Eduovisual
Gastrointestinal
Hereditary hemochromatosis: diagnosis and management
— C282Y homozygosity accounts for ~85–90% of clinically penetrant cases in patients of Northern European ancestry
— C282Y/H63D compound heterozygotes may have mild iron overload but rarely develop end-organ disease without a cofactor (alcohol, NAFLD, hepatitis C)
— Non-HFE forms (juvenile HH from HJV or HAMP, TFR2, ferroportin disease) are rare but cause earlier, more severe disease
— Persistently elevated transferrin saturation (TSAT) >45% with or without elevated ferritin on routine labs
— Unexplained elevated AST/ALT, hepatomegaly, or cirrhosis without alcohol/viral etiology
— Type 2 diabetes + hyperpigmentation + arthropathy ("bronze diabetes" — late finding)
— Early-onset arthropathy of the 2nd and 3rd MCP joints, hook osteophytes on x-ray
— Restrictive or dilated cardiomyopathy, conduction disease in a young/middle-aged adult
— Hypogonadism, ED, amenorrhea, fatigue
— First-degree relative with confirmed HH
Board pearl: USPSTF does not recommend universal population screening for HH, but cascade testing of first-degree relatives of a proband is standard of care. Order HFE genotyping plus iron studies in adult siblings and children (after age 18, or earlier if symptomatic).
— Abnormal iron studies on routine chemistry panel or workup of fatigue
— Family history of HH triggers cascade testing
— Elevated transaminases on metabolic syndrome workup
— Skin hyperpigmentation (slate-gray or bronze, sun-exposed areas)
— Diabetes mellitus from pancreatic islet iron deposition
— Hepatomegaly/cirrhosis
— Liver: fatigue, RUQ discomfort, elevated AST/ALT (ALT often > AST early), cirrhosis, HCC (200× relative risk in cirrhotic HH)
— Cardiac: dyspnea on exertion, palpitations, dilated or restrictive cardiomyopathy, atrial fibrillation, conduction block, sudden death (juvenile HH)
— Endocrine: type 2 DM, hypogonadotropic hypogonadism (loss of libido, ED, amenorrhea, infertility, osteoporosis), hypothyroidism, adrenal insufficiency (rare)
— Joints: symmetric arthropathy of 2nd/3rd MCPs, wrists, hips; pseudogout from CPPD crystal deposition
— Skin: bronze/slate hyperpigmentation from melanin + iron
— Infectious susceptibility: Vibrio vulnificus (raw oysters, seawater wounds), Listeria, Yersinia enterocolitica, Pasteurella — iron-loving organisms
— Northern European ancestry, family history of HH/cirrhosis/early MI/diabetes
— Alcohol intake (synergistic hepatic injury), vitamin C/iron supplement use (accelerates absorption)
— Hepatitis B/C status, NAFLD risk factors
— Menstrual/pregnancy history in women (delays presentation)
— Raw shellfish consumption (Vibrio risk)
Key distinction: Fatigue + arthralgia + elevated transaminases in a middle-aged man of Northern European descent → order TSAT and ferritin before liver biopsy or rheum workup. Missing this triad is a classic Step 3 trap that leads to inappropriate downstream testing.
— Hyperpigmentation: slate-gray or bronze discoloration, most prominent on sun-exposed skin, axillae, groin, genitalia, old scars; due to increased melanin (not iron directly) stimulated by dermal iron
— Cachexia or sarcopenia in advanced cirrhosis
— Hepatomegaly (most common physical finding, present in >90% of symptomatic patients)
— Splenomegaly suggests portal hypertension (advanced disease)
— Stigmata of chronic liver disease: spider angiomata, palmar erythema, gynecomastia, caput medusae, ascites, asterixis
— Testicular atrophy from hypogonadism
— Signs of heart failure: elevated JVP, S3, displaced PMI, peripheral edema, rales
— Irregular rhythm (atrial fibrillation), bradyarrhythmias from conduction block
— In restrictive phenotype: Kussmaul sign, pericardial knock mimic
— Tenderness and bony enlargement of 2nd and 3rd MCP joints ("iron fist" — pathognomonic appearance)
— Reduced grip strength, squared knuckles
— Hip, knee, ankle involvement; acute monoarthritis from CPPD pseudogout
— Loss of body hair, small testes, gynecomastia (hypogonadism)
— Diabetic findings: acanthosis nigricans usually absent (HH is not typical insulin-resistance DM)
— Hypothyroid features: cool dry skin, bradycardia
— Right-sided HF predominates in restrictive cardiomyopathy
— Hypotension in adrenal crisis (rare)
Step 3 management: A patient with MCP arthropathy + hepatomegaly + impaired fasting glucose should have TSAT, ferritin, AST/ALT, and fasting glucose ordered at the same visit — do not split workup across multiple encounters. Bundling labs reduces missed diagnoses and is a value-based care principle tested on Step 3.
