The problem with pumping too much iron

Transcription

1 The problem with pumping too much iron Stephen D. Zucker, M.D. Professor of Medicine Director of Hepatology

2 Disclosures NONE* * Would be pleased to entertain any reasonable offer

3 Brief History of Hemochromatosis Armand Trousseau (1865) First described a case of the association of diabetes mellitus, cirrhosis, fibrosis of the pancreas, and skin pigmentation

4 Key Events in Hemochromatosis (2) Friedrich Daniel von Recklinghousen (1889) Coined the term hemochromatosis ( iron from the blood )

5 Key Events in Hemochromatosis (3) Joseph H. Sheldon (1935) Published 311 cases & originated the familial (autosomal recessive) pattern of inheritance

6 Key Events in Hemochromatosis (4) J.N. Feder (1996) Identified a common mutation in an MHC Class I-like gene in patients with hereditary hemochromatosis Nature Genetics 1996; 13:

7 The HFe C282Y Mutation The C282Y (cysteine to tyrosine) mutation is located in the highly conserved beta-2 microglobulin (β2m) binding domain of the HFe (High Iron Fe) gene Mice with this mutation have expanded iron stores

8 HFe mutations Robson K J H et al. J Med Genet 2004;41:

9 Percent of Patients with Hepatic Iron Overload that Possess the C282Y Mutation Study % patients homozygous Feder et al. 83 Utah 89 USA 82 French 91 Australia 100

10 Pathophysiology of Hemochromatosis

11 Overview of Iron Homeostasis Papanikolaou G and Pantopoulos K, Toxicol Appl Pharmacol 2005; 202: 204

12 Iron absorption (%) Intestinal Iron Absorption is Closely Regulated Normal Adults Lynch SR et al. Blood 1989; 74: Serum ferritin (µg/l)

13 Iron absorption (%) Iron Absorption is Excessive in C282Y- Associated Hereditary Hemochromatosis Treated Untreated Homozygous Heterozygous Serum ferritin (µg/l) Lynch SR et al. Blood 1989; 74:

14 Primary Cause of Iron Overload in Hereditary Hemochromatosis Pumping too much iron Normal iron absorption Hemochromatosis

15 Proteins involved in Intestinal Iron Uptake Gut Lumen HCP1: heme carrier protein-1 DcytB: duodenal cytochrome B Enterocyte DMT1: divalent metal transporter-1 Cp: ceruloplasmin NTBI: non-transferrin-bound iron Blood Swinkels DW et al., Clin Chem 2006; 52:

16 Hepcidin is the Principal Hormone that Controls Iron Homeostasis Biochim Biophys Acta. 2012;1823:

17 Hepcidin Regulates Iron Transport Hepcidin Bacon BR, et al. Hepatology 2011; 54:

18 Hepcidin Inhibits Ferroportin Activity Hematology Am Soc Hematol Educ Program 2011;2011:538-42

19 The C282Y Mutation Leads to an Inappropriate Reduction in Hepcidin Levels Pietrangelo A, N Engl J Med 2004; 350: 2389

20 Hepcidin Expression Protects Mice Against Iron Overload Hepcidin Nicolas G, et al., Nature Genet 2003; 34:

21 How Does HFe Modulate Hepcidin Levels?

22 Iron Sensing by Hepatocytes Hepcidin Biochim Biophys Acta. 2012;1820:

23 Multiple Genes Regulate Hepcidin Release X X Swinkels DW et al., Clin Chem 2006; 52:

24 Hereditary Hemochromatosis: Clinical Manifestations Iron Man

25 How Chronic Iron Overload Causes Organ Damage Excess iron accumulation causes: DNA strand breaks / hypermethylation Membrane damage (peroxidation) Lysosomal rupture Organelle dysfunction Cellular necrosis Increased fibrinogenesis

26 Clinical Manifestations of Hereditary Hemochromatosis AASLD slide set

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28 MR Imaging in Iron Overload Hereditary Hemochromatosis Transfusional Siderosis

29 Hepatocellular Carcinoma

30 Iron Overload in the Heart

31 Chrondrocalcinosis and Degenerative Arthritis

32 Arthritis in Hereditary Hemochromatosis

33 Bronzing of the Skin

34 % of patients Changes in the Presenting Manifestations of Hereditary Hemochromatosis 's 1990's 0.0 Symptoms Signs

35 Diagnosis This woman suffers from "Iron Overload"

36 Transferrin Saturation Normally 1/3 saturated (20-50%) Rises with increasing iron stores Saturation >55% (50% likelihood of HH) Cutoff in menstruating women > 45%

