6  Iron Physiology, Iron Overload & the Porphyrias

Key Points
  • Hepcidin & ferroportin regulate iron homeostasis; HFE C282Y most common hereditary hemochromatosis, low penetrance
  • Cirrhosis & HCC irreversible; iron overload manifestations similar regardless of etiology
  • Screen high-risk groups (TSAT >45%, ferritin ↑, European ancestry, 1° relatives)
  • Phlebotomy = 1° treatment; target ferritin 50–100 ng/mL
  • Porphyrias = heme biosynthesis defects; AIP, VP, EPP distinct presentations (neurological, blistering, photosensitive)
  • Spot urine PBG = gold standard for acute porphyria; DNA testing confirms & enables family screening

6.1 Regulation of Iron Homeostasis

6.1.1 Body Iron Economy

  • Daily intake: 15–25 mg dietary iron; ~10% absorbed = 1–2 mg
  • Daily loss: ~1 mg GI epithelial cell shedding
  • Total body iron: 3–4 g (↓ in menstruating women)
    • Hemoglobin: ~1,800 mg (RBCs)
    • Liver: ~1,000 mg
    • Bone marrow: ~300 mg
    • Macrophages: ~600 mg
    • Other tissues: ~400 mg
  • Plasma iron: ~20–25 mg/dL bound to transferrin
  • Serum ferritin: steady-state marker of total body iron (caveat: acute phase reactant)

6.1.2 Intestinal Iron Absorption

  • Food iron: mostly Fe³⁺ (ferric); reduced to Fe²⁺ by ferric reductase
  • Absorption pathways:
    • Heme iron: unknown transporter
    • Nonheme iron: DMT1/NRAMP1 (apical entry)
  • Basolateral export: ferroportin (only iron exporter)
  • Hephaestin (HEPH): catalyzes Fe²⁺→Fe³⁺; facilitates transferrin loading
  • Bioavailability factors: phytates, polyphenols, ascorbate, meat, iron stores, inflammation

6.1.3 Cellular Iron Uptake, Storage & Recycling

  • Transferrin receptor (TFRC): binds holo-transferrin → endocytosis → iron release
  • Ferritin: 24-subunit cage; stores iron (insoluble, redox-inactive)
  • Erythrocyte recycling:
    • Macrophages clear senescent RBCs → heme → bilirubin + iron
    • ~20–25 mg iron recycled daily
  • BMP6 pathway:
    • Liver sinusoidal endothelium produces BMP6 (↑ iron loading)
    • Binds BMP receptor + co-receptors (HJV, BMPR2)
    • SMAD1/5/8 phosphorylation → hepcidin transcription

6.1.4 Hepcidin: Master Iron Regulator

Definition: peptide hormone (liver); suppresses iron absorption & storage release

Regulation: - ↑ by: iron stores, inflammation (IL-6 → STAT3), BMP6 - HFE-TFR1 sensing: holo-transferrin binds TFR1 → HFE displaced → stable HFE-BMP receptor → ↑ hepcidin - Tissue iron loading → BMP6 production → hepcidin ↑ - ↓ by: erythropoiesis (ERFE), hypoxia - Iron sensing: extracellular (TFR1, TFR2, HFE) & intracellular (FECH, mitochondrial iron)

Mechanism: - Binds ferroportin → internalization & degradation - ↓ intestinal iron absorption - ↓ macrophage iron release

Clinical Pearl: - Low hepcidin in HFE mutations → ↑ iron overload - High hepcidin in chronic inflammation → iron-restricted erythropoiesis (anemia of chronic disease)

