CMAJ CME Practice

Decisions A 42-year-old man with elevated ferritin

Matthew B. Lanktree MD PhD, Bekim Sadikovic PhD, Mark A. Crowther MD MSc

Competing interests: None A 42-year-old businessman of South Asian conditions may lead to elevated ferritin.2 Envi- declared. descent presents with a prolonged history of ronmental exposures including diet, alcohol and This article has been peer fatigue and bothersome joint pain in his medications, particularly iron administered reviewed. hands and wrists. The patient takes metformin orally or intravenously, can also elevate ferritin Correspondence to: for type 2 diabetes and ramipril for hyperten- and increase the risk of pathological iron accu- Matthew Lanktree, sion. He consumes 3 martinis per night and mulation. Elevated ferritin in the context of ele- ­matthew.lanktree​ does not smoke. A physical examination shows vated transferrin saturation suggests iron @­medportal.ca no active joints, and his abdomen is normal ­accumulation.2 CMAJ 2015. DOI:10.1503 with no evidence of chronic liver disease. Pre- /cmaj.140259 vious laboratory investigations showed ele- What investigations should be done? vated ferritin (660 [normal < 300] µg/L) and A detailed history should be taken and a physical hemoglobin (178 [normal 115–165] g/L), and examination should be performed. In addition, normal liver enzyme levels. iron stores should be assessed by measuring transferrin saturation, and renal function should What is the most likely diagnosis? be assessed by measuring serum creatinine. Alcoholic and nonalcoholic fatty liver disease Chronic hepatitis infection and inflammation can are the most likely causes for the patient’s ele- be ruled out by serology and by determining the vated ferritin, but hereditary hemochromatosis is erythrocyte sedimentation rate, respectively. The also possible. Hereditary hemochromatosis is a patient should undergo investigations to assess genetic condition in which elevated iron stores for metabolic syndrome, including glycated lead to iron deposition in the liver, heart, pan- he­moglobin, fasting glucose and a lipid profile. creas, skin, joints, pituitary gland and testis, Finally, liver ultrasonography should be done to resulting in cirrhosis of the liver, heart failure, determine whether nonalcoholic fatty liver dis- diabetes, skin bronzing, arthritis, endocrine ease and cirrhosis are present.2 abnormalities and cancer.1 However, the classic “bronze diabetes” presentation is uncommon.1 Should the patient undergo genetic testing for hemochromatosis? What other diagnoses should be Genetic testing should not be used to screen for considered? hemochromatosis, but current guidelines3,4 sug- Acute and chronic inflammation resulting from gest testing in patients with elevated transferrin infection, malignant growths, renal failure, liver saturation (> 0.45%) and ferritin (> 300 µg/L) disease, metabolic syndrome and autoimmune (Box 1). Testing typically involves genotyping two polymorphisms, C282Y and H63D, in the Box 1: Summary of recommendations from current clinical hemochromatosis gene (HFE). A positive result guidelines3,4 is defined as two copies (homozygosity) of the • Genetic testing should not be used to screen for hemochromatosis. C282Y allele, or a C282Y allele on one chromo- • Patients with elevated transferrin saturation (> 0.45%) and ferritin some and an H63D allele on the other chromo- 5 (> 300 μg/L) should undergo testing for the C282Y and H63D alleles of some (compound heterozygosity). Less than the HFE gene. 0.5% of people with European ancestry are • Phlebotomy should be performed in patients with elevated transferrin homozygous for C282Y, with even lower preva- saturation and ferritin who have a positive result on genetic testing. lences in other ethnicities.5 Although C282Y • Patients who show evidence of iron overload, but who do not have a homozygosity is found in about 80% of patients positive result on genetic testing, should still be considered for with clinical hemochromatosis, iron overload phlebotomy or liver biopsy if no other cause is apparent. will not develop in 60%–80% of patients with a • Elevated ferritin is very sensitive, but not specific, for iron-related liver positive test result.3 Other genetic causes of damage. hemochromatosis have been described, and iron

