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  • 1. Tinjauan Pustaka Hematologi
    ASPEK LABORATORIS ANEMIA MEGALOBLASTIK
    dr. Sri Kartika Sari/dr. Arifoel Hajat, SpPK
    Rabu, 16 Desember 2009
  • 2. Pendahuluan
    Gangguan sintesis DNA
    Anemia megaloblastik
    Sel megaloblastik
    Ketidaksinkronan maturasi inti
    2
  • 3. Penyebab anemia megaloblastik
    3
  • 4. Vitamin B₁₂
    Biokimia vitamin B₁₂
    Methylcobalamin terbanyak dalam
    serum
    Protein transport : transcobalamin (TC)
    TC I, II dan III
    4
  • 5. P
    TISSUE
    Protein source
    Vitamin B₁₂
    Oral intake
    Celullar uptake
    TC receptor
    STOMACH
    Parietal cell
    Pancreatic protease
    OH-Cbl
    CN-Cbl
    IF-binding
    LIVER
    IF-Cbl
    Holo-TC II
    Cubilin
    TC II
    Intestinal uptake
    storage
    5
    Gbr. Absorbsi, penyimpanan dan transportasi Vitamin B₁₂
  • 6. Folat
    Biokimia folat
    Terlibat dalam fungsi metabolisme penting :
    Methyltetrahydrofolate
    terbanyak di serum
    6
  • 11. Metabolisme folat
    DNA
    dATP
    dGTP
    dTTP
    dCTP
    dTDP
    DHF polyglutamate
    THF polyglutamate
    dTMP
    5,10 methylene THF polyglutamate
    THF
    dUMP
    methionine
    homocysteine
    Membran sel
    Methyl THF
    Methyl THF
    plasma
    Folat dari makanan
    Usus halus
    7
  • 12. 8
    Gbr. Konversi Methylmalonil-coA
    dan sintesis methionine
  • 13. Defisiensi vitamin B₁₂
    9
  • 14. Intake kurang
    Kebutuhan
    malabsorbsi
    Defisiensi folat
    Gangguan metabolik
    kehilangan
    10
  • 15. Gambaran klinis
    Anemia berjalan lambat, memburuk perlahan
    Inefektif eritropoiesis
    Kelainan epitel
    Gejala defisiensi vitamin B₁₂ :
    Neuropati progresif gangguan metilasi mielin
    Gejala pada ibu hamil defek tabung saraf pada janin
    Peningkatan homocysteine miokard infark, vascular disease, trombosis vena.
    Kemandulan
    11
  • 16. Pemeriksaan laboratorium
    MCV
    Hapusan Darah Tepi
    Vitamin B₁₂ serum
    Folat serum dan eritrosit
    Methylmalonic acid (MMA) dan homocysteine
    Antibodi antiparietal cell dan anti IF
    Tes Schilling
    12
  • 17. Mean Corpuscular Volume (MCV)
    MCV > 100 fL
    Penyebab makrositosis :
    Megaloblastik atau non megaloblastik
    MCV meningkat sebelum terjadi penurunan kadar Hb.
    Bila defisiensi vitamin B₁₂ bersamaan dengan defisiensi besi MCV normal
    MCV kurang spesifik
    13
  • 18. Oval makrosit kesan penyakit megaloblastik
    Stomatosit dengan makrosit alkoholism
    Hipersegmentasi sensitif dan spesifik untuk anemia megaloblastik
    Hapusan darah tepi
    14
  • 19. Vitamin B₁₂ serum
    Digunakan untuk diagnosis dan monitoring terapi defisiensi vitamin B₁₂
    Batas bawah normal biasanya sekitar 148 pmol/L (200 pg/mL)
    Belum ada baku emas  sensitivitas dan spesifisitasnya bervariasi lebar.
    Metode pemeriksaan : automated non-isotopic procedure menggunakan chemiluminescence
    15
  • 20. Lanjutan vitamin B₁₂ serum....
