What is hemochromatosis?

What is Hemochromatosis

Hemochromatosis is a genetic disorder of iron homeostasis characterized by increased transferrin saturation and progressive iron accumulation primarily in the liver, caused by deficiency or impairment in hepcidin synthesis or function due to pathogenic gene variants. 1

Definition and Core Pathophysiology

Hemochromatosis is a disease of genetic origin defined by increased transferrin saturation and liver iron overload in the absence of anemia or reticulocytosis. 1 The fundamental defect involves:

• Hepcidin deficiency or dysfunction due to pathogenic variants in genes regulating hepcidin production or function 1
• Increased intestinal iron absorption and enhanced iron release from macrophages 1
• Expanded circulating iron pool reflected by elevated transferrin saturation, which is the diagnostic hallmark of the disease 1, 2
• Progressive body iron accumulation that predominantly manifests in the liver, not the spleen 1

Genetic Basis

The most common genetic cause varies by ancestry:

• C282Y homozygosity in the HFE gene (located on chromosome 6p) accounts for more than 90% of hemochromatosis cases in individuals of European origin 1
• Prevalence of C282Y homozygosity is approximately 1 in 200 people of Northern European descent 1, 2
• Compound heterozygosity (C282Y/H63D) accounts for only 3-5% of cases 1
• Non-HFE hemochromatosis is caused by rarer variants in other genes (such as TFR2, HJV, HAMP, or SLC40A1) and occurs in non-European populations or Europeans without HFE mutations 1

Clinical Manifestations and Organ Damage

Early Disease Stages

At early stages, hepatic iron deposition primarily affects periportal hepatocytes but not Kupffer cells, and spleen iron overload is typically absent. 1

Progressive Complications if Untreated

The disease can result in severe morbidity and mortality through:

• Liver complications: fibrosis, cirrhosis, and hepatocellular carcinoma 1
• Metabolic complications: diabetes and osteoporosis 1
• Musculoskeletal: arthropathy 1
• Severe or early-onset disease: hypogonadotrophic hypogonadism, hypothyroidism, and heart failure 1

Common Symptoms and Signs

Typical presentations include weakness, fatigue, and greyish-brown skin discoloration. 1 Males are affected significantly more frequently than females, and disease prevalence increases with age. 1

Diagnostic Approach

Biochemical Markers

Provisional iron overload is diagnosed based on serum iron parameters:

• Females: TSAT >45% and ferritin >200 µg/L 1
• Males and post-menopausal women: TSAT >50% and ferritin >300 µg/L 1

Genetic Testing

In patients homozygous for p.Cys282Tyr in HFE, elevated serum iron parameters are sufficient to diagnose hemochromatosis. 1 For patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires hepatic iron overload on MRI or liver biopsy. 1

Important Caveat

Transferrin saturation can also be increased in patients with advanced cirrhosis, low transferrin, acute liver failure, or acute liver injury, which may be confused with hemochromatosis. 1 Hepcidin measurement is not necessary for diagnosis, as persistently increased transferrin saturation is a sufficiently specific marker of hepcidin deficiency. 1

Treatment and Prognosis

Phlebotomy Therapy

Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy, and other complications. 1 Treatment targets are:

• Induction phase: ferritin <50 µg/L 1
• Maintenance phase: ferritin <100 µg/L 1

Prognostic Importance

Survival is normal in patients treated before the development of cirrhosis or diabetes. 2 The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. 1 Patients with advanced fibrosis should be included in a screening program for hepatocellular carcinoma. 1

Penetrance Considerations

Even among C282Y homozygotes, penetrance is incomplete—while 100% have elevated transferrin saturation, only 58% develop progressive tissue iron overload. 1, 2 This makes hemochromatosis a multifactorial disease where genetic and lifestyle cofactors (especially alcohol and dysmetabolic features) significantly modulate clinical expression. 2