— Fasting transferrin saturation (TSAT) = serum iron / TIBC × 100
— TSAT >45% is the threshold for further workup (sensitivity ~90%)
— Fasting sample reduces diurnal/dietary variation
— Serum ferritin
— Men >300 ng/mL, women >200 ng/mL (premenopausal) suggest iron overload
— Ferritin is an acute-phase reactant — interpret cautiously with inflammation, NAFLD, alcohol, malignancy
— Both elevated → proceed to HFE genotyping
— TSAT elevated, ferritin normal → repeat fasting; may be early/pre-clinical HH
— CBC (anemia argues against HH; suggests thalassemia, sideroblastic anemia, MDS as alternative iron-overload cause)
— CMP: AST, ALT (often 2–3× ULN), alkaline phosphatase, albumin, bilirubin, glucose, creatinine
— Fasting glucose / HbA1c for diabetes screen
— Hepatitis B and C serologies to exclude/co-diagnose
— TSH, free testosterone (AM), LH, FSH if hypogonadal symptoms
— Coags (PT/INR) if cirrhosis suspected
— Abdominal ultrasound as initial hepatic imaging — assess for hepatomegaly, cirrhosis morphology, focal lesions
— MRI with R2/T2 sequences quantifies hepatic and cardiac iron concentration non-invasively — increasingly replaces biopsy for iron quantification
— Cardiac MRI T2 mandatory if cardiac involvement suspected (T2 <20 ms = iron overload; <10 ms = severe)
— Low voltage, conduction delays, AV block, atrial fibrillation, nonspecific ST-T changes
— Baseline ECG in all newly diagnosed HH patients
Board pearl: Elevated TSAT is more specific than ferritin for HH because ferritin rises in any inflammatory state (alcohol, NAFLD, infection). On a stem with elevated ferritin alone and normal TSAT, think NAFLD or inflammation first, not HH.
— Test for C282Y and H63D mutations
— C282Y/C282Y homozygote with elevated TSAT and ferritin → diagnosis confirmed
— C282Y/H63D compound heterozygote with iron overload → diagnosis supported, but search for cofactor (alcohol, viral hepatitis, NAFLD)
— H63D/H63D or single heterozygote rarely causes overload — investigate alternatives
— Negative HFE testing with iron overload → consider non-HFE HH (HJV, HAMP, TFR2, SLC40A1) or secondary iron overload (transfusion, ineffective erythropoiesis, chronic liver disease)
— MRI R2/T2 (FerriScan or equivalent) is now first-line non-invasive quantification
— Liver biopsy with hepatic iron index (HII = µmol Fe/g dry weight / age in years) historically diagnostic (HII >1.9), now reserved for:
— Ferritin >1000 ng/mL
— Elevated AST/ALT
— Hepatomegaly
— Age >40 with risk factors for fibrosis
— Biopsy primarily for staging fibrosis/cirrhosis, not diagnosis
— Transient elastography (FibroScan) non-invasive stiffness measurement
— FIB-4 and APRI scores from routine labs
— If cirrhosis confirmed → abdominal US ± AFP every 6 months
— All first-degree relatives ≥18 years → iron studies + HFE genotyping
— Children of a proband: consider testing the unaffected parent first to determine child's risk (if parent is wild-type, child is at most a heterozygote and testing can be deferred)
Step 3 management: Ferritin >1000 ng/mL + elevated transaminases + C282Y homozygote → these three together predict significant fibrosis or cirrhosis and mandate either liver biopsy or non-invasive elastography plus HCC surveillance enrollment.
