Transcript Slide 1

CPC
Jaji Bettadpur MD
MED-PEDS
Jan 14th 2005
CASE
Chief Complaint:
Generalised fatigue and weakness.
HPI: Pt is a 68 year old white male
1-2 month h/o worsening fatigue.
Mild shortness of breath
. No fevers ,chills,nausea or vomting.
No cough or sick contacts
No chest pain/palpitations/orthopnea
Mild dyspnea on exertion.
CASE
No weight loss or changes in appetite,
Occasional constipation.
No hematochezia, melena, dysuria or hematuria.
Denies rashes
notes several small bruises on his legs.
PMH : HTN – diagnosed in 1972
Atrial fibrillation- diagnosed in July 2004
Osteoarthritis
GERD
Hyperlipidemia
BPH
CASE
MEDICATIONS
Aspirin 325 mg qd
Lisinopril 40 mg qd
Meclizine 25 mg tid prn
Terazosin 5 mg qhs
Amiodarone 200 mg qd
Hydralazine 25 mg tid
Simvastatin 20 mg qhs
CASE
Social History :
Tobacco –quit in 1972 after 45 pack/year
history
Alcohol –quit in 1972.Drank socially
Drugs-denies
Retired veteran and airport maintenance
supervisor
CASE
Family History:
Aunt with DM
No Family history of CAD or
Cancers.
CASE
Physical Exam:
Vitals : T-97.5, P-74 BP 118.74,R 20
General; Alert,oriented in NAD
HEENT-PERRL,EOMI ,mucous
membranes moist, pale
conjunctiva,Oropharynx-normal ,no
thyromegaly,No JVD, no LAD,no carotid
bruits.
CASE Continued…
CVS-RRR with soft systolic murmur 2/6 at
apex
LUNGS-CTA –Bilaterally. No wheezing or
rhonchi.
ABDOMEN-soft,NT,ND ,normal BS,no
splenomegaly, no masses.
EXTREMITIES -mild1+edema,good
peripheral pulses,multiple small petechiae
on legs.
LABS
Na- 138
K 3.2
Chloride -104
Bicarb 26
BUN 20
Creatinine 1.8
Glucose 88
Calcium-8.7
Magnesium 2.2
LABS
TSH 10.57
FT4 0.9 Normal(0.4 - 5.7)
Iron studies :
Fe 43
TIBC 307
CBC
03/04
WBC- 7.0
08/04
WBC 5.1
10/04
WBC 3.7
Hgb 16.6
Hgb 12.9
Platelets 180
Platelets 153
Hgb 9.3
MCV 94
Retic 0.5%
Platelets 86
Signs and Symptoms
Pertinent Positives:
Pale conjunctiva
Worsening fatigue
Mild Shortness of breath
Constipation
soft systolic murmur
petechiae on legs.
history of Atrial fibrillation
Signs and Symptoms
Pertinent Negatives:
No weight loss
No change in appetite
No fevers or chills
No cough
No hematuria
No adventitious sounds on lung examination
No thyromegaly
No splenomegaly
Problem list
Pancytopenia
Low Reticulocyte count
Atrial Fibrillation on Amiodarone
Hypothyroidism
Bone Marrow Failure
The study of bone marrow failure is
traditionally dated to 1888.
Paul Ehrlich described a patient who died
after an explosive short illness.
In 1904 Vaquez and Aubertin presented a
case report and first named the disease.
BONE MARROW Failure
Cabot stressed the marrow’s distinctive
pathology and emphasized the need for
it’s examination.
Tissues from patients were only examined
during autopsy in the earlier cases of AA.
In practice Pancytopenia was often
equated with aplastic anemia. The
etymologic root of the term aplastique!
Aplastic Anemia
Severe AA
Moderate AA
At least 2 of the following:
ANC <0.5x109/L
Platelet count <20 x 109/L
Anemia with corrected Retic
count <1%
Those with Pancytopenia
who do not fulfill the criteria
of severe disease.
AND
One of the following:
Bone marrow cellularity <25%
Bone Marrow cellularity <50%
with fewer than
Pancytopenia
With Hypocellular Bone marrow:
Acquired Aplastic Anemia
Inherited Aplastic anemia
Some Myelodysplasia syndromes.
