Definition/General
Introduction:
Iron overload represents excessive accumulation of iron in body tissues, including bone marrow
It results from increased iron absorption, repeated blood transfusions, or genetic defects in iron regulation
Bone marrow shows markedly increased stainable iron (Grade 3-4+) in macrophages
The condition can be primary (hereditary hemochromatosis) or secondary (transfusional, dietary).
Origin:
Primary iron overload results from genetic mutations affecting iron regulatory proteins (HFE, TFR2, HAMP, HJV)
Secondary iron overload from repeated transfusions, excessive dietary iron intake
Ineffective erythropoiesis (thalassemia, sideroblastic anemia) leads to increased iron absorption
Chronic liver disease impairs iron regulation
Parenteral iron administration bypasses regulatory mechanisms.
Classification:
Primary iron overload: Hereditary hemochromatosis (HFE-related, non-HFE types)
Secondary iron overload: Transfusional hemosiderosis, dietary hemosiderosis
Ineffective erythropoiesis-associated: Thalassemia intermedia/major, sideroblastic anemia
Chronic liver disease-associated: Alcohol-related, viral hepatitis
Porphyria cutanea tarda: Associated iron overload.
Epidemiology:
Hereditary hemochromatosis: 1:200-400 individuals of Northern European descent
HFE C282Y mutation: 10-15% carrier frequency in Caucasians
India: lower prevalence of HFE mutations, other genetic variants more common
Transfusional iron overload: common in thalassemia patients
Male predominance in manifest disease (testosterone effect).
Clinical Features
Presentation:
Asymptomatic in early stages
Hepatomegaly (most common early sign)
Skin hyperpigmentation (bronze diabetes)
Diabetes mellitus (pancreatic iron deposition)
Arthralgia especially metacarpophalangeal joints
Cardiomyopathy in severe cases.
Symptoms:
Fatigue and lethargy
Abdominal pain from hepatomegaly
Joint pain and stiffness
Loss of libido (hypogonadism)
Cardiac symptoms (dyspnea, palpitations)
Skin darkening (melanin and iron deposition)
Mood changes and depression.
Risk Factors:
Male sex (lack of menstrual iron loss)
Family history of hemochromatosis
Northern European ancestry (HFE mutations)
Chronic transfusion therapy (thalassemia, sickle cell disease)
Chronic liver disease (alcoholism, hepatitis C)
Dietary iron supplements (inappropriate use)
Cooking in iron utensils (prolonged exposure).
Screening:
Transferrin saturation (>45% suggests iron overload)
Serum ferritin (>300 ng/mL men, >200 ng/mL women)
HFE genetic testing (C282Y, H63D mutations)
Liver function tests (elevated ALT/AST)
Glucose tolerance test (diabetes screening)
Family screening for first-degree relatives.
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Gross Description
Appearance:
Bone marrow aspirate shows abundant dark brown granules in macrophages
Heavy iron deposition visible even in unstained preparations
Normocellular bone marrow in most cases
Hemosiderin-laden macrophages scattered throughout.
Characteristics:
Dense, coarse iron granules in reticuloendothelial cells
Extracellular iron deposits between cells
Normal hematopoietic cell morphology initially
Progressive fibrosis in severe, chronic cases.
Size Location:
Diffuse iron deposition throughout bone marrow spaces
Peritrabecular concentration of iron-laden macrophages
Vascular areas show prominent iron deposition
Interstitial iron deposits in advanced cases.
Multifocality:
Systemic iron overload: liver, heart, pancreas, endocrine glands
Hepatic cirrhosis in advanced hereditary hemochromatosis
Cardiac involvement: restrictive cardiomyopathy, arrhythmias
Pancreatic diabetes from islet cell damage
Hypogonadism from pituitary iron deposition.
Microscopic Description
Histological Features:
Massively increased hemosiderin in bone marrow macrophages (Grade 3-4+)
Coarse, dark brown granules filling macrophage cytoplasm
Extracellular iron deposits in severe cases
Normal trilineage hematopoiesis initially preserved
Progressive myelofibrosis in advanced cases.
Cellular Characteristics:
Iron-laden macrophages with abundant cytoplasm filled with hemosiderin
Prussian blue-positive granules throughout cytoplasm
Preserved cellular morphology of hematopoietic precursors
Increased sideroblasts (iron-containing erythroblasts)
Normal megakaryocyte morphology.
Architectural Patterns:
Preserved bone marrow architecture in early stages
Diffuse distribution of iron-laden macrophages
Perivascular iron accumulation
Reticulin fibrosis in chronic, severe cases
Trabecular bone changes in advanced disease.
Grading Criteria:
Iron stores grading: Grade 3+ (markedly increased), Grade 4+ (massive increase)
Prussian blue stain intensity: strong, diffuse positivity
Sideroblast percentage: often >40% (normal <20%)
Extracellular iron: present in grades 3-4+
Clinical correlation with serum ferritin levels.
