Hemosiderosis

1. Hemosiderosis Dr. David Cao Faculty: Dr. Weitz

2. Outline • Case Presentation • What’s the matter with iron? • Histopathology • Management • Complications of treatment • Back to our patient • Conclusion • Faculty Discussion

3. Learning Objectives Identify what causes Hemosiderosis Know the current management strategies for hemosiderosis Recognize common side effects of chelation therapy Learn which patients can be at risk Learn how much iron is involved with transfusion

4. Case Presentation The patient is a 63 y/o F w/ h/o Right breast cancer, stage IIIc; invasive lobular carcinoma s/p Right radical mastectomy, +ve 16/17 LNs, hormone receptor + (per notes), Her2neu not amplified, s/p adj. Chemo w/ taxol/ adriamycin/ cytoxan and XRT on aramidex till 2007 with tumor markers increasing so switched to faslodex, then disease progression s/p right iliac biopsy showing multi-focal invasion in 5/08 and gastric invasion 6/9/09. The patient has been requiring frequent therapeutic paracentesis every 7-10 days.

5. Case Presentation The husband states that pt. has been jaundiced/ “yellow eyes” x 1 week. Pt. c/o early satiety/ restless/ SOB x 1 night PTA. Decrease in appetite/ poor po intake. Denies pruritis. The patient was admitted for jaundice, increasing abdominal girth, and decrease PO intake.

6. Case Presentation Past medical history: Breast Cancer, h/p MAHA Past surgical history: right radical mastectomy 2002, right breast re-constructive surgery 2002, car accident s/p left eye enucleation s/p replacement by artificial eye at age 8 Allergies: Vancomycin ( ? red man syndrome) Medications: Lasix 20 mg po prn (last use 1 week ago) Prilosec 20 mg po qday prn Folic acid 1 mg po qday Family history: Mom: breast cancer, Dad: prostate cancer

7. Case Presentation Social history: No tobacco, ethanol, or drugs Review of systems: per HPI

8. Case Presentation Physical Exam: Vital signs: T 35.6 HR 85 RR 18 BP 110/54 Sat 99% RA PE: Gen: NAD, pleasant, AAO x 4 HEENT: Alopecia. Positive scleral icterus in the right eye. Positive spider angiomata Chest: decrease BS at b/l bases, post R masectomy surgical scar Heart: RRR, NL S1, S2, no mrg Abd: +BS, NT, + shifting dullness, and fluid thrill Ext: 2-3+ BLE pitting edema

9. Case Presentation Paracentesis History: 5/17/2010 US paracentesis 2.4 L yellow fluid 5/18 Abd US Liver looks nml, ascites 5/28 US paracentesis 4.7 L yellow fluid 6/7 4 L yellow fluid paracentesis 6/14 1.8 L yellow fluid paracentesis 6/16 6 L yellow fluid paracentesis 6/22 4 L yellow fluid paracentesis 6/28 2 L yellow fluid paracentesis 6/30 2 L yellow fluid paracentesis

10. Case Presentation WBC 5.9 Hgb 11.4 Hct 33.3 Platelets 116 MCV 106 RDW 25.6 Na 107 K 5.8 Cl 81 HCO3 20 BUN 53 Creatinine 0.7 Glucose 103 Calcium 8.1 Mg 2.3 Albumin 1.9

11. Case Presentation Alk Phos 731 Total protein 5.8 Albumin 1.9 ALT 106 AST 245 Total bilirubin 8.2 Direct Bilirubin 5.6 Indirect Bilirubin 2.6 INR 1.2 UA – 15 mg/dL prot, 1 mg/dl bili, 4 mg/dL urobilinogen, 25 blood, 10-20 WBC,4-5 RBC, many bacteria, few epith, 1-2 hyal cast, 1+ amorphous casts, few mucus Serum Prot 0.8 Serum Alb 0.5

12. Differential DiagnosisAbdominal Girth/jaundice MALIGNANCY: new vs metastatic spread Cirrhosis with portal hypertension ascites Constipation or bowel obstruction Hemolytic anemia Chemotherapy side effect Hypoalbuminemia Hyponatremia Budd-Chiari

13. Case Presentation 6/25/10 Abd US: 1. Features consistent with cirrhosis and portal hypertension, with portal flow direction away from the liver 2. Upper abdominal ascites 3. Nonspecific gallbladder wall thickening, attributable to liver disease 5/18/10: Abd US: no e/o biliary obstruction, ascites, GBW thickening, R pleural effusion, nml liver 04/06/10: Abd US: splenomegaly, trace ascites, nml liver

