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.
🔒 Free preview limit reached
Keep reading — start your free trial
You've read your 2 free diagnosis previews. Create your free account to unlock the full Hereditary Hemochromatosis outline — plus all 514 diagnoses, 3,500+ 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 (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)
Practice Gastrointestinal questions on FirstPassPA
Turn this outline into retention. 3,500+ 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. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants.