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Agents used in anemia

Anemia (ภาวะโลหิ�ตจาง)

เป็�นภาวะที่�มีการลดลงของเมี�ดเล�อดแดง หร�อ hemoglobin ส่�งผลให�มีการขนส่�ง O2 ไป็ส่��เน� อเยื่��อต่�างๆของร�างกายื่ลดลงCauses of anemia

increased RBCs loss (e.g. acute or chronic blood loss) decreased production of RBCs (e.g. iron, folic acid or vitamin B12 deficiency) increased destruction of RBCs (e.g. hemolysis)

Classification of anemia Microcytic, hypochromic anemia e.g. iron deficiency anemia Normochromic, normocytic anemia e.g. recent blood loss Macrocytic anemia e.g. folic acid deficiency, vitamin B12 deficiency

Iron deficiency anemia (Microcytic, hypochromic anemia)- most common cause of anemia

folic acid

cell membrane

N5N10-methylene-

THF

N5-me-THF

uridylat

e

thymidylat

e

DNADHF

reductase

N5-me-THF Vit.B

12 succinyl Co-A

L-methylmalonyl-CoA

homocysteine

methionine

THF

DHF

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- a state of negative iron balanceEtiology

blood loss, increased iron requirements, decreased iron absorption, poor diet

Treatment

ร$กษาต่ามีส่าเหต่& และ/หร�อ iron supplement

Megaloblastic anemias Etiology- deficiency of vitamin B12 or folate (cofactors required for the normal maturation of red blood cells)Treatment

- ร$กษาต่ามีส่าเหต่& เช่�น vitamin B12 or folic acid supplement

Agents used in anemias• Iron• Vitamin B12 • Folic acid

Role of iron- essential metallic component of heme - heme combined with appropriate globin chains forms hemoglobin (Hb) Pharmacokinetics: Absorption

Iron is best absorbed in ferrous form (Fe2+) Absorption is maximum in duodenum because acid medium of stomach and mucopolysaccharide

chelator substances that prevent iron from precipitating maintain iron in soluble form Food interferes with iron absorption therefore it should be administered 1 hr or more before meal Iron must be taken with food if patients experience nuasea and diarrhea when taking on empty

stomach At alkaline pH, iron tend to form insoluble complex (unavailable for absorption) Antacid or medication that reduce stomach acid production impairs iron absorption

Clinical use Treatment or prevention of iron deficiency anemiaOral iron products Ferrous sulfate ----60-65 mg/300- or 325-mg tablet

Parenteral formulation: iron dextran Adverse effect

oral iron therapy: GI tract upsets (e.g. nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea, feces discoloration)

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parenteral iron therapy: immediate hypersensitivity reaction (a small test dose of iron dextran should always be given)

Iron toxicityAcute toxicity - most common in children & usually occurs as a result of accidental ingestion of iron therapy - urgent treatment is necessary lavage with carbonate solutions, desferoxamine, deferiprone

(licensed in UK)

Chronic iron toxicity (iron overload) - occurs most often in patients who must receive frequent transfusions, and in those with hemochromatosis (a disorder characterized by excessive iron absorption) Iron toxicity

2 categories: corrosive and cellular toxicities Iron is extremely corrosive in GI system manifested as hematemesis or diarrhea Severe overdose causes impaired oxidative phosphorylation and mitochondria dysfunction, which can

result in cellular death The most affected organ is liver and others including heart, kidneys, lungs and hematologic systems

DesferoxamineUsed to prevent and treat iron overload

Adverse effect

Tinnitus “Not related to deferoxamine dosage”

Reversible transient hearing loss

ferrous

sulfate 300 mg

ferrous

fumarate 200 mg

ferrous

gluconate

300 mg

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Less common: decresed night vision

iv infusion > 15 mg/kg/hr may induce hypotension and shock Allergic reaction including anaphylaxis (not common) Hydrocortisone can be mixed with desferoxamine to reduce allergic reaction Diluting desferoxamine reduces irritation at the site of administration Excessive iron chelation will cause growth disturbance in children and mineral deficiency

Vitamin B12 (cyanocobalamin)

is a cofactor in the transfer of one-carbon units (step necessary for DNA synthesis)

essential nutrient for hematopoiesis, maintenance of myelin in the nervous system, and production of epithelial cell