    Pada gagal ginjal vitamin B₁₂ serum  tinggi
    Defisiensi vitamin B₁₂ pada penderita penyakit mieloproliferatif, gangguan ginjal/liver  kadar vitamin B₁₂ bisa normal/tinggi
    Kolonisasi bakteri usus  tinggi palsu
    16
  • 21. Folat serum dan folat eritrosit
    Batas bawah normal folat serum : 6,8 nmol/L
    Kadar folat serum  dipengaruhi diet.
    Kadar folat eritrosit  lebih mencerminkan simpanan folat jaringan.
    Belum ada metode baku emas
    17
  • 22. Methylmalonic acid (MMA) dan homocysteine
    Defisiensi vitamin B₁₂  MMA dan homocysteine
    Defisiensi folat  homocysteine
    MMA dan homocysteine  sensitif untuk diagnosis defisiensi vitamin B₁₂
    Hati-hati interpretasi peningkatan metabolit bila tanda-tanda defisiensi (-)
    Setelah 7-14 hari pemberian terapi  kadar metabolit menjadi normal
    18
  • 23. 19
  • 24. Antibodi anti sel parietal dan anti Intrinsic Factor (IF)
    Antibodi anti sel parietal :
    Non spesifik
    Terdapat pada penderita autoimun, orang sehat
    Antibodi anti IF :
    Tidak sensitif, namun cukup spesifik, walaupun masih mungkin ada pada penderita Graves disease.
    20
  • 25. Tes Schilling
    Untuk konfirmasi gangguan absorbsi vitamin
    Terdiri dari 2 tahap :
    21
  • 26. Interpretasi hasil tes Schilling pada defisiensi vitamin B₁₂
    Tahap I : N (≥8%)
    Tahap I : Abn (<8%);
    Tahap II : N (≥8%)
    Tahap I dan II : Abn (<8%)
    Kemungkinan :
    • Defisiensi diet
    • 27. Malabsorbsi
    kompleks protein-
    Cbl :
    • Hipokhlorhidria
    • 28. Partial
    gastrectomy
    • Kongenital
    defisiensi TC II
    Kemungkinanan :
    • Ileal disease
    • 29. Anemia pernisiosa dgn
    disfungsi ileal sekunder
    • Anemia pernisiosa dgn
    pengumpulan urine tidak
    adequat
    • Renal insufisiensi
    • 30. Pengumpulan urine tidak
    adequat
    • Bacterial overgrowth
    syndromes
    • Fish tapeworm infestation
    • 31. Insufisiensi pankreas
    Kemungkinan :
    • Anemia pernisiosa
    • 32. Gastrectomy
    • 33. Disfungsi/ IF tidak
    ada (kongenital)
    • Pengumpulan
    urine tahap I
    tidak adequat
    22
  • 34. Pendekatan diagnosis penderita dengan kelainan hematologi
    Vitamin B₁₂
    < 74 pmol/L
    >221 pmol/L
    74-221 pmol/L
    Folat
    Folat N
    Folat N
    Folat
    Folat
    Folat N
    Defisiensi vitamin B₁₂
    Defisiensi vitamin B₁₂ dan folat
    Bukan Defisiensi vitamin B₁₂ dan folat
    Def. folat
    Defisiensi vitamin B₁₂
    Tx. folat
    Indeterminate
    Gbr.7
    Tes Schilling
    Penyebab lain
    Gbr.7
    Tes Schilling
    23
  • 35. 24
    Gbr. 7. Pendekatan penderita dengan vitamin B₁₂ < 74 pmol/L
  • 36. Tabel 6. Evaluasi penderita dengan kelainan hematologi dan vitamin B₁₂ <74 pmol/L
    25
  • 37. Gbr. 8. Evaluasi penderita yang diduga defisiensi vitamin B₁₂ dengan CBC normal
    26
  • 38. Diagnosis defisiensi vitamin B₁₂ dan folat
    hal yang kompleks.
    Belum ada tes yang mudah sebagai baku emasnya
    Perlu integrasi hasil laboratorium, klinis, respon terapi
    27
  • 39. TERIMA KASIH
    28
  • 40. 29
    Gambar 6. Prinsip Beckman ACCESS Immunoassay System
    untuk pengukuran Vitamin B12. Serum.5
  • 41. 30
    Treatment
    B12 can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; intranasal spray; or by injection. B12 is available singly or in combination with other supplements. B12 supplements are available in forms including cyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin (sometimes called "cobamamide" or "dibencozide"). Oral treatments involve giving 250 ug to 1 mg of B12 daily.[28]
    Vitamin B12 can be given as intramuscular injections of hydroxycobalamin, methylcobalamin, or cyanocobalamin. Body stores (in the liver) are refilled with half a dozen injections in the first couple of weeks and then maintenance with monthly to quarterly injections throughout the life of the patient.
