hemosiderosis dr. david cao faculty: dr. weitz. outline case presentation case presentation what’s...

HemosiderosisHemosiderosis

Dr. David CaoDr. David Cao

Faculty: Dr. WeitzFaculty: Dr. Weitz

OutlineOutline

Case PresentationCase Presentation What’s the matter with iron?What’s the matter with iron? HistopathologyHistopathology ManagementManagement Complications of treatmentComplications of treatment Back to our patientBack to our patient ConclusionConclusion Faculty DiscussionFaculty Discussion

Learning ObjectivesLearning Objectives

Identify what causes HemosiderosisIdentify what causes Hemosiderosis Know the current management Know the current management

strategies for hemosiderosisstrategies for hemosiderosis Recognize common side effects of Recognize common side effects of

chelation therapychelation therapy Learn which patients can be at riskLearn which patients can be at risk Learn how much iron is involved Learn how much iron is involved

with transfusionwith transfusion

Case PresentationCase Presentation

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


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.

Case PresentationCase Presentation Past medical history: Breast Cancer, h/p MAHAPast medical history: Breast Cancer, h/p MAHA Past surgical history: right radical mastectomy Past surgical history: right radical mastectomy

2002, right breast re-constructive surgery 2002, right breast re-constructive surgery 2002, car accident s/p left eye enucleation s/p 2002, car accident s/p left eye enucleation s/p replacement by artificial eye at age 8replacement by artificial eye at age 8

Allergies: Vancomycin ( ? red man syndrome)Allergies: Vancomycin ( ? red man syndrome) Medications: Lasix 20 mg po prn (last use 1 Medications: Lasix 20 mg po prn (last use 1

week ago)week ago) Prilosec 20 mg po qday prnPrilosec 20 mg po qday prn Folic acid 1 mg po qdayFolic acid 1 mg po qday

Family history: Mom: breast cancer, Dad: Family history: Mom: breast cancer, Dad: prostate cancerprostate cancer


Social history: No tobacco, ethanol, Social history: No tobacco, ethanol, or drugsor drugs

Review of systems: per HPIReview of systems: per HPI


Physical Exam:Physical Exam: Vital signs: T 35.6 HR 85 RR 18 BP 110/54 Sat Vital signs: T 35.6 HR 85 RR 18 BP 110/54 Sat

99% RA 99% RA PE: Gen: NAD, pleasant, AAO x 4PE: Gen: NAD, pleasant, AAO x 4 HEENT: Alopecia. Positive scleral icterus in the HEENT: Alopecia. Positive scleral icterus in the

right eye.right eye.Positive spider angiomataPositive spider angiomata Chest: decrease BS at b/l bases, post R Chest: decrease BS at b/l bases, post R

masectomy surgical scarmasectomy surgical scar Heart: RRR, NL S1, S2, no mrgHeart: RRR, NL S1, S2, no mrg Abd: +BS, NT, + shifting dullness, and fluid thrillAbd: +BS, NT, + shifting dullness, and fluid thrill Ext: 2-3+ BLE pitting edemaExt: 2-3+ BLE pitting edema


Paracentesis History: Paracentesis History: 5/17/2010 US paracentesis 2.4 L yellow fluid5/17/2010 US paracentesis 2.4 L yellow fluid 5/18 Abd US Liver looks nml, ascites5/18 Abd US Liver looks nml, ascites 5/28 US paracentesis 4.7 L yellow fluid5/28 US paracentesis 4.7 L yellow fluid 6/7 4 L yellow fluid paracentesis6/7 4 L yellow fluid paracentesis 6/14 1.8 L yellow fluid paracentesis6/14 1.8 L yellow fluid paracentesis 6/16 6 L yellow fluid paracentesis6/16 6 L yellow fluid paracentesis 6/22 4 L yellow fluid paracentesis6/22 4 L yellow fluid paracentesis 6/28 2 L yellow fluid paracentesis6/28 2 L yellow fluid paracentesis 6/30 2 L yellow fluid paracentesis6/30 2 L yellow fluid paracentesis


WBC WBC 5.95.9 Hgb Hgb 11.411.4 Hct Hct 33.333.3 Platelets Platelets 116116 MCV 106MCV 106 RDW 25.6RDW 25.6

Na 107Na 107 K 5.8K 5.8 Cl 81Cl 81 HCO3 20HCO3 20 BUN BUN 5353 Creatinine Creatinine 0.70.7 Glucose Glucose 103103 Calcium 8.1Calcium 8.1 Mg 2.3Mg 2.3 Albumin 1.9Albumin 1.9

