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cardio.acute-hf.hemochromatosis-iron-overload.v1

Acute HF — hemochromatosis / iron-overload cardiomyopathy

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Phase E variant of cardio.acute-hf.core.v1 — iron-overload cardiomyopathy (HFE C282Y homozygote ~80% of HH or chronic transfusional) decompensating to acute HF. Sister to cardio.acute-hf.amyloidosis.v1 infiltrative dossier (both restrictive then dilated phenotypes; different mechanisms drive different treatments). Pathophysiology: iron deposition in cardiomyocytes (via NTBI uptake through L-type calcium channels) → catalyzes Fenton-reaction free radical generation → mitochondrial dysfunction + apoptosis → restrictive then dilated cardiomyopathy + conduction system involvement (AV block, sick sinus). Cardiac iron deposition lags hepatic iron by years. Diagnostic anchors: ferritin >1000 ng/mL + transferrin saturation >50% + HFE genotyping (C282Y, H63D, S65C) for HH confirmation OR transfusion history (20+ lifetime units pushes iron load past threshold) for transfusional. Cardiac MRI T2* GOLD STANDARD per Anderson PMID 11713075: T2* <20 ms = iron loading; <10 ms severe; <6 ms imminent HF risk. Liver MRI R2 (FerriScan) for hepatic iron concentration (>7 mg/g significant; >15 mg/g severe). Treatment: standard ADHF (IV loop diuretic per DOSE PMID 21366472) + GDMT 4-pillar (ARNI/ACEi + BB + MRA + SGLT2i) standard for HFrEF. PHLEBOTOMY for HH (1 unit q1-2wk until ferritin <50; maintenance 2-6/year per EASL 2022 PMID 36064151) — NOT for transfusion-dependent. IRON CHELATION for transfusion-dependent OR HH-intolerant: deferasirox 21 mg/kg PO daily first-line per EHA-EBMT 2022 PMID 35139194 (excellent cardiac penetration; monitor eGFR + LFT + CBC); deferoxamine 40-60 mg/kg/day SC infusion for severe; deferiprone 75-100 mg/kg/day PO TID for cardiac iron clearance per Pennell PMID 16735649 (agranulocytosis risk — weekly CBC); combination deferiprone + deferoxamine for severe cardiac iron (T2* <6 ms) per Tanner PMID 17389272 TIC trials. Multidisciplinary management: cardiology (ADHF + GDMT + ICD) + hematology (chelation strategy) + hepatology (cirrhosis + HCC surveillance per AASLD 2011) + endocrinology (DM, hypogonadism, hypothyroidism — common iron-deposition complications). Family genotype screening (siblings + first-degree relatives per EASL 2022). AVOID: iron supplements (check med list), vitamin C megadoses, raw shellfish (Vibrio vulnificus), alcohol if cirrhosis, NSAIDs if cirrhosis. Manifest pointer reuses cardio.acute-hf.core.v1 manifest. Design-brief pointer reuses parent (iron-overload specifics documented inline). Status INTEGRATED until terminology + RxNav-validated drug codes are reconciled. Authored 2026-05-15 by shard-06-cardio-acute as Phase E wave 23 variant.

Entry points (6)

  • lab_abnormality
    Ferritin >1000 ng/mL + transferrin saturation >50% + new HF symptoms (dyspnea, edema, fatigue) → suspect iron-overload cardiomyopathy
    ferritin_above_1000_with_transferrin_sat_above_50_with_hf
  • history
    Known HFE C282Y homozygote or compound heterozygote with new HF symptoms — likely cardiac iron deposition; cardiac MRI T2* needed
    known_hereditary_hemochromatosis_with_new_hf
  • history
    Chronic transfusion-dependent patient (β-thalassemia major, sickle cell, MDS, aplastic anemia) with 20+ lifetime units + new HF — transfusional iron-overload cardiomyopathy
    chronic_transfusion_dependence_with_new_hf
  • imaging
    Cardiac MRI T2* <20 ms (especially <10 ms severe; <6 ms imminent HF risk) per Anderson PMID 11713075 + new LV dysfunction → confirmed cardiac iron-overload cardiomyopathy
    cardiac_mri_t2star_below_20ms_with_lv_dysfunction
  • symptom
    Constellation suggestive of HH — bronze skin pigmentation + new-onset DM + arthralgia (especially MCP/PIP joints) + hepatomegaly + hypogonadism + new HF (classic late-stage HH presentation)
    iron_deposition_constellation_skin_dm_arthralgia_with_hf
  • lab_abnormality
    Unexplained chronic LFT elevation + ferritin >1000 + transferrin sat >50% + new HF — HH workup (HFE genotyping + liver MRI R2 + cardiac MRI T2*)
    unexplained_lft_elevation_with_high_ferritin_and_hf

