Post on 25-Sep-2020
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UPDATE IN HEMATOLOGY
Lisa B. Weissmann, MD
UPDATE IN HEMATOLOGY
Update on common problems that drive primary care providers crazy Iron deficiency anemia Neutropenia/ Neutrophilia Thrombocytosis Monoclonal Gammopathy
Iron deficiency Iron deficiency
Most common form of anemia Microcytic
R/o Thalessemia, lead toxicity Daily requirement of 5-10mg/day
15mg/day menstruating women 30 mg/day in pregnancy/nursing
IRON DEFICIENCY ETIOLOGY
DIET Need 5-10 mg/day Heme iron (meat) has greater bioavailibility than non-
heme iron Achlorhydria, intestinal disease can diminish absorption
Celiac, gastric bypass, Chrohn’s, H. pylori
BLOOD LOSS Each cc of blood has 0.5mg iron therefore just 10-15cc of
blood loss/day can lead to deficiency Normal menstrual loss is 100-250cc/month(!) Iron deficiency in men/post-menopausal women
MANDATES gi evaluation, including celiac
IRON DEFICIENCY ANEMIA DISTINGUISHING IRON DEFICIENCY FROM ANEMIA OF CHRONIC
DISEASE IRON DEF. ACD SERUM IRON* +/- +/- TIBC HIGH LOW %SAT LOW/VAR NORMAL/VAR FERRITIN** LOW/VAR HIGH FEP*** HIGH (>100) NORMAL sTfR**** HIGH NORMAL BONE MARROW ABSENT STORES ABUNDANT
• *SERUM IRON REFLECTS IRON IN BLOOD AT THAT MOMENT IN TIME • ** FERRITIN CAN BE ELEVATED IN INFLAMMATORY STATES • *** FREE ERYTHROCYTE PROTOPORHYRIN • **** SERUM TRANSFERRIN RECEPTOR
TREATMENT Iron supplementation
Dietary repletion quite difficult once deficient 3oz liver= 7.5mg iron; spinach=2.5mg etc Ascorbic acid enhances absorption Cereals, tanins(tea), antacids inhibit absorption
Supplements: Aim for 60-120mg elemental iron/day Treat for 6 weeks after MCV normalizes or Ferritin over
50 (do not stop for normal Hct/Hgb)
IRON SUPPLEMENTS Oral supplements
Ferrous Fumarate - 33mg elemental iron (Feostat, Fumerin, Homocyte)
Ferrous Gluconate - 36mg elemental iron (Fergon, Fermalat)
Ferrous Sulfate - 60mg elemental iron (Feosol, Slow-Fe, Ferratab)
Ferrous Polysaccharide - 150mg (Niferex, Nu-iron)
Parenteral supplements: LMW Dextan, iron sucrose, iron gluconate, ferumoxytol
Fatigue and low Ferritin Blood, 2011. Krayenbuehl, et al. 118:3222-3227
Neutrophilia
Definition Leukocytosis >11,000
Neutrophils, not lymphocytes, monocytes, etc
Chronic or Acute Primary or Reactive
Neutrophilia
Reactive Cigarettes – can persist for years Infections Inflammation
Autoimmune, stress Paraneoplastic
Lung, kidney, others Medications
Steroids, Lithium Other
Thyroid storm, asplenia
Neutrophilia
Primary/Myeloproliferative CML – bcr-abl mutation P.Vera, Essential Thrombocythemia,
Myloid Metaplasia JAK2 – 99% concordance in PVera MPL 505 Calreticulin (NEJM 12/2013)
Neutrophilia - evaluation History/Physical
Systemic symptoms of infection or Inflammation Fevers, arthralgias, rash, abdominal pain, diarrhea
Splenomegaly, adenopathy, bleeding
Labs CBC – shift to left; toxic granulations – reactive
- immature cells (especially pro-myelocytes/blasts) primary and requires urgent investigation
basophilia/splenomegaly – CML/MPD CRP/ESR; elevated LDH, coagulopathy Bone Marrow aspirate and biopsy
Neutropenia in the Outpatient Adult
ANC<1500 cells/microL 1,000-1500 MILD 500-1,000 MODERATE <500 SEVERE
Isolated Check Hgb and platelets
Acquired or Chronic Chronic –
Benign Ethnic Neutropenia Hereditary Neutropenias
Chronic Neutropenia Extrinsic
Nutritional - B12, Folate, Copper, Protein/Calorie Malnutrition (Anorexia) Immune