— Genotype only, normal iron studies → monitor annually with TSAT/ferritin; no phlebotomy
— Elevated TSAT, ferritin <300 (M) / <200 (F) → observe, lifestyle counseling, recheck in 6–12 months
— Ferritin elevated but <1000, no symptoms, normal LFTs → initiate phlebotomy, low risk of fibrosis
— Ferritin >1000 ng/mL OR elevated AST/ALT OR hepatomegaly → high risk of advanced fibrosis; phlebotomy + fibrosis staging + HCC surveillance if cirrhotic
— Induction phase: reduce ferritin to 50–100 ng/mL
— Maintenance phase: keep ferritin 50–100 ng/mL and TSAT <50% lifelong
— Avoid alcohol (synergistic hepatotoxicity); strict abstinence if cirrhotic
— Avoid vitamin C supplements >500 mg/day (enhances iron absorption and oxidative injury)
— Avoid iron supplements and iron-fortified multivitamins
— Avoid raw shellfish (Vibrio vulnificus risk)
— Moderate red meat is acceptable; no need for strict low-iron diet (phlebotomy is far more effective)
— Hepatitis A and B vaccination if non-immune
— Fasting glucose/HbA1c, lipid panel
— Echocardiogram if any cardiac symptoms or ferritin >1000
— DEXA scan if hypogonadal
— Testosterone, TSH
Board pearl: A C282Y homozygote with normal iron studies has incomplete penetrance — do not initiate phlebotomy. Penetrance to clinical disease is only ~10–30% in men and <5% in women. Treat the biochemical and clinical phenotype, not the genotype alone.
— Induction: remove 500 mL whole blood (~200–250 mg iron) weekly or biweekly
— Monitor hematocrit/hemoglobin before each session; hold if Hgb <11 g/dL
— Check ferritin every 4–12 weeks during induction; TSAT may remain elevated until iron stores depleted
— Target induction endpoint: ferritin 50–100 ng/mL
— Typical induction duration: 1–2 years depending on baseline burden (1 g iron ≈ 4 phlebotomies)
— Maintenance: 2–4 phlebotomies per year to keep ferritin 50–100 ng/mL
— Used when phlebotomy is contraindicated or poorly tolerated (severe anemia, poor venous access, cardiac decompensation, severe HF)
— Deferasirox (oral) — first-line chelator; monitor renal function, LFTs, CBC
— Deferoxamine (parenteral, subcutaneous infusion) — older agent, less convenient
— Deferiprone — risk of agranulocytosis, requires weekly CBC monitoring
— Chelation is standard for transfusion-dependent secondary iron overload (thalassemia, MDS) rather than HH
— Erythropoietin rarely used to support more aggressive phlebotomy in select patients
— Proton pump inhibitors (incidental finding): reduce dietary iron absorption — may decrease phlebotomy frequency in some patients (not a primary therapy)
— CBC, ferritin every 4–8 weeks
— TSAT every 3 months
— LFTs every 3–6 months
— Symptom reassessment: fatigue, arthralgia often improve; arthropathy, diabetes, cirrhosis, hypogonadism typically do not reverse
Step 3 management: Patient on induction phlebotomy presents with Hgb 10.2 — hold the session, recheck in 2 weeks, do not give iron. Ordering iron supplementation in an HH patient is a classic safety error and a tested Step 3 patient-safety stem.