Absorption requires “intrinsic factor” from parietal cell of stomach

Frequent cause of Vit.B12 deficiency is atrophic gastritis leading to lack of intrinsic factor

Besides megaloblastic anemia, damage to mucosal linings and degeneration of myelin sheats with neurologic sequelae will occur (pernicious anemia)

Vit. B12 is essential in 2 reactions:

1.conversion of homocysteine to methionine (is essential for normal production of RBCs)

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2.conversion of methylmalonyl-CoA to succinyl-CoA (essential for lipid metabolism)

Clinical use

- available as hydroxocobalamin & cyanocobalamin (have equivalent effects)

- oral cyanocobalamin is well absorbed (peak serum conc.being reached 8-12 hr after ingestion)

- caused by inadequate absorption therapy should be parenteral

Folic acid is necessary for synthesis of purines & for the formation of thymidylic acid body store is very low, so a decrease in dietary intake is followed by anemia within a few months Folates are found in fresh foods but rapidly destroyed by heating during food preparation

Cause of deficient Insufficient intake Malabsorption in GI diseases Increased requirement during pregnancy Antiepileptis drugs (phenytoin, primidone, phenobarbital) may decrease FA absorption

Clinical use

Megaloblastic anemias

Folic acid deficiency due to malabsorption syndrome and due to continuous use of anticonvulsants, particular primidone and phenytoin

Administration of FA can mask Vit.B12 deficiency.

Inhibition due to B12 deficiency is compensated by increased FA intake.

The anemia is readily corrected but nerve degeneration progresses unchecked.

Therefore, indiscriminate use of FA-containing multivitamin preparations can be harmful.

Haemopoietic Growth Factors

Erythropoietin

Colony-stimulating factors

Thrombopoietin

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Blood cell development

Erythropoietin Regulates red cell production 2 forms of recombinant human erythropoietin: epoetin alfa and epoetin beta (similar activity) Given iv.,sc. or ip. Greatest response with sc.injection Fastest response with iv.injection

Clinical uses Anemia of chronic renal failure

Pluripoten

t stem cell

Erythropoietin

GM-CSF

Thrombopoietin

Megakaryocyte

ErythrocytesPlateletsMonocytesNeutrophilsEosinophilsBasophilsB lymphocytes

T lymphocytes

Interleukins 1,2,4,6,7

Thymus

Monocyte-

granulocyte precursor

Committe

d progenitor cell

IL-3

GM-CSF

GM-CSF

IL-3

IL-3

IL-3

M-CSF

GM-CSFGM-CSF

G-CSFGM-

CSFIL-3

IL-5

IL-3

IL-1, IL-3, IL-6,

GM-CSF, SCF

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Anemia during chemotherapy for cancer Prevention of anemia that occurs in premature infants To increase yield of autologous blood before donation Anemia of AIDS (which is exacerbated by zidovudine treatment) Anemia of chronic inflammatory conditions such as rheumatoid arthritis

Adverse effects Transeint influenza-like symptoms Hypertension Encephalopathy with headache, disorientation and sometimes convulsions Iron deficiency due to more iron is required for the enhanced erythropoiesis

Colony-stimulating factors Stimulate committed progenitor cells and cause irreversible differentiation GM-CSF: granulocyte-macrophage colony-stimulating factors G-CSF: granulocyte colony-stimulating factors Given sc. or iv.

Clinical uses of CSFs To reduce severity and duration of neutropenia induced by cytotoxic drugs during To stimulate release into circulation of progenitor cells To expand the number of harvested cells ex vivo before re-infusing them For persistent neutropenia in advanced HIV infection Aplastic anemia

Adverse effectsGM-CSF can cause:fever, skin rashes, muscle pain, hypotension, GI symptoms, and arterial oxygen desaturation

Thrombopoietin Stimulate proliferation of progenitor cells of platelets Recombinant thrombopoietin is being tested clinically

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LYMPHOID NEOPLASMS

• Lymphoma • Hodgkin lymphoma • Acute leukemia• Acute lymphoblastic leukemia• Acute myeloid leukemia• Chronic leukemia• Chronic lymphocytic leukemia• Chronic myeloid leukemia

HEMATOPOIETIC AND LYMPHOID NEOPLASMSWHO classification Neoplasms of Hematopoietic and lymphoid tissue 2001