    B12 has traditionally been given parenterally to ensure absorption. However, oral replacement is now an accepted route, as it has become increasingly appreciated that sufficient quantities of B12 are absorbed when large doses are given. This absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose [3]. By contrast, the typical Western diet contains 5–7 µg of B12 (Food and Drug Administration (FDA) Daily Value [29]).
  • 42. 31
  • 43. 32
  • 44. 33
    Hematological findings
    The blood film can point towards vitamin deficiency:
    Decreased red blood cell (RBC) count and hemoglobin levels[citation needed]
    Increased mean corpuscular volume (MCV, >95 fl) and mean corpuscular hemoglobin (MCH)
    Normal mean corpuscular hemoglobin concentration (MCHC, 32-36 g/dL)
    The reticulocyte count is decreased due to destruction of fragile and abnormal megaloblastic erythroid precursor.
    The platelet count may be reduced.[citation needed]
    Neutrophil granulocytes may show multisegmented nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils, which increase numbers of nuclear segments with age.[citation needed]
    Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
    Macrocytes (larger than normal RBCs) are present.
    Ovalocytes (oval-shaped RBCs) are present.
    Howell-Jolly bodies (chromosomal remnant) also present.
    Blood chemistries will also show:
    In increased lactic acid dehydrogenase (LDH) level. The isozyme is LDH-2 which is typical of the serum and hematopoetic cells.
    Increased homocysteine and methylmalonic acid in B12 deficiency
    Increased homocysteine in folat
  • 45.
  • 46. 35
  • 47. 36
  • 48. 37
  • 49. Consequences of impaired folate status or metabolism
    Metabolic Disruption
    Biochemical Markers
    Clinical Associations
    CancerCVDdemyelinationNTDs
    S-adenosylmethionine (MTHFR, MS, B12 deficiency)
    Thymidylate
    Purines (A,G)
    Hypomethylated DNA
    Elevated homocysteine
    Reduced methylation
    CancerNTDsAnemia
    Increased uracil in DNADecreased DNA synthesis & reduced cell division
    Decreased DNA synthesis & reduced cell division
    Anemia
  • 50. 39
  • 51. 40
    5 jenis sel kelenjar lambung:
    • sel chief : enzim
    pepsin dan lipase
    • sel parietal (oxyntic) :
    asam lambung dan IF
    • sel leher mukosa :
    mukus
    • sel stem
    • 52. sel neuroendokrin :
    gastrin
  • 53. 41
    Vitamin B12 Analogues
    Vitamin B12 is a coenzyme: it is needed for enzymes to do their job of changing one molecule into another. As vitamins go, B12 is large. One part of its structure is known as the corrin nucleus, which holds an atom of cobalt. The corrin resembles the heme of hemoglobin which holds an atom of iron. Any molecule that contains a corrin nucleus is considered a corrinoid.
    The corrin plus other atoms make up the cobalamin part of B12. There are many different cobalamins and they are named after their attachments. For example, methylcobalamin is cobalamin with a methyl group (one carbon and three hydrogens) attached.
    All corrinoids (including all cobalamins) are considered B12 analogues. Many corrinoids, and possibly even some cobalamins, are not useable by human B12 enzymes. These are considered inactive B12 analogues.
