2CASE Chief Complaint: Generalised fatigue and weakness. HPI: Pt is a 68 year old white male1-2 month h/o worsening fatigue.Mild shortness of breath. No fevers ,chills,nausea or vomting.No cough or sick contactsNo chest pain/palpitations/orthopneaMild dyspnea on exertion.
3CASE No weight loss or changes in appetite, Occasional constipation. No hematochezia, melena, dysuria or hematuria.Denies rashesnotes several small bruises on his legs.PMH : HTN – diagnosed in 1972Atrial fibrillation- diagnosed in July 2004OsteoarthritisGERDHyperlipidemiaBPH
5CASE Social History : Tobacco –quit in 1972 after 45 pack/year history Alcohol –quit in 1972.Drank sociallyDrugs-deniesRetired veteran and airport maintenance supervisor
6CASEFamily History:Aunt with DMNo Family history of CAD orCancers.
7CASE Physical Exam: Vitals : T-97.5, P-74 BP 118.74,R 20 General; Alert,oriented in NADHEENT-PERRL,EOMI ,mucous membranes moist, pale conjunctiva,Oropharynx-normal ,no thyromegaly,No JVD, no LAD,no carotid bruits.
8CASE 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.
9LABS Na- 138 K 3.2 Chloride -104 Bicarb 26 BUN 20 Creatinine 1.8 Glucose 88Calcium-8.7Magnesium 2.2
12Signs and Symptoms Pertinent Positives: Pale conjunctiva Worsening fatigueMild Shortness of breathConstipationsoft systolic murmurpetechiae on legs.history of Atrial fibrillation
13Signs and Symptoms Pertinent Negatives: No weight loss No change in appetiteNo fevers or chillsNo coughNo hematuriaNo adventitious sounds on lung examinationNo thyromegalyNo splenomegaly
14Problem list Pancytopenia Low Reticulocyte count Atrial Fibrillation on AmiodaroneHypothyroidism
15Bone Marrow FailureThe 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.
16BONE MARROW FailureCabot 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!
17Aplastic Anemia Severe AA Moderate AA At least 2 of the following:ANC <0.5x109/LPlatelet count <20 x 109/LAnemia with corrected Retic count <1%Those with Pancytopenia who do not fulfill the criteria of severe disease.ANDOne of the following:Bone marrow cellularity <25%Bone Marrow cellularity <50% with fewer than 30%hematopoietic cells.
18Pancytopenia With Hypocellular Bone marrow: Acquired Aplastic Anemia Inherited Aplastic anemiaSome Myelodysplasia syndromes.Acute LeukemiaSome Lymphomas of the Bone Marrow
22Pancytopenia 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
23PANCYTOPENIA SECONDARY TO SYSTEMIC DISEASES: SLE Sjogren’s syndrome HypersplenismVitaminB12, folate deficiencyOverwhelming infectionAlcoholBrucellosisEhrlichiosisSarcoidosisTuberculosis and atypical mycobacteria
24PANCYTOPENIA HYPOCELLULAR BONE MARROW with or without CYTOPENIA: Q feverLegionnaires’ diseaseMycobacteriaAnorexia nervosaHypothyroidisimMild pancytopenia occurs after repeated 131I therapy, but myelodysplasia leading to aplastic anaemia is rare and likely to occur only in patients with extensive bone metastases who have received a high cumulative dose
25Narrowed Differential Myelodysplastic syndromeAcute LeukemiaAcquired Aplastic Anemia :Drugs causing PancytopeniaIdiopathic AAHypothyroidismWill explain in the previous slides as to why each one of the others are not a high probability.
26HYPOTHYROIDISM High TSH Low FT4 Symptoms of Fatigue Constipation PallorUsually normocytic anemia.
27HypothyroidA 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)
29Myelodysplastic syndromes Cytopenia with a cellular Bone marrowMorphologic abnormalities in 2 or more cell lines.Usually idiopathicMay be seen after chemotherapyIneffective hematopoeisis
30Myelodysplastic syndrome May evolve into AMLFrequent abnormalities involving long arm of chromosome 5Deletions of chromosome 5 and 7
31MYELODYSPASIA and the % which convert to Acute Leukemia RA with ring sideroblastsRareRefractory anemia5- 15 %Refractory anemia with excessive blasts25- 40%Refractory anemia with excessive blasts in transformation (RAEB-T)70-90%CMML25-40%
32RAEBRAEB. Note agranular myelocytes and agranular poorly segmented neutrophil, and abnormal basophil with dense nuclear chromatin (arrowed).
34A cluster of proerythroblast cells Contain curdled chromatin. Result of ineffective erythropoiesis
35Findings Age over 60 Asymptomatic with abnormal blood count Fatigue Infections or bleedingCourse indolentMay have splenomegaly
36Laboratory findings Anemia MCV normal or increased Reticulocyte count usually reducedNeutropenia commonNeutrophils exhibit Pelger Huet cellsMyeloid series may be left shifted.Small number of blasts or promyelocytes may be seen.Platelets normal or reduced.
38Bone Marrow Hypercellular / Hypocellular Erythroid hyperplasia is commonSigns of abnormal erythropoiesis include megaloblastic features,nuclear budding or multinucleated erythroid precursors.
