Hereditary Hemochromatosis & Wilson Disease
Two metals, two genes: catch the overload before the organs fail
Hereditary hemochromatosis
Mechanism. Classic hemochromatosis is autosomal recessive homozygosity for HFE C282Y, common in people of northern European ancestry. Faulty iron sensing leaves hepcidin inappropriately low, so ferroportin keeps exporting iron from duodenal enterocytes and macrophages; transferrin saturates and non-transferrin-bound iron deposits in the liver, pancreas, heart, joints, pituitary and skin. Penetrance is low. Men present in their 40s–50s; women present later, usually after menopause, because menstruation and pregnancy shed iron.
- Fatigue and arthralgia—often the first symptoms
- 2nd/3rd MCP arthropathy with hook-like osteophytes; chondrocalcinosis and CPPD
- Bronze-gray skin and diabetes ("bronze diabetes," with cirrhosis the classic late triad)
- Hepatomegaly, cirrhosis and hepatocellular carcinoma
- Restrictive, later dilated, cardiomyopathy with arrhythmias
- Hypogonadotropic hypogonadism: low libido, impotence, amenorrhea
Infections. Siderophilic organisms thrive: Vibrio vulnificus from raw oysters or seawater wounds causes fulminant sepsis with hemorrhagic bullae, and Yersinia enterocolitica and Listeria monocytogenes infections are more common. Deferoxamine acts as a siderophore for Yersinia and Rhizopus, raising their risk during chelation.
Hemochromatosis: diagnosis and treatment
- Iron studiesFasting transferrin saturation >45% with a raised ferritin; ferritin alone is nonspecific (acute-phase reactant raised by inflammation, alcohol and MASLD).
- HFE genotypingC282Y homozygosity confirms the diagnosis.
- Stage the liverFerritin >1000 ng/mL or raised aminotransferases → liver biopsy or MRI iron quantification with elastography; ferritin <1000 with normal enzymes → no biopsy needed.
- PhlebotomyAbout 500 mL weekly until ferritin is 50–100 ng/mL, then maintenance every few months.
Treatment details. If anemia or heart failure prevents phlebotomy, chelate with deferoxamine (parenteral) or deferasirox (oral). Patients avoid iron and vitamin C supplements (vitamin C boosts iron absorption), alcohol and raw shellfish; a strict low-iron diet is unnecessary, and tea, if anything, reduces iron absorption. Screen first-degree relatives, especially siblings, with transferrin saturation, ferritin and HFE genotyping.
Phlebotomy improves fatigue, skin pigmentation, liver enzymes and cardiomyopathy, but not established cirrhosis, arthropathy or hypogonadism—cirrhotic patients still need HCC surveillance after iron depletion.
Wilson disease
Mechanism. Autosomal recessive mutations in ATP7B, a copper-transporting ATPase on chromosome 13, prevent hepatocytes from excreting copper into bile and loading it onto ceruloplasmin. Copper accumulates in the liver, then spills into the basal ganglia, cornea, kidneys and red cells. Most patients present between ages 5 and 35; consider Wilson disease in anyone under 40 with unexplained liver disease or a new movement or psychiatric disorder.
Hepatic disease. Presentations range from an asymptomatic ALT rise to chronic hepatitis, cirrhosis or acute liver failure. Fulminant Wilson disease has a signature: Coombs-negative hemolysis from copper released by necrotic hepatocytes, a very low ALP (ALP:bilirubin ratio <4), AST:ALT >2.2 and acute kidney injury. It is essentially fatal without liver transplantation because chelators act too slowly.
Neuropsychiatric disease. Basal ganglia copper causes tremor (classically "wing-beating"), dysarthria, dystonia, drooling and parkinsonism, with depression, personality change, psychosis or falling school performance. Kayser-Fleischer rings—golden-brown copper in Descemet membrane at the corneal margin—appear on slit-lamp exam in about 95% of patients with neurologic disease but only about half of those with liver disease alone.
Wilson disease: diagnosis and treatment
Diagnosis. Start with serum ceruloplasmin (<20 mg/dL), 24-hour urinary copper (>100 μg/day) and a slit-lamp exam. Ceruloplasmin is an acute-phase reactant and can be falsely normal. Total serum copper misleads because most circulating copper is ceruloplasmin-bound. Unclear cases are settled by hepatic copper content on biopsy or ATP7B genetic testing.
Treatment. Chelate with D-penicillamine (hypersensitivity, proteinuria or nephrotic syndrome, lupus-like syndrome, marrow suppression; give pyridoxine) or the better-tolerated trientine, often preferred for neurologic disease because penicillamine can transiently worsen neurologic symptoms. Zinc induces enterocyte metallothionein, which traps dietary copper; it is used for maintenance and for presymptomatic patients. Patients limit copper-rich foods (shellfish, liver, nuts, chocolate), and therapy is lifelong. Liver transplantation, which corrects the defect, is indicated for fulminant failure. Siblings carry a 25% risk and are screened with ceruloplasmin, liver tests, urine copper, slit-lamp exam and ATP7B testing, so treatment can start before symptoms.
| Feature | Hemochromatosis | Wilson disease |
|---|---|---|
| Gene | HFE C282Y (autosomal recessive) | ATP7B (autosomal recessive) |
| Metal and defect | Iron: low hepcidin, excess absorption | Copper: impaired biliary excretion |
| Typical age | Men 40s–50s; women after menopause | 5–35; suspect if under 40 |
| Key tests | Transferrin saturation, ferritin, HFE genotype | Ceruloplasmin, 24-h urine copper, slit lamp |
| Treatment | Phlebotomy; deferoxamine if anemic | Penicillamine or trientine; zinc; transplant if fulminant |