820 CMAJ, August 11, 2015, 187(11) ©2015 8872147 Canada Inc. or its licensors Practice overload may still develop in patients with a and glycated hemoglobin results suggested ade- negative result on standard HFE testing, particu- quate glucose control while taking metformin. larly if the patient is not of European descent.3 Mildy elevated triglycerides and reduced high- density lipoprotein cholesterol were present; What is this patient’s prognosis? however, a waist circumference of 88 cm In the presence or absence of a positive result on excluded­ a diagnosis of metabolic syndrome. A HFE testing, patients with biochemical evidence transferrin saturation of 60% suggested hemo- of iron overload are at risk of cirrhosis of the chromatosis, but genetic testing showed no cop- liver, cardiomyopathies, arthropathies and endo- ies of the C282Y allele and a single copy of the crinopathies resulting from the accumulation of H63D allele. Despite these results, the patient nontransferrin-bound iron. Hemochromatosis- was counselled that his clinical presentation was related cirrhosis typically occurs in patients with consistent with iron overload and arrangements ferritin levels higher than 1000 μg/L.3,4 Less than were made for therapeutic phlebotomy, which 10% of patients with HFE hemochromatosis would assist in confirming a diagnosis of hemo- show end-organ manifestations.4 chromatosis. In addition, the patient was coun- selled to stop consuming alcohol. Are further investigations required if hemochromatosis is diagnosed? References In cases of hemochromatosis with a ferritin level 1. Pietrangelo A. Hereditary hemochromatosis — a new look at an old disease. N Engl J Med 2004;350:2383-97. higher than 1000 μg/L, a biopsy of the liver 2. Camaschella C, Poggiali E. Towards explaining “unexplained should be considered.3 Initial noninvasive inves- hyperferritinemia.” Haematologica 2009;94:307-9. tigation with transient elastography can identify 3. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010;​ advanced fibrosis and cirrhosis, although access 53:3-22. to such imaging may be limited in smaller cen- 4. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and man- 3 agement of hemochromatosis: 2011 practice guideline by the tres. In patients with hemochromatosis-induced American Association for the Study of Liver Diseases. Hepatology cirrhosis of the liver, ultrasound surveillance for 2011;54:328-43. 5. Steinberg KK, Cogswell ME, Chang JC, et al. Prevalence of hepatocellular carcinoma should be performed C282Y and H63D mutations in the hemochromatosis (HFE) every 6 to 12 months.4 Because cardiac involve- gene in the United States. JAMA 2001;285:2216-22. ment is unusual, electrocardiography and echo- Affiliations: Department of Medicine (Lanktree, Crowther) cardiography are reserved for patients with clini- and Pathology (Sadikovic, Crowther), McMaster University, cal indications.3 Radiological evaluation of Hamilton, Ont. affected joints is appropriate.3 Contributors: All of the authors contributed to the conception of the article and the fictitious patient. Matthew Lanktree drafted the manuscript. Bekim Sadikovic and Mark Crowther revised Does this patient require phlebotomy? the manuscript for important intellectual content. All of the Phlebotomy is a safe procedure that is both ther- authors approved the final version submitted for publication. apeutic and diagnostic for hemochromatosis. It Acknowledgements: The authors thank Dr. Bruce Lanktree should be performed in patients with elevated and Dr. Guillaume Paré for their valuable contributions to the ferritin and transferrin saturation.3 A patient’s development of the fictitious patient and for providing feed- response to phlebotomy is diagnostic; patients back on the final manuscript. with pathological iron overload will require mul- tiple phlebotomies, whereas patients with other Decisions is a series that focuses on practical causes of elevated ferritin will show a rapid evidence-based approaches to common presenta- decrease in ferritin.3 The recommended schedule tions in primary care. The articles address key involves biweekly phlebotomy (500 mL), with decisions that a clinician may encounter during ini- measurement of hemoglobin and ferritin at each tial assessment. The information presented can visit, continuing until the patient’s ferritin level usually be covered in a typical primary care appoint- is less than 50 μg/L.3 ment. Articles should be no longer than 650 words, may include one box, figure or table and should Case resolution begin with a very brief description (75 words or Investigations for secondary causes of elevated less) of the clinical situation. The decisions ad- ferritin (i.e., creatinine, erythrocyte sedimenta- dressed should be presented in the form of tion rate, hepatitis serology and ultrasonography questions. A box providing helpful resources for the patient or physician is encouraged. of the liver) had normal results. Fasting glucose

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