Required inputs (16)

  • agerequired
    demographic • used at CONTEXT
    HH typically presents 30-50 in men (faster iron accumulation absent menstrual losses); 50-70 in women (post-menopause); transfusional iron-overload across ages depending on transfusion duration
  • sex
    demographic • used at CONTEXT
    Men present earlier with HH (~10-20 years younger than women due to absent menstrual iron losses); women often spared until post-menopause; transfusional iron-overload sex-independent
  • ancestry_northern_european
    demographic • used at CONTEXT
    HFE C282Y homozygote prevalence ~1:200-1:400 in Northern European descent (highest in Irish, Scottish); much lower in non-European populations; non-HFE hemochromatosis can occur in any population
  • family_history_of_hh_or_unexplained_cirrhosis_or_dm
    history • used at CONTEXT
    HH is autosomal recessive — first-degree relatives have 25% homozygote risk; family history of unexplained cirrhosis, DM, arthropathy, or HF should trigger HH workup
  • transfusion_history_for_lifetime_units_and_underlying_diseaserequired
    history • used at CONTEXT
    Transfusion-dependent disorders (β-thalassemia major, sickle cell, MDS, aplastic anemia, hereditary spherocytosis); 20+ lifetime units pushes iron load past threshold; lifetime burden quantified in mg iron (~200-250 mg/unit pRBC)
  • sbp_dbp_for_perfusion_and_shock_screenrequired
    vital • used at RED_FLAGS
    SBP <90 + lactate ≥2 + cool extremities = SCAI C+ shock → ROUTE to shock dossier; this engine handles SCAI A-B (warm + wet) only
  • serum_ferritinrequired
    lab • used at INITIAL_WORKUP
    Ferritin >1000 ng/mL is threshold for significant iron overload (per EASL 2022 + AASLD 2011); >2500 portends end-organ damage; note ferritin is acute-phase reactant — interpret with CRP
  • transferrin_saturationrequired
    lab • used at INITIAL_WORKUP
    Transferrin saturation >45% (women) or >50% (men) is screening threshold; >50% with elevated ferritin = HH likely; >70% in advanced disease
  • hfe_genotyping_c282y_h63drequired
    lab • used at BRANCHING_WORKUP
    C282Y homozygote (pY282Y) is most common HH genotype (~80% of HH); compound heterozygote (C282Y/H63D) lower penetrance; H63D homozygote rarely causes clinically significant overload; non-HFE HH if iron overload + negative HFE genotype
  • cbc_with_diffrequired
    lab • used at INITIAL_WORKUP
    Anemia screen (transfusion-dependent disorders); cytopenias may limit chelation tolerance; baseline before chelation initiation (deferiprone agranulocytosis monitoring)
  • cmp_with_lft_for_cirrhosis_and_egfrrequired
    lab • used at INITIAL_WORKUP
    LFT elevation suggests hepatic iron deposition + cirrhosis; eGFR for diuretic + chelator dosing (deferasirox renal monitoring); albumin for nutritional + cirrhosis assessment
  • bnp_or_nt_probnprequired
    lab • used at INITIAL_WORKUP
    Marker of HF severity; trend during admission for response to diuresis; NT-proBNP often markedly elevated in iron-overload cardiomyopathy
  • cardiac_mri_t2star_for_iron_quantificationrequired
    imaging • used at BRANCHING_WORKUP
    GOLD STANDARD for cardiac iron quantification per Anderson PMID 11713075 + Pennell PMID 16735649; T2* <20 ms = iron loading; <10 ms = severe; <6 ms = imminent HF risk; quantitatively guides chelation intensity
  • liver_mri_r2_ferriscan_for_lic
    imaging • used at BRANCHING_WORKUP
    Liver iron concentration (LIC) by MRI R2 (FerriScan); >7 mg/g dry weight = significant overload; >15 mg/g = severe; complements cardiac T2* for total body iron burden assessment
  • echocardiogram_for_lv_rv_functionrequired
    imaging • used at INITIAL_WORKUP
    Restrictive then dilated phenotype; LV/RV dysfunction; conduction system involvement (AV block); pericardial effusion screen; serial echo for chelation response
  • ecg_for_arrhythmia_av_block_low_voltagerequired
    imaging • used at INITIAL_WORKUP
    Conduction system iron deposition (AV block, sick sinus, intraventricular block); arrhythmia (AF common); low voltage in restrictive phase; serial ECG q3mo for conduction surveillance

