Transcript Gastrointestinal Stromal Tumor

Hemosiderosis
Dr. David Cao
Faculty: Dr. Weitz
Outline
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Case Presentation
What’s the matter with iron?
Histopathology
Management
Complications of treatment
Back to our patient
Conclusion
Faculty Discussion
Learning Objectives
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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
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.
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.
Case Presentation
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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)
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Prilosec 20 mg po qday prn
Folic acid 1 mg po qday
Family history: Mom: breast cancer, Dad: prostate
cancer
Case Presentation
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Social history: No tobacco, ethanol, or drugs
Review of systems: per HPI
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
Case Presentation
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Paracentesis History:
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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
Case Presentation
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WBC 5.9
Hgb 11.4
Hct 33.3
Platelets 116
MCV 106
RDW 25.6
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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
Case Presentation
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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
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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
Differential Diagnosis
Abdominal Girth/jaundice
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MALIGNANCY: new vs metastatic spread
Cirrhosis with portal hypertension
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ascites
Constipation or bowel obstruction
Hemolytic anemia
Chemotherapy side effect
Hypoalbuminemia
Hyponatremia
Budd-Chiari
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
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
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
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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
20.9
LDH 542
Haptoglobin <7
Ddimer 3809
Fibrinogen 349
Serum Osmo 258
Urine Osmo 696
Urine Na <10
TSH 3.79
FT4 0.9
Patient’s problem list
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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
Hemosiderosis
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Iron deposition into tissues
Genetic ie hemachromatosis
 Transfusional
 Abnormal clearance/use
 Increase absorption
 Abnormal Hepcidin
 Hemolytic anemia
 Hemotropic parasites
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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
Complications of Iron Overload
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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
0.7 g
60 kg woman
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
Iron stores transferrin, ferritin,
hemosiderin
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
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
Hepcidin in Iron-loading
Anemias
Increased erythropoietic
drive suppresses hepcidin
production (yellow
arrow)
Excessive iron
absorption, elevated
transferrin saturation and
accumulation of nontransferrin-bound iron
(NTBI)
Hepcidin regulation by
iron remains blunted
resulting in iron overload
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-transferrinbound iron (NTBI)
Iron Overload
Transfusional Hemosiderosis
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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 200300mg of iron)
March 2010 5 RBC
 April 2010 5 RBC
 May 2010 2 RBC
 June 2010 2 RBC
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Diagnosis
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Liver Biospy is the most definitive test for
diagnosis
CT and MRI T2 and R2 can accurately determine
iron deposition noninvasively
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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
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Ferritin can be elevated in liver disease, inflammatory disease,
obesity, and malignancy
Treatment
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Oral iron chelator: Deferasirox, Deferoxamine,
Deferiprone
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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
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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
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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 Effects
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Iron Chelators
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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 patientyears (deferiprone)
Associated with Mucor, Yersinia, Vibrio vulnificus infections
(deferoxamine)
Phlebotomy: can cause hypovolemia or anemia in some
patients
Current Recommendations
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Chelation Therapy if not tolerable of phlebotomy
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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
Prognosis
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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
Who to Screen
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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 Methods
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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
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Back to our patient…
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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
Conclusion
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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
References
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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.
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Neufeld, EJ. Blood 2006; 107:3436.
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And a big thanks to…
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Dr. Weitz
Dr Ben-Ari
Dr. Holman