Chronic myeloproliferative diseases Myelodysplastic/Myeloproliferative diseases Myelodysplastic syndrome Acute myeloid leukemia

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B-lymphoid cell neoplasms T-lymphoid and NK-lymphoid cell neoplasms Histiocytic and dendritic-cell neoplasms Mastocytosis and mast cells neoplasms

Chronic myeloproliferative diseases Myelodysplastic syndrome Acute myeloid leukemia

Chronic myeloproliferative diseases• Chronic myelogenous leukemia• Essential thrombocythemia • Polycythemia vera • Chronic idiopathic myelofibrosis

Lymphoid NeoplasmsB-cell neoplasms

• Precursor B-cell neoplasms • Mature B-cell neoplasms

T-cell and NK-cell neoplasms • Precursor T-cell and NK-cell neoplasms • Mature T-cell and NK-cell neoplasms

Lymphoma

Lymphoid (lymphocytic) leukemia Plasma cell myeloma (Multiple myeloma) Hodgkin lymphoma

NON-HODGKIN LYMPHOMAS

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Proliferation of neoplastic lymphoid cells without definite Reed-Sternburg cells

Clinical Features

Nodal Painless lymphadenopathy B-symptoms

o Fever > 38 °Co Night sweat o Weight loss > 10% of body

weight

Extranodal Upper respiratory tract : nasal cavity Gastrointestinal tract Skin

Classification

Rappaport classification Lukes and Collins classification Keil/Lennert classification Working formulation REAL classification WHO classification

Working formulation • Depend on clinicopathologic features

Cellular morphology

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Arrangement Clinical course Low grade

• Intermediate grade• High grade• Miscellaneous

• Low grade • ML, Small lymphocytic• ML, Follicular, small cleaved cell• ML, Follicular, mixed small cleaved

and large cell• Intermediate grade

• ML, Follicular, large cell• ML, Diffuse, small cleaved cell• ML, Diffuse, mixed small and large cell • ML, Diffuse, large cell

• High grade • ML, Immunoblastic • ML, Lymphoblastic • ML, Small non-cleaved cell

• Miscellaneous • Composite• Mycosis fungoides • Histiocytic • Extramedullary plasmacytoma • Unclassifiable

WHO classification Morphology Immunophenotype Genetics Clinical informations

Precursor cells : immature cellsPeripheral cells : mature cells

B-cellsT-cells and NK-cells

• Precursor B-cell neoplasms

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Acute lymphoblastic leukemia/lymphoma • Precursor T-cell neoplasms

Acute lymphoblastic leukemia/lymphoma

• Peripheral B-cell neoplasms

o Chronic lymphocytic leukemia/Small lymphocytic lymphoma

o Lymphoplasmacytic lympoma o Splenic marginal zone lymphomao Extranodal marginal zone lymphomao Nodal marginal zone lymphomao Hairy cell leukemia o Plasma cell myeloma o Follicular lymphoma o Mantle cell lymphomao Diffuse large B-call lymphomao Burkitt lymphoma/Burkitt cell leukemia

• Peripheral T-cell neoplasmo Adult T-cell leukemia/lymphomao Extranodal NK/T-cell lymphoma, nasal typeo Mycosis fungoides/Sézary syndrome o Anaplastic large cell lymphoma, primary

cutaneous o Anaplastic large cell lymphoma, primary systemic o Angioimmunoblastic T-cell lymphomao Peripheral T-cell lymphoma, unspesified o Angioimmunoblastic T-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL)

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Follicular lymphoma

Marginal zone B-cell lymphoma

o Extranodal marginal zone lymphomao Nodal marginal zone lymphomao Splenic marginal zone lymphoma

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Anaplastic large cell lymphoma

LYMPHOID NEOPLASMS PRESENTING WITH LEUKEMIA OR LYMPHOMA/LEUKEMIAAcute lymphoblastic leukemia/lymphoma

Acute lymphoblastic leukemia (ALL) Lymphoblastic lymphoma (LBL)

Burkitt lymphoma/leukemia

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Chronic lymphocytic leukemia (CLL)/ Small lymphocytic lymphoma (SLL)

HODGKIN LYMPHOMASClinical FeaturesNodal

Painless lymphadenopathy : cervical region B-symptoms (25%)