12-phase flow (10)

  1. 1FRAME
    Cardiac iron-overload cardiomyopathy decompensation: HH (HFE C282Y homozygote ~80%) or transfusional (chronic transfusion-dependent); restrictive then dilated phenotype; conduction system involvement; cardiac MRI T2* gold standard; phlebotomy (HH) or chelation (transfusion-dependent or HH-intolerant); GDMT 4-pillar standard
    inputs: echocardiogram_for_lv_rv_function
    advance: iron-overload cardiomyopathy framed
  2. 2ENTRY
    Recognize ADHF in iron-overload context; bedside echo for LV function; ECG; ferritin + transferrin saturation screening; SCAI shock screen (route to shock dossier if C+); admit cardiology / telemetry
    inputs: sbp_dbp_for_perfusion_and_shock_screen, echocardiogram_for_lv_rv_function
    advance: shock excluded + admission decided
  3. 3CONTEXT
    Family HH history; ancestry; transfusion history (lifetime units + indication); endocrinopathy history (DM, hypogonadism, hypothyroidism — pituitary iron deposition); skin pigmentation; arthropathy; hepatology history (cirrhosis, HCC); medication review (iron supplements, vit C, NSAIDs)
    inputs: age, family_history_of_hh_or_unexplained_cirrhosis_or_dm, transfusion_history_for_lifetime_units_and_underlying_disease
    advance: context complete
  4. 4RED_FLAGS
    Progression to SCAI C+ shock (route to shock dossier); high-grade AV block requiring temporary pacing (iron-deposition conduction disease); sustained VT/VF requiring ACLS + ICD eval; severe iron overload with cardiac T2* <6 ms (imminent HF risk requires aggressive combination chelation); cirrhosis with hepatorenal syndrome; coexisting endocrinopathies (DKA from new-onset DM, adrenal insufficiency)
    inputs: sbp_dbp_for_perfusion_and_shock_screen, ecg_for_arrhythmia_av_block_low_voltage
    actions: acute_pulm_edema, cardiogenic_shock
    advance: red flags screened
  5. 5INITIAL_WORKUP
    CBC with diff + CMP with LFT + ferritin + transferrin saturation + HbA1c (DM screen) + thyroid function + LH/FSH/testosterone (hypogonadism screen) + troponin + BNP/NT-proBNP + lactate + ECG + CXR + bedside echo (LV/RV function, restrictive vs dilated, conduction)
    inputs: serum_ferritin, transferrin_saturation, cbc_with_diff, cmp_with_lft_for_cirrhosis_and_egfr, bnp_or_nt_probnp, echocardiogram_for_lv_rv_function, ecg_for_arrhythmia_av_block_low_voltage
    actions: acute_pulm_edema, panel.cardiac, panel.renal
    advance: workup documented
  6. 6BRANCHING_WORKUP
    HFE genotyping (C282Y, H63D, S65C) for HH confirmation; non-HFE genes if iron overload + negative HFE; cardiac MRI T2* for cardiac iron quantification (gold standard per Anderson PMID 11713075); liver MRI R2 (FerriScan) for hepatic iron concentration; hepatology consult if cirrhosis suspected (US + AFP for HCC surveillance per AASLD); endocrinology for endocrinopathy management; hematology for transfusional iron-overload chelation strategy