  • 54. Vitamin B12 Deficiency
    homocysteine and methylmalonyl CoA
    Increase in methylmalonyl CoA
    Increased enzyme activity in fatty acid synthesis
    Build up of odd fatty acids around peripheral nerves
    Increase in homocysteine
    Vascular/nervous problems
  • 55. Transcobalamin I
    • R-type binding protein
    • 56. 33% is carbohydrate
    • 57. Molecular weight = 125,000-150,000
    • 58. Beta globulin
    • 59. Contains more sialic acid than transcobalamin III
    • 60. Carries ~80% of Vitamin B12 in blood
    • 61. Vitamin B12 has half-life of 10-12 days when bound to it
  • Transcobalamin II
    • Molecular weight = 38,000
    • 62. Alpha globulin
    • 63. NOT a glycoprotein
    • 64. Carries less than 25% of Vitamin B12 in blood
    • 65. Vitamin B12 has half-life of under 1 ½ hours when bound to it
    • 66. Encourages absorption in a number of tissues
    • 67. Degenerates once B12 is released
    • 68. B12 then recirculates
    • 69. Transcobalamin II deficiency results in pernicious anemia
  • Antibacterial Roles of Transcobalamin I & III
    • Binds to large amounts of vitamin B12 and carries it to liver
    • 70. Excreted in bile
    • 71. Prevents bacteria from using the vitamin for growth
  • 72. 47
  • 73. 48
  • 74. 49
    Reference Values Folat serum : > or = 3.5 ug/L
  • 75. 50
  • 76. 51
  • 77. 52
  • 78. 53
  • 79. 54
  • 80. 55
  • 81. 56
  • 82. 57
    Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonate.
    Pathology
    Increased methylmalonic acid levels may indicate a vitamin B12 deficiency. However, it is sensitive without being specific. MMA is elevated in 90-98% of patients with B12 deficiency. This test may be overly sensitive, as 25-20% of patients over the age of 70 have elevated levels of MMA, but 25-33% of them do not have B12 deficiency. For this reason, MMA is not routinely recommended in the elderly. [1]
    An excess is associated with methylmalonicacidemia.
    MMA concentrations in blood are measured by Gas chromatographicMass spectrometry
  • 83. 58
    Folic acid and vitamin B12Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency [3,5] without correcting the neurological damage that also occurs [1,31]. Moreover, preliminary evidence suggests that high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency [6,11]. Permanent nerve damage can occur if vitamin B12 deficiency is not treated. For these reasons, folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy individuals [5].
  • 84. Diet
    Methyltetrahydrofolate
    Vitamin B12
    Methionine
    Methyl B12
    Homocysteine
    CH3
    tetrahydrofolate
    Serine
    Dihydrofolate
    Purine and pyrimidine synthesis
    + B6
    DNA
    Glycine
    Thymidylate
    Deoxyuridylate
    5,10 methylenetetrahydrofolate
    Gambar 4. Jalur metabolik asam folat dan vitamin B12.2.
    59
  • 85. Symptoms/Effects of Vitamin B12 Deficiency
    • Pernicious Anemia (Vitamin B12 is necessary for RBC production)
    • 86. Lethargy
    • 87. Weight loss
    • 88. Weakness
    • 89. Dementia
    • 90. Leucopenia
    • 91. Thrombocytopenia
    • 92. Axonal degeneration
    • 93. Demyelination
    • 94. Urethral Sphincter problems
    • 95. Depression
    • 96. Alzheimer’s Disease
    • 97. Increased liver weight
    • 98. Fat accumulation around heart, liver, peripheral nerves
  • Symptoms/Effects of Vitamin B12 Deficiency
  • 62
  • 119. 63
    The present invention relates to a new method named the COBASORB test, which can be used for testing the cause of cobalamin malabsorption in humans. The COBASORB test contains three separate tests (first, second and third test) than can be performed separately, sequentially or in random order and number. The first test use non-radioactive cobalamin for ingestion, the second test uses non-radioactive cobalamin and recombinant intrinsic factor for ingestion and the third test uses recombinant haptocorrin saturated with cobalamin for ingestion. All three tests involve analysis of changes in the concentration of cobalamin saturated transcobalamin (holo-TC) and cobalamin saturated haptocorrin (holo-HC) in the blood. Also disclosed are fits suitable for use in these methods.
  • 120. 64
    Salivary haptocorrin, also known as the R-protein, binds strongly to Vitamin B12 (after it is released from food by gastric pepsin), stabilizing it and preventing its breakdown in the low-pH environment of the stomach. The complex is absorbed by ilealvilli into the blood. HC accounts for 10-40% of B12 serum level.