Iron Homeostasis Proteins
Protein Location Function
Transferrin receptor (TFRC) Cell surface Cellular iron uptake; TFR1 on erythroid; TFR2 on hepatocytes
Ferritin Intracellular (all cells) Iron storage; reflects body iron stores
Ferroportin (FPN1) Basolateral intestine, macrophages, hepatocytes Only iron exporter; hepcidin → degradation
Hephaestin (HEPH) Basolateral intestinal membrane Fe²⁺→Fe³⁺ oxidation; facilitates transferrin loading
Hepcidin (HAMP) Hormone (liver) Master regulator: ↓ absorption & storage release
Hemojuvelin (HJV) Hepatocyte surface BMP co-receptor; integrates iron & erythropoietic signals
DMT1 Apical enterocyte, endosome Nonheme iron transporter (NRAMP1); H⁺-dependent
SMAD4/SMAD1/5 Intracellular Relay BMP6 signaling to hepcidin transcription

6.2 Hereditary Hemochromatosis & Iron Overload

6.2.1 HFE Hemochromatosis

Epidemiology & genetics: - Most common hereditary iron overload disorder - HFE C282Y: autosomal recessive founder allele - Prevalence: 1 in 10 Northern Europeans (10–15% heterozygotes) - Rare in other ethnicities - Compound heterozygotes (C282Y/H63D): occasional mild iron overload; H63D <10% penetrance - Clinical penetrance (C282Y/C282Y): 1–25% variable - Factors: gender, alcohol, environmental modifiers, genetic modifiers

Pathophysiology: - HFE point mutations → impaired hepcidin signaling - Relative hepcidin deficiency → ↑ intestinal absorption & ↑ storage release - Loss of iron-sensing via TFR1/HFE → inappropriately low hepcidin

Iron deposition: - Liver (hepatic fibrosis, cirrhosis, HCC risk ~10–16%) - Joints (arthritis, cartilage damage) - Pancreas (β-cell dysfunction, diabetes) - Cardiac conduction system (arrhythmias, cardiomyopathy) - Gonads (hypogonadism)

6.2.2 Other Hereditary Hemochromatosis Types

Causes of Iron Overload
Type Gene Mechanism Phenotype
HFE hemo HFE Relative hepcidin ↓ Adult-onset
TFR2 hemo TFR2 Relative hepcidin ↓ Varied ethnicity; adult
HJV hemo HJV Absolute hepcidin ↓ Juvenile (adolescence)
HAMP hemo HAMP Absolute hepcidin ↓ Juvenile
Ferroportin disease SLC40A1 missense Loss of function (macrophage type) Hepcidin-resistant; ↑ storage release
Ferroportin disease SLC40A1 mutations Gain of function (hepatic type) Hepcidin-resistant; ↑ hepatic uptake
African iron overload SLC40A1 ± diet ↑ TSAT & ferritin Hepatic & RES iron
Aceruloplasminemia CP ↓ Ferroxidase activity ↓ Macrophage/hepatocyte mobilization; neurological
Atransferrinemia TF ↓ Iron delivery ↑ GI absorption; ↓ erythropoiesis

6.2.3 Clinical Presentation & Diagnosis

Classic triad: - Hepatomegaly w/ skin bronzing (melanin deposition, not hemosiderin) - Arthritis: MCP joints; osteoarthritis-like, premature - Diabetes: 50% insulin-dependent; pancreatic damage

Other manifestations: - Fatigue, malaise, abdominal pain - Erectile dysfunction, gonadal failure

Risk factors for expression: male sex, alcohol, hepatitis coinfection, genetic modifiers

Biochemical diagnosis: - TSAT >45% & ferritin >300 ng/mL (men) or >200 ng/mL (women) = screening abnormalities - Liver iron quantification: - MRI (T2): noninvasive, specific - Biopsy: gold standard, rarely needed now - Molecular genotyping (HFE*): confirms diagnosis, enables family screening

Screening (controversial; recommend high-risk groups): - European ancestry - Fasting TSAT >45% - Ferritin ↑ (age & sex-adjusted) - 1° relatives of affected patients

6.2.4 Treatment of Iron Overload

Phlebotomy (1° treatment for HFE hemochromatosis): - Initiation: TSAT >45% & ferritin >300 (women: >200) ng/mL - Frequency: 1–2 week intervals; remove 500 mL (~250 mg iron) - Goal ferritin: 50–100 ng/mL - Hemoglobin target: >11 g/dL - Monitoring: TSAT & ferritin after 4–5 phlebotomies, then by trend - Maintenance: lifelong (typically 4–6/year) after goal achieved

Outcomes: - ↑ survival if initiated early - Cirrhosis & HCC risk persistent if established

Avoid: iron chelation in HFE hemochromatosis (ineffective)

Clinical Pearl: Cirrhosis & HCC

Cirrhosis & HCC risk irreversible; phlebotomy prevents progression but not reversal. Treat early.