Acute Leukemia
Some Lymphomas of the Bone Marrow
Acquired Aplastic Anemia
Irradiation
Drugs
Viruses EBvirus (infectious Mononucleosis) ,Hepatitis, Parvovirus,
HIV.
Immune diseases
Idiopathic aplastic anemia
With Hypocellular Bone marrow:
Acquired Aplastic Anemia
Inherited Aplastic anemia
Some Myelodysplasia syndromes.
Acute Leukemia
Some Lymphomas of the Bone Marrow
APLASTIC ANEMIA
Pancytopenia


WITH CELLULAR BONE MARROW:
Primary Bone marrow disorders:
* Myelodysplasia syndromes
* Paroxysmal Nocturnal hemoglobinuria
* Myelofibrosis with myeloid metaplasia
* Some aleukemic leukemias
* Myelopthisis
* Bone marrow lymphoma
* Hairy cell leukemia
PANCYTOPENIA
SECONDARY TO SYSTEMIC DISEASES:
1.
SLE
2.
Sjogren’s syndrome
3.
Hypersplenism
4.
VitaminB12, folate deficiency
5.
Overwhelming infection
6.
Alcohol
7.
Brucellosis
8.
Ehrlichiosis
9.
Sarcoidosis
10.
Tuberculosis and atypical mycobacteria
PANCYTOPENIA
1.
2.
3.
4.
5.
HYPOCELLULAR BONE MARROW with
or without CYTOPENIA:
Q fever
Legionnaires’ disease
Mycobacteria
Anorexia nervosa
Hypothyroidisim
Narrowed Differential
Myelodysplastic syndrome
Acute Leukemia
Acquired Aplastic Anemia :
Drugs causing Pancytopenia
Idiopathic AA
Hypothyroidism
HYPOTHYROIDISM
High TSH
Low FT4
Symptoms of Fatigue
Constipation
Pallor
Usually normocytic anemia.
Hypothyroid
A case of a 68 year old woman who presented
with myxedema coma and was found to be
anemic.
Further investigations showed a pancytopenia
and a hypoplastic anemia confirmed by bone
marrow.
Following treatment she became euthyroid and
was found to have resolution of her
pancytopenia and bone marrow returned to
normal.(Song SH et al 1998)
DIFFERENTIAL
Hypothyroidism
Myelodysplastic syndrome
Acute Leukemia
Acquired Aplastic Anemia :
Drugs causing Pancytopenia
Idiopathic AA
Myelodysplastic syndromes
Cytopenia with a cellular Bone marrow
Morphologic abnormalities in 2 or more
cell lines.
Usually idiopathic
May be seen after chemotherapy
Ineffective hematopoeisis
Myelodysplastic syndrome
May evolve into AML
Frequent abnormalities involving long
arm of chromosome 5
Deletions of chromosome 5 and 7
MYELODYSPASIA and the %
which convert to Acute Leukemia
RA with ring sideroblasts
Rare
Refractory anemia
5- 15 %
Refractory anemia with
25- 40%
excessive blasts
Refractory anemia with 70-90%
excessive blasts in
transformation (RAEB-T)
CMML
25-40%
RAEB
RAEB. Note agranular myelocytes and agranular poorly
segmented neutrophil, and abnormal basophil with
dense nuclear chromatin (arrowed).
RARS
RARS. Left-shifted megaloblastoid erythropoiesis.
A cluster of proerythroblast cells
Contain curdled chromatin. Result of ineffective erythropoiesis
Findings
Age over 60
Asymptomatic with abnormal blood count
Fatigue
Infections or bleeding
Course indolent
May have splenomegaly
Laboratory findings
Anemia
MCV normal or increased
Reticulocyte count usually reduced
Neutropenia common
Neutrophils exhibit Pelger Huet cells
Myeloid series may be left shifted.
Small number of blasts or promyelocytes may be
seen.
Platelets normal or reduced.
Pelger Huet cells
Bone Marrow
Hypercellular / Hypocellular
Erythroid hyperplasia is common
Signs of abnormal erythropoiesis include
megaloblastic features,nuclear budding or
multinucleated erythroid precursors.