— Cirrhosis present at diagnosis → enroll in HCC surveillance (US ± AFP every 6 months); risk persists even after iron normalization
— Variceal screening EGD at cirrhosis diagnosis, repeat per AASLD intervals
— Vaccinate against hepatitis A and B; pneumococcal vaccine
— Avoid hepatotoxins (alcohol, acetaminophen >2 g/day in cirrhosis)
— Refer for liver transplant evaluation if decompensated cirrhosis or HCC within Milan criteria; post-transplant outcomes are comparable to other etiologies
— Restrictive or dilated cardiomyopathy → guideline-directed HF therapy (beta-blocker, ACEi/ARB, diuretics, ARNI as appropriate)
— Aggressive phlebotomy or chelation can reverse early iron cardiomyopathy
— Atrial fibrillation → rate/rhythm + anticoagulation per CHA2DS2-VASc
— Pacemaker for high-grade AV block
— Diabetes: standard ADA management; insulin often required because of pancreatic beta-cell destruction (not just insulin resistance); diabetes rarely reverses with phlebotomy
— Hypogonadism: testosterone replacement in men after confirming low AM testosterone + inappropriately low/normal LH; estrogen in women as indicated; DEXA scan and bisphosphonate if osteoporosis
— Levothyroxine for hypothyroidism
— NSAIDs with caution (renal/hepatic disease), acetaminophen, intra-articular steroids
— Phlebotomy does not reliably improve established arthropathy — set expectations
— Joint replacement for severe destructive disease
— Counsel against raw shellfish (Vibrio vulnificus), unpasteurized dairy (Listeria)
— Wound care for marine exposures; empiric coverage with doxycycline + ceftriaxone if Vibrio suspected
CCS pearl: When managing an HH inpatient with new HF, order cardiac MRI T2*, echo, BNP, troponin, ferritin, TSAT, HFE genotype simultaneously; consult cardiology and hepatology; initiate diuresis and GDMT while planning phlebotomy after stabilization.
— HH may present late in men who escaped earlier detection; women often present post-menopause as menstrual protection ends
— Higher baseline cardiac and cerebrovascular comorbidity — phlebotomy of 500 mL may cause orthostasis, angina; consider reduced-volume phlebotomy (250–350 mL) or longer intervals
— Monitor for iatrogenic anemia; hold for Hgb <11 g/dL or symptomatic
— Address fall risk if hypogonadism + osteoporosis
— Polypharmacy review: avoid iron-containing multivitamins (often in "senior" formulations)
— Goals of care discussion if cirrhosis is advanced and transplant is not an option
— Phlebotomy itself is well-tolerated and does not require dose adjustment
— Deferasirox is nephrotoxic — contraindicated in CrCl <40 mL/min; monitor SCr weekly initially, then monthly
— Deferoxamine acceptable in renal disease but check renal function
— Erythropoietin-treated CKD patients may have altered phlebotomy response
— Watch for cardiorenal interactions if iron cardiomyopathy + CKD
— Compensated cirrhosis: phlebotomy proceeds; avoid alcohol absolutely; HCC surveillance every 6 months
— Decompensated cirrhosis (ascites, encephalopathy, jaundice, coagulopathy):
— Phlebotomy may worsen anemia and hypotension — use cautiously, smaller volumes, or defer until stabilization
— Chelation preferred in some decompensated cases
— Refer for transplant; MELD score drives priority
— Deferasirox carries hepatotoxicity black box warning — monitor LFTs
— Avoid NSAIDs (renal + variceal bleeding risk); cautious acetaminophen ≤2 g/day
Step 3 management: Elderly C282Y homozygote with ferritin 1500, Hgb 10.5, CAD, and CrCl 35 → start low-volume phlebotomy (250 mL every 2–4 weeks) rather than full-volume weekly; chelation alternative if intolerant. Do not prescribe deferasirox due to CrCl <40.
— Pregnancy is generally protective (iron diverted to fetus, expanded plasma volume, no menses postpartum until cycles resume)
— Do not perform routine phlebotomy during pregnancy unless ferritin markedly elevated and end-organ disease present; consult MFM and hepatology
— Avoid iron supplements unless documented iron deficiency or anemia of pregnancy — check TSAT/ferritin before prescribing prenatal vitamins with iron in a known HH patient
— Chelation agents are teratogenic — deferasirox and deferiprone contraindicated; deferoxamine only if life-threatening overload
— Genetic counseling: partner HFE testing helps determine fetal risk
— Labor: usually uncomplicated; postpartum hemorrhage may transiently lower iron stores
— Adult-onset HFE-HH rarely causes clinical disease in childhood — defer testing of asymptomatic minors until age 18 unless juvenile HH suspected
— Juvenile hemochromatosis (HJV, HAMP): presents in 2nd–3rd decade with severe cardiomyopathy and hypogonadism; aggressive phlebotomy/chelation; high mortality without treatment
— Genetic testing of children of a proband: test the unaffected parent first — if wild-type, child cannot be homozygous
— Men present 10–20 years earlier than women due to menstrual iron loss
— Postmenopausal women catch up in risk
— Pregnancy and lactation delay presentation in women
— HFE-HH is overwhelmingly a disease of Northern European ancestry; rare in African, Asian, Hispanic populations
— In non-European patients with iron overload, consider non-HFE HH, thalassemia, sickle cell with transfusion overload, sideroblastic anemia
Board pearl: A pregnant patient with known C282Y homozygosity should not receive routine iron-containing prenatal vitamins without confirming her iron status; default prescribing is a tested patient-safety pitfall.