6.2.5 Other Causes of Iron Overload

Congenital anemias (β-thalassemia, hereditary spherocytosis): - ↑ Erythropoiesis & ↑ iron absorption (despite anemia)

Myelodysplastic syndromes: - Transfusion-dependent ± ineffective erythropoiesis

Alcoholic cirrhosis w/ iron overload: - Alcohol impairs iron metabolism - Screen cirrhotic patients w/ ↑ ferritin/TSAT for HFE mutations

6.3 Cellular Consequences of Iron Overload

6.3.1 Oxidative Stress & Free Radicals

Iron-catalyzed ROS (Fenton reaction): - Fe²⁺ + H₂O₂ → Fe³⁺ + OH• + •OH - ↑ Free radicals → lipid peroxidation, protein damage, DNA damage

Mitochondrial effects: - ROS activate uncoupling proteins (UCP) - ↓ Bioenergetics → impaired erythroid development

6.3.2 Organ-Specific Iron Toxicity

  • Liver: hepatic fibrosis, cirrhosis, HCC (~10–16% risk)
    • Mechanisms: ROS, mitochondrial dysfunction
  • Joints: cartilage iron deposition → osteoarthritis-like arthritis (MCP characteristic)
  • Pancreas: β-cell dysfunction & fibrosis → diabetes
  • Cardiac: conduction system & myocardial iron → arrhythmias, cardiomyopathy
  • Gonadal: iron deposition → hypogonadism

6.4 The Porphyrias

6.4.1 Introduction & Heme Synthesis

Porphyrias = heme biosynthesis defects → porphyrin/precursor accumulation

Heme synthesis site: - ~85% bone marrow erythroid cells - ~15% liver

Pathway: glycine + succinyl-CoA → δ-ALA → … → heme (iron-protoporphyrin IX) - Rate-limiting step: glycine + succinyl-CoA → δ-aminolevulinic acid (δ-ALA) - Catalyzed by: ALAS2 (erythroid), ALAS1 (liver) - ALAS1: ↓ by heme (negative feedback) - ALAS2: constitutive; regulated by iron (IREs) & heme - Porphobilinogen (PBG): next intermediate (δ-ALA dehydratase → PBG) - Ferrochelatase (FECH): final step (iron + protoporphyrin IX → heme)

Control: - Hepatic pathway: heme feedback inhibition - Erythroid pathway: ↑ ALAS2 expression; different regulation (iron, IREs)

6.4.2 Classification

By organ origin: - Hepatic porphyrias: liver = primary site - Erythropoietic porphyrias: bone marrow erythroid cells = primary site

By manifestation: - Acute hepatic (neurological): AIP, VP, HCP - Cutaneous (blistering ± neurological): EPP, PCT - Overlap: VP & HCP have both neurological & cutaneous features

6.4.3 Acute Intermittent Porphyria (AIP)

Inheritance: autosomal dominant; 85% penetrance - ~90% of heterozygotes remain unaffected

Pathophysiology: - Porphobilinogen deaminase (PBGD) deficiency - ↓ Heme synthesis → ↑ ALAS1 induction - ↑ ALA & PBG accumulation → neurological toxicity (likely)

Acute attack features: - Cardinal symptom: abdominal pain (cramping, severe; mimics surgical abdomen but no peritonitis) - Neurological: - Tachycardia, hypertension, autonomic dysfunction - Peripheral neuropathy (motor >> sensory) - Confusion, seizures, psychosis - Respiratory compromise (phrenic nerve involvement) - GI: nausea, vomiting, constipation, ileus - Psychiatric: anxiety, depression, personality changes - Severity: mild to life-threatening respiratory failure; days to weeks duration