BONE MARROW
Prussian blue stain may show ring
sideroblasts.
Characteristic abnormality is the presence
of dwarf megakaryocytes with a unilobed
nucleus.
TREATMENT
Patients supported with transfusions.
GCSF or GMCSF.
Erythropoietin subcutaneously weekly
Azacitidine improves both symptoms and
blood counts and prolongs time to
conversion to acute leukemia.
Revimid (CC-5013) may hold promise in
patients with low risk myelodysplasia.
Prognosis
It is ultimately a fatal disease.
Risk of transformation to AML depends on
the percentage of blasts in the bone
marrow.
PROGNOSIS
Those with excessive blasts or CMML
have short survival usually less than 2
years and have a higher risk of developing
AML
Findings with full deletions is associated
with a poor prognosis.
DIFFERENTIAL
Myelodysplastic syndromes
Acute Leukemia
Acquired Aplastic Anemia :
Drugs causing Pancytopenia
Idiopathic AA
ACUTE LEUKEMIA
Malignancy of the hematopoietic progenitor cell.
Most cases arise with no clear cause.
The malignant cells proliferate in an uncontrolled
fashion and replace normal bone marrow.
The cases which arise after toxin or
chemotherapy exposure often develop from a
myelodysplastic prodrome and are associated
with abnormalities in chromosome 5 and 7.
ACUTE LEUKEMIA
Short duration of symptoms.
Fever, fatigue and bleeding. Cytopenia or
pancytopenia.
Bone marrow may have more than 20%
blasts.
AML is an adult disease with a median age
of presentation of 60 years and an
increasing incidence with advanced age.
AML
ACUTE LEUKEMIA
SYMPTOMS and SIGNS:
Fever
Dyspnea
Gingival bleeding or epistaxis
Neutropenia
Tiredness.
ACUTE LEUKEMIA
On examination patients are pale with
petechiae and may not have signs of
infection.
Gum hypertrophy,stomatitis and bone or
joint pain may be present.
Splenomegaly and lymphadenopathy may
be present in AML but less remarkable
than in ALL
FAB
This classification lists M0 –M7
In M3 patients Organomegaly is
uncommon. High frequency of DIC is
seen.
In M4 Leukocyte count is markedly
elevated. Organomegaly and
lymphadenopathy are common. Leukemic
skin and Gum deposits noted
FAB classification
M5 is associated with a relatively high
incidence of organomegaly,
lymphadenopathy and leukemic skin and
gum deposits.
M6 –many cases evolve from MDS or
present as a secondary leukemia.
M7 associated with Down’s syndrome
WHO
This classification incorporates cytogenetic
and molecular findings in addition to
morphologic ,cytochemical and
immunophenotype features.
Major change is, the reduction of the
number of blasts required for the diagnosis
of AML from 30-20%
DIAGNOSIS
Peripheral blood smear shows circulating
blasts. Auer rods are seen in leukemic
blasts. If blasts sparse then
Definitive diagnosis by BM biopsy.
Infiltration of bone marrow with leukemic
blasts is seen.
ACUTE LEUKEMIA
Blast forms must be identified as myeloid
and not lymphoid lineage.
It should be classified as the appropriate
variant according to the FAB and WHO
classifications.
TREATMENT
Induction therapy aims to reduce the total
body leukemic cell population .
Hence the goal of remission induction
therapy is to restore normal bone marrow
function.
Postinduction or remission consolidation
therapy requires one or more courses of
chemotherapy or BM transplantation.
TREATMENT
Cytogenetic testing is recommended prior
to starting therapy in every newly
diagnosed patient
The most common remission Induction
therapy employs cytarabine and
daunorubicin.
TREATMENT
Depending on age and patient selection,
60-80% attain complete remission with this
regimen.
The same chemotherapy regimen used for
remission induction can be repeated for
one or more cycles as consolidation
treatment.
AML
Auer rods
DIFFERENTIAL
Myelodysplastic syndromes
Acute Leukemia
Acquired Aplastic Anemia :
-Drugs causing Pancytopenia
-Idiopathic AA
DRUGS
1.
2.
3.
4.