— Cirrhosis (15–25% of symptomatic untreated HH); risk markedly increased with alcohol, hepatitis C, NAFLD, obesity, diabetes
— Hepatocellular carcinoma — relative risk ~20–200× in cirrhotic HH; lifetime HCC incidence in cirrhotic HH ~1–6% per year
— Risk persists even after iron normalization if cirrhosis already developed → lifelong HCC surveillance
— Portal hypertension, varices, hepatic decompensation
— Dilated cardiomyopathy (early/juvenile HH) or restrictive cardiomyopathy (later HFE-HH)
— Atrial fibrillation, conduction block, sudden cardiac death
— Heart failure was historically a leading cause of death; modern phlebotomy reduces incidence
— Type 2 diabetes mellitus (irreversible once established)
— Hypogonadotropic hypogonadism → ED, infertility, osteoporosis with fragility fractures
— Hypothyroidism, rare adrenal insufficiency, hypoparathyroidism
— Chronic destructive arthropathy of MCPs, wrists, hips, knees
— CPPD pseudogout flares
— Osteoporosis from hypogonadism
— Vibrio vulnificus sepsis from raw oysters or seawater wounds — high mortality
— Listeria monocytogenes, Yersinia enterocolitica, Pasteurella multocida, Salmonella
— These siderophilic organisms thrive in iron-rich environments
— Iatrogenic iron deficiency anemia from over-phlebotomy
— Vasovagal reactions during phlebotomy
— Deferasirox: renal failure, hepatotoxicity, GI bleeding, agranulocytosis
— Deferoxamine: injection-site reactions, ototoxicity, retinopathy with long-term use
Key distinction: HCC surveillance is lifelong in HH patients with established cirrhosis, even after iron stores have been normalized. Stopping surveillance after "successful" phlebotomy is a Step 3 trap.
— Ferritin >1000 ng/mL
— Elevated AST/ALT
— Hepatomegaly on exam or imaging
— Suspected cirrhosis or HCC
— Liver transplant evaluation in decompensated disease
— Coordination of HCC surveillance, variceal screening
— Any cardiac symptom (dyspnea, palpitations, syncope)
— Abnormal ECG or echo
— Need for cardiac MRI T2* interpretation
— Cardiomyopathy management and possible cardiac transplant evaluation
— Hypogonadism requiring hormone replacement
— Difficult-to-control diabetes
— Suspected pituitary or adrenal involvement
— Family planning counseling
— Complex genotypes (non-HFE HH)
— Juvenile HH suspicion
— Decompensated cirrhosis (ascites refractory to outpatient management, hepatic encephalopathy, variceal bleed, SBP)
— Acute HF or arrhythmia
— Vibrio vulnificus sepsis — ICU admission, aggressive IVF, doxycycline + ceftriaxone empirically, surgical debridement for necrotizing soft tissue infection
— Symptomatic anemia from over-phlebotomy
— Septic shock, especially with siderophilic organisms
— Cardiogenic shock from iron cardiomyopathy
— Acute liver failure (rare in HH alone but possible with superimposed insult)
CCS pearl: HH patient admitted with septic shock after eating raw oysters → empirically cover Vibrio vulnificus with ceftriaxone + doxycycline (or fluoroquinolone), obtain blood cultures, aggressive fluids, vasopressors PRN, surgical consult for any cellulitis with bullae (urgent debridement). Do not wait for cultures to confirm before starting Vibrio coverage.