14. Case Presentation 6/29/10 MRI Abdomen with and without contrast: 1. Hemosiderosis 2. Cirrhosis and portal hypertension 3. No gross evidence of metastatic disease , however the study is extremely technically limited and cannot be completely excluded 4. Questionable left portal vein nonocclusive thrombus 5. Bilateral pleural effusions and adjacent atelectasis 6. L renal cyst

15. Liver in T2 haste, very dark, same intensity as spleen

16. 72-year-old female with hemochromatosis suggested by MRI. T1-weighted images show a black hypointense liver characteristic of iron overload (small arrows) and a similar low intensity of the spleen (large arrow).Courtesy of Martina Morrin, MD. (uptodate)

17. Additional Labs • Cortisol 20.9 • LDH 542 • Haptoglobin <7 • Ddimer 3809 • Fibrinogen 349 • Serum Osmo 258 • Urine Osmo 696 • Urine Na <10 • TSH 3.79 • FT4 0.9 • Unbound iron <16 • TIBC too low to quantify • Iron Sat too low to quantify • Iron 99 • Ferritin 11234 (nml 200) • Hep B surface Ag Neg • Hep B core Ab neg • Hep C Ab Neg

18. Patient’s problem list Hemosiderosis Cirrhosis with portal HTN and ascites Left portal vein nonocclusive thrombus Metastatic Breast cancer SIADH causing hyponatremia H/o microangiopathic hemolytic anemia Bilateral pleural effusions

19. Hemosiderosis • Iron deposition into tissues • Genetic ie hemachromatosis • Transfusional • Abnormal clearance/use • Increase absorption • Abnormal Hepcidin • Hemolytic anemia • Hemotropic parasites

20. Liver Hemosiderosis A: Dark blue lumps of hemosiderin are abundant in sinusoidal macrophages B: Scarce amounts of liver hemosiderin C: Lumps of hemosiderin in sinusoidal macrophages and granular deposits of hemosiderin in hepatocytes Prussian blue stain A and B: Bar = 100 μm C: Bar = 20 μm Courtesy of www.nature.com

21. Complications of Iron Overload  • Cardiac failure • Liver cirrhosis/fibrosis/cancer • Diabetes mellitus • Infertility • Arthritis • Skin hyperpigmentation

22. Iron Regulation

23. Distribution of body iron in men and women

24. Role of Hepcidin Increase in plasma iron increase hepcidin production (yellow arrow) This inhibits iron flow into the plasma from macrophages, hepatocytes and the duodenum Thus lowering plasma iron

25. Hepcidin in Anemia of Inflammation IL-6 and other cytokines induce hepcidin production (yellow arrow) Hepcidin inhibit from macrophages, from hepatic storage and from the duodenum Hypoferremia and less erythropoiesis

26. Hepcidin in Iron-loading Anemias Increased erythropoietic drive suppresses hepcidin production (yellow arrow) Excessive iron absorption, elevated transferrin saturation and accumulation of non-transferrin-bound iron (NTBI) Hepcidin regulation by iron remains blunted resulting in iron overload

27. Hepcidin in Hereditary Hemochromatosis (HH) HH by hepcidin deficiency or hepcidin resistance Low hepcidin allows excessive iron absorption: increased plasma iron, transferrin saturation and accumulation of non-transferrin-bound iron (NTBI) Iron Overload

28. Transfusional Hemosiderosis • First reported by Kark 1937 in a 39 yo male who got 290 transfusions over a 9 year period. • Patient’s transfusion record at UH per blood bank: (granted the patient medical history started prior to UH, each unit has 200-300mg of iron) • March 2010 5 RBC • April 2010 5 RBC • May 2010 2 RBC • June 2010 2 RBC

29. Diagnosis • Liver Biospy is the most definitive test for diagnosis • CT and MRI T2 and R2 can accurately determine iron deposition noninvasively • SQUID (superconducting quantum interference device) • Cannot determine the stage of fibrosis, cirrhosis or the cellular location of the iron • Serum Iron studies: ie ferritin used to monitor Tx • Ferritin can be elevated in liver disease, inflammatory disease, obesity, and malignancy

