Guideline sources The following summarized guidelines for the evaluation and management of dysmetabolic hyperferritinemia are prepared by our editorial team based on guidelines from the Metabolic Hyperferritinemia Consensus Group (MHF-CG 2023) and the American Association for the Study of Liver Diseases (AASLD 2018). 1 2 Guidelines 1. Screening and diagnosis Risk factors: Recognize that insulin resistance and features of metabolic dysfunction are associated with specific alterations of iron metabolism regulation, which are epidemiologically linked with organ damage and clinical outcomes. B Recognize that the pathophysiology of this alteration of iron metabolism regulation seems to be triggered by lipotoxicity in the presence of permissive environmental and genetic determinants. B https://web.pathway.md/diseases/recx1YQ2VZ0pesNbl 1/3 6/29/23, 10:24 PM Dysmetabolic hyperferritinemia Pathway Diagnostic criteria: Consider defining the condition of hyperferritinemia related to metabolic dysfunction as metabolic hyperferritinemia. Consider grading the severity of metabolic hyperferritinemia according to serum levels of ferritin thresholds (grades 1-3). C Consider defining dysmetabolic iron overload syndrome as increased hepatic iron stores in patients with metabolic hyperferritinemia. C 2. Diagnostic investigations Serum ferritin levels: Consider measuring serum ferritin levels for noninvasive diagnosis and assessment of iron metabolism alteration, namely thr metabolic hyperferritinemia, associated with glucose and lipid metabolism dysregulation and with hepatic lipid accumulation. B Consider measuring serum ferritin levels after at least 3 months of lifestyle changes, if possible. C Magnetic resonance imaging: consider obtaining a noninvasive estimation of iron concentration in the liver by MRI in the context of a clinical trial, given the initial evidence that serum levels of ferritin might be associated with iron accumulation in tissue in patients with stable metabolic hyperferritinemia. Consider obtaining it in patients with high serum levels of ferritin (grade 2, but in particular, grade 3) and/or additional clinical risk factors for iron overload. Prefer iron concentration in tissues over serum ferritin levels, when available, for grading metabolic hyperferritinemia. B 3. Diagnostic procedures Liver biopsy: As per MHF-CG 2023 guidelines, do not perform a liver biopsy for the diagnosis of metabolic hyperferritinemia or dysmetabolic iron overload syndrome unless otherwise indicated for the management of an associated liver disease or for specific research purposes. D As per AASLD 2018 guidelines, consider performing a liver biopsy in patients with suspected nonalcoholic fatty liver disease, persistently high serum ferritin, and increased iron saturation, especially in the context of homozygote or heterozygote C282Y HFE mutation. E 4. Medical management Management of cardiovascular risk factors: focus the clinical management on lifestyle factors associated with increased risk of cardiometabolic risk factors (such as caloric intake and dietary patterns, alcohol intake, fructose and salt intake, and sedentary lifestyle) and the pharmacological control of cardiovascular risk factors. B Iron depletion therapy: consider initiating iron depletion therapy as an experimental therapy in patients with metabolic hyperferritinemia and dysmetabolic iron overload syndrome in the context of well-powered controlled trials. C https://web.pathway.md/diseases/recx1YQ2VZ0pesNbl 2/3 6/29/23, 10:24 PM Dysmetabolic hyperferritinemia Pathway 5. Therapeutic procedures Blood donation: recognize that blood donation is not contraindicated in patients with metabolic hyperferritinemia with controlled cardiovascular risk factors, without organ damage or other contraindications to phlebotomy. B References 1. Luca Valenti, Elena Corradini, Leon A Adams et al. Consensus Statement on the definition and classification of metabolic hyperferritinaemia. Nat Rev Endocrinol. 2023 Feb 17;1 12. Open 2. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67 1 328 357. Open https://web.pathway.md/diseases/recx1YQ2VZ0pesNbl 3/3