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Clinical approach to increased serum ferritin

Clinical approach to increased serum ferritin. Yuly Paulin Mendoza DAS hepatology - University of Bern 14 th November 2018. Female B.B. Born 18.9.55. Referred Sep 2018 from obesity consultation for increased serum ferritin . Asymptomatic Medical and personal history

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Clinical approach to increased serum ferritin

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  1. Clinicalapproachtoincreasedserumferritin Yuly Paulin Mendoza DAS hepatology - University of Bern 14thNovember 2018

  2. Female B.B. Born 18.9.55 ReferredSep 2018 fromobesityconsultationforincreasedserumferritin. Asymptomatic Medical and personal history Obesesinceher30s; 2016 Sleeve-Gastrectomy (reduction 48kg – initial 148kg now 100 kg); Depression No alcohol, No smoking. Medication: VitaminD3, Vitamin B12, Vitamins, Spurenelemente, Amitriptylin 50mg/day, Trazodon 100mg/day

  3. Physicalexamination, US and TE Physicalexamination: 63 yearold160cms, 100kg, BMI 39 kg/m2 Bloodpressure149/80 mmHg Waistcircumference110 cm No spider naevi, no ascitis, no asterixis, No lower edema LiverStiffnessby TE 11.09.2018: 3.1 ± 0.7kPa, IQR/Med 23%, CAP 220 ± 49 dB/m (10/10 valide Messungen) Abdominal ultrasound11.09.2018 Hepatic steatosis, no evidence of a significant Liver fibrosis. Cholecystolithiasis.

  4. Laboratory test

  5. WhenFerritinishigh, themost crucial questionstoaskare: isitsecondaryto a knownclinicalcondition, and isitassociatedwithironoverload?

  6. Causes of hyperferritinemia More than 90% of cases 40–50% of cases are explainedby a combination of 2or more diseases B. Lorcerie et al. PresseMed. 2017 Sim Y. EuropeanJournal of InternalMedicine. 2016

  7. Hepcidin • Hepcidin • -Alcohol • -Hereditaryhemochromatosis • ▪HFE-associated • ▪ non-HFE-associated forms • - Anaemia Adaptedfrom B. Lorcerie et al. La Revue de médecineinterne.2015 AdaptedFromPowell LW, Seckington RC, Deugnier Y. Lancet. 2016

  8. Hepcidin Hepcidin -Inflammatorysyndrome (IL 6) -Metabolicsyndrome • Hepcidin • -Alcohol • -Hereditaryhemochromatosis • ▪HFE-associated • ▪ non-HFE-associated forms • - Anaemia CytolysisDamage to cellscontaininglargeamounts of ferritin, can lead to releasedintothe plasma (acuteorchronic hepatitis). Adaptedfrom B. Lorcerie et al. La Revue de médecineinterne.2015 AdaptedFromPowell LW, Seckington RC, Deugnier Y. Lancet. 2016

  9. Laboratory Adaptedfrom B. Lorcerie et al. PresseMed. 2017 Adapte fromAltesA, et al. MedClin (Barc). 2014

  10. Laboratory B. Lorcerie et al. PresseMed. 2017 AltesA, et al. MedClin (Barc). 2014

  11. Laboratory Thevalues in females are lowestthanmale, as a result of ironlossfrommenstruation and pregnancies ( starttoriseafter 50 years). Theprotectiveeffecttoiron-overload-disease 28·4% vs 1·2% prevalences Powell LW, et al.Lancet. 2016 Allen KJ, et al.NEngl J Med 2008

  12. Clinical case HFE –Gens isPositivefor Mutation ofHereditaryHemochromatosis (C282Y homozygotes) _

  13. Clinical case HFE –Gens isPositivefor Mutation ofHereditaryHemochromatosis C282Y homozygotes Hemojuvelin (HJV) Hepcidin antimicrobial peptide(HAMP) Transferrin receptor (TR2) Ferroportin

  14. Male K.W. Born 07.06.56 • ReferredSep 2009 forincreasedserumferritin • Asymptomatic • Medical and personal history • ObesehisAdolecens • 2007 Arterial hypertension; • 2009 dyslipidaemia • 2 adultchildren, Landwirt • No alcohol, No smoking, 1 coffe/day. • Medication: candesartan 0.5mg/day.