Intrinsic Myelodysplasia Acquired bone marrow failure – Aplastic Anemia Congenital bone marrow failure
Isolated neutropenia - Severe congenital neutropenia; cyclic neutropenia Neutropenic Syndromes – other findings Chédiak-Higashi syndrome, Cohen syndrome, Griscelli syndrome type 2, Hermansky-
Pudlak syndrome typ2, and p14 deficiency Disorders of metabolism: glycogen storage disease type 1b, Barth syndrome, Pearson
syndrome Disorders of immune function: hyper-IgM syndrome; warts,hypogammaglobulinemia,
infections, and myelokathexis (WHIM)syndrome; cartilage-hair hypoplasia; Schimke immuno-osseous dysplasi
Disorders of molecular homeostasis: dyskeratosis congenita, Fanconi anemia, Shwachman-Diamond syndrome
Benign Ethnic Neutropenia (BEN)
Higher prevalence in people of African descent also seen in Yemenites, Sephardic Jews, etc
Related to Duffy Antigen Receptor polymorphism SNP (rs2814778) – DARC Homozygosity linked to lower white cell counts (shift of
curve) 80% of African Blacks have homozygositiy and 15% have
absolute neutropenia Not associated with increased infections May offer some protection from malaria
Acquired/Acute Neutropenia
Most common causes: Drug/Toxin Infections
Viral, Bacterial, Rickettsial Autoimmune Nutritional – B12, Folate, Copper
Less common/associated findings Leukemia, PNH, MDS
Severe Agranulocytosis (0 white cells) Almost always drug induced May have genetic susceptibility (HLA subtypes)
Causes of Transient Neutropenia
Infection
Viral – CMV, EBV, HIV, Flu, Parvovirus B19 Bacterial – Brucella, Typhoid, TB, Tularemia, Rickettsia, Anaplasma Protozoan - Malaria
Drugs Anticonvulsant – Carbamazepine, Valproate Antimicrobial – Sulfonamides, Penicillins, Bactrim Antipsychotic- Clozapine, Olanzapine,Phenothiazines Antirheumatic – Gold, Levamisole, Penicillamine Antithyroid - Methimazole, Propylthiouracil Other – Chemotherapy/Rituximab, Cocaine/Levamisole, Ticlopidine, Dipyrone
Autoimmune Disorders SLE, Sjogren’s, RA/Feltys, Crohn’s
Neonatal isoimmune Other
Trali
Evaluation in Outpatient Setting
Asses severity and concomitant illness/infection Severe neutropenia, infection – rapid/urgent evaluation
“Well” patient, mild/moderate neutropenia: Prior CBC, family history, prior infections Repeat CBC with manual differential
Asses other cell lines Asses new drugs/alcohol/ toxins/occupational hazards Infectious exposures – HIV, CMV, tick borne Asses autoimmune disorders Exams for splenomegaly, lymphadenopathy, oral ulcers
Most common reasons for incidentally discovered neutropenia are drugs, nutritional and autoimmune
Monitor every 2-4 weeks until normalization or prove chronic
Thrombocytosis
Reactive – Infectious, Inflammatory, Malignancy – most common in
inpatient setting Iron deficiency – probably most common in outpatient setting Splenectomy
Primary – Essential Thrombocythemia
50% JAK2; 30% Calreticulin P.Vera
99% JAK2 Myelofibrosis
MPL, TET2 mutations
Essential Thrombocythemia Can be associated with classic gene alterations
(JAK2,Calreticulin, etc) but also without Diagnosis of exclusion (reactive and primary)
Can be associated with acquired VWD Large VW multimers “stick” to platelets Usually only seen with very high levels (>1 million)
Do NOT need to treat unless high risk for thrombosis Prior clot, Age >60
If low risk – aspirin daily If high risk – Hydroxyurea to bring platelets<600,000
Monoclonal Gammopathy of Unknown Significance (MGUS)
Monoclonal protein found on
immunoelectrophoresis Very common as we age
