What are the clinical findings and management of thalassemia?

Clinical Findings and Management of Thalassemia

Clinical Findings

Thalassemia presents with a spectrum of severity ranging from asymptomatic carrier states to severe transfusion-dependent anemia with life-threatening complications from chronic iron overload affecting multiple organ systems. 1, 2

Hematologic Findings

• Severe anemia typically presenting within the first two years of life in thalassemia major, with hemoglobin levels requiring regular transfusion support 1
• Microcytosis with mean corpuscular volume (MCV) <80 fL, particularly useful for screening carrier states 3
• Ineffective erythropoiesis resulting from precipitation of excess unpaired globin chains causing both mechanical and oxidative damage to red blood cell precursors 2

Physical Examination Findings in Untreated/Poorly Managed Disease

• Growth retardation and poor musculature from chronic anemia and metabolic demands 1
• Skeletal deformities including characteristic facial changes from bone marrow expansion 1
• Hepatosplenomegaly from extramedullary hematopoiesis and iron deposition 1
• Pallor and jaundice from chronic hemolysis 1

Iron Overload Complications

Cardiac Manifestations

• Iron cardiomyopathy is the most common and feared complication, but importantly is reversible with intensive chelation therapy 4
• *Cardiac T2 <6 ms on MRI** confers a 47% risk of developing heart failure within one year, with relative risk of 270 compared to patients with T2* >10 ms 4
• Dilated cardiomyopathy leading to heart failure, which remains the leading cause of death despite improved management 4, 1
• Arrhythmias from iron toxicity affecting cardiac conduction 5

Endocrine Complications

• Hypogonadotropic hypogonadism is the most common endocrinopathy observed 4
• Growth hormone deficiency contributing to growth