Guideline:Thalassemia intermedia

Definition
The clinical phenotypes of thalassaemia intermedia (TI) lie between those of thalassaemia minor (heterozygous state) and major (homozygous state), although there is substantial clinical overlap between the three conditions. TI was first described in 1955 by Rietti-Greppi-Micheli, who referred to patients as being ‘too haematologically severe to be called minor, but too mild to be called major’.

Thalassaemia intermedia encompasses a wide clinical spectrum. Mildly affected patients are completely asymptomatic until adult life, experiencing only mild anaemia and maintaining haemoglobin levels between 7- 10g/dL. These patients require only occasional blood transfusions, if any. Patients with more severe thalassaemia intermedia generally present between the ages of 2 and 6 years, and although they are able to survive without regular transfusion therapy, growth and development can be retarded. The clinical spectrum of thalassaemia intermedia indicates the need for an individualised treatment approach. Despite the availability of a number of treatment options, the lack of clear guidelines can present a significant clinical challenge (Taher, 2006; Camaschella and Cappellini, 1995).

Mechanism of TI
The pathophysiology of thalassaemias is based on an imbalance of globin-chain synthesis. In the case of‚β-thalassaemia intermedia, the imbalance is greater than that seen in‚ β-thalassaemia trait and less than that of‚ β-thalassaemia major.

Most TI patients are homozygotes or compound heterozygotes for ‚β-thalassaemia, meaning that both‚ β-globin loci are affected.

The mild clinical characteristics of TI compared with thalassaemia major are primarily the result of the following three mechanisms:


 * inheritance of a mild ‚+ mutation;
 * presence of a polymorphism for the enzyme Xmn-I in the GÁ- promoter region, associated with increased HbF; and
 * co-inheritance of β-thalassaemia on the‚ β-globin locus.

The phenotype of TI may also result from the increased production of α-globin chains, occurring either by the triplication of α-genotype associated with ‚β-heterozygosity, or by the interaction of‚ β- and δβ-thalassaemia (Taher, 2006).

Analysis of the genotypes of patients with thalassaemia intermedia is important for an early diagnosis of the milder disease, thus avoiding unnecessary blood transfusions.

Predicting phenotype from genotype in TI is still difficult, due to the interaction of genetic and environmental factors. Primary genetic modifiers are the numerous genetic alleles at the‚ β-chain locus, which can cause either complete or marked reduction in ‚β- chain synthesis. Secondary genetic modifiers are those that have a direct effect on modifying the amount of excess α-chains (inheritance of abnormal α- or γ-chain genes). Tertiary modifiers are polymorphisms occurring at loci involved in bone, iron and bilirubin metabolism that can affect clinical expression. Relevant environmental factors include social conditions, nutrition and the availability of medical care (Taher, Ismaeel and Cappellini, 2006).

Differential diagnosis
Differentiation at presentation between thalassaemia major and thalassaemia intermedia is essential for designing appropriate treatment for an individual patient. The accurate prediction of a mild phenotype may avoid needless transfusions and their complications, while the timely diagnosis of thalassaemia major will allow an early start to a transfusion programme, thus preventing or delaying hypersplenism and reducing the risk of red cell antigen sensitisation. Unfortunately, however, the accurate identification of these two phenotypes at the onset is remarkably difficult. Nevertheless, a careful analysis of clinical, haematological, genetic and molecular data may allow a reasonable conclusion for treatment (Taher, 2006; Wainscoat, 1987; Weatherall, 2001). (see Table 1 for an outline of the major differences between thalassaemia intermedia and major).

At Diagnosis (prior to first transfusion)
 * 1) Complete Blood Count and Red cell morphology
 * 2) Reticulocyte count
 * 3) Number of nucleated re cells per 100 leukocytes in the peripheral blood.
 * 4) Hb pattern analysis (Electophoresis or HPLC) - repeat HbF levels at intervals in patients taking an HbF modifying substance
 * 5) Extended Red Cell Antigen typing, including at least C, c, E, e, and kell.
 * 6) Complete genotype - α and β globin mutations
 * 7) G-6PD
 * 8) HbsAg, Anti-Hbc, Anti-HBs, Anti-HCV, Anti-HIV, Anti-HAV, Anti-CMV, Anti-EBV; Toxoplasma, Rugeolla, Coxcackie, Parvo Β19, Η. Pylori, Yersinia seroprevalence maybe high after multiple transfusions)
 * 9) Serum Homocysteine - in case of increased values repeat 2 months after initiating treatment.
 * 10) Lipoprotein α

