MDS:- The myelodysplastic syndromes are a heteroge­neous group of hematologic disorders broadly characterized by cyto­penias associated with a dysmorphic (or abnormal appearing) and usu­ally cellular bone marrow, and consequent ineffective blood cell production (Table 109-5). The current nomenclature was developed by the French-American-British (FAB) Cooperative Group and, while increasing recognition of the syndromes, is not entirely satisfactory: chronic myelomonocytic leukemia, while associated with dysplastic morphology, behaves as a myeloproliferative disease; sideroblasric anemias likely have a distinctive etiology; and the borderline between refractory anemia with excess blasts in transformation and acute my­eloid leukemia is so arbitrary as to have been abandoned in the most recent World Health Organization classification. The F AB scheme has been recently supplemented by the International Prognostic Scoring System (IPSS; Table 109-6).

EPIDEMIOLOGY Idiopathic MDS is a disease of the elderly; the mean age at onset is 68 years. There is a slight male preponderance. MDS is a relatively common form of bone marrow failure, with in­cidence rates reported of 35 to > 100 per million persons in the general population and 120 to >500 per million in the aged. MDS is rare in children, but monocytic leukemia can be seen. Therapy-related MDS is not age-related and may occur in as many as 15% of patients within a decade following intensive combined modality treatment for cancer. Rates of MDS have increased over time, due to the recognition of the syndrome by physicians and the aging of the population.

ETIOLOGY AND PATHOPHYSIOLOGY The myelodys­plastic syndromes have been convincingly linked to environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a stereotypical late toxicity of cancer treatment, usually with a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea or procarbazine (with a latent period of 5 to 7 years) or the DNA topoisomerase inhibitors (2 years). Both acquired aplastic anemia fol­lowing immunosuppressive treatment and Fanconi's anemia can evolve into MDS. MDS is a clonal hematopoietic stem cell disorder leading to im­paired cell proliferation and differentiation. Cytogenetic abnormalities are found in about half of patients, and some of the same specific lesions are also seen in frank leukemia; deletions are more frequent than translocations. Both presenting and evolving hematological manifestations result from the accumulation of multiple genetic lesions, loss of tumor suppressor genes, activating oncogene mutations, or other harmful alterations. Cytogenetic abnormalities are not random (loss of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology (llq23 following topoisomerase II inhibitors); chronic myelomono­c}1ic leukemia is often associated with t(5; 12) that creates a chimeric tel-PDGF{3 gene. The type and number of cytogenetic abnormalities strongly correlate with the probability of leukemic transformation and survival. Mutations of N-ras (an oncogene), p53 and IRF-I (tumor suppressor genes), Bcl-2 (an antiapoptotic gene), and others have been reported in some patients but may occur relatively late in the sequence leading to leukemic transformation. Apoptosis of marrow cells is in­creased in MDS, presumably due to these acquired genetic alterations or possibly to an overlaid immune response. Sideroblastic anemia may be related to mutations in mitochondrial genes.

Most cases are sporadic, although familial forms have

ported. One is associated with von Hippel-Lindau (VHL) syndrome Nearly 35% of patients with VHL disease develop renal cell can(\! An increased incidence has also been reported for patients with sclerosis and polycystic kidney disease.                .

Most of the cancers arise from the epithelial cells of the prom tubules. A number of genetic alterations have been described, ofwrurn abnormalities on chromosome 3 are most frequent. At (3;8) translocation was first described in a pedigree of patients with the familial  form of the disease, while deletions of 3p21-26 (where VHLID1I have been identified in familial as well as sporadic tumors. Mutations are identified in a high proportion of sporadic. Non papillary renal cell cancers and associated cell lines.

Microscopy shows large number of character­istically distended and enlarged macrophages called Gaucher cells which are found in the spleen, liver,

bone marrow and lymph nodes, and in the case of

neuronal involvement, in the Virchow-Robin space. The cytoplasm of these cells is abundant, granular and fibrillar resembling crumpled tissue paper. They have mostly a single nucleus but occasion­ally may have two or three nuclei (Fig. 1.9). Gaucher cells are positive with PAS, oil red 0, and Prussian-blue reaction indicating the nature of accumulated material as glycolipids admixed with haemosiderin. These cells often show erythrophagocytosis and are rich in acid phosphatase.

Alpha-I-antitrypsin deficiency is an autosomal dominant condition in which the homozygote state produces liver disease (cirrhosis), pulmonary disease (emphysema), or both (page 459). a.l­antitrypsin is a glycoprotein normally synthesised in the rough endoplasmic reticulum of the hepatocytes and is the most potent protease inhibi­tor (Pi). A single autosomal dominant gene coding for a.l-antitrypsin is located on long arm of chro­mosome 14 that codes for immunoglobulin light chains too. Out of 24 different alleles labelled al­phabetically, PiMM is the most common normal phenotype, while the most frequent abnormal phe­notype in a.l-antirypsin deficiency leading to liver and/or lung disease is PiZZ in homozygote form. Other phenotypes in which liver disease occurs are PiSS and Pi-null in which serum a.l-antitrypsin value is nearly totally deficient. Intermediate phe­notypes, PiMZ and PiSZ persons are perdisposed to develop hepatocellular carcinoma.

A. Symptoms and Signs: As a rule, the only symptoms of Iron deficiency anemia are those of the anemia itself (easy fatigability, tachycardia, 1}Palpita­tions and tachypnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, Dysphagia because of the formation of esophageal webs (plummmer-Vinson syndrome) also occurs. Many iron-defi­cient patients develop pica, craving for specific foods

(ice chips, lettuce, etc , often not rich in iron.

B. Laboratory Findings: Iron deficiency devel­ops in stages. The first is depletion of jron stores. At this point, there is' anemia and no changes in red blood cell size. The serum ferritin will become abnor­mally low. A ferritin value less than 30 IlgIL nearly always indicates absent iron stores and is a highly re­liable indicator of iron deficiency. The serum tQ1.al iron-binding capacity (TIBC) rises.

After iron stores haye been depleted, red blood ceIl formation will continue with deficient suppli~ of iron. Serum iron values will begin to fall to less than 30 Ilg/dL, and transferrin saturation will fall to less

than 15%.                                      ­

In the early stages, the MCV remains normal. Sub­sequently, the MCV falls and the blood sample shows hypochromic microcvtic cells. With further progression, anisocytosis (variations in red blood cell size) followed by poikilocytosis (variation in shape of red cells) will develop.