37 Serum Ferritin Concentration Levels correlate with total mobilizable iron > 200 µg/l in men; > 150 µg in women is considered abnormal Ferritin is an acute phase reactant, so it is also elevated in inflammatory conditions, malignancy, rheumatic diseases May be normal in some HH patients Ferritin > 1000 µg/l had 100% sensitivity and 70% specificity for cirrhosis in 1 study

38 Serum Iron Studies and the Detection of C282Y Homozygosity Transferrin saturation Screening cutoff: 45% Ferritin Sensitivity: 94% Specificity: 94% PPV: 6% NPV: 99.96% Screening cutoff: 300 µg/l Sensitivity: 50% Specificity: 87% PPV: 2% NPV: 99.69% Yen, A. W. et al. Am J Med 2006; 119:

39 Liver Biopsy Gold standard: Quantitative analysis of hepatic iron levels (μg iron / g liver tissue) Typically >22,000 μg/g (normal <1,800 μg/g) Qualitative assessment of stainable iron (scale: 0 4) Distribution of iron (hepatocellular) Degree of damage and extent of fibrosis Downside: Invasive procedure

40 Staining for Hepatic Iron H & E Prussian Blue

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42 Diagnosis of Iron Overload Due to Hereditary Hemochromatosis At least 1 of the following on liver biopsy: Hepatic iron index 1.9 Grade 3 to 4 iron stores on qualitative staining Hepatic iron concentration > 80 µmol / g dry wt or 4 g iron removed by phlebotomy (16-20 U) * In the absence of known causes of secondary iron overload

43 Main Indications for Liver Biopsy Stage the degree of liver disease in C282Y homozygotes if elevated ALT, AST or ferritin is greater than 1000 µg/l Establish the diagnosis in patients with phenotypic markers of iron overload who are not homozygous for C282Y

44 Hepatic iron Quantification by MR Relaxometry J Magn Reson Imaging 2012; 36:

45 Treatment

46 Treatment Therapeutic phlebotomy 500 ml (1 unit) of whole blood contains mg of iron In normal individuals hepatic stores (~ 1 g) generally are depleted within 4-5 units Weekly phlebotomy removes g iron/year

47 Effect of Phlebotomy on Biochemical Parameters of Iron Stores

48 Therapeutic Erythrocytapheresis Erythrocytes are removed by centrifugation and remaining blood components returned to donor Permits removal of 2 to 4 times more red blood cells per treatment Rombout-Sestrienkova E et al. Transfus Apher Sci. 2007; 36: 261-7

49 Monitoring Response to Phlebotomy Hematocrit (Hgb), ferritin, transferrin saturation (every 5 10 phlebotomies) Target: Ferritin < 100 ng/ml, TS < 50% Hematocrit should fall no less than 20% (Can try using erythropoietin to maintain) Maintenance phlebotomy of 1U every 2-3 months (target ferritin > 50 and < 100 ng/ml)

50 Results of Phlebotomy Preventable: all clinical manifestations Reversible: cardiac dysfunction, glucose intolerance, hepatomegaly, pigmentation Irreversible: arthropathy, hypogonadism, cirrhosis, risk of hepatocellular carcinoma Improves survival

51 Dietary Recommendations Avoid supplemental iron Consume ethanol in moderation* Avoid supplemental vitamin C Cook shellfish well, particularly from warm water areas (prevent Vibrio vulnificus) * Persons with evidence of liver damage should consume little to no alcohol Lynch SR, Cook JD. Ann N Y Acad Sci.1980; 355: 32-44

52 Iron Content of Foods

53 Dietary Recommendations Don t drink blood! Hemochromatosis: a bad disease to have if you are a vampire

54 For those who must forego phlebotomy Desferrioxamine Leeches Bed bugs Deferasirox Hepcidin agonists

55 Outcomes of Liver Transplantation for Hereditary Hemochromatosis Crawford DHG et al., Hepatology 2004; 39: 1658

56 Natural History of Hereditary Hemochromatosis

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58 Mortality Ratio (Obs/Exp) Causes of Death in Hereditary Hemochromatosis

59 Screening for Hemochromatosis

60 Prevalence of Inherited Liver Diseases Disease Homozygote Frequency Heterozygote Frequency Hemochromatosis 1:400 1:10 A-1-AT Deficiency 1:1,600 1:20 Cystic Fibrosis 1:2,500 1:25 PKU 1:10,000 1:80 Wilson s Disease 1:30,000 1:85

