What is the appropriate workup for a patient with hemochromatosis and reported changes in cognition?

Workup for Hemochromatosis Patient with Cognitive Changes

A patient with hemochromatosis presenting with 3 weeks of cognitive changes requires urgent evaluation for brain iron deposition, particularly if they have aceruloplasminemia or severe iron overload, along with assessment for other neurological complications and metabolic derangements.

Immediate Neurological Assessment

Brain MRI with Iron Quantification

• Obtain brain MRI immediately to evaluate for iron deposition in the brain, particularly in patients with suspected aceruloplasminemia, as MRI can detect and quantify iron distribution in the brain 1
• Brain iron deposition can cause movement disorders, cerebellar syndrome, tremor, and cognitive dysfunction in hemochromatosis patients 2
• High-field T2-weighted MRI should be used to assess for hyperintense signals in white matter and evaluate for cerebellar or cerebral atrophy 2

Cognitive and Neurological Examination

• Document specific cognitive deficits: memory impairment, executive dysfunction, attention problems, and "brain fog" (reported in 60.4% of hemochromatosis patients in surveys) 1
• Assess for associated neurological symptoms including movement disorders, cerebellar signs, tremor, myoclonus, or parkinsonian features 2
• Evaluate for depression (38% prevalence in hemochromatosis patients), which can mimic or coexist with cognitive dysfunction 1

Systemic Iron Overload Assessment

Laboratory Evaluation

• Measure serum ferritin and transferrin saturation immediately to assess current iron burden 1
• Check complete blood count with reticulocytes to exclude anemia or other hematologic disorders 1
• Monitor hemoglobin levels, as anemia in a hemochromatosis patient may indicate another underlying condition requiring investigation 3
• Measure liver enzymes (ALT, AST) and platelet count, as ferritin >1,000 μg/L with elevated transaminases predicts cirrhosis in 80% of cases 1

Cardiac Evaluation

• Obtain ECG and echocardiography if severe iron overload is present (ferritin >1,000 μg/L), as cardiac iron deposition can cause arrhythmias and dysfunction 1
• Consider cardiac MRI with T2* relaxation time measurement if cardiac symptoms are present or if severe iron overload is documented 1, 3

Metabolic and Endocrine Assessment

Glucose and Endocrine Testing

• Check fasting glucose or HbA1c to evaluate for diabetes mellitus, a common complication of hemochromatosis 1
• Measure sex hormone concentrations (testosterone in men, estradiol in women) to assess for hypogonadotropic hypogonadism 1
• Consider thyroid function tests, as endocrine dysfunction can contribute to cognitive symptoms 1

Hepatic Assessment

• Perform non-invasive fibrosis assessment with transient elastography or FIB-4 score to evaluate for advanced liver disease 1
• If ferritin >1,000 μg/L or liver enzymes are elevated, consider liver biopsy to assess for cirrhosis 1
• Patients with cirrhosis require HCC screening with abdominal ultrasound every 6 months 1

Additional Considerations

Rule Out Alternative Causes

• Investigate for portosystemic encephalopathy if cirrhosis is present, though this is typically not the cause of cognitive dysfunction in hemochromatosis without hepatic insufficiency 2
• Check vitamin B12 and folate levels, especially if the patient has undergone numerous phlebotomies 1, 4
• Consider alcohol history, as chronic alcohol intake can cause both cognitive impairment and altered iron metabolism that mimics hemochromatosis 5

Genetic Confirmation

• If hemochromatosis diagnosis has not been genetically confirmed, obtain HFE gene testing (C282Y and H63D mutations) 1
• For patients of non-European origin or with atypical presentations, consider sequencing of non-HFE genes (HJV, TFR2, CP, SLC40A1) 1

Critical Pitfalls to Avoid

• Do not dismiss cognitive symptoms as "just depression" or aging—73.1% of hemochromatosis patients report psychological or cognitive difficulties, and this may represent true neurological involvement 1
• Failing to obtain brain MRI in patients with movement disorders or progressive cognitive decline may miss rare but serious neurological complications of iron overload 2
• Vitamin C supplements must be avoided, as they increase iron absorption and can worsen iron toxicity 1, 3
• Unexpected changes in ferritin or transferrin saturation should always be investigated, as significant fluctuations are not typical of hemochromatosis and may indicate another process 1, 4