— Beta-thalassemia major/intermedia — transfusion-dependent + GI absorption overload; microcytic anemia, target cells, elevated HbA2/F
— Sideroblastic anemia (congenital or acquired) — ring sideroblasts on marrow
— Myelodysplastic syndromes — cytopenias, dysplasia, may require transfusions → iron overload
— Hereditary spherocytosis with chronic hemolysis — rarely causes overload without transfusion
— Each unit pRBC contains ~200–250 mg iron
— Patients with ≥20 lifetime transfusions are at risk
— Sickle cell disease on chronic transfusion, aplastic anemia
— Treatment: chelation (deferasirox), not phlebotomy (worsens anemia)
— Juvenile HH (type 2): HJV (hemojuvelin) or HAMP (hepcidin) mutations; severe, early-onset, cardiac/endocrine prominent
— TFR2 mutations (type 3): intermediate phenotype
— Ferroportin disease (type 4): SLC40A1 mutations; autosomal dominant; high ferritin, normal/low TSAT; macrophage iron loading
— Aceruloplasminemia: iron overload + neurodegeneration + diabetes; low ceruloplasmin
— Associated with traditional iron-brewed beer; possible SLC40A1 modifier
— Hepatic iron contributes to UROD inhibition; photosensitive skin blistering, elevated urinary uroporphyrins; often associated with HCV, alcohol, HFE mutations
Key distinction: Phlebotomy is the answer for HH and PCT; chelation is the answer for transfusion-dependent overload and thalassemia. Confusing these is a classic Step 3 mismatch.
— Acute or chronic inflammation — ferritin is an acute-phase reactant; CRP, ESR elevated; TSAT normal
— Non-alcoholic fatty liver disease (NAFLD) — elevated ferritin in 30–50%; metabolic syndrome features; TSAT usually normal or mildly elevated; dysmetabolic iron overload syndrome (DIOS) describes this overlap
— Alcoholic liver disease — elevated ferritin, AST:ALT >2:1, GGT elevated
— Chronic hepatitis C — elevated ferritin and mild TSAT elevation common; check HCV antibody + RNA
— Malignancy — especially lymphoma, HCC; very high ferritin
— Adult-onset Still's disease / hemophagocytic lymphohistiocytosis (HLH) — ferritin often >10,000 ng/mL; fever, rash, cytopenias
— Hyperthyroidism, chronic kidney disease
— Rheumatoid arthritis (symmetric MCP involvement but with synovitis, positive RF/anti-CCP, erosions in different pattern)
— Osteoarthritis (typical DIP/PIP, base of thumb — different distribution)
— CPPD/pseudogout primary
— Addison's disease (mucosal hyperpigmentation, hypotension, hyperkalemia)
— Chronic kidney disease, amiodarone, minocycline, Wilson disease (Kayser-Fleischer)
— Copper overload mimicking HH conceptually; presents <40 years with hepatic + neuropsychiatric features; low ceruloplasmin, high 24-hr urinary copper, Kayser-Fleischer rings; treat with chelation (penicillamine, trientine, zinc)
Board pearl: Isolated elevated ferritin with normal TSAT in an obese patient with metabolic syndrome → think NAFLD/DIOS, not HH. HFE genotyping is low-yield; manage metabolic syndrome aggressively.
— 2–6 sessions/year to keep ferritin 50–100 ng/mL and TSAT <50%
— Individualized based on rate of re-accumulation
— Alcohol: abstinence if cirrhosis or significant fibrosis; otherwise strict moderation (<1 drink/day women, <2/day men, ideally none)
— Avoid vitamin C supplements >500 mg/day; vitamin C with meals enhances non-heme iron absorption
— Avoid iron supplements and iron-fortified multivitamins — verify all OTC products
— Avoid raw shellfish and unpasteurized dairy
— Tea and coffee with meals modestly inhibit iron absorption (minor effect)
— Maintain healthy weight, exercise, diabetes control
— Hepatitis A and B if non-immune (essential)
— Annual influenza
— Pneumococcal vaccine (PCV20 or PCV15+PPSV23) given liver risk
— COVID-19 boosters per CDC
— Standard adult vaccines
— Aggressive lipid, BP, glucose control
— Osteoporosis: DEXA, calcium, vitamin D, bisphosphonate if T-score ≤−2.5 or fragility fracture
— Testosterone replacement after confirmed hypogonadism (monitor PSA, hematocrit)
— If cirrhotic: abdominal US ± AFP every 6 months for life
— Liver MRI/CT for indeterminate nodules
— All first-degree relatives screened with TSAT, ferritin, HFE genotyping
— Counsel on autosomal recessive inheritance, partner testing for reproductive risk
Step 3 management: At every follow-up visit, review the medication list for hidden iron (multivitamins, prenatal vitamins, "energy" supplements) and vitamin C >500 mg — counseling drift is a common longitudinal care failure.