Immunohistochemistry
Positive Markers:
Prussian blue stain: intense, diffuse positivity (Grade 3-4+)
Perls stain: abundant blue granules in macrophages
Ferritin immunostain: strongly positive in iron-laden cells
CD68: positive in iron-containing macrophages
Transferrin: may show altered distribution.
Negative Markers:
Congo red: negative (excludes amyloidosis)
PAS stain: may be positive but non-specific
Reticulin stain: normal to increased in advanced cases
Trichrome stain: may show fibrosis in chronic cases.
Diagnostic Utility:
Prussian blue stain: gold standard for iron assessment
Quantitative iron grading: essential for monitoring
Sideroblast enumeration: increased in iron overload
Liver biopsy correlation: assesses systemic iron load
Response to chelation therapy: serial monitoring.
Molecular Subtypes:
HFE-related hemochromatosis: C282Y/C282Y, C282Y/H63D genotypes
Non-HFE hemochromatosis: TFR2, HAMP, HJV mutations
Ferroportin disease: SLC40A1 mutations
Secondary iron overload: normal iron regulatory genes
Acquired causes: transfusional, dietary, liver disease.
Molecular/Genetic
Genetic Mutations:
HFE gene mutations: C282Y (most common), H63D, S65C
TFR2 mutations: transferrin receptor 2 deficiency
HAMP mutations: hepcidin deficiency
HJV mutations: hemojuvelin deficiency (juvenile hemochromatosis)
SLC40A1 mutations: ferroportin disease
CYBRD1 mutations: duodenal cytochrome B deficiency.
Molecular Markers:
Hepcidin levels: inappropriately low in primary iron overload
Soluble transferrin receptor: normal to low
Non-transferrin bound iron: elevated in severe overload
Labile plasma iron: increased, promotes oxidative damage
Ferritin glycosylation: altered patterns in iron overload.
Prognostic Significance:
Early diagnosis prevents organ damage
Liver fibrosis: irreversible in advanced cases
Cardiac iron overload: major cause of mortality
Diabetes mellitus: may be reversible with early treatment
Arthropathy: often irreversible despite iron removal
Hypogonadism: may improve with chelation.
Therapeutic Targets:
Phlebotomy: first-line treatment for hereditary hemochromatosis
Iron chelation therapy: deferoxamine, deferiprone, deferasirox
Dietary modifications: avoid iron supplements, vitamin C, alcohol
Treatment of complications: diabetes, heart failure, arthritis
Family screening and genetic counseling
Regular monitoring: ferritin, transferrin saturation.
Differential Diagnosis
Similar Entities:
Hemosiderosis (tissue iron without organ damage)
Sideroblastic anemia (ring sideroblasts, different pattern)
Chronic transfusion therapy (history of transfusions)
Chronic liver disease (alcohol, hepatitis C)
Porphyria cutanea tarda (associated iron accumulation)
Dysmetabolic iron overload (metabolic syndrome).
Distinguishing Features:
Hereditary hemochromatosis: genetic mutations, early onset, family history
Secondary iron overload: known cause (transfusions, liver disease)
Sideroblastic anemia: ring sideroblasts, anemia present
Hemosiderosis: tissue iron without clinical consequences
Chronic liver disease: moderate iron increase, liver dysfunction prominent.
Diagnostic Challenges:
Early vs
advanced disease: clinical manifestations may be subtle
Primary vs
secondary: requires genetic testing and history
Compound heterozygotes: variable penetrance and expression
Iron overload in liver disease: determining primary vs
secondary cause
Monitoring chelation therapy: assessing treatment response.
Rare Variants:
Juvenile hemochromatosis: HJV mutations, early cardiac involvement
Ferroportin disease: dominant inheritance, macrophage iron loading
Transferrin deficiency: severe anemia with iron overload
Aceruloplasminemia: neurodegeneration with iron accumulation
African iron overload: dietary and genetic factors.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Cellularity
Bone marrow cellularity: [percentage]% with M:E ratio of [ratio]
Iron Stain (Prussian Blue)
Iron stores: Grade [3-4+], markedly to massively increased. Sideroblasts: [percentage]%
Iron Distribution
Heavy iron deposition in [macrophages/extracellular spaces] with [diffuse/focal] pattern
Hematopoiesis
Trilineage hematopoiesis with [normal/abnormal] maturation and morphology
Reticulin Fibrosis
Reticulin fibrosis: Grade [0-4], [present/absent] in this case
Final Diagnosis
Bone marrow with iron overload (Grade [3-4+] iron stores)
Recommendations
Correlate with serum ferritin and transferrin saturation. Consider genetic testing for hereditary hemochromatosis