61 Prevalence of HFE Carrier State by Ethnicity Adams PC et al., N Engl J Med 2005; 352: 1770

62 Prevalence of HFE Genotypes by Ethnic Group Adams PC et al., N Engl J Med 2005; 352: 1770

63 Main Indications to Screen for Hereditary Hemochromatosis Symptomatic patients with clinical features suggestive of iron overload Asymptomatic patients with biochemical features of iron overload First degree relatives of HH patients

64 Screening of First-degree Relatives Relationship to C282Y Homozygote Risk of Homozygosity None (general population) 1:400 (0.26%) Sibling 1:4 (25%) Parent 1:20 (5%) Child 1:20 (5%) Niece/Nephew 1:80 1:160 (1%)

65 Case Presentation JS is 50 yo Caucasian gentleman who is seen in consultation for management of hereditary hemochromatosis The patient was seen for evaluation of fatigue and impotence and was diagnosed with hypogonadotropic hypogonadism. He admits to binge drinking on weekends As part of his workup, he was found to have: Iron 206 µg/dl, TIBC 360 µg/dl (57% sat), ferritin 182 ng/ml. AST 34 U/L, ALT 54 U/L, AP 64 U/L, TB 0.9 mg/dl, Alb 5.0 g/dl, plt 192, Hgb 16.9 g/dl Genetic testing revealed that he is a compound heterozygote for the H63D and S65C HFe mutations

66 HFe Genotype in Patients with Documented Hepatic Iron Overload Genotype % of individuals with hepatic iron overload C282Y / C282Y 80 90% C282Y / H63D 4 5% C282Y / Wt 0 1% H63D / H63D 0 2% H63D / Wt 3 4% Wt / wt 0 7%

67 Correlation between HFE Genotypes and Associated Medical Conditions C282Y/C282Y C282Y/H63D OR decreased increased

68 Iron Indices in Chronic Alcoholics Transferrin Saturation Serum Ferritin Transferrin sat (%) Ferritin (ng/ml) actively drinking 2 weeks abstinent 0 Cirrhotic Non-cirrhotic 0 Cirrhotic Non-cirrhotic Conte D et al. Ital J Gastroenterol Hepatol. 1998;30(5):

69 Approach to Screening for HH Bacon BR, et al. Hepatology 2011; 54:

70 Population Screening Bacon BR, et al. Hepatology 2011; 54:

71 Evolution of Serum Ferritin in Untreated C282Y Homozygotes Yamashita C and Adams PC Clin Gastroenterol Hepatol 2003; 1: 388 Normal ferritin Normal TS 2 / 22 developed abormal ferritin over 4 year follow-up Normal ferritin TS > 45% (women) > 50% (men)

72 Melbourne Collaborative Cohort Study 12 year longitudinal study (age: 40 69) C282Y homozygotes who developed ironoverload related disease: Men: 21 / 74 (28.4%) Women: 1 / 84 (1.2%) (Risk of disease highest if ferritin 1000 µg/l) Only 1 / 242 compound heterozygotes developed disease (none with other mutational combinations) Allen KJ et al. N Engl J Med 2008; 358:

73 Genetic Testing Cannot Exclude Hepatic Iron Overload Iron Overload Bacon B et al. Ann Intern Med. 1999;130:

74 Genes Associated with Hereditary Hemochromatosis TfR2 HFe Hemojuvelin Ferroportin Hepcidin Bacon BR, et al. Hepatology 2011; 54:

75 Mutated Genes Associated with Altered Iron Homeostasis Gene Gene product Features Inheritance HFe HFe (C282Y) Common, late onset AR TfR2 HJV HAMP Transferrin receptor 2 Hemojuvelin Hepcidin SLC40A1 Ferroportin Very rare, presents like HFe Severe, onset 3 rd decade Very rare, early onset Mild, RE iron due to export AR AR AR AD Deicher R and Hörl WH, Eur J Clin Invest 2006; 36:

76 Genetic Defects Leading to Iron Overload Pietrangelo A. Gastroenterology 2010; 139:

77 Diagnostic Algorithmn Hereditary Hemochromatosis Autosomal recessive TS to normal TS Autosomal dominant 30 y < 30 y Adult Juvenile Ferroportin disease HFe TfR2 HJV HAMP SLC40A1 (Gly320Val) Rev Bras Hematol Hemoter 2012; 34:

78 Keep on Pumping Iron!

79 Serum Transferrin Saturation in Men and Women According to HFe Genotype Adams, P. C. et al. N Engl J Med 2005;352:

80 Serum Ferritin Levels in Men and Women According to Genotype Adams, P. C. et al. N Engl J Med 2005;352: