In a 48‑year‑old woman with normal complete blood count, iron studies, transferrin saturation, hemoglobin A1c, and thyroid function, but borderline elevated low‑density lipoprotein cholesterol and high vitamin B12, who is taking estrogen‑containing hormone replacement therapy and semaglutide, what is the most likely cause of an isolated elevated ferritin?

Elevated Ferritin in a Woman on HRT and Semaglutide: Most Likely Cause

The isolated elevated ferritin of 1400 ng/mL with normal transferrin saturation, normal iron studies, and normal inflammatory markers most likely represents secondary hyperferritinemia from metabolic syndrome/insulin resistance, potentially exacerbated by estrogen-containing hormone replacement therapy, rather than true iron overload. 1, 2

Immediate Diagnostic Priority: Rule Out Iron Overload

You must measure fasting transferrin saturation immediately to differentiate true iron overload from secondary causes. 1, 3 This single test determines your entire diagnostic pathway:

• If transferrin saturation ≥45%: Suspect primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations 1
• If transferrin saturation <45%: Iron overload is unlikely; over 90% of cases are caused by inflammation, metabolic syndrome, liver disease, or tissue damage 1

Why This Pattern Suggests Metabolic/Hormonal Etiology

Metabolic Syndrome as Primary Driver

The constellation of findings strongly points to metabolic dysfunction:

• LDL of 110 mg/dL indicates dyslipidemia, a core component of metabolic syndrome 2
• Ferritin elevation with normal transferrin saturation is the classic pattern of metabolic syndrome-associated hyperferritinemia, where ferritin reflects hepatocellular injury and insulin resistance rather than iron overload 1, 2
• Patients with metabolic syndrome and persistent hyperferritinemia (resistant to dietary modification) have a 77% prevalence of NASH, with ferritin levels correlating with severity of hepatic steatosis 2

Estrogen's Role in Ferritin Elevation

Hormone replacement therapy independently elevates ferritin through multiple mechanisms:

• Estrogen increases hepatic ferritin synthesis as an acute-phase reactant 4, 5
• HRT can cause mild hepatocellular inflammation, releasing ferritin independent of iron stores 5
• The combination of metabolic syndrome plus estrogen creates additive ferritin elevation 2

Semaglutide Context

Semaglutide itself does not directly cause hyperferritinemia, but the clinical context matters:

• If she recently started semaglutide for weight loss, this confirms underlying metabolic syndrome 2
• As metabolic parameters improve with weight loss, ferritin should gradually decline 2

The Markedly Elevated B12 (1400 pg/mL): Clinical Significance

Elevated B12 in this context is NOT a cause of elevated ferritin but may share common etiologies:

• Liver disease causes both elevated ferritin and elevated B12 through hepatocellular release 5
• Metabolic syndrome/NAFLD can elevate both markers simultaneously 2
• B12 >1000 pg/mL warrants evaluation for occult malignancy, myeloproliferative disorders, or liver disease 6

Algorithmic Diagnostic Workup

Step 1: Confirm Pattern with Transferrin Saturation

Order fasting transferrin saturation (morning sample preferred, avoid iron supplements/iron-rich foods for 24 hours prior). 1, 3

Step 2: If Transferrin Saturation <45% (Expected Scenario)

Evaluate for metabolic liver disease:

• Comprehensive metabolic panel including ALT, AST, albumin, bilirubin 1
• Inflammatory markers: CRP and ESR to exclude occult inflammation 1
• Abdominal ultrasound to assess for hepatic steatosis (NAFLD) 1
• Fasting glucose and insulin to calculate HOMA-IR (insulin resistance index) 2

Expected findings supporting metabolic etiology:

• Mildly elevated ALT (often 1.5-2× upper limit of normal) 2
• Fatty liver on ultrasound 1, 2
• Insulin resistance (HOMA-IR >2.5) 2
• Normal or mildly elevated CRP 1

Step 3: Risk Stratification by Ferritin Level

At ferritin 1400 ng/mL, she falls in the intermediate-risk category:

• Ferritin <1000 μg/L: 94% negative predictive value for advanced fibrosis; low risk 1
• Ferritin 1000-10,000 μg/L: Requires additional evaluation for fibrosis risk 1
• Ferritin >10,000 μg/L: Rarely represents simple metabolic disease; urgent specialist referral 1, 6

Calculate fibrosis risk using non-invasive scores:

• FIB-4 score or NAFLD Fibrosis Score to stratify need for advanced imaging 1
• If high-risk score, proceed to liver MRI or transient elastography 1

Step 4: Exclude Other Secondary Causes

Given the clinical context, systematically rule out:

• Chronic alcohol consumption: Detailed history (>14 drinks/week for women) 1
• Viral hepatitis: Hepatitis B surface antigen, hepatitis C antibody 1
• Occult malignancy (given B12 >1400): CBC with differential, consider age-appropriate cancer screening 6
• Hemolysis or cell necrosis: LDH, haptoglobin, creatine kinase 1, 5

Management Strategy

Primary Intervention: Treat Metabolic Syndrome

The treatment target is the underlying metabolic dysfunction, NOT the elevated ferritin itself. 1, 7

Lifestyle modifications:

• Weight loss goal of 7-10% body weight 2
• Mediterranean diet with reduced refined carbohydrates 2
• Regular aerobic exercise (150 minutes/week) 2

Continue semaglutide as it directly addresses insulin resistance and should improve ferritin over time 2

Optimize cardiovascular risk factors:

• Consider statin therapy for LDL 110 mg/dL if additional risk factors present 1
• Monitor A1C every 3-6 months (currently normal but at risk) 2

HRT Considerations

Do NOT discontinue HRT solely based on elevated ferritin, but consider:

• Reassess indication and duration of HRT therapy 4
• If ferritin continues rising despite metabolic improvement, trial discontinuation may help differentiate contribution 4
• Transdermal estrogen may have less hepatic first-pass effect than oral formulations 4

Monitoring Plan

Recheck ferritin and transferrin saturation in 3-6 months:

• Declining ferritin with metabolic improvement confirms diagnosis 2
• Rising ferritin or development of elevated transferrin saturation requires hepatology referral 1

Serial monitoring of liver enzymes and fibrosis scores every 6-12 months 1

Critical Pitfalls to Avoid

Never Diagnose Iron Overload Without Elevated Transferrin Saturation

Ferritin alone cannot distinguish true iron overload from secondary causes. 1, 3 In the general population with normal transferrin saturation, iron overload is NOT the most common cause of elevated ferritin. 1

Do Not Initiate Phlebotomy

Therapeutic phlebotomy is contraindicated when transferrin saturation is <45%, as iron is sequestered in storage sites and unavailable for erythropoiesis. 1, 7 Phlebotomy will not improve ferritin and may worsen functional iron deficiency. 7

Do Not Supplement Iron

Iron supplementation is absolutely contraindicated with ferritin >300 ng/mL and low transferrin saturation, as this represents inflammatory iron block where iron is trapped in storage sites. 7 Supplementation will not improve anemia and may promote oxidative stress. 7

Recognize When to Escalate

Immediate hepatology referral if:

• Ferritin rises above 4000-5000 ng/mL with persistent symptoms 1, 6
• Transferrin saturation becomes ≥45% on repeat testing 1
• ALT >2× upper limit of normal with ferritin >1000 μg/L 1
• Platelet count <200,000/μL (suggests advanced fibrosis) 1
• Evidence of cirrhosis on imaging or clinical examination 1

Expected Clinical Course

With appropriate metabolic management, ferritin should gradually decline over 6-12 months. 2 Persistent or rising ferritin despite weight loss and metabolic improvement suggests:

• Unrecognized liver disease requiring biopsy 1
• Contribution from HRT requiring trial discontinuation 4
• Occult inflammatory or neoplastic process 6, 5

The combination of normal CBC, iron studies, A1C, and thyroid function with isolated hyperferritinemia and dyslipidemia creates a highly specific pattern for metabolic syndrome-associated hyperferritinemia in a woman on HRT. 2, 1