— CBC before each phlebotomy session (hold if Hgb <11 g/dL)
— Serum ferritin every 4–12 weeks until target 50–100 ng/mL reached
— TSAT every 3 months — lags ferritin response
— LFTs every 3–6 months
— Symptom reassessment: fatigue, energy, libido, arthralgia
— Ferritin and TSAT every 6–12 months; adjust phlebotomy frequency
— LFTs annually
— Fasting glucose/HbA1c annually
— Echocardiogram if baseline cardiac involvement or new symptoms
— DEXA every 2 years if hypogonadism
— HCC surveillance every 6 months if cirrhotic (US ± AFP)
— EGD for variceal surveillance per AASLD intervals
— Reinforce alcohol abstinence/moderation
— Confirm avoidance of iron and high-dose vitamin C supplements
— Raw shellfish avoidance reminder
— Skin protection, dermatologic monitoring (porphyria-like lesions if present)
— Family screening compliance — ask about untested siblings/children
— Physical therapy for arthropathy
— Sexual health counseling for hypogonadism
— Depression and fatigue screening (PHQ-2/9)
— Hepatology support groups, patient advocacy resources (Iron Disorders Institute)
— Primary care quarterback; hepatology, cardiology, endocrinology as needed
— Communicate HH diagnosis to all providers; flag in chart to prevent inadvertent iron prescribing
CCS pearl: A common Step 3 stem: HH patient on maintenance phlebotomy presents with "increased fatigue" — check Hgb (over-phlebotomy iatrogenic anemia) before assuming disease progression. Solution is lengthen the phlebotomy interval, not iron supplementation.
— Obtain informed consent specifically for genetic testing — discuss implications for insurance, employment, family members
— GINA (Genetic Information Nondiscrimination Act, 2008) prohibits health insurance and employer discrimination based on genetic information, but does NOT cover life, disability, or long-term care insurance — disclose this to patients before testing
— Document discussion of psychological impact and family implications
— Encourage but do not coerce family testing; respect autonomy
— Provider may offer to facilitate communication but cannot directly contact relatives without proband's consent (HIPAA)
— Children: defer testing until adulthood unless symptomatic juvenile HH suspected, to preserve future autonomy
— At hospital discharge, explicitly remove iron-containing supplements from medication reconciliation; verify discharge med list
— Hand-off communication to outpatient PCP must include HH diagnosis, current phlebotomy schedule, ferritin target, and avoidance list
— In pregnant patients with HH, hold default prenatal vitamins with iron unless lab-confirmed deficiency
— Never give iron supplements to a known HH patient without confirmed iron deficiency anemia
— Verify blood bank protocols: therapeutic phlebotomy blood from HH patients is allowed for donation under FDA rules if facility participates in approved variance program; otherwise discard
— Monitor for vasovagal reactions and falls post-phlebotomy, especially elderly
— Many HH patients can donate via therapeutic phlebotomy programs that meet FDA criteria — discuss as option
— Liver transplant candidacy: ongoing alcohol use, advanced age, comorbidity influence eligibility; multidisciplinary committee review
Step 3 management: Before ordering HFE genotyping, document in the chart: indication, discussion of GINA protections and insurance limitations, family implications, and patient consent — a tested ethical competency.
