Israel Medical Association Journal

Background: Chronic childhood autoimmune hemolytic anemia is an uncommon disorder that is associated with significant morbidity. Treatment with high dose steroids, splenectomy and frequent blood transfusions results in a myriad of complications including growth failure, bone demineralization, Cushing’s syndrome, immunosuppression, and transfusional hemosiderosis.

Objectives: To investigate the efficacy of the monoclonal anti-CD20 antibody, rituximab, in treating children with AIHA[1].

Methods: Four children with chronic AIHA, including two with prior splenectomy, who were dependent on high dose steroids and refractory to other immunosuppressive regimens were treated with four to six weekly doses of rituximab at a dose of 375 mg/m².

Results: All four patients became transfusion-independent and were taken off prednisone completely. Adverse effects included infusion-related reactions that were mild, and infectious complications of Pneumocystis carinii pneumonia and varicella pneumonia.

Conclusions: Treatment with rituximab appears promising for refractory AIHA; it may obviate the need for prednisone and may result in sustained disease remissions in some patients.

Systemic infection or inflammation causes a decrease in intestinal iron absorption and impairs the release of recycled iron from macrophages. Decreased availability of iron may deny this essential element to invading pathogens and may inhibit their multiplication and other metabolic processes but also results in anemia of chronic disease. This article reviews recent discoveries that shed light on the regulation of iron metabolism during infection and iron overload, and point to the central role of a newly discovered peptide, hepcidin. Evidence to date indicates that hepcidin is a negative regulator of intestinal iron absorption, placental iron transport, and the release of iron from macrophages that recycle iron from senescent red cells. It may also be the central mediator of iron sequestration during infections and inflammatory states and the mediator of anemia of chronic disease. Rapid progress in this area is a good example of the beneficial effects of improvements in peptide analysis and chemistry, advances in genomics, and the increasing use of transgenic mice to determine the function of newly discovered genes and proteins.

Fanconi anemia is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancy. FA cells are sensitive to DNA cross-linking agents. Complementation analysis of FA cells using somatic cell fusion has facilitated the identification of eight complementation groups, suggesting that FA is a genetically heterogeneous disorder. Six genes (FANCA, FANCC, FANCD2, FANCE, FANGF, FANCG) have been cloned so far. The majority of affected patients belong to FA group A. Of the 32 unrelated Israeli patients with FA that we studied, 6 carried the FANCC mutations and 15 the FANCA mutations. Among the Jewish patients, ethnic-related mutations were common. Recent cumulative evidence suggests that the FA proteins are repair proteins. FANCC, FANCA and FANCG bind and interact in a protein complex found in the cytoplasm and nucleus of normal cells. FANCD2 exists in two isoforms; the long active form, FANCD2-L, is absent from FA cells of all complementation groups. FANCD2 co-localized with BRCA1 in unclear foci, probably as part of a large genomic surveillance complex. Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-g hypersensitivity and show progressive apoptosis. The definition of the molecular basis of FA in many affected families now enables prenatal diagnosis.

Background: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4+4A®T for Fanconi anemia complementation group C.

Objectives: To provide additional verification of the mutation rate of BLM and FACC[1] in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation.

Methods: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto^TM kit to verify the results in 244 samples and there was an excellent match.

Results: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto^TM kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population.

Conclusions: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS[2] and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.

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[1] FACC = Fanconi anemia complementation group C

Objectives: To evaluate the diagnostic yield of gastroscopy, colonoscopy and fecal occult blood testing of hospitalized IDA patients, plus follow-up.

Methods: IDA was defined as hemoglobin <12.5 g/dl (men) and 11 g/dl (women), and serum iron <50 g/dl. The study group comprised 90 patients (42% male) with a mean age of 65±15 years and mean Hb 8.1 g/dl.

Results: Gastroscopy and colonoscopy revealed a bleeding source in 28.8% and 14.4% respectively. Gastrointestinal symptoms were found in 23% of patients with diseases of the upper gastrointestinal tract and in 15.3% of the lower. The sensitivity of fecal occult blood tests in detecting lesions in the lower and upper GI tracts was 100% and 30.7% respectively. Forty-four patients (48.9%) were discharged from the hospital with IDA of unknown origin. Over the following year, 20 of the 44 patients required further hospitalization, and of these, 13 were found to have anemia. Of the remaining 24 patients who were not hospitalized again, 15 had anemia. Four patients (9%) had significant gastrointestinal lesions and two died during the follow-up.

Conclusions: Fecal occult blood is a sensitive examination for lower but not for upper GI tract lesions.

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IDA= iron deficiency anemia

Methods: We compared the cost of treating anemia of prematurity in two consecutive 12-month periods: before and after the introduction of EPO therapy in our unit. The cost of blood bank charges as well as disposable items and the cost of EPO were compared.

Results: A significantly smaller number of infants required blood transfusions in the EPO group (2 of 25 vs. 9/21 before EPO was introduced). The cost of therapy for anemia of prematurity was significantly smaller in the EPO group (128±168 US$ per infant vs. 151±189 US$ per infant before the introduction of EPO).

Conclusion: We conclude that EPO is an efficient and cost-effective alternative to blood transfusions in VLBW infants.

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(1) VLBW = very low birthweight

(2) EPO = erythropoietin