Triggers (avoid): - Porphyrinogenic drugs: barbiturates, sulfonamides, estrogen contraceptives, many anticonvulsants (except gabapentin, levetiracetam) - Other: fasting, infection, stress, menstrual cycle, alcohol, hepatic disease - Mechanism: CYP450 induction → ↓ heme → ↑ ALAS1 → porphyrin accumulation

Diagnosis: - Spot urine PBG (during acute attack) = gold standard - Marked ↑ (>5× ULN) - Must normalize to urinary creatinine (report as g creatinine) - Plasma & fecal porphyrins: normal or mildly ↑ (unlike VP/HCP) - DNA testing: confirms diagnosis, enables family screening

Acute attack management: - Hemin (heme arginate): 3–4 mg/kg IV (preferred) - Suppresses ALAS1 → ↓ precursor synthesis - ~70–80% efficacy; 1–2 infusions typical (more if severe) - Reconstitute w/ albumin per protocol - Supportive care: - IV dextrose (5–10%): carbohydrate loading suppresses ALAS1 - Volume repletion, opioid analgesia (morphine safe) - Electrolyte management (correct hyponatremia if present) - Beta-blockers: control tachycardia/hypertension - Benzodiazepines: seizure control (lorazepam safe) - Avoid: porphyrinogenic drugs, fasting, dehydration

Attack prevention: - Medication avoidance: maintain safe drug list - Safe: acetaminophen, NSAIDs (most), penicillin, benzodiazepines, opioids, propranolol, doxycycline - Avoid: barbiturates, sulfonamides, phenytoin, carbamazepine, phenobarbital, estrogen contraceptives - Lifestyle: regular meals w/ adequate carbohydrate, no alcohol/smoking, stress management - Medical alert bracelet essential - Genetic counseling: autosomal dominant; ~50% of relatives carry mutation - Prophylactic hemin: reserved for frequent attacks (>4/year) - Menstrual prophylaxis: some women benefit from perimenstrual infusions

Pregnancy: - HIGH RISK; ↑ exacerbations during pregnancy & postpartum - Coordinate w/ high-risk OB & hematology - Avoid porphyrinogenic drugs; prepare hemin on hand for postpartum attacks

6.4.4 Variegate Porphyria (VP)

Inheritance: autosomal dominant Enzyme defect: protoporphyrinogen oxidase deficiency

Clinical features: - Acute attacks: similar to AIP (abdominal pain, neurological symptoms) - Cutaneous: photosensitivity → blistering, fragile skin, hyperpigmentation, hypertrichosis (sun-exposed) - Distinction: acute + cutaneous (AIP = acute only; HCP = acute + mild cutaneous)

Diagnosis: - Plasma & fecal porphyrins: markedly ↑ - Protoporphyrin ↑ (plasma) - Coproporphyrin ↑ (feces)

Treatment: - Hemin for acute attacks (same as AIP) - Sun protection & porphyrinogenic drug avoidance

6.4.5 Hereditary Coproporphyria (HCP)

Inheritance: autosomal dominant Enzyme defect: coproporphyrinogen oxidase deficiency

Clinical features: - Acute attacks: neurological (similar to AIP) - Cutaneous: blistering (less severe than VP)

Diagnosis: - Fecal & urine coproporphyrins: markedly ↑ (distinctive pattern)

Treatment: - Hemin for acute attacks - Preventive strategies (similar to AIP)

6.4.6 Porphyria Cutanea Tarda (PCT)

Epidemiology: - Most common porphyria - Types: 1 = acquired, 2 = familial, 3 = sporadic familial

Pathophysiology: - Uroporphyrinogen decarboxylase (UROD) inhibition by: - Iron, alcohol, estrogens - Viruses (HCV, HBV, HIV) - ↑ Uroporphyrinogen & hepatic iron loading