Case PresentationCase Presentation Alk Phos Alk Phos 731731 Total protein 5.8Total protein 5.8 Albumin 1.9Albumin 1.9 ALT ALT 106106 AST 245AST 245 Total bilirubin 8.2Total bilirubin 8.2 Direct Bilirubin 5.6Direct Bilirubin 5.6 Indirect Bilirubin Indirect Bilirubin

2.62.6 INR 1.2INR 1.2

UA – 15 mg/dL UA – 15 mg/dL prot, 1 mg/dl bili, 4 prot, 1 mg/dl bili, 4 mg/dL mg/dL urobilinogen, 25 urobilinogen, 25 blood, 10-20 blood, 10-20 WBC,4-5 RBC, WBC,4-5 RBC, many bacteria, few many bacteria, few epith, 1-2 hyal cast, epith, 1-2 hyal cast, 1+ amorphous 1+ amorphous casts, few mucuscasts, few mucus

Serum Prot 0.8Serum Prot 0.8 Serum Alb 0.5 Serum Alb 0.5

Differential DiagnosisDifferential DiagnosisAbdominal Girth/jaundiceAbdominal Girth/jaundice

MALIGNANCY: new vs metastatic MALIGNANCY: new vs metastatic spreadspread

Cirrhosis with portal hypertensionCirrhosis with portal hypertension ascitesascites

Constipation or bowel obstructionConstipation or bowel obstruction Hemolytic anemiaHemolytic anemia Chemotherapy side effectChemotherapy side effect HypoalbuminemiaHypoalbuminemia HyponatremiaHyponatremia Budd-Chiari Budd-Chiari


6/25/10 Abd US:1. Features consistent with cirrhosis and portal

hypertension, with portal flow direction away from the liver

2. Upper abdominal ascites3. Nonspecific gallbladder wall thickening,

attributable to liver disease5/18/10: 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


6/29/10 MRI Abdomen with and without contrast:6/29/10 MRI Abdomen with and without contrast:

1. Hemosiderosis1. Hemosiderosis

2. Cirrhosis and portal hypertension2. Cirrhosis and portal hypertension

3. No gross evidence of metastatic disease , 3. No gross evidence of metastatic disease , however the study is extremely technically however the study is extremely technically limited and cannot be completely excludedlimited and cannot be completely excluded

4. Questionable left portal vein nonocclusive 4. Questionable left portal vein nonocclusive thrombusthrombus

5. Bilateral pleural effusions and adjacent 5. Bilateral pleural effusions and adjacent atelectasisatelectasis

6. L renal cyst6. L renal cyst

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

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)

Additional Labs 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

Cortisol 20.9LDH 542Haptoglobin <7Ddimer 3809Fibrinogen 349Serum Osmo 258Urine Osmo 696Urine Na <10TSH 3.79FT4 0.9

Patient’s problem listPatient’s problem list

HemosiderosisHemosiderosis Cirrhosis with portal HTN and Cirrhosis with portal HTN and

ascitesascites Left portal vein nonocclusive Left portal vein nonocclusive

thrombusthrombus Metastatic BMetastatic Breast cancerreast cancer SIADH causing hyponatremia SIADH causing hyponatremia H/o microangiopathic hemolytic H/o microangiopathic hemolytic

anemiaanemia Bilateral pleural effusionsBilateral pleural effusions

Hemosiderosis

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

Liver HemosiderosisLiver Hemosiderosis

A: A: Dark blue lumps of hemosiderin are abundant in Dark blue lumps of hemosiderin are abundant in sinusoidal macrophagessinusoidal macrophagesB: Scarce amounts of liver hemosiderinB: Scarce amounts of liver hemosiderinC: Lumps of hemosiderin in sinusoidal macrophages C: Lumps of hemosiderin in sinusoidal macrophages and granular deposits of hemosiderin in hepatocytes and granular deposits of hemosiderin in hepatocytes Prussian blue stainPrussian blue stainA and B: Bar = 100 μmA and B: Bar = 100 μmC: Bar = 20 μmC: Bar = 20 μm

Courtesy of www.nature.com

Complications of Iron Overload

Cardiac failure Liver cirrhosis/fibrosis/cancer Diabetes mellitus Infertility Arthritis Skin hyperpigmentation

