Also known as: hereditary hemochromatosis, HH, HFE hemochromatosis, iron overload
Overview
Most commonly an autosomal recessive disorder of iron metabolism due to mutations in HFE (chromosome 6, overwhelmingly C282Y homozygosity; C282Y/H63D compound heterozygosity usually causes at most mild overload unless cofactors are present), producing inappropriately low hepcidin and consequent excessive intestinal iron absorption. Non-HFE forms (juvenile hemochromatosis, TfR2, ferroportin) are rare.
Epidemiology
Most common genetic disorder in people of Northern European descent — C282Y homozygosity in ~1 in 200-300 individuals; clinical penetrance is much lower (~10-30% in men, lower in women due to menstruation/pregnancy). Symptoms typically emerge after age 40 in men and after menopause in women.
Try two board-style Hereditary Hemochromatosis questions
Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.
Question 1GastrointestinalMedium
A 52-year-old man of Northern European descent presents with several months of fatigue and aching in the second and third knuckles of both hands. He reports decreased libido. He drinks alcohol socially and takes no supplements. Examination shows hepatomegaly and slate-gray skin discoloration over sun-exposed areas. Fasting laboratory studies reveal a transferrin saturation of 68% and a ferritin of 920 ng/mL. Which of the following is the most appropriate next diagnostic test?
ALiver biopsy with hepatic iron index
BHFE gene mutation analysis on blood
CTransient elastography of the liver
DHepatic MRI with iron quantification
ENon-HFE iron gene panel testing
Reveal answer & full explanation
Correct answer: B — HFE gene mutation analysis on blood
ALiver biopsy with hepatic iron index
BHFE gene mutation analysis on blood✓
CTransient elastography of the liver
DHepatic MRI with iron quantification
ENon-HFE iron gene panel testing
Why HFE gene mutation analysis on blood is correct
This patient has biochemical iron overload (transferrin saturation >50% in a man, ferritin >300 ng/mL) plus classic features of hereditary hemochromatosis: arthropathy of the 2nd/3rd MCP joints, hypogonadism, hepatomegaly, and slate-gray hyperpigmentation.
With abnormal fasting screening labs (here both transferrin saturation and ferritin are elevated), the guideline-endorsed next step is HFE genotyping for C282Y and H63D. C282Y homozygosity confirms the diagnosis noninvasively; other genotypes such as C282Y/H63D rarely cause significant overload on their own and require confirmation of hepatic iron and a search for secondary causes.
The AASLD diagnostic pathway is an elevated Tsat or ferritin, then HFE testing, with liver evaluation reserved for staging only if needed.
Why the others are wrong
Hepatic MRI with iron quantification — a valid noninvasive way to quantify liver iron that is increasingly used in place of biopsy, but it does not establish the etiology; genetic confirmation comes first when the clinical picture and labs point to HFE-related disease.
Liver biopsy with hepatic iron index — historically the gold standard, now reserved for staging fibrosis when ferritin exceeds 1000 ng/mL, transaminases are elevated, or hepatomegaly raises cirrhosis concern, which is done after genotyping rather than before it.
Non-HFE iron gene panel testing — covers the rare hemojuvelin, hepcidin, transferrin receptor 2, and ferroportin mutations and is pursued only after HFE genotyping is negative in unexplained overload; ordering it first misses the far more likely C282Y disease in a Northern European man with this classic phenotype.
Transient elastography of the liver — the hepatomegaly makes fibrosis staging tempting, and liver stiffness measurement is a noninvasive way to look for advanced fibrosis in iron overload, but it neither quantifies hepatic iron nor identifies the cause, and staging follows HFE genotyping rather than preceding it.
Question 2GastrointestinalMedium
A 52-year-old man of Northern European descent presents with fatigue, arthralgias of the second and third metacarpophalangeal joints, and slate-gray skin. Fasting transferrin saturation is 78% and ferritin is 1,240 ng/mL. HFE genetic testing confirms C282Y homozygosity, establishing a diagnosis of hereditary hemochromatosis. Which of the following best explains the iron overload in this patient?
AImpaired biliary iron excretion causing hepatic iron accumulation
BIncreased ferroportin degradation limiting enterocyte iron export
CIneffective erythropoiesis suppressing hepcidin and raising iron uptake
DRepeated red-cell transfusions delivering iron beyond storage capacity
EInappropriately low hepcidin allowing excess dietary iron absorption
Reveal answer & full explanation
Correct answer: E — Inappropriately low hepcidin allowing excess dietary iron absorption
AImpaired biliary iron excretion causing hepatic iron accumulation
BIncreased ferroportin degradation limiting enterocyte iron export
CIneffective erythropoiesis suppressing hepcidin and raising iron uptake
DRepeated red-cell transfusions delivering iron beyond storage capacity
EInappropriately low hepcidin allowing excess dietary iron absorption✓
Why Inappropriately low hepcidin allowing excess dietary iron absorption is correct
HFE protein normally signals hepcidin synthesis in proportion to body iron stores; the C282Y mutation blunts this response, so hepcidin stays inappropriately low.