30. Treatment Oral iron chelator: Deferasirox, Deferoxamine, Deferiprone Chelated iron excreted mainly in feces (< 10% in urine) Iron chelators can be given to remove iron load Iron chelators can be given with each blood transfusion to reduce uptake Phlebotomy Normal men have 1 gram Iron stores. Each 500ml phlebotomy can remove 200-250mg iron, thus 4-5 phlebotomies over 4-8 week period can produce iron deficiency. (Iron overloaded patients will have at least 5 grams of iron stores) Cheapest and safest way if tolerated

31. Prevention vs Costs • Giving iron chelators with transfusions for prevention

32. Side Effects Iron Chelators Gastrointestinal side effects (NVD abd pain) and rash Elevated liver enzymes Increases in liver transaminases Auditory and visual neurotox with chronic use, low BP, anaphylaxis (deferoxamine) Neutropenia and agranulocytosis 2.1 and 0.4 per 100 patient-years (deferiprone) Associated with Mucor, Yersinia, Vibrio vulnificus infections (deferoxamine) Phlebotomy: can cause hypovolemia or anemia in some patients

33. Current Recommendations Chelation Therapy if not tolerable of phlebotomy Not proven to improve organ function, reduce morbidity, or prolong survival in MDS patients with iron overload Few clinical trials on impact of iron chelation on patients with sickle cell anemia Chelation therapy early shows marked improvement in survival of patients with beta thalassemia major thus standard of care Reduce iron free radicals which can cause organ damage thus reducing morbidity and mortality

34. Prognosis Long-term benefit of iron chelation therapy in high risk patients is likely to be small because of their markedly reduced survival Evidence from randomized studies that iron chelation reverses iron-related organ damage, reduces morbidity, and prolongs survival in cancer patients does not yet exist

35. Who to Screen • Screen 1st degree relatives of Hereditary Hemachromatosis who have the C282Y/C282Y HFE genotype, compound heterozygotes H63D • Check ferritin on patients who receive frequent blood transfusions (10 units in a life time!) and are at risk of iron overload.

36. Screening Methods • CT/MRI • Routine Iron Studies: (each with sources of error) • Plasma iron concentration • Transferrin conc: can be altered in homozygous HFE mutations, naturally higher in Asians and Pacific islanders • Plasma ferritin: increased in certain liver disease (hepatitis, alcohol, NASH) and by inflammatory cytokines (RA, obesity, malignancy), naturally higher in Asians and Pacific islanders

37. Back to our patient… Hematology and Liver was consulted and deferoxamine therapy was not suggested It was believed to be a cytokine mediated inflammatory response vs an underlying liver dysfunction. With the iron from the blood transfusions pushing her over. Thus deferoxamine would not help The patient had a pleurex catheter placed on 7/9/10 for the frequent paracentesis

38. Conclusion Due to the worse prognosis of the liver disease, the patients chemo therapy is severely limited An unfortunate complication of treatment She had Breast Cancer, MAHA, SIADH, hemosiderosis, cirrhosis

39. References Radiology. 2004 Feb;230(2):479-84. Epub 2003 Dec 10. MR quantification of hepatic iron concentration. http://www.about-blood-disorders.com/articles/iron-disorders/hemosiderosis.php Uptodate Pediatrics. 2003 Jan;111(1):91-6. Iron overload in children who are treated for acute lymphoblastic leukemia estimated by liver siderosis and serum iron parameters. Am J Clin Pathol. 2005 Jan;123(1):146-52. Variability in hepatic iron concentration in percutaneous needle biopsy specimens from patients with transfusional hemosiderosis Lab Invest. 2008 Dec;88(12):1349-57. Epub 2008 Oct 6. Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis? Am J Hematol. 2008 Dec;83(12):932-4 Acquired iron overload associated with antitransferrin monoclonal immunoglobulin: a case report. Health Technol Assess. 2009 Jan;13(1):iii-iv, ix-xi, 1-121. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Indian J Pediatr. 2010 Feb;77(2):185-91. Epub 2010 Feb 23. Deferasirox: oral, once daily iron chelator--an expert opinion. http://www.intrinsiclifesciences.com/iron_reg/ J clin Path 1969 22, 567-575 Transfusional siderosis and liver cirrhosis. R Sinniah Andrews NC. N Engl J Med. 1999;341:1986-1995. Neufeld, EJ. Blood 2006; 107:3436.

40. And a big thanks to… • Dr. Weitz • Dr Ben-Ari • Dr. Holman