Iron Deficiency Anemia (IDA)

Iron Metabolism - Foundation

• Iron is lost at only 1-2 mg/day via shed epithelial cells. There is no regulated excretory pathway.
• Daily dietary intake in the US: 10-20 mg; only ~20% of heme iron and 1-2% of nonheme iron is absorbed.
• Transferrin is the plasma carrier; normally ~one-third saturated, giving serum iron of ~120 µg/dL (males) and ~100 µg/dL (females). Total iron-binding capacity (TIBC) is normally 300-350 µg/dL.

Etiology and Causes

1. Dietary Lack

• Rare in high-resource countries where ~2/3 of dietary iron is heme (animal products).
• High-risk groups: infants (breast milk provides only 0.3 mg/L), the impoverished, older adults with restricted diets, and vegans (no heme iron).
• Bioavailability is enhanced by: ascorbic acid, citric acid, amino acids, sugars.
• Bioavailability is reduced by: tannins (tea), carbonates, oxalates, phosphates.

2. Impaired Absorption

• Sprue (celiac disease), fat malabsorption, chronic diarrhea.
• Post-gastrectomy: reduced gastric acidity + rapid transit through duodenum.

3. Increased Requirement

• Infants, children, adolescents (rapid growth).
• Premenopausal women, especially during pregnancy.
• Chronic kidney disease patients on hemodialysis + erythropoietin therapy.

4. Chronic Blood Loss (most common cause in developed countries)

• GI tract (men and postmenopausal women): ulcers, cancers, hookworm infection. In adult males and postmenopausal females, GI blood loss must be presumed until proven otherwise - overlooking this risks missing a GI cancer.
• Uterus: menstrual blood loss (~30 mg iron per cycle); heavy menorrhagia causes significantly more.
• Urinary tract, other sites.

Stages of Progression

1. Pre-latent - Storage depletion. Bone marrow iron stores fall; serum ferritin decreases. Hemoglobin and serum iron remain normal.
2. Latent - Transport iron depletion. Serum iron falls, TIBC rises, transferrin saturation drops. No anemia yet, but erythroid hyperplasia appears in bone marrow.
3. Frank IDA - Iron-deficient erythropoiesis. Anemia appears; microcytic, hypochromic red cells on smear. All iron indices are abnormal. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Morphology

• Mild to moderate increase in erythroid progenitors (compensatory erythroid hyperplasia).
• Absence of stainable iron in macrophages - the most diagnostically significant finding; confirmed with Prussian blue stain.

• Microcytosis (MCV < 80 fL)
• Hypochromia (MCHC < 30%): zone of central pallor enlarged beyond 1/3 of cell diameter; hemoglobin visible only at the rim.
• Poikilocytosis: characteristic "pencil cells" (small, elongated red cells).

Laboratory Diagnosis

Clinical Features

• Koilonychia - spoon-shaped nails
• Alopecia
• Atrophic glossitis - smooth, painful tongue
• Gastric mucosal atrophy
• Pica - craving for non-food substances (clay) or items like ice (pagophagia) or starch; linked to iron depletion in the CNS
• Intestinal malabsorption
• Plummer-Vinson syndrome (rare triad): microcytic hypochromic anemia + atrophic glossitis + esophageal webs

Workup and Investigation

• Colonoscopy first, then upper endoscopy + push enteroscopy if colonoscopy negative.
• Duodenal biopsy to screen for celiac disease.
• Test and treat H. pylori if present (reduces iron absorption; can cause microerosions).
• If all three endoscopic procedures are negative: capsule endoscopy.
• Only after negative GI workup: pursue non-GI causes.

Treatment

Oral Iron (first-line for most patients)

• Target: 200-400 mg of elemental iron/day (about 25% is absorbed = 50-100 mg incorporated into Hgb daily).
• Continue treatment for 3-6 months after correcting the underlying cause to replenish stores.
• Response monitoring: reticulocytosis appears in 5-7 days; hemoglobin and red cell indices normalize over weeks.
• GI side effects (nausea, cramps, constipation, diarrhea) are dose-related; can be mitigated by taking with meals or switching to a different ferrous salt. Black stools are expected.

Parenteral Iron (for specific indications)

• Cannot tolerate or absorb oral iron (malabsorption, post-gastrectomy, IBD involving proximal small bowel)
• Have very high ongoing iron requirements (hemodialysis + erythropoietin)
• Need rapid repletion

• Iron dextran (50 mg elemental iron/mL) - can be given as a total-dose infusion; risk of anaphylaxis requires a test dose first.
• Sodium ferric gluconate complex - lower risk of anaphylaxis vs. iron dextran; multiple infusions needed.
• Iron sucrose - low risk; commonly used in CKD patients.
• Ferric carboxymaltose (newer) - high-dose single infusion; favorable safety profile.

Differentiation from Anemia of Chronic Inflammation

• Anemia of chronic inflammation (ACI) results from IL-6-driven hepcidin upregulation, which sequesters iron in macrophages and restricts delivery to erythroid precursors.
• Unlike IDA, ACI shows elevated ferritin, elevated storage iron in marrow macrophages, and reduced TIBC.
• Red cells in ACI may be normocytic/normochromic or mildly microcytic/hypochromic.
• Treatment of ACI targets the underlying disease; erythropoietin helps some patients (especially those with cancer). - Robbins, Cotran & Kumar Pathologic Basis of Disease

Turner Syndrome - OBG Perspective

Incidence & Genetics

• Incidence: ~1 in 2000-2500 live female births (1 in 3000 by some sources). However, ~99% of 45,X fetuses abort spontaneously; it is the most common cytogenetic abnormality in spontaneous abortions, accounting for ~18% of all chromosomally abnormal abortions.
• Origin of error: In ~75-80% of cases, the X chromosome retained is maternal in origin - i.e., the paternal X or Y is missing (error in paternal gametogenesis/nondisjunction).

Karyotypes

Mosaicism may be detected in up to 75% of cases with sensitive molecular techniques - conventional cytogenetics detects only ~30%. Mosaicism with a higher proportion of 46,XX cells = milder phenotype; a very small number can even conceive spontaneously. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Pathogenesis of Gonadal Failure

• Fetal ovaries develop normally for the first 18 weeks of gestation.
• The second X chromosome is required to maintain oocytes - without it, accelerated apoptotic loss of oocytes occurs.
• By age 2 years, all oocytes are lost - "menopause occurs before menarche."
• Ovaries are replaced by streak gonads: white, fibrous, 2-3 cm structures in the broad ligament, devoid of follicles and oocytes.
• Result: no estrogen/progesterone production → elevated FSH and LH (hypergonadotropic hypogonadism). - Robbins, Cotran & Kumar; Campbell Walsh Urology

Clinical Features (OBG-Relevant)

In Infancy/Neonatal Period

• Cystic hygroma / nuchal lymphedema (cystic distension of lymphatic channels at the nape)
• Peripheral lymphedema of hands and feet at birth
• Webbed neck (residual from resolved lymphedema)
• Low posterior hairline

In Childhood/Adolescence

• Short stature (below 3rd percentile) - universal in non-mosaic Turner syndrome
• Failure of puberty in ~90% of affected females
• Primary amenorrhea (most common presentation in teens)
• Absent or minimal secondary sexual characteristics (no breast development, minimal pubic hair)
• Infantile genitalia
• Shield chest with widely spaced nipples
• Cubitus valgus (increased carrying angle of arms)
• Short 4th metacarpals; hypoplastic nails
• High-arched palate; multiple pigmented nevi; low-set ears; micrognathia; hypertelorism

Cardiovascular (most common cause of death in childhood)

• Coarctation of aorta (~30%) - 5% of females with coarctation have Turner syndrome
• Bicuspid aortic valve (most common structural defect)
• Aortic root dilation (30% of patients)
• 100-fold increased risk of aortic dissection

Other Systemic Features

• Horseshoe kidney (renal anomaly)
• Hashimoto thyroiditis (autoimmune hypothyroidism in up to 50%, especially isochromosome Xq)
• Glucose intolerance, insulin resistance, obesity, NAFLD - metabolic syndrome in a subset
• Sensorineural hearing loss
• Subtle deficits in visual-spatial processing (intelligence generally normal)
• Osteoporosis (from chronic estrogen deficiency)

OBG-Specific: Amenorrhea Classification

• Elevated FSH and LH (reflecting absent gonadal feedback)
• No endogenous estrogen production
• Streak ovaries on pelvic imaging

