Elevated serum ferritin: Diagnosis and management 

Ferritin, the body's primary iron storage protein, is synthesized by the liver and regulated by the hormone hepcidin. It holds 10-20% of the body's total iron and also functions as an acute-phase reactant, serving as a marker of inflammation.¹

Alcohol consumption and fatty liver disease are the most common causes of elevated serum ferritin (SF). Damaged hepatocytes leak ferritin into the serum.  

Non-alcoholic fatty liver disease is now termed metabolic dysfunction associated steatotic liver disease (MASLD). This new term emphasises the key metabolic factors of insulin resistance, vascular dysfunction, dyslipidaemia and obesity and minimises stigma associated with the term ‘fatty’. MASLD is the most common liver disorder worldwide, affecting approximately 25% of the population.²  

Studies have demonstrated a link between alcohol consumption and elevated serum ferritin. Daily consumption of 2 or more standard units of alcohol may contribute to elevated SF. Repeating full iron studies after a period of abstinence may provide diagnostic clarification.  

Hereditary haemochromatosis (HH) and genetic iron-loading conditions are responsible for elevated SF in a minority of cases. HH is an autosomal recessive condition due to hepcidin deficiency, causing disruption of iron homeostasis, resulting in iron overload. Only 15% of patients with HH develop iron overload.  End organ damage is associated with SF levels raised persistently above 1000 µg/L. This results in iron deposition in the liver, pancreas, heart, endocrine glands, skin and joints.

Identification of this patient group with institution of regular venesection reduces the risk of end organ damage.²  Symptoms are insidious, often resulting in delayed diagnosis. 
 

In the presence of an initial raised SF level repeat iron studies should be performed. Patients should be advised to defer repeat testing until after any acute illnesses have resolved.

The key laboratory investigations in the evaluation of body iron stores are:

1. Serum ferritin: this may be elevated due to increased hepatic iron stores or other non-specific causes.
2. Transferrin saturation: transferrin binds iron. The transferrin saturation measures the percentage of available iron-binding sites on transferrin that are occupied by iron.

Further investigations are directed by clinical history and consideration of differential diagnosis. These may include HbA1c, creatinine, complete blood count, liver function tests, lipid studies and CRP.  

Note: Former guidelines advocated morning fasting iron studies. Evidence suggests that diurnal variation is not statistically significant.   
 

Acute illness

• Delay and repeat investigations after illness has resolved
• Investigation: CRP.

Exogenous iron supplementation

• Iron supplementation/infusion, blood transfusion
• History including over-the-counter supplements/alternative medicines
• Investigation: Repeat iron studies after withholding supplementation for a few days.

Metabolic dysfunction

• MASLD/NAFLD, metabolic syndrome, obesity, type II diabetes
• Elevated BMI, hypertension, impaired glucose tolerance
• Investigation: Lipid studies, HbA1c.

Alcohol consumption

• History and quantification
• Investigation: CBC, LFT with AST, coagulation studies, albumin.

Other causes of liver disease

• Viral hepatitis, autoimmune hepatitis
• Hepatomegaly, features of cirrhosis on examination, history of autoimmune disease
• Investigation: CBC, LFT with AST, coagulation studies, albumin, liver autoantibodies, directed viral serology, abdominal ultrasound.

Inflammatory conditions and chronic infection

• Autoimmune and inflammatory disease
• Investigation: CRP and serology as appropriate.

Malignancy

• Investigation: Targeted investigation, ensure screening is up to date.

Some anaemias with ineffective erythropoiesis 

• Consider myelodysplastic syndrome
• Consider B12 and folate deficiency
• Consider a congenital haemolytic anaemia
• Investigation: CBC, blood film, reticulocyte count
• Haemochromatosis
• Signs and symptoms of iron overload, family history
• Investigation: HFE genotype.

Diagnostic steps^1,3 include:

Initial clinical assessment

Clinical history:

• Assess alcohol consumption, risk factors for liver disease, acute illness, and red flags for malignancy, including ensuring screening is up to date. 
• Check over-the-counter medicine and supplement use, including whether iron supplements have been taken within the last month.

Clinical examination:

• Looking for signs of chronic liver disease, metabolic risk, inflammatory conditions, iron overload, infection and malignancy. 

Assess for iron overload

• Repeat iron studies, including ferritin and transferrin saturation, after any acute illness has resolved. 
• Borderline transferrin saturation levels should be repeated.

Assess for serious underlying disease

• Investigations should be directed based on clinical history and examination.
• Core investigations include CBC, CRP, LFT, HbA1c, creatinine and lipids.
• Consider other investigations according to likelihood of differential diagnosis.

Consider iron overload if transferrin saturation remains ≥ 45%

• HFE genotyping should be considered if transferrin saturation remains ≥ 45%.
• Haematology advice should be sought if the HFE genotype is inconsistent with HH and blood results are suggestive of iron overload. 

Identify high-risk groups

• Patients with persisting ferritin > 1000 μg/L should be referred for gastroenterology assessment depending on local health pathways.
• Paediatric advice should be sought for persisting elevated SF in children. Juvenile haemochromatosis is a rare condition caused by mutations in genes other than HFE.  
   