Clinical features: - Cutaneous only (no neurological): photosensitivity → blistering (dorsum of hands) - Scarring & hypertrichosis: increased hair, thickened skin - Urine: reddish (excess porphyrins) - Liver dysfunction: cirrhosis & HCC risk if untreated

Diagnosis: - Urine uroporphyrins: markedly ↑ (distinctive pattern) - Plasma porphyrins: ↑ - Fecal porphyrins: normal or mildly ↑

Treatment: - Therapeutic phlebotomy: removes iron, suppresses UROD inhibition - Goal ferritin <50 ng/mL - Adjust frequency by ferritin trend - Hydroxychloroquine (low-dose): 200–250 mg daily - Mobilizes iron, improves photosensitivity - Avoid: alcohol, estrogens, iron supplements, hepatotoxic drugs - Monitoring: HCC surveillance (ultrasound + AFP) if cirrhosis develops

6.4.7 Erythropoietic Protoporphyria (EPP)

Pathophysiology: - Ferrochelatase (FECH) deficiency - Protoporphyrin IX accumulates (mitochondrial) → escapes → photosensitivity

Clinical features: - Severe photosensitivity: acute burning pain w/ sun exposure (unlike blistering in other porphyrias) - Erythema, edema, pain disproportionate to visible lesions - Skin findings: recurrent erythematous lesions, scarring, lichenification (if recurrent) - Hepatobiliary: iron accumulation → cirrhosis, cholestasis, liver failure risk - Hematologic: hemolytic anemia from RBC protoporphyrin toxicity - Teeth: erythrodontia (reddish teeth; UV fluorescence)

Diagnosis: - Protoporphyrin markedly ↑ (RBCs & feces) - Plasma porphyrins: normal or mildly ↑ - Characteristic fluorescence: UV light exposure

Treatment: - Sun avoidance & protective clothing; broad-spectrum sunscreen - β-Carotene: 120–180 mg daily - Antioxidant; reduces ROS-mediated photosensitivity - Variable efficacy - Bone marrow transplant: only curative option - Limited to severe cases w/ end-organ complications - Supportive: pain management, serial liver monitoring (ultrasound for HCC/cirrhosis)

6.4.8 Congenital Erythropoietic Porphyria (CEP)

Pathophysiology: - Uroporphyrinogen III synthase deficiency - Type I porphyrins accumulate → severe photosensitivity & hemolytic anemia

Clinical features: - Severe photosensitivity: early childhood onset; recurrent blistering → scarring, hypertrichosis - Hemolytic anemia: chronic hemolysis from RBC porphyrin toxicity; bone marrow hyperplasia - Erythrodontia: reddish-brown teeth (UV fluorescence) - Splenomegaly: from hemolysis - Disfigurement risk: photoscarring, bone resorption if untreated

Diagnosis: - Type I uroporphyrins: marked ↑ (urine & feces) - UV fluorescence: characteristic - Genetic testing: confirms

Treatment: - Strict sun/light protection: avoid sunlight; protective clothing & broad-spectrum sunscreen - Supportive care: folic acid (hemolytic anemia), pain management - Bone marrow transplant: only cure; considered for severe disease w/ progressive complications - Stem cell therapy: emerging option; may improve erythropoiesis & ↓ photosensitivity

6.5 Diagnosis of Acute Porphyria

Clinical suspicion essential: - Acute abdominal pain w/ autonomic symptoms - Neuropathy, neuropsychiatric manifestations - Blistering photosensitivity (type-dependent)

First-line testing (perform during acute attack): - Spot urine PBG + urine ALA (normalized to creatinine) = gold standard - Acute hepatic porphyrias: AIP, VP, HCP - PBG >5–10× ULN = confirmation - Critical: normalize to urinary creatinine (g creatinine) - If unavailable: plasma & fecal porphyrins (less sensitive)