Prenatal Diagnosis

• Ultrasound findings: increased nuchal translucency, cystic hygroma, lymphedema, coarctation of aorta, renal anomalies
• Cell-free fetal DNA (cfDNA) screening
• Amniocentesis/CVS karyotyping: definitive

Important counseling point: ~90% of fetuses with incidentally detected 45,X/46,XX or 45,X/46,XY mosaicism prenatally will have a normal phenotype at birth ("ascertainment bias"). This has profound implications for prenatal genetic counseling. - Campbell Walsh Urology

Diagnosis

1. Karyotype (gold standard) - at least 25-30 cells analyzed; FISH for Y-material if needed
2. Hormonal profile: markedly elevated FSH and LH, low estradiol
3. Pelvic ultrasound: streak ovaries, infantile uterus
4. Echocardiography: bicuspid aortic valve, coarctation
5. Renal ultrasound: horseshoe kidney
6. Bone age radiograph
7. Thyroid function tests (TSH, anti-TPO antibodies)
8. Audiogram (sensorineural hearing loss)
9. Fasting glucose / HbA1c

Management

1. Growth Hormone (GH) Therapy

• Recombinant human GH at higher-than-replacement doses (~67 µg/kg/day)
• Often combined with oxandrolone (anabolic androgen) to improve final height
• Estrogen therapy is delayed to allow maximal GH-driven growth
• Mean adult height gain: ~5 cm greater compared to no treatment - Goodman & Gilman's; Creasy & Resnik's

2. Estrogen Replacement Therapy (HRT)

• Started at age ~11-12 years (or bone age ~11) once growth is maximized
• Goal: induce puberty, develop secondary sexual characteristics, protect bone health, prevent cardiovascular metabolic effects of estrogen deficiency
• Regimen:
  • Low-dose estradiol started first (to mimic early puberty)
  • Gradually increased over 2-3 years
  • Cyclic progesterone added once breakthrough bleeding occurs or after 1-2 years of estrogen - to protect endometrium
  • Continued until average age of menopause (~50 years)
• Estrogen therapy significantly improves bone mineral density; also associated with neurocognitive and behavioral benefits in girls with Turner syndrome

3. Y Chromosome Material - Gonadectomy

• Mandatory karyotyping to exclude Y-chromosomal material (PCR for SRY if standard karyotyping uncertain)
• 5-10% of Turner patients have Y-cell lines (full 45,X/46,XY or Y-chromosome fragments)
• Risk of gonadoblastoma (in-situ germ cell cancer) is ~12% in those with Y material
• Gonadoblastoma can undergo malignant transformation to dysgerminoma
• Gonadectomy is recommended in all patients with confirmed Y chromosomal material - Berek & Novak's; Campbell Walsh Urology

4. Fertility and Reproductive Options

• Extremely rare in classic 45,X (~1-2%)
• More common in mosaic patients (45,X/46,XX) - spontaneous puberty in up to 30%, but premature ovarian failure is common and oocyte reserve must be assessed urgently
• Pregnancy rate with hypergonadotropic amenorrhea approximately 6-8% (Goldman-Cecil)

• Oocyte/embryo cryopreservation is considered experimental but offered to selected mosaic patients with residual follicles
• Must be done before complete follicular depletion

• Oocyte donation (donor oocytes + partner sperm → IVF → embryo transfer) is the primary option
• The uterus and fallopian tubes are normal - successful pregnancy via donor oocytes is possible
• Endometrium is prepared with exogenous estrogen and progesterone

Women with Turner syndrome contemplating pregnancy have a markedly increased risk of aortic root rupture/aortic dissection during pregnancy (due to pre-existing aortic root dilation and bicuspid aortic valve). This is potentially fatal.

• Baseline aortic imaging (MRI/CT) is mandatory before pregnancy
• Aortic dissection risk is 100-fold higher than the general population
• Goldman-Cecil: "Whether women with gonadal dysgenesis should be offered pregnancy via donor oocytes is now the subject of debate because of markedly increased incidence of aortic rupture secondary to medial necrosis during pregnancy."
• All women with Turner syndrome must be counseled regarding cardiovascular risks before attempting pregnancy. - Goldman-Cecil Medicine; Berek & Novak's Gynecology

Multidisciplinary Surveillance (Lifelong)

Key OBG Summary Points