incidence of 1-2% in general population 6% from age 62-79 14% over age 90 Higher incidence in African Americans (as for
multiple myeloma)
MGUS - Definition
Immunoglobulin < 3gm Less than 10% plasma cell in the
marrow Absence of related findings
no anemia, hypercalcemia, renal insufficiency
MGUS
Determining “benign” from malignant always problematic Long term follow-up of MGUS
long term studies (since 1956!) show 27% develop lymphoproliferative disorder, 57% die of other disorders, 16% without disease
Kyle, Mayo Clin Proceed July, 2004
IgG, IgA can progress to Myeloma IgM can progress to lymphoma, CLL or
Waldenstrom’s Macroglobulinemia
EVALUATION OF MGUS
Initial Evaluation quantitative IG
supression of other immunoglobulins Bence Jones Protein Hct, Calcium, BUN/Cr Skeletal survey if M spike >2 grams
not bone scan (myeloma associated with lytic lesions which can be missed on bone scans)
Abdominal CT scan if IgM Bone Marrow - ?always needed - should be done if M
spike >3 grams or abnormal Hct, ESR, calcium
Evaluation of MGUS
High Risk for transformation M spike greater than 3grams IgA/IgM subtype (?) Supression of other immunoglobulins Bence Jones Proteinuria
None of these absolutely predict behaviour
MGUS evaluation
New methods to determine behavior: Kappa/lambda light chain ratios
Serum Bence Jones Abnormal ratios can be independent predictor
of progression (Rajkumar et al, Blood 2005) When combined with other risk factors can be
highly predictive of behavior Type of immunoglobulin,amount, FLC ratio
Kyle et al, Oncology, 25:7, 2011
RISK STRATIFICATION FOR MGUS
RISK PROGRESSION AT 20 YEARS
LOW NORMAL FLC, IGG SUBTYPE, M-SPIKE<1.5GM
3%
LOW-INT ANY 1 RISK 10%
HIGH-INT ANY 2 RISK 18%
HIGH ALL 3 RISK 27%
Follow Up for MGUS If low risk
No need for bone marrow IPEP annually for life
If intermediate risk Bone marrow recommended check every 6 months for 2-5 years then annually for life
If high risk Bone marrow Check every 3 months for 2-3 years then every 6 months for
life Repeat skeletal survey, bone marrow only if significant
progression of M spike or other laboratory abnormalities
Selected Bibliography Provan D. Mechanisms and management of iron deficiency anaemia. Br J Haematol 1999;105 Suppl
1:19-26. Ajioka RS, Kusher JP. Clinical consequences of iron overload in hemochromatosis homozygotes. Blood
2003 May 1; 101(9); 3351-3. Bacon BR, et al. Diagnosis and Management of Hemachromatosis: 2011 Practice Guidelines of the
American Association for the Study of Liver Disease. Hepatology 2011; 54:1. Whitloch EP Garlitz, BA, Harris EL, et al. Screening for hereditary Hemochromatosis: A systematic
review for the US Preventive Services Task Force. Ann Int Med 2006 Aug 145(3): 209-223 Boxer, LA. How To Approach Neutropenia. ASH Education Book December 8, 2012 Vol 2012 #1: 174-182. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group
guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7.
Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. New England J of Med 2002 Feb 21; 346(8):564-569
Rajkumar SV et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of unknown significance. Blood 2005; 106(3); 812-817
Kyle RA, Buadi F, Rajkumar SV. Management of Monoclonal Gammopathy of Undetermined Significance and Smoldering myeloma. Oncology 2011; 25:7
Conclusion “Before I came here I was confused
about this subject, but now having heard your lecture I am still confused, but at a higher level”
Enrico Fermi, Nobel Laureate, 1938