5.
6.
Innumerable drugs
Drugs taken by patient
Amiodarone
Lisinopril
Hydralazine
Aspirin
Meclizine
Simvastatin
DRUGS
Medical drug use is frequently associated
with Aplastic anemia.
At the end of the 19th century Chemicals
like Benzene were linked to marrow
function.
This concept was further supported by the
association with amidopyrine and later
with Chloramphenicol in the 1960s
Classification
1.
2.
3.
4.
5.
Agents that regularly produce marrow
depression
Cytotoxic drugs used in cancer chemotherapy:
Alkylating agents
Antimetabolites
Antimitotics
Some antibiotics
Benzene and less often benzene containing
chemicals.
CLASSIFICATION
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Agents probably associated with aplastic anemia but with a
relatively low probability relative to their use:
Chloramphenicol
Insecticides
Antiprotozoals
NSAIDS
Anticonvulsants
Gold and Arsenic
Sulfonamides as a class.
Antithyroid medications
Antidiabetes drugs
Carbonic anhydrase
D-Pencillamine
2 Chlordeoxyadenosine
CLASSIFICATION
1.
2.
3.
Agents more rarely associated with Aplastic Anemia:
Antibiotics
Antihistamines.
Sedatives and Tranqulizers
4. Antiarrhythmics
5.
6.
7.
8.
Lithium
Thiocyanate
Carbimazole
Amphetamines
9. Lisinopril
Drugs
LISINOPRIL
Hematological effects:
* Rare causes of Bone marrow depression has
been reported including anemia,neutropenia and
thrombocytopenia
* One case of Pancytopenia has been reported in
a 79 year old woman after 12 months of
Lisinopril therapy 5mg/day (Schratzlseer et al
1994)
* Small reduction in hemoglobin has been seen
frequently in some patients.
Lisinopril
A single case of Hemolytic anemia has
been reported which resolved after
stopping the drug and treating with a
tapering steroid therapy
No cases of Thyroid abnormalities
reported.
HYDRALAZINE
Pancytopenia has been reported in a 63
year old male who was treated with 25 mg
qid for 10 days. He was also noted to have
obstructive jaundice.
The patient recovered within 2 weeks of
withdrawal from Hydralazine.
Constipation seen
No thyroid abnormalities noted.
ASPIRIN
Anemia, thrombocytopenia seen.
No thyroid abnormalities.
AMIODARONE
Antiarrhythmic agent Class 111
Has innumerable side effects reported.
Causes Pulmonary toxicity
Thyroid problems:Hypothyroidism (1% to 22%)
Hyperthyroidism (<3%),
Gastrointestinal: Nausea, vomiting, anorexia and
constipation (10% to 33%),
Rare cases of Pancytopenia
AMIODARONE
Iodinated benzofuran derivative.
Contains 2 iodine atoms
It’s metabolisim in the liver releases
approximately 3 mg of inorganic iodine per 100
mg of Amiodarone into the systemic circulation.
A typical American diet has an average iodine
intake of 0.3 mg/day.
Therefore 6 mg of iodine associated with a
200mg dose significantly increases the daily
load.
AMIODARONE
Elimination from the body occurs with a
half-life of about 100 days.
Hence toxicity can occur well after
withdrawal.
Effects of Amiodarone on Thyroid
function are divided into 2 categories:
1. Intrinsic effects on Thyroid
2. Effects due to Amiodarone’s iodine
content.
INTRINSIC EFFECTS on
THYROID
It inhibits the outer ring of T4 hence decreases
production of T3
reverses T3 accumulation since it is not
converted to T2.
Blocks T3 receptor binding to nuclear receptors
and decreases expression of some thyroid
hormone related genes.
Direct effect on thyroid follicular
cellsdestructive Thyroiditis
Effects due to Iodine content
Normal autoregulation of Iodine prevents normal
individuals from becoming hyperthyroid after
exposure to an iodine load(radiocontrast)
When a critical high is reached in intrathyroidal
concentrations the Wolff-Chaikoff effect takes
place.
AMIODARONE
With underlying disease there are defects
in Iodine autoregulation.
People with autoimmune thyroid disease
fail to escape from the WC effect.
