia and reduced school performance.

Diagnosis and differential investigations

Endocrine anemia must be suspected in the presence of:

• A hypoproliferative anemic picture, normocytic or mildly microcytic, not explained by nutritional deficiencies or chronic losses
• Clinical and/or laboratory signs of endocrine dysfunction (TSH, FT4, cortisol, ACTH, FSH/LH, testosterone/estradiol, IGF-1 and, when indicated, dynamic testing of the GH axis, parathyroid hormone, blood glucose)
• Association with other endocrine or autoimmune manifestations

Key tests:

• Complete blood count, reticulocytes, iron indices (ferritin, serum iron, transferrin, sTfR), inflammatory markers (ESR, CRP)
• Assessment of thyroid, adrenocortical, gonadal, pituitary, parathyroid and glycemic function
• Plasma EPO measurement, rarely used in routine clinical practice
• In selected cases, endocrine imaging (thyroid/adrenal ultrasound, pituitary MRI, bone densitometry, etc.)

The differential diagnosis must exclude pure iron deficiency anemia, systemic chronic diseases such as malignancy, kidney disease and chronic inflammation, myelodysplastic syndromes and hemolytic forms.

Principles of treatment and specialist management

Treatment of anemia due to endocrine disorders is based on three pillars:

• Correction of the underlying hormonal abnormality: targeted replacement therapy, including thyroxine in hypothyroidism, hydrocortisone in adrenal insufficiency and fludrocortisone only in primary forms with mineralocorticoid deficiency, testosterone in male hypogonadism when clinically indicated, and GH in documented GH deficiency, frequently leads to progressive normalization of the hematologic picture.
• Iron and vitamin supplementation: indicated only in the presence of a documented deficiency; in the absence of absolute or functional iron deficiency and documented vitamin deficiencies, supplementation is not indicated.
• Management of associated conditions: control of inflammation, kidney disease and documented nutritional deficiencies, with assessment of individual cardiovascular risk.

Recombinant erythropoietin is not indicated for isolated endocrine anemia and is reserved for the presence of a distinct clinical indication, such as coexisting anemia in chronic kidney disease.

Prognosis, complications and research perspectives

The prognosis of anemia due to endocrine disorders is generally favorable, and early, adequate correction of hormonal dysfunction may lead to partial or complete recovery from anemia. Diagnostic delay, persistence of multiple deficiencies or the presence of other comorbidities may nevertheless expose the patient to:

• Worsening physical and cognitive performance and quality of life
• Delayed growth and pubertal milestones in children and adolescents

New research perspectives concern pharmacologic modulation of hormonal axes, early identification of risk biomarkers and personalization of replacement therapy in vulnerable subgroups such as children, older adults and patients with multiple comorbidities.

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