Second-line testing (distinguish subtypes): - Plasma porphyrins & fecal porphyrins: pattern helps classify - AIP: PBG/ALA ↑; plasma/fecal normal - VP: plasma coproporphyrin ↑; fecal coproporphyrin ↑ - HCP: fecal coproporphyrin ↑ (distinctive pattern)

Confirmatory testing: - DNA sequencing: genes relevant to suspected porphyria - Acute hepatic: PBGD, PROTO, CPOX, FECH - Cutaneous: UROS, UROD - Enables family screening (autosomal dominant; variable penetrance)

Diagnostic algorithm: - Suspected acute porphyria → spot urine PBG, total porphyrins, creatinine (during symptoms) - Urine PBG substantially ↑ → acute porphyria confirmed (AIP, HCP, or VP); start hemin - Urine PBG normal; porphyrins ↑ → measure plasma & fecal to distinguish HCP vs. VP - Urine ALA ↑; plasma/fecal normal → ALAD porphyria (rare); confirm w/ genetic testing - Nonspecific or normal → acute porphyria excluded if PBG normal

Clinical Pearl: Timing of Testing

Urine PBG normalized between attacks. Test during acute symptoms; false reassurance from negative results during remission. Repeat if attack recurs.

6.6 Treatment of Acute Porphyrias

Hemin (heme arginate): 3–4 mg/kg IV - Suppresses ALAS1 expression → ↓ porphyrin precursor synthesis - ~70–80% efficacy (depends on severity & timing) - Typical: 1–2 infusions; more if severe/recurrent - Reconstitute w/ albumin per protocol; flush w/ saline

Supportive care: - IV dextrose (5–10%): suppresses ALAS1, ↓ precursor accumulation - IV fluid: volume repletion; correct hyponatremia if present (SIADH possible) - Analgesia: opioids safe (morphine, fentanyl); avoid porphyrinogenic NSAIDs - Beta-blockers: control tachycardia & hypertension - Seizure prophylaxis: benzodiazepines (lorazepam safe); avoid phenytoin & porphyrinogenic anticonvulsants - Avoid: porphyrinogenic drugs, fasting, dehydration, infection

Recurrent attack prevention: - Strict medication avoidance: consult porphyria registry (APF, EPN) before prescribing - Safe medications: acetaminophen, NSAIDs (most), penicillin, benzodiazepines, opioids, propranolol, doxycycline - Avoid: barbiturates, sulfonamides, phenytoin, carbamazepine, phenobarbital, estrogen contraceptives - Lifestyle: regular meals w/ adequate carbohydrate, no alcohol/smoking, stress management - Medical alert bracelet/wallet card essential

High-risk situations: - Prophylactic hemin: reserved for severe cases w/ frequent attacks (>4/year) - Menstrual prophylaxis: perimenstrual hemin infusions for exacerbation-prone women - Pregnancy: HIGH RISK - Coordinate w/ high-risk OB & hematology - Avoid porphyrinogenic drugs - Prepare hemin on hand for postpartum exacerbations - Postpartum attacks common

6.7 General Counseling & Management

Patient education: - Understand specific porphyria type, inheritance, triggers - Medical alert bracelet/wallet card (essential) - Know safe vs. unsafe medications

Medication management: - Maintain written safe/unsafe drug list - Consult registries before prescribing - American Porphyria Foundation: www.porphyriafoundation.com - European Porphyria Network: www.porphyria-europe.org

Genetic testing & family counseling: - Inheritance: autosomal dominant (acute & most cutaneous); autosomal recessive (CEP) - Family screening: offer testing to 1° relatives - Asymptomatic carriers: know diagnosis, avoid triggers

Multidisciplinary care: - Hematology, hepatology, dermatology, neurology (acute attacks) - Pain management, psychological support (chronic cutaneous porphyrias) - OB/GYN coordination (pregnancy planning)

Psychosocial support: - Chronic cutaneous porphyrias → disfigurement, isolation, depression - Acute porphyrias → unpredictable attacks, comorbidities, medication restrictions - Counseling, support groups, patient education essential