Before Each Transfusion
 * 1) Complete blood count
 * 2) Complete cross-match
 * 3) Screen for new antibodies
 * 4) Number of nucleated red blood cells per 100 leukocytes in peripheral blood in splenectomised patients.
 * 5) Indirect Coomb's test before and 8-15 days after each transfusion. Every month during pregnancy

Every 3-4 months

1. Routine biochemical indices including: liver enzymes, s. bilirubin, LDH, Proteins (Total, Albumin & globulin), γ-GT, glucose, urea, creatinine, uric acid, cholesterol, HDL & LDL, triglycerides, Calcium, Phosphorus, Sodium, Magnesium, Zinc and S. Iron and TIBC.

2. Complete Blood Count - in steady state and with infections or complications

Every 6 months


 * 1) Prothrombin time, PTT, INR - and upon indication
 * 2) Fibrinogen - and upon indication
 * 3) D-DImers and Fibrin Degratation Products (FDP) - more often in patients who have evidence of Thrombophilia (Protein C, Protein S, APCR according to clinical indications)
 * 4) Lupus anticoagulant - when prolonged PTT or upon indication
 * 5) Direct Coombs (more often in auto and/or allo-immunised patients)
 * 6) Indirect Coombs (every month during pregnancy)
 * 7) S. Ferritin
 * 8) Endocrinology tests - Prolactin, FSH, LH, estradiol, progesterone, testosterone, ACTH, Cortisol, BGP (osteocalcin), iPTH, CEA), FTS, FT4, TSH (if high then Anti-raicrosomial antibodies and anti-thyroglobulin antibodies)
 * 9) a-fetoprotein
 * 10) CA-15-3, CA 125 in adult women
 * 11) CA-19
 * 12) PSA-in men over 50 years old
 * 13) Erythropoietin

Every 1-3 years or on clinical indication

1) 2- Hour Urine Collection (fasting) Hydroxyproline, pyridium cross-links and creatinine and calcium (especially for patients with renal calculi and to investigate bone turnover and parathyroid disorders)

24-hour urine collection. For urea creatinine, calcium or protein (rarely needed)

2) Autoantibodies e.g. ΑΜΑ (anti-mitochondrial), ASMA (anti-smooth muscle), APCA (anti-parietal cell), ANCA (anti-neutrophil cytoplasmic). Such autoantibodies are commonly found among patients with clironic HCV1 infection and in chronic GVHD2

ΕΝΑ (extractable nuclear antigens) -

3) Immunology - C3, C4, CIC (Circulating Immune Complex), Immunoglobulins (quantitative) and Immune precipitation (upon clinical indication)

4) Vitamin Β12 and Folic Acid - rarely an indication

5) Sp02 measurement - upon indication

6) Oral glucose tolerance test - 2-5 samples

7) Hblc

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1 Ghonaim Μ et. al. Autoantibodies in chronic liver disease, Egypt J. Immunol. 2005,12(2): 101-11

2 Patriarca F et. al. Autoantibodies after allogeneic stem ceil transplantation, Exp. Hematol, 2006, 34(3):389-96

Cardiac Monitoring
 * 1) ECG -1 -2 times a year: more often if cardiac rhythm abnormalities have been detected
 * 2) Echocardiography - 1 -2 times per year
 * 3) Holter - on indication of arrhythmias
 * 4) Cardiac MRI - Every 1-2 years
 * 5) MRA - upon indication

Radiography


 * 1) Chest X-ray every 1 -3 years
 * 2) Bone age - if growth retardation suspected
 * 3) Hip, Lumbar spine and sinuses upon clinical indication
 * 4) DEXA - this is low dose radiation and can be performed annually. However in children or anyone less than 20 years, use the criteria set by the International Society for Clinical Densitometry (www.iscd.org) using Z-scores instead of Tscores etc. For adults use the WHO criteria.

Ultra Sound


 * 1) Abdomen-every 2-5 years and upon clinical indication
 * 2) Breast in adult women- every 6 months - 2 years
 * 3) Thyroid - upon indication

Radiolabelled Scan

Of thyroid, bones or parathyroid-only on cHnical indication

CT


 * 1) Abdomen and retro-peritoneum - every 2-3 years in patients not on regular transfusons


 * 1) Spine-upon indication

MRI


 * 1) Heart and liver - every 2-3years
 * 2) Pituitary - every 2 -4 years
 * 3) Pancreas - ?
 * 4) Bones especially spine for microfractures and degenera