Hepcidin is the master negative regulator of iron — low hepcidin leaves ferroportin active on enterocytes and macrophages, allowing continuous, unrestrained absorption of dietary iron.
Excess iron then deposits as hemosiderin in hepatocytes, pancreatic islets, cardiac myocytes, pituitary, synovium, and skin, producing the MCP arthropathy, hyperpigmentation, and organ injury seen here.
Why the others are wrong
Repeated red-cell transfusions delivering iron beyond storage capacity — this is the mechanism of secondary (transfusional) iron overload in thalassemia, sickle cell, or MDS; HFE genetic testing would be negative and this patient has no transfusion history.
Increased ferroportin degradation limiting enterocyte iron export — this is the high-hepcidin state of inflammation and anemia of chronic disease; internalizing ferroportin traps iron inside enterocytes and macrophages and produces iron restriction, the exact opposite of the absorptive overload caused by C282Y homozygosity.
Ineffective erythropoiesis suppressing hepcidin and raising iron uptake — seen in iron-loading anemias such as thalassemia and sideroblastic anemia, where expanded erythroid marrow suppresses hepcidin; this patient has a primary HFE defect, not an erythropoietic drive.
Impaired biliary iron excretion causing hepatic iron accumulation — this borrows the Wilson disease mechanism, in which ATP7B mutation impairs biliary copper excretion so copper builds up in the liver; the body has no regulated pathway for excreting iron (losses come mainly from shed gut and skin cells and from bleeding), so iron balance is set at the point of absorption, and C282Y overload reflects low hepcidin and unrestrained uptake.
That's 2. Get 7,700+ more.
Unlock the full FirstPassPA bank: 7,700+ board-style questions, flashcards, and an AI tutor that explains every answer. Your 7-day free trial includes everything, and there's no credit card required.
You've read your 2 free diagnosis previews. Create your free account to unlock the full Hereditary Hemochromatosis outline — plus all 514 diagnoses, 7,700+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
Increased dietary iron, iron supplementation, vitamin C supplementation
Alcohol use (accelerates hepatic injury)
Concomitant hepatitis C, NAFLD, or porphyria cutanea tarda
Pathophysiology
HFE protein normally signals hepcidin synthesis in proportion to iron stores. HFE mutations blunt hepcidin response, allowing unrestrained intestinal absorption of dietary iron. Excess iron deposits as hemosiderin in hepatocytes, pancreatic islets, cardiac myocytes, anterior pituitary, joint synovium, and skin melanocytes, producing oxidative injury and fibrosis in affected organs.
Clinical presentation
Symptoms
Fatigue, weakness, malaise (early, nonspecific)
Arthralgia, especially 2nd and 3rd MCP joints ('iron fist'); chondrocalcinosis
Diabetes ('bronze diabetes' from pancreatic deposition)
Hepatic: hepatomegaly, abdominal pain, evolving to cirrhosis with stigmata of chronic liver disease
Cardiac: cardiomyopathy (restrictive or dilated), arrhythmias, congestive heart failure
Skin: slate-gray or bronze hyperpigmentation (sun-exposed areas)
Signs / physical exam
Hepatomegaly with or without splenomegaly
Hyperpigmentation
Loss of body hair, testicular atrophy
Findings of advanced liver disease in late stages
MCP joint tenderness, swelling
Classic findings
Classic 'bronze diabetes' tetrad: cirrhosis, diabetes, hyperpigmentation, and hypogonadism in a middle-aged man of Northern European descent.
Differential diagnosis
Secondary iron overload — Transfusion-dependent anemias (thalassemia, sickle cell, MDS), repeated transfusions; ferritin high but mutation analysis negative
Nonalcoholic fatty liver disease — Metabolic syndrome, steatosis on imaging; iron studies may show modest elevation but not severe overload
Alcoholic liver disease — Heavy alcohol use, AST:ALT >2:1, GGT elevation; can coexist and accelerate iron-related injury
Wilson disease — Copper, not iron; younger patients, neuropsychiatric features, Kayser-Fleischer rings
Porphyria cutanea tarda — Photosensitive vesicles, urine fluoresces under Wood lamp; often coexists with HH
Inflammation-related ferritin elevation — Ferritin is an acute-phase reactant; transferrin saturation distinguishes overload from inflammation
Diagnostic workup
Diagnostic criteria
Elevated Tsat and ferritin with C282Y homozygosity establishes the diagnosis; with other HFE genotypes (C282Y/H63D, H63D/H63D), confirm hepatic iron overload (MRI or biopsy) and exclude secondary causes (alcohol, MASLD, hematologic disease). Liver biopsy if biochemical evidence of overload without typical genotype, or to stage fibrosis.
