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CHRONIC MYELOID LEUKEMIA

DEFINITION CML is a malignant clonal disorder of hematopoietic stem cells that results in increases in not only myeloid cells but also erythroid cells and platelets in peripheral blood and marked myeloid hyperplasia in the bone marrow. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

ETIOLOGY The etiology of CML is unclear. Some associations with genetic and environmental factors have been reported, but, in most cases, no such factors can be identified. 1. Genetic factors 2. Environmental factors Nuclear and radiation exposures, including therapeutic radiation, have been associated with the development of CML. Chronic Myeloid Leukemia Initiated by the translocation t(9;22) that produces the BCR/ABL fusion tyrosine kinase. Constitutive activity of the BCR/ABL enzyme is responsible for the unrestrained growth of CML cells.

PATHOGENESIS CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. In this translocation, parts of two chromosomes (the 9th and 22nd by conventional karyotypic numbering) switch places. The bcr-

abl fusion gene product is also a tyrosine kinase


As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins which control the cell cycle, speeding up cell division

CLINICAL MANIFESTATION Symptoms of CML may include: malaise, low-grade fever, gout, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising (although an increased platelet count (thrombocytosis) may also occur in CML). Splenomegaly may also be seen. CML usually runs a biphasic or triphasic course. This process includes an initial chronic phase and a terminal blastic phase, which is preceded by an accelerated phase in 60% to 80% of patients.

Chronic phase Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, patients are usually asymptomatic or have only mild symptoms.

Accelerated phase The WHO criteria define the accelerated phase by any of the following: 1. 10 19% myeloblasts in the blood or bone marrow 2. >20% basophils in the blood or bone marrow 3. Platelet count <100,000, unrelated to therapy 4. Platelet count >1,000,000, unresponsive to therapy 5. Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome 6. Increasing splenomegaly or white blood cell count, unresponsive to therapy

Blast crisis Blast crisis is the final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival.[2] Blast crisis is diagnosed if any of the following are present in a patient with CML: 1. >20% myeloblasts or lymphoblasts in the blood or bone marrow 2. Large clusters of blasts in the bone marrow on biopsy

TREATMENT

The goal of chronic myelogenous leukemia treatment is to eliminate the blood cells that contain the abnormal BCR-ABL gene that causes the overabundance of diseased blood cells. 1. Targeted drugs In chronic myelogenous leukemia, the target of these drugs is the protein produced by the BCR-ABL gene tyrosine kinase. Targeted drugs that block the action of tyrosine kinase include Imatinib (Gleevec),Dasatinib (Sprycel),Nilotinib (Tasigna). 2. Blood stem cell transplant (bone marrow transplant) 3. Chemotherapy 4. Biological therapy The biological drug interferon is a synthetic version of an immune system cell. Interferon may help reduce the growth of leukemia cells.

GOUT
DEFINITION Gout is a disease that results from an overload of uric acid in the body. Uric acid is a breakdown product of purines that are part of many foods we eat. This overload of uric acid leads to the formation of tiny crystals of urate that deposit in tissues of the body, especially the joints. When crystals form in the joints, it causes recurring attacks of joint inflammation (arthritis). Gout is considered a chronic and progressive disease. Chronic gout can also lead to deposits of hard lumps of uric acid in the tissues, particularly in and around the joints and may cause joint destruction, decreased kidney function, and kidney stones.