You arrange repeat blood tests to be done when he is well, including:

• serum ferritin
• transferrin saturation
• CBC
• LFT including AST
• CRP
• lipids.

Metabolic management

Metabolic conditions should be actively managed, including:

• hypertension
• hyperuricaemia
• hyperlipidaemia
• diabetes.

Lifestyle changes should be supported including smoking and alcohol cessation, dietary advice, weight loss and encouraging physical activity.  A modest 5-10% weight loss may be beneficial.  

Physical activity in the absence of weight loss has been shown to improve insulin sensitivity.  

Lifestyle modification support should be considered including green prescription and multidisciplinary comprehensive primary care team support.

If MASLD is suspected, the NAFLD fibrosis score or FIB4 should be calculated to stratify the risk and determine the need for further assessment.  Note that these algorithms both require AST, which will need to be specifically requested.  

Refer to local health pathways for MASLD monitoring, imaging and referral thresholds.   
 

Iron overload should be suspected if significant inflammation has been excluded, with a persistent raised ferritin (reference intervals vary with age and sex, some international reference intervals are inappropriately low for the NZ population) and transferrin saturation (≥ 45%) levels.

1 in 200 people of Caucasian descent are homozygous for the C282Y mutation.  The prevalence of risk alleles in Māori is unknown.

Of all the HFE genotypes, it is primarily C282Y homozygotes who have a high risk of iron overload. 

Compound heterozygous C282/H63D have a slightly increased risk of iron overload, but most compound heterozygotes with elevated ferritin have an additional cause, such as fatty liver disease.  

Males are more likely to develop iron overload.  

Further details on inheritance patterns and penetrance are available in the bpac^nz article, Identifying and managing hereditary haemochromatosis in adults.

Interpreting HFE genotype results

Homozygous C82Y/C282Y: Confirms hereditary haemochromatosis (HH) and is likely to be a primary cause of elevated SF.

Compound heterozygous C282Y/H63D: HH is likely to be a significant cause but look for contributing factors.

All other HFE genotypes: Not associated with genetic iron overload.

Symptoms and signs

These are insidious and non-specific and include:

• fatigue (can occur early)
• joint pain (can occur early)
• chronic liver disease sometimes progressing to cirrhosis and carcinoma
• recent studies have shown a mild increase in the prevalence of diabetes, whereas skin hyperpigmentation, hypogonadism, and cardiomyopathy were not increased compared to control populations.

Management

Therapeutic venesection should be arranged according to local health pathway processes if the patient meets the following criteria:

• genotype either homozygous C282Y/C282Y or compound heterozygous C282Y/H63D
• venesection guidelines current vary across the country
• elevated ferritin (a specific cut-off is poorly defined in guidelines)
• patients with a very high transferrin saturation and/or symptoms may benefit from venesection at lower ferritin levels
• other causes of elevated SF have been excluded or actively managed 
• patient age ≥ 16 years.

Individuals with HH are at increased risk of liver disease, which may cause fibrosis, cirrhosis and hepatocellular carcinoma (HCC).  

• All patients with confirmed HH and ferritin > 1000 ug/L should be referred for gastroenterology assessment.  
• Gastroenterology advice for persistently abnormal LFT in patients with confirmed HH should be sought.
• Liver health should be optimised for all HH patients.
• Care should be taken when prescribing hepatotoxic medications, including NSAIDS and antibiotics.  Consider a clinical pharmacist medication review.
• Clinicians should ensure patients with HH are vaccinated against hepatitis B and A.  
• Patients with HH and cirrhosis should be monitored for development of HCC. A plan for monitoring should be formulated in conjunction with a specialist gastroenterologist.  

Patient education

HH is a manageable lifelong condition requiring monitoring and maintenance venesection to remove iron and complications of iron overload.

Patients should be advised to:

• Minimise alcohol intake.
• Avoid alternative/herbal remedies.
• Avoid supplements, including iron supplementation and high-dose vitamin C supplements.
• Minimise red meat, offal and fortified products.
• Avoid raw seafood (increased risk of severe Vibrio vulnificus infection).

Family screening and testing

Family screening is advised for first-degree relatives of C282Y homozygotes aged ≥ 18 years.  Full iron studies are the preferred test.  

HFE genotype testing is indicated if: 

• transferrin saturation ≥ 45%, or
• ferritin ≥ 200 ug/L in women or ≥ 300 ug/L in men.

In relatives aged < 30 years with normal iron studies, consider repeating the iron studies between ages 30 and 40 years to exclude later development of iron overload.

HFE genetic testing of children in affected families is seldom indicated until they are aged ≥ 18 years, as significant iron overload from HH seldom occurs until adulthood.
 

This MedCase was created Dr Danuta Amelung, BHB, MbChB, FRNZCGP, AFRACMA, Dip. Paed, PGCertWHlth, PGDipTrvMed with expert review by Dr Ian Morison, Haematologist.