Iron Regulation

Distribution of body iron in men and women

70 kg man 60 kg woman

Iron stores - transferrin, ferritin, hemosiderin

0.7 g 0.3 g*

Hemoglobin 2.5 g 1.9 g

Myoglobin 0.14 g 0.13 g

Heme enzymes 0.01 g 0.01 g

TOTAL 3.35 g 2.34 g

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

Role of Hepcidin

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

Hepcidin in Anemia of Inflammation

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

Hepcidin in Iron-loading Anemias

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

Hepcidin in Hereditary Hemochromatosis (HH)

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

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

TreatmentTreatment

Oral iron chelator: DeferasiroxDeferasirox, 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

Prevention vs Costs Giving iron chelators with transfusions for

prevention Annual Costs Deferoxamine Deferiprone Deferasirox

Moderate dose regimen

(mg/kg/day) 25 75 20

United States 16,200 NA 39,000

Italy 4000 6700 NA

India ND 800 NA

Higher dose regimen

(mg/kg/day) 40 100 30

United States 26,000 NA 58,500

Italy 6400 8900 NA

India ND 1100 NA

Side EffectsSide Effects Iron ChelatorsIron 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

Current Current RecommendationsRecommendations

Chelation Therapy if not tolerable of Chelation Therapy if not tolerable of phlebotomyphlebotomy Not proven to improve organ function, reduce Not proven to improve organ function, reduce

morbidity, or prolong survival in MDS patients morbidity, or prolong survival in MDS patients with iron overloadwith iron overload

Few clinical trials on impact of iron chelation on Few clinical trials on impact of iron chelation on patients with sickle cell anemiapatients 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

PrognosisPrognosis

Long-term benefit of iron chelation Long-term benefit of iron chelation therapy in high risk patients is likely therapy in high risk patients is likely to be small because of their to be small because of their markedly reduced survivalmarkedly 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

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.

Screening MethodsScreening Methods CT/MRICT/MRI Routine Iron Studies: Routine Iron Studies: (each with sources of (each with sources of

error)error) Plasma iron concentrationPlasma iron concentration Transferrin conc: can be altered in Transferrin conc: can be altered in

homozygous HFE mutations, naturally homozygous HFE mutations, naturally higher in Asians and Pacific islandershigher in Asians and Pacific islanders

Plasma ferritin: increased in certain liver Plasma ferritin: increased in certain liver disease (hepatitis, alcohol, NASH) and by disease (hepatitis, alcohol, NASH) and by inflammatory cytokines (RA, obesity, inflammatory cytokines (RA, obesity, malignancy), naturally higher in Asians and malignancy), naturally higher in Asians and Pacific islandersPacific islanders

Back to our patient… Back to our patient… Hematology and Liver was consulted and Hematology and Liver was consulted and

deferoxamine therapy was not suggesteddeferoxamine therapy was not suggested It was believed to be a cytokine mediated It was believed to be a cytokine mediated

inflammatory response vs an underlying inflammatory response vs an underlying liver dysfunction. With the iron from the liver dysfunction. With the iron from the blood transfusions pushing her over. blood transfusions pushing her over. Thus deferoxamine would not helpThus deferoxamine would not help

The patient had a pleurex catheter The patient had a pleurex catheter placed on 7/9/10 for the frequent placed on 7/9/10 for the frequent paracentesisparacentesis

ConclusionConclusion

Due to the worse prognosis of the Due to the worse prognosis of the liver disease, the patients chemo liver disease, the patients chemo therapy is severely limitedtherapy is severely limited

An unfortunate complication of An unfortunate complication of treatmenttreatment

She had Breast Cancer, MAHA, She had Breast Cancer, MAHA, SIADH, hemosiderosis, cirrhosisSIADH, hemosiderosis, cirrhosis

ReferencesReferences Radiology. 2004 Feb;230(2):479-84. Epub 2003 Dec 10. MR quantification of Radiology. 2004 Feb;230(2):479-84. Epub 2003 Dec 10. MR quantification of

hepatic iron concentration.hepatic iron concentration. http://www.about-blood-disorders.com/articles/iron-disorders/hemosiderosis.phphttp://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.

And a big thanks to…And a big thanks to…

Dr. WeitzDr. Weitz Dr Ben-AriDr Ben-Ari Dr. HolmanDr. Holman

hemosiderosis dr. david cao faculty: dr. weitz. outline case presentation case presentation what’s...

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