Hemosiderosis

1
Hemosiderosis

• Dr. David Cao
• Faculty Dr. Weitz

2
Outline

• Case Presentation
• Whats 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 lt7
• Ddimer 3809
• Fibrinogen 349
• Serum Osmo 258
• Urine Osmo 696
• Urine Na lt10
• TSH 3.79
• FT4 0.9

• Unbound iron lt16
• 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
Patients 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
  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
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-bou
nd 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.
• Patients 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 (lt 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

 Annual Costs Deferoxamine Deferiprone Deferasirox
Moderate dose regimen Moderate dose regimen Moderate dose regimen 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 Higher dose regimen Higher dose regimen Higher dose regimen
(mg/kg/day) 40 100 30
United States 26,000 NA 58,500
Italy 6400 8900 NA
India ND 1100 NA
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 Feb230(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 Jan111(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 Jan123(1)146-52.
  Variability in hepatic iron concentration in
  percutaneous needle biopsy specimens from
  patients with transfusional hemosiderosis
• Lab Invest. 2008 Dec88(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 Dec83(12)932-4 Acquired iron
  overload associated with antitransferrin
  monoclonal immunoglobulin a case report.
• Health Technol Assess. 2009 Jan13(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 Feb77(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. 19993411986-1995.
• Neufeld, EJ. Blood 2006 1073436.

40
And a big thanks to

• Dr. Weitz
• Dr Ben-Ari
• Dr. Holman