What is the next step in managing a 45-year-old patient with excessive fatigue, erectile dysfunction, low fasting cortisol, normal ACTH and cosyntropin test response, normal TFTs and pituitary hormones, elevated ferritin, and normal TSAT?

Management of a 45-Year-Old with Fatigue, ED, and Elevated Ferritin

The next step in managing this patient should be genetic testing for hereditary hemochromatosis (HFE gene mutations), particularly p.C282Y, given the elevated ferritin level of 692 μg/L with normal transferrin saturation. 1

Clinical Assessment

This 45-year-old patient presents with:

• Excessive fatigue and erectile dysfunction
• Low fasting cortisol (4.4) with normal ACTH (12.5)
• Normal cosyntropin test response (cortisol 24 after 80 minutes)
• Normal thyroid function tests and pituitary hormones
• Elevated ferritin (692 μg/L)
• Normal transferrin saturation (42%)
• Negative family history
• No medications

Interpretation of Laboratory Findings

Iron Studies

• The elevated ferritin (692 μg/L) with normal transferrin saturation (42%) suggests possible early hemochromatosis or another cause of hyperferritinemia
• According to EASL guidelines, elevated ferritin levels (>300 μg/L in men) with normal-to-high transferrin saturation warrant further investigation 1
• The patient's symptoms of fatigue and erectile dysfunction align with common presentations of hemochromatosis 2

Adrenal Function

• The low fasting cortisol but normal response to cosyntropin testing indicates intact adrenal function
• The normal ACTH level (12.5) suggests the hypothalamic-pituitary-adrenal axis is functioning properly
• A cortisol response >500 nmol/L (or approximately 18 μg/dL) after cosyntropin administration is considered normal 3

Recommended Management Algorithm

1. Genetic testing for HFE mutations (particularly p.C282Y homozygosity or C282Y/H63D compound heterozygosity) 1

2. If genetic testing is positive:

   • Proceed with liver function tests and liver imaging (MRI for hepatic iron quantification)
   • Consider liver biopsy if ferritin >1000 μg/L (associated with 20-45% risk of cirrhosis) 1
   • Initiate therapeutic phlebotomy if confirmed hemochromatosis

3. If genetic testing is negative:

   • Evaluate for other causes of hyperferritinemia:
     • Inflammatory conditions
     • Malignancy (one of the most common causes of markedly elevated ferritin) 4
     • Metabolic syndrome and non-alcoholic fatty liver disease
     • Alcohol use

4. Additional workup:

   • Liver function tests and abdominal ultrasound to assess for hepatomegaly or liver disease
   • Fasting glucose to rule out diabetes
   • Joint examination for arthropathy (particularly second and third metacarpophalangeal joints)

Clinical Considerations

• Hemochromatosis often presents with fatigue, erectile dysfunction, and loss of libido, which align with this patient's symptoms 2
• According to the American Association for the Study of Liver Diseases, patients with hemochromatosis may present with these symptoms even before developing end-organ damage 2
• Early diagnosis and treatment of hemochromatosis can prevent progression to cirrhosis, diabetes, and other complications 5

Common Pitfalls to Avoid

1. Don't dismiss the elevated ferritin as incidental. Even with normal transferrin saturation, this finding warrants investigation, especially with symptoms consistent with iron overload.

2. Don't focus exclusively on adrenal insufficiency. The normal cosyntropin test effectively rules out primary adrenal insufficiency as the cause of symptoms.

3. Don't initiate phlebotomy without confirming the diagnosis. Therapeutic phlebotomy should only be started after confirming iron overload through genetic testing and/or additional studies.

4. Don't overlook other causes of hyperferritinemia. While hemochromatosis is a strong possibility, other conditions including malignancy, inflammatory disorders, and metabolic syndrome must be considered, particularly if genetic testing is negative.