Labs
Fasting transferrin saturation (Tsat) — first-line screening; elevated >45% (women) or >50% (men) suggests iron overload
Ferritin — elevated >200 ng/mL (premenopausal women) or >300 ng/mL (men and postmenopausal women); higher levels (>1000) correlate with risk of cirrhosis
If either is abnormal (Tsat ≥45% or ferritin elevated) → HFE genetic testing (C282Y, H63D)
LFTs, glucose/A1c, lipid panel
TSH, testosterone, FSH/LH if hypogonadism suspected
ECG, echocardiogram if cardiac involvement suspected
Imaging
MRI with T2* or R2 quantification of liver iron — noninvasive iron quantification, increasingly used over biopsy
Liver biopsy with hepatic iron index — historically gold standard; reserved for evaluating fibrosis when ferritin >1000, elevated transaminases, or hepatomegaly
Diagnostic algorithm
flowchart TD
A["Fatigue + arthralgia + LFT elevation<br/>± diabetes / cardiomyopathy / bronze skin"] --> B["Fasting transferrin saturation<br/>+ ferritin"]
B --> C{"Tsat ≥45% or<br/>ferritin elevated?"}
C -->|No| D["Iron overload unlikely:<br/>consider other diagnoses"]
C -->|Yes| E["HFE genotype<br/>C282Y, H63D"]
E --> F{"C282Y/C282Y?"}
F -->|Yes| G[Hereditary hemochromatosis]
F -->|No| H["Other genotype: confirm hepatic iron (MRI or biopsy),<br/>exclude secondary causes, consider non-HFE"]
G --> I["Therapeutic phlebotomy<br/>weekly until ferritin 50-100"]
I --> J["Maintenance phlebotomy<br/>+ screen for cirrhosis/HCC<br/>+ family screening"]
Diagnostic and treatment algorithm for hereditary hemochromatosis.
Treatment
First-line
Therapeutic phlebotomy — mainstay; remove 500 mL whole blood (~250 mg iron) weekly to biweekly until ferritin 50-100 ng/mL and Tsat <50%
Maintenance phlebotomy every 2-4 months thereafter to keep ferritin ~50-100
Avoid iron and vitamin C supplements; moderate dietary iron (limit red meat, organ meats); avoid raw shellfish (Vibrio vulnificus risk)
Limit or avoid alcohol
Screen and treat associated conditions: diabetes, hypogonadism (testosterone replacement after iron normalization), cardiomyopathy (standard HF therapy), arthropathy (NSAIDs, joint replacement if severe)
Second-line / adjunct
Iron chelation (deferoxamine, deferasirox, deferiprone) — for patients who cannot tolerate phlebotomy (anemia, poor venous access, cardiac decompensation)
Erythrocytapheresis — alternative for patients with cardiac compromise
Cirrhosis screening: HCC surveillance with ultrasound (± AFP) every 6 months in patients with cirrhosis or advanced fibrosis, continued after iron depletion
Liver transplantation for decompensated cirrhosis or HCC; iron overload generally improves post-transplant but does not always normalize hepcidin
Complications
Cirrhosis (up to 25% of homozygous men eventually)
Hepatocellular carcinoma (up to 100-fold relative risk; develops almost exclusively in cirrhotics)
Diabetes mellitus
Cardiomyopathy and arrhythmias
Hypogonadism and infertility
Arthropathy and chondrocalcinosis
Increased risk of Listeria, Yersinia, Vibrio vulnificus infections (iron-loving organisms)
PANCE pearls
Order Tsat AND ferritin together — Tsat alone is more specific; ferritin alone is an acute-phase reactant and easily misleading.
Phlebotomy aggressively until ferritin 50-100, then maintenance — do not 'normalize' to mid-range (risk of re-accumulation).
Counsel against raw oysters and shellfish — Vibrio vulnificus is highly lethal in iron-overloaded patients.
HCC surveillance (ultrasound ± AFP every 6 months) is for cirrhosis or advanced fibrosis and continues even after iron depletion; HH without advanced fibrosis does not need routine HCC surveillance.
C282Y heterozygotes (single copy) are not at risk for iron overload from HH alone, though minor lab abnormalities can occur in the setting of another liver insult.
References
AASLD 2011 — Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases (Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS; Hepatology 2011;54:328-343)
EASL 2022 — EASL Clinical Practice Guidelines on haemochromatosis (J Hepatol 2022)
ACG 2019 — ACG Clinical Guideline: Hereditary Hemochromatosis (Kowdley et al., Am J Gastroenterol 2019)
Practice Gastrointestinal questions on FirstPassPA
Turn this outline into retention. 7,700+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.