39BONE MARROW Prussian blue stain may show ring sideroblasts. Characteristic abnormality is the presence of dwarf megakaryocytes with a unilobed nucleus.
40TREATMENT Patients supported with transfusions. GCSF or GMCSF. Erythropoietin subcutaneously weeklyAzacitidine 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.
41Prognosis It is ultimately a fatal disease. Risk of transformation to AML depends on the percentage of blasts in the bone marrow.
42PROGNOSISThose with excessive blasts or CMML have short survival usually less than 2 years and have a higher risk of developing AMLFindings with full deletions is associated with a poor prognosis.
44ACUTE 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.
45ACUTE 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.
47ACUTE LEUKEMIA SYMPTOMS and SIGNS: Fever Dyspnea Gingival bleeding or epistaxisNeutropeniaTiredness.
48ACUTE LEUKEMIAOn 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
49FAB 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
50FAB classificationM5 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
51WHOThis 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%
52DIAGNOSISPeripheral blood smear shows circulating blasts. Auer rods are seen in leukemic blasts. If blasts sparse thenDefinitive diagnosis by BM biopsy.Infiltration of bone marrow with leukemic blasts is seen.
53ACUTE LEUKEMIABlast 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.
54TREATMENTInduction 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.
55TREATMENTCytogenetic testing is recommended prior to starting therapy in every newly diagnosed patientThe most common remission Induction therapy employs cytarabine and daunorubicin.
56TREATMENTDepending 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.
59DRUGS Innumerable drugs Drugs taken by patient Amiodarone Lisinopril HydralazineAspirinMeclizineSimvastatin
60DRUGS 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
61Classification Agents that regularly produce marrow depression Cytotoxic drugs used in cancer chemotherapy: Alkylating agentsAntimetabolitesAntimitoticsSome antibioticsBenzene and less often benzene containing chemicals.
62CLASSIFICATIONAgents probably associated with aplastic anemia but with a relatively low probability relative to their use:ChloramphenicolInsecticidesAntiprotozoalsNSAIDSAnticonvulsantsGold and ArsenicSulfonamides as a class.Antithyroid medicationsAntidiabetes drugsCarbonic anhydraseD-Pencillamine2 Chlordeoxyadenosine
63CLASSIFICATION Antiarrhythmics Lisinopril Agents more rarely associated with Aplastic Anemia:AntibioticsAntihistamines.Sedatives and TranqulizersAntiarrhythmicsLithiumThiocyanateCarbimazoleAmphetaminesLisinopril
64Drugs 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.
65LisinoprilA single case of Hemolytic anemia has been reported which resolved after stopping the drug and treating with a tapering steroid therapyNo cases of Thyroid abnormalities reported.
66HYDRALAZINEPancytopenia 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 seenNo thyroid abnormalities noted.
68AMIODARONE Antiarrhythmic agent Class 111 Has innumerable side effects reported.Causes Pulmonary toxicityThyroid problems:Hypothyroidism (1% to 22%)Hyperthyroidism (<3%),Gastrointestinal: Nausea, vomiting, anorexia and constipation (10% to 33%),Rare cases of Pancytopenia
69AMIODARONE 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.
70AMIODARONEElimination 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:Intrinsic effects on ThyroidEffects due to Amiodarone’s iodine content.
71INTRINSIC EFFECTS on THYROID It inhibits the outer ring of T4 hence decreases production of T3reverses 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 cellsdestructive Thyroiditis
72Effects 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.
73AMIODARONEWith 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.
74AMIODARONE 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 patientsHypothyroidism can occur as soon as 2 weeks and as late as 39 months after initiating therapy.
75AMIODARONE 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.
76AMIODARONE 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 knownIn 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.
77AMIODARONE 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.
78AMIODARONE 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.
79AMIODARONEIn 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 marrowAmiodarone was discontinued.However in both cases amiodarone could not conclusively be implicated as no follow up bone marrow was done.
80Epitheloid GranulomaWill mention that Bone marrow granulomas seem to be associated with cytopenias in patients with Amiodarone
82AMIODARONEIn 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.
83AMIODARONEIn 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.
84DIAGNOSIS Myelodysplastic syndrome AML Acquired Aplastic Anemia: Amiodarone induced Pancytopenia and hypothyroidism
86REFERENCES Practical diagnosis of Hematology 3rd ed Carl Kjeldsberg MD CRC desk reference for Hematology N.K. ShentonHoffman : Hematology: Basic principles and Practice 3rd ed.Micromedex Healthcare seriesUptodateHypoplastic anemia complicating myxoedema coma Song SH,McCallum CJ,Campbell IWAmiodarone induced bone marrow granulomas steven k. Moran and Arumugan Manoharan.Amiodarone induced bone granulomas N.Y.Z. Boutros,S.DillyUnexplained Bone Marrow granulomas: Is Amiodarone the culprit? A report of 2 casesAmiodarone –associated granuloma in bone marrow.
87The EndTo receive credit for having studied the CPC, please send Dr. Oliver (TAMU 407i)a list of the differential diagnoses for this patient.