  15. Physicalexamination, US and TE Physicalexamination: 53 yearold 167cms, 90kg BMI 33 kg/m2 Bloodpressure 145/115 mmHg, Waistcircumference117 cm No spider naevi, no ascitis, no asterixis No lower edema LiverStiffnessby TE: 6.7 ± 1.2 kPa, Successrate 83% , CAP 340 ± 49 dB/m Abdominal ultrasound Esteatosis, no focal lesión. No ascites, spleen 10cm

  16. Laboratory test

  17. ResultsandBiopsy Macrovesicularsteatosis (50-60%) Minimal insignificant perisinusoidal fibrosis S2A3F1 Metabolichyperferritinemia HFE –Gens isNegativefor Mutation ofHereditaryHemochromatosis

  18. Diagnosis of hyperferritinemia in thedysmetabolicpatient Dysmetabolicironoverloadsyndrome (DIOS)≠ Metabolichyperferritinemia

  19. Dysmetabolicironoverloadsyndrome (DIOS) In theabsence of any identificable cause of ironexcess Mildincrease in bothliver and bodyironstores (MRI orBiopsy) Oneorseveralcomponents of metabolicsyndrome Deugnier Y. EASL-ILC.2014 Valenti L, et al. Gastroenterology 2010;138:905–12.

  20. DIOS50% • 30- 50% Deugnier Y. EASL-ILC.2014 Valenti L, et al. Gastroenterology 2010;138:905–12.

  21. WhetherthisHyperferritinemia in metabolicsyndromecorrespondtoironexcess ( DIOS) or not? LiverBiopsy Abdominal MRI

  22. Istherereallyironexcess (DIOS) ? • Hepaticironoverload (DIOS): • Mixed • Parenchymalandmesenchymal • Mild • hepatic iron excess <150 mmol/g

  23. Istherereallyironexcess (DIOS) ? • Noclinicalsymptomsnorbiochemicalfindingorliverdamage • Hepaticironoverload (DIOS): • Mixed • Parenchymalandmesenchymal • Mild • hepatic iron excess <150 mmol/g

  24. Pathophysiology of DIOS

  25. Evolution of Clinical Case in the last 4 years The patient had lost only 1.5 kg of weight and persist Ferritin, ST and M30 elevated. Fibroscan10.10.16: Stiffness 4.2 ± 0.4 kPa, IQR8%, CAP 384 ±15 dB/m

  26. Management Tobleedotnottobleed?

  27. Effect of phlebotomyonLiverhistology in NAFLD studyof 128 non- diabeticpatientswith NAFLD Improvement in seruminsulin, serumglucose and HOMA Valenti et al. Am J Gastroenterol. 2007 Valenti et al. World J Gastroenterol2014 Fernandez-Real JM.Diabetes 2002 Houschyar KS, et al. BMC Med 2012

  28. Effect of phlebotomyonLiverhistology in NAFLD Phase II trial in 31 patienteswith NAFLD Bloodremovaluntilserumferritin >50 Improvement in liverhistology (NAS score) Beaton M. AlimentaryPharmacology and Therapeutics. 2013

  29. Effect of phlebotomyonLiverhistology in NAFLD RCT 74 patientswith NAFLD (notdiagnosedwith a biopsy) phlebotomiestoachieveferritinlevels <45 ng/mLx 6months Notimproveliverenzymes, hepaticfat, or IR in subjects Only 36 patientshadincreasedferritin. Adams LA, et al. Hepatology 2015

  30. Effect of phlebotomyonLiverhistology in NAFLD RCT 274 patientswithDIOS (hepaticiron >50 lmol/g in RMN) Phlebotomies (<50 lg/L)1 year vs lifestyle Notimprovemetabolic and hepaticfeatures weightgainand wasnotwelltolerated Laine F, et al. Hepatology 2017.

  31. Effect of phlebotomyonLiverhistology in NAFLD Meta-analysis 9 studieswith 820 patientswithDIOS and/or NAFLD (427 hadphlebotomy, 393 lifestylechangesalone). MuraliA. Hepatology Research 2018

  32. Hyperferritinemia • Inflamation, cellnecrosis, alcohol, metabolicsyndrome Transferrin Saturation* N C282Y HFE Test Treatandcheck Hepatic iron (MRI or biopsy) 50-150μmol/g >150μmol/g ≤50 μmol/g Dysmetaboliciron overloadsyndrome (DIOS) Ferroportin ceruloplasmin L ferritin Adaptedfrom EASL. J Hepatol2010 andPowell LWet al. Lancet. 2016

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