ETIOLOGY

Gout is often related to an inherited abnormality in the body to process uric acid. Uric acid levels can become elevated by eating a lot of purine-rich foods such as meats, by the overproduction of uric acid by the body, or if the kidneys do not eliminate excess uric acid. When uric acid reaches a certain level in the blood it precipitates out in the form of monosodium urate crystals. In gout, the crystals are deposited in connective tissue and joint spaces evoking intense inflammation. Risk Factors of Gout. There are several factors that may caused gout : 1. Genetic defect in metabolism, which cause overproduction and retention of uric acid. 2. Kidney impairment that prevents normal elimination of uric acid. 3. Disease of the blood cells and blood forming organs, certain cancers. 4. Other factors such as alcohol abuse and a purine rich diet

PATHOGENESIS Gout occurs when crystals of uric acid, in the form of monosodium urate, precipitate in joints, on tendons, and in the surrounding tissues.[4] These crystals may then trigger a local immune mediated inflammatory reaction.[4] The triggers for precipitation are not well understood. While uric acid may crystallize at normal levels, it is more likely to do so as levels increase.[4][16] Other factors believed to be important in triggering an acute episode of arthritis include: cool temperatures, rapid changes in uric acid levels, and acidosis.[17][18] The increased precipitation at low temperatures partly explains why the joints in the feet are most commonly affected.[2] Rapid changes in uric acid may occur due to a number of factors including: trauma, surgery, chemotherapy, diuretics, and stopping or starting allopurinol.[1]

1. 2. 3.

CLINICAL MANIFESTATION Recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint) Spiked rods of uric acid (MSU) crystals photographed under a microscope with polarized light from a synovial fluid sample Blood tests Hyperuricemia is a classic feature of gout. Hyperuricemia is defined as a plasma urate level greater than 420 mol/L (7.0 mg/dL) in males and 360 mol/L (6.0 mg/dL) in females. A definitive diagnosis of gout is based upon the identification of monosodium urate (MSU) crystals in synovial fluid or a tophus.[3] Under polarized light microscopy they have a needle-like morphology and strong negative birefringence.

TREATMENT The initial aim of treatment is to settle the symptoms of an acute attack (nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and steroids[2] ).[2] Repeated attacks can be prevented by different drugs used to reduce the serum uric acid levels.[2] Ice applied for 20 to 30 minutes several times a day decreases pain.[2][3] Avoiding or restrict foods high in purine always be suggested to this patients.

THE CORRELATION BETWEEN CHRONIC MYELOID LEUKEMIA AND GOUT


Myelogenous leukemia and gout, two distinct diseases of different etiology, have in common disorder of uric acid metabolism which is manifested clinically by an elevation of the blood uric acid. Chronic myelogenous (or myeloid) leukemia (CML), also known as chronic granulocytic leukemia (CGL), is a cancer of the white blood cells. The term myelogenous im chronic myelogenous leukemia refers to the type of cells affected by this cancer. Chronic myelogenous (or myeloid) leukemia it is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells (granulocytes, monocytes, erythrocytes, platelets) in the bone marrow and the accumulation of these cells in the blood. The accumulation of those immature cells in the blood commonly rubbing each other and susceptible to be divided, because of that it will be much easier to them to be catabolism.

The massive catabolism of those immature cells will results the catabolism of purine, which is one of the components in nucleic acid that is within the cells. Purine will be catabolism to hypoxanthine, then xanthine. Xanthine will be oxidased by xanthine oxidase and become uric acid. Uric acid is the terminal catabolic product of purine metabolism in humans. Uric acid is more toxic to tissues than either xanthine or hypoxanthine. Normally uric acid stays in solution in the blood. It moves through the circulation, gets filtered by the kidneys, and it excreted in the urine. But in this disease, because of the massive catabolism of the cells build up uric acids in the blood stream, a condition known as hyperuricemia. Hyperuricemia doesn t always cause gout. Gout occurs when the sharp uric acid crystal accumulate in the synovial fluid of the joint. In response to the irritation caused by the uric acid crystal, the skin covering the affected area rapidly becomes tight, inflamed, swollen, and red. It happens because white blood cells recognizing the uric acid crystal and flood into the joint and surround the crystals which cause inflamation. The classical signs of inflammation, together with sudden and extreme pain, strongly suggest an acute attack of gout. The diagnosis is confirmed by laboratory findings of uric acid crystals in fluid taken from the affected joint.

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