What is hemochromatosis in an adult patient with a coarsened liver echotexture and possible history of metabolic syndrome?

What is Hemochromatosis?

Hemochromatosis is a genetic disease characterized by increased transferrin saturation and progressive iron accumulation primarily in the liver, caused by deficiency or impairment in hepcidin synthesis, leading to excessive intestinal iron absorption that can result in organ damage including cirrhosis, diabetes, cardiomyopathy, and death if untreated. 1

Pathophysiology

Hemochromatosis results from pathogenic variants in genes regulating hepcidin production or function, which leads to:

• Increased intestinal iron absorption and iron release from macrophages, creating an expanded circulating iron pool reflected by elevated transferrin saturation 1
• Progressive iron deposition primarily in parenchymal cells of the liver (peri-portal hepatocytes initially), not Kupffer cells or the spleen 1, 2
• Tissue damage and organ failure when iron accumulation exceeds approximately 20 grams of parenchymal iron storage 1

The disease evolves through distinct stages: clinically insignificant iron accumulation (0-20 years, 0-5g storage), iron overload without disease (20-40 years, 10-20g storage), and finally iron overload with organ damage (>20g storage) 1

Genetics

• HFE p.Cys282Tyr homozygosity is by far the most common genetic variant in individuals of European origin 1
• Only approximately 70% of C282Y homozygotes demonstrate elevated ferritin, indicating incomplete penetrance 3
• Fewer than 10% of C282Y homozygotes develop full clinical manifestations such as cirrhosis, diabetes, and skin pigmentation 3
• In non-European populations or those without C282Y mutations, rarer variants in HFE or non-HFE genes cause the disease 1

Clinical Manifestations

Common Symptoms and Signs

• Weakness, fatigue, and greyish-brown skin discoloration are typical presenting features 1
• Males are affected significantly more frequently than females, with disease prevalence increasing with age 1
• At early stages, the disease is usually asymptomatic 1

Organ-Specific Damage

• Liver: Hepatomegaly, elevated liver enzymes, cirrhosis, and hepatocellular carcinoma 1, 4
• Pancreas: Type 2 diabetes mellitus (approximately 50% of patients), particularly with hepatomegaly 1, 5
• Heart: Cardiomyopathy and heart failure 1, 4
• Skin: Melanoderma (bronze pigmentation) 4, 6
• Joints: Early-onset atypical arthropathy, often in non-weight-bearing joints, which is not reversible even with treatment 1, 4
• Endocrine: Sexual dysfunction, hypogonadism, testicular atrophy 1, 7, 4

Diagnosis

Biochemical Testing

• Transferrin saturation (TS) ≥45% and elevated serum ferritin are the primary screening tests 3
• Fasting TS exceeding 50% for women and 60% for men has sensitivity of 0.92 and specificity of 0.93 1
• Important caveat: Transferrin saturation can also be increased in advanced cirrhosis, low transferrin, acute liver failure, and acute liver injury, which may be confused with hemochromatosis 1

Genetic Testing

• Strongly recommended for individuals with elevated TS and ferritin, unexplained persistently elevated TS, or first-degree relatives of confirmed cases 1
• Testing for HFE mutations (particularly p.Cys282Tyr homozygosity) should be performed after informed consent 1

Imaging and Biopsy

• Patients with increased liver iron on MRI or liver biopsy should be clinically assessed and biochemically tested 1
• Liver biopsy documents increased hepatic iron concentrations associated with elevated ferritin 1

Target Populations for Evaluation

High Priority Groups 1

• First-degree relatives of confirmed hemochromatosis cases
• Patients with unexplained liver disease or abnormal serum iron markers
• Type 2 diabetes with hepatomegaly, elevated liver enzymes, or atypical cardiac disease
• Individuals with unexplained elevation of liver enzymes or radiologic detection of enhanced liver attenuation
• Patients with early-onset atypical arthropathy, cardiac disease, or sexual dysfunction

Context for Your Patient

In an adult with coarsened liver echotexture and possible metabolic syndrome, hemochromatosis should be considered as:

• Chronic liver disease (including metabolic syndrome) can cause iron overload separate from hereditary hemochromatosis 3
• The coarsened liver texture may represent cirrhosis from iron overload or metabolic dysfunction-associated liver disease 1
• Check transferrin saturation and ferritin to distinguish between hemochromatosis and metabolic syndrome-related iron overload 1, 3

Prognosis and Mortality

• Major causes of death: Decompensated cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy, occurring 10- to 119-fold higher than expected 1
• Survival is normal when treatment is initiated before development of cirrhosis or diabetes 1
• Early diagnosis before age 40 and before organ damage is critical to prevent mortality 1

Treatment Principles

• Phlebotomy (venesection) is the mainstay of therapy to achieve iron depletion and normalize body iron stores 8, 9
• Treatment goals include early diagnosis to prevent organ damage, screening asymptomatic cases to reduce mortality, and adequate iron removal 1
• Some manifestations are reversible (skin pigmentation, cardiac damage) while others are not (liver cirrhosis, endocrine damage, arthropathy) 4
• Lifelong vigilant follow-up and maintenance treatment are required for all cases 1