Patients with autonomous function in a
nodular goitre do not autoregulate iodine.
Hence the effects of Iodine in Amiodarone
is dependent on the underlying status of
the patient.
AMIODARONE
HYPOTHYROIDISM
TSH elevation may be transient during the first
few months of therapy.
Small increases in TSH (10-20) and low normal
serum T4 concentrations occur in about 20% of
patients
Hypothyroidism can occur as soon as 2 weeks
and as late as 39 months after initiating therapy.
AMIODARONE
Treatment of Hypothroidism:
It resolves on discontinuation of therapy in
patients with no underlying disease.
Amiodarone is usually not discontinued
Thyroid function can be normalised with
T4 therapy.
AMIODARONE
Pancytopenia is seen in <1 % of cases.
Other hematologic adverse effects have been
reported in the literature in about 1-3% such as
coagulation abnormalities.
Precise mechanism of these toxic reactions are
not known
In Feb of 2004 ,2 cases in which each of the 2
patients who were on Amiodarone were noted to
have developed pancytopenia.
Further investigations led to granulomas in their
bone marrow.
AMIODARONE
In June of 2000 a case was reported where
Patient was noted to have thrombocytopenia.
She had been receiving Amiodarone for 8
months prior to this.
Her bone marrow biopsy showed multiple
noncaseating epitheloid granulomas.
These on repeat BM biopsy were fewer on
cessation of the drug.
It was concluded that a Bone marrow biopsy is
required in any blood dyscrasia associated with
amiodarone.
AMIODARONE
Rosenbaum et al in 1998 presented 2 case
reports.
In the first case the patient had a diagnosis of
myeloproliferative disorder for about 10 years
and had been on aspirin for several years.
She was started on Amiodarone and a follow up
Bone marrow biopsy showed granulomas.
All tests including fungal TB were negative.
It was concluded that Amiodarone was directly
responsible for these granulomas.
AMIODARONE
In the second case a 78 year old with atrial
fibrillation was started on Amiodarone and 18
months later a bone marrow biopsy was done to
investigate polyclonal gammopathy.
Granulomas were noted in the bone marrow
Amiodarone was discontinued.
However in both cases amiodarone could not
conclusively be implicated as no follow up bone
marrow was done.
Epitheloid Granuloma
Granuloma
AMIODARONE
In 2001 another case described a patient with
indolent myeloma on therapy with Amiodarone
who was noted to have bone marrow
granulomas which resolved on cessation of
therapy.
He was noted to have anemia and no clinical or
laboratory evidence for mycobacteria ,fungal or
sarcoidosis.
Following cessation of the Amiodarone the bone
marrow granulomas dissappeared .
The anemia resolved.
AMIODARONE
In Feb of 2004, 2 cases of Amiodarone induced
Bone Marrow granulomas were reported in
patients being investigated for pancytopenia and
refractory anemia respectively.
The patient had been on Amiodarone for 2 years
200 mg/day.
By exclusion it was attributed to the drug
Amiodarone.
DIAGNOSIS
Myelodysplastic syndrome
AML
Acquired Aplastic Anemia:
Amiodarone induced Pancytopenia and
hypothyroidism
CONCLUSION
Stop Amiodarone .
TESTS REQUIRED
1)Peripheral Blood smear.
2)Bone marrow biopsy.
REFERENCES
Practical diagnosis of Hematology 3rd ed Carl Kjeldsberg MD
CRC desk reference for Hematology N.K. Shenton
Hoffman : Hematology: Basic principles and Practice 3rd ed.
Micromedex Healthcare series
Uptodate
Hypoplastic anemia complicating myxoedema coma Song
SH,McCallum CJ,Campbell IW
Amiodarone induced bone marrow granulomas steven k. Moran and
Arumugan Manoharan.
Amiodarone induced bone granulomas N.Y.Z. Boutros,S.Dilly
Unexplained Bone Marrow granulomas: Is Amiodarone the culprit? A
report of 2 cases
Amiodarone –associated granuloma in bone marrow.
The End
To receive credit for having studied the
CPC, please send Dr. Oliver (TAMU 407i)
a list of the differential diagnoses for this
patient.