— C282Y/C282Y — classic HFE-HH, ~85–90% of clinical cases
— C282Y/H63D — mild, needs cofactor
— HJV, HAMP — juvenile HH (cardiac + endocrine, early death)
— TFR2 — adult, intermediate
— SLC40A1 (ferroportin) — autosomal dominant; low/normal TSAT, high ferritin, macrophage iron
— TSAT >45% + ferritin elevated → screen with HFE genotyping
— Ferritin >1000 ng/mL + elevated AST/ALT → high fibrosis risk, biopsy or elastography
— Hepcidin is functionally low in HH (loss of HFE → loss of hepcidin → iron absorption unchecked)
— "Bronze diabetes" = hyperpigmentation + diabetes + cirrhosis
— MCP arthropathy with hook osteophytes on x-ray
— CPPD pseudogout flares
— Vibrio vulnificus sepsis from raw oysters
— Hypogonadotropic hypogonadism with low LH/FSH (pituitary iron)
— HCC risk ~200× in cirrhotic HH
— Cardiomyopathy — restrictive (HFE) or dilated (juvenile)
— 500 mL whole blood ≈ 200–250 mg iron
— Target ferritin 50–100 ng/mL (induction and maintenance)
— Phlebotomy is first-line; chelation reserved for anemia, severe HF, transfusion overload
— Avoid vitamin C >500 mg/day, iron supplements, raw shellfish
— Reversible: fatigue, abdominal pain, transaminitis, early cardiomyopathy, skin pigmentation (partial)
— Irreversible: cirrhosis, established diabetes, arthropathy, hypogonadism, advanced cardiomyopathy
— USPSTF: insufficient evidence for population screening
— Cascade screening of first-degree relatives is standard
— Test relatives at age ≥18
Board pearl: "Diabetic on insulin + new atrial fibrillation + bronze skin + Northern European ancestry" — order TSAT and ferritin, not a primary cardiac workup first. Single highest-yield Step 3 stem template for HH.
— Asymptomatic 45-year-old man with elevated AST/ALT on routine screening, fasting TSAT 65%, ferritin 850
— Next step: HFE genotyping
— Trap answer: liver biopsy first (no — non-invasive workup precedes biopsy)
— Middle-aged man with new-onset DM, hepatomegaly, skin bronzing, ED
— Diagnosis: hereditary hemochromatosis
— Best initial test: fasting transferrin saturation
— Confirmatory: HFE genotyping (C282Y/C282Y)
— 22-year-old asymptomatic daughter of a man with confirmed C282Y/C282Y HH
— Next step: TSAT, ferritin, HFE genotyping (after age 18, with consent)
— Counsel on GINA and reproductive implications
— HH patient with severe CHF, Hgb 9.5, ferritin 1200
— Best treatment: iron chelation (deferasirox) — phlebotomy contraindicated by anemia/HF
— Trap: "weekly phlebotomy"
— HH patient with hemorrhagic bullae and septic shock after raw oyster ingestion
— Empiric therapy: ceftriaxone + doxycycline, urgent surgical debridement
— Trap: vancomycin/piperacillin-tazobactam alone (misses Vibrio coverage)
— HH cirrhotic patient with normalized ferritin for 5 years — does he still need HCC surveillance?
— Answer: Yes, lifelong US ± AFP every 6 months
— Newly diagnosed HH patient asks if she should keep her daily multivitamin and 1000 mg vitamin C
— Counseling: stop iron-containing multivitamins; reduce vitamin C to <500 mg/day
— Pregnant woman with known HH on prenatal vitamins with iron
— Action: discontinue iron supplementation; check iron studies
— Asymptomatic C282Y homozygote with normal TSAT and ferritin
— Management: annual iron studies, no phlebotomy, lifestyle counseling
Key distinction: Most wrong answers on HH stems are either (a) treating genotype without phenotype, (b) ordering biopsy before genotyping, or (c) prescribing iron because the patient "feels tired." Recognize these patterns.
Hereditary hemochromatosis is an autosomal recessive HFE-mediated iron overload disorder diagnosed by elevated transferrin saturation and ferritin with C282Y homozygosity, treated with lifelong therapeutic phlebotomy to a target ferritin of 50–100 ng/mL, and complicated by cirrhosis, HCC, cardiomyopathy, diabetes, hypogonadism, and arthropathy — many of which are irreversible once established, so early detection through cascade family screening is the highest-yield clinical lever.
Board pearl: When the stem gives you a middle-aged man of Northern European descent with fatigue, MCP arthropathy, transaminitis, and impaired fasting glucose — the answer is almost always TSAT and ferritin, and the diagnosis is HH until proven otherwise.