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, especially C282Y homozygosity or C282Y/H63D compound heterozygosity), 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.
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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?
ANon-HFE iron gene panel testing
BHFE gene mutation analysis on blood
CHepatic MRI with iron quantification
DLiver biopsy with hepatic iron index
Reveal answer & full explanation
Correct answer: B — HFE gene mutation analysis on blood
ANon-HFE iron gene panel testing
BHFE gene mutation analysis on blood✓
CHepatic MRI with iron quantification
DLiver biopsy with hepatic iron index
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.
Once both fasting screening labs (transferrin saturation AND ferritin) are elevated, the guideline-endorsed next step is HFE genotyping for C282Y and H63D. C282Y homozygosity (or C282Y/H63D compound heterozygosity with overload) confirms the diagnosis noninvasively.
The AASLD diagnostic pathway is elevated Tsat plus ferritin, then HFE testing, with liver evaluation reserved for staging only if needed.
Why the others are wrong
Hepatic MRI with iron quantification is a valid noninvasive way to quantify liver iron and 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 was historically the gold standard but is 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.
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?
AIneffective erythropoiesis suppressing hepcidin and raising iron uptake
BIncreased ferroportin degradation limiting enterocyte iron export
CRepeated red-cell transfusions delivering iron beyond storage capacity
DInappropriately low hepcidin allowing excess dietary iron absorption
Reveal answer & full explanation
Correct answer: D — Inappropriately low hepcidin allowing excess dietary iron absorption
AIneffective erythropoiesis suppressing hepcidin and raising iron uptake
BIncreased ferroportin degradation limiting enterocyte iron export
CRepeated red-cell transfusions delivering iron beyond storage capacity
DInappropriately 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.
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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 (or C282Y/H63D with iron overload) establishes the diagnosis. 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 both abnormal → 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 >45/50%<br/>and ferritin elevated?}
C -->|No| D[Consider other diagnoses]
C -->|Yes| E[HFE genotype<br/>C282Y, H63D]
E --> F{C282Y/C282Y or<br/>C282Y/H63D with overload?}
F -->|Yes| G[Hereditary hemochromatosis]
F -->|No| H[Consider non-HFE / secondary iron overload<br/>± liver biopsy]
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 cirrhotic patients
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.
Hepatocellular carcinoma surveillance only if cirrhotic; non-cirrhotic HH does not require 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 2019 — AASLD Practice Guidance on Hemochromatosis (Bacon et al., Hepatology 2011; AASLD 2019 update)
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)
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