    inputs: hfe_genotyping_c282y_h63d, cardiac_mri_t2star_for_iron_quantification, liver_mri_r2_ferriscan_for_lic
    advance: iron mechanism confirmed (HH vs transfusional) + cardiac T2* quantified
  7. 7TREATMENT
    Standard ADHF: IV loop diuretic per DOSE PMID 21366472 + supplemental O2 + nitroglycerin if hypertensive; INITIATE GDMT 4-pillar (ARNI/ACEi + BB + MRA + SGLT2i) standard for HFrEF; PHLEBOTOMY for HH (1 unit q1-2wk until ferritin <50 ng/mL; maintenance 2-6/year per EASL 2022 PMID 36064151) — NOT for transfusion-dependent patients; IRON CHELATION for transfusion-dependent OR HH-intolerant: deferasirox (Exjade/Jadenu) 21 mg/kg PO daily first-line per EHA-EBMT 2022 PMID 35139194 (excellent cardiac penetration); deferoxamine (Desferal) 40-60 mg/kg/day SC infusion for severe; deferiprone (Ferriprox) 75-100 mg/kg/day PO TID for cardiac iron clearance per Pennell PMID 16735649 (agranulocytosis risk — weekly CBC); combination deferiprone + deferoxamine for severe cardiac iron (T2* <6 ms) per Tanner PMID 17389272 TIC trials; AVOID iron supplements + vit C high-dose supplementation; manage endocrinopathies (insulin for DM, levothyroxine, testosterone replacement); ICD if EF <35 despite chelation; transplant referral if end-stage
    inputs: serum_ferritin, cardiac_mri_t2star_for_iron_quantification, cmp_with_lft_for_cirrhosis_and_egfr
    advance: iron-removal strategy + GDMT initiated + endocrine management coordinated
  8. 8DISPOSITION
    Cardiology floor for stable ADHF; CICU if hemodynamically borderline or arrhythmia; coordinate with hematology (chelation strategy) + hepatology (cirrhosis monitoring) + endocrinology (DM/hypogonadism/hypothyroidism); transition to outpatient with phlebotomy/chelation schedule
    advance: unit + multidisciplinary team + phlebotomy/chelation schedule documented
  9. 9MONITORING
    Continuous telemetry (arrhythmia + AV block surveillance); daily weight + I/O; daily BMP for diuresis safety + GDMT initiation + chelator monitoring (eGFR for deferasirox; CBC for deferiprone); ferritin q3mo on phlebotomy/chelation (trend down toward <50 for HH; <500 for transfusion-dependent); cardiac MRI T2* annually for chelation response; LFT + endocrine panel q6-12mo
    inputs: serum_ferritin, cmp_with_lft_for_cirrhosis_and_egfr, cbc_with_diff
    actions: panel.cardiac, panel.renal
    advance: monitoring schedule active
  10. 10FOLLOWUP
    Cardiology follow-up at 1-2 wks + 3 mo + 6 mo + 12 mo; phlebotomy (HH) every 1-2 wks until ferritin <50, then maintenance 2-6/year; chelation (transfusion-dependent) lifelong with q3mo ferritin trend + annual T2* MRI; family genotype screening (siblings + first-degree relatives per EASL 2022); endocrinology follow-up (DM, hypogonadism, hypothyroidism); hepatology follow-up with annual US + AFP for HCC surveillance per AASLD 2011 (cirrhosis present); transplant evaluation if end-stage despite optimized GDMT + iron removal
    advance: long-term plan + multidisciplinary follow-up + family screening documented