Extranodal Rare Splenomegaly

• Reed sternberg cells (RS cells) • Classic RS cells• Mononuclear variant• Lacunar variant• Lymphocytic and histiocytic (L&H) variant• Pleomorphic variant

• Other inflammatory cells

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• Lymphocytes• Eosinophils • Plasma cells• Neutrophils

WHO classification

• Nodular lymphocyte predominance Hodgkin lymphoma (nLPHL)

• Classical Hodgkin lymphoma (CHL)• Nodular sclerosis• Mixed cellularity • Lymphocyte-rich• Lymphocyte depleted

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PLASMA CELL NEOPLASMS

• Immunosecretory disorders• Expansion of single clone of immuno-secreting B-cells • Secrete single homogeneous immunoglobulin M-component or monoclonal component

ClassificationWHO classification of Plasma cell neoplasm• Plasma cell myeloma (multiple myeloma : MM)• Plasmacytoma • Immunoglobulin deposition disease• Osteosclerotic myeloma (POEMS syndrome)• Heavy chain disease

Plasma cell myeloma• Bone marrow-base multifocal plasma cell neoplasms

Clinical & Laboratory features• Anemia • Bone disease

• Bone pain • Osteolytic lesion

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• Monoclonal protein (M-component)• Intact immunoglobulin or fragments of immunoglobulin (free light chain)

IgG 52% IgA 20% IgD 2% Free light chain (Bence Jones protein) 16%

• 99% of myeloma patients 93% of pt : serum 70% of pt : urine

• Alpha-globulin Alpha1-globulin : Alpha1-antitrpsin Alpha2-globulin : Haptoglobin

• Beta-globulin Lipoprotein, Transferrin, Plasminogen and complement

• Gamma-globulin Immunoglobulin

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• Hypercalcemia • Renal insufficiency

M-component (IgD, Bence Jones protein) Hypercalcemia DehydrationHyperuricemia Nephrotoxic dugs

• Infection

Pathology of Lymph node

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LYMPHADENOPATHIESLymph nodes enlargement

• Reactive lymphadenopathy • Reactive hyperplasia• Atypical hyperplasia• Lymphadenopathy associated with clinical syndrome

• Infection • Neoplasm : lymphoma, leukemia, metastatic tumor

REACTIVE LYMPHADENOPATHYReactive lymphoid hyperplasia (reactive hyperplasia

• Increased cellularity of lymph nodes• Palpable mass ~ 1 cm.• Axilla, inguinal, cervical and supratrochlear

Atypical lymphoid hyperplasia (atypical hyperplasia)• Condition between benign and malignant condition

Reactive condition Malignant lymphoma

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Lymphadenopathy associated with clinical syndromeSLE lymphadenopathy

• SLE increased risk of lymphoma and infectionLymph node biopsy Exclude these conditions

Dermatopathic lymphadenopathy • Associated with chronic skin lesion

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Kimura lymphadenopathy • Asian• Female > male, 27-40 yrs• Slowly lymph node enlergement • Head and neck auricular area • Eosinophilia • Increased serum level of IgE

Kikuchi-Fugimoto lymphadenopathy • Asian, female• Painless cervical lymphadenopahty with fever and myalgia

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Castleman disease (angiofollicular hyperplasia)• Idiopathic • Multiple lymph node enlargement

INFECTIOUS LYMPHADENITIS• Bacterial lymphadenitis

• Ordinary bacterial lymphadenitis• Mycobacterium lymphadenitis• Mycobacterium avium-intracellulare lymphadenitis• Cat-scratch disease

• Fungal lymphadenitis • Viral lymphadenitis

• HIV lymphadenitis• Infectious mononucleosis lymphadenitis

• Protozoal lymphadenitis

HIV lymphadenitis

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Infectious mononucleosis lymphadenitis• Ebstein-Barr virus• Fever, pharyngitis, lymphadenopathy • Teenagers and young adults• Peripheral blood atypical lymphocytes (monocytoid lymphocytes, Downey cells)

Cat-scratch disease• Rochalimaea hensalae • Incubation period ~ 3 weeks• Self-limited lymphadenopathy

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METASTATIC CARCINOMA IN LYMPH NODES• Adjacent to or distant foci from primary site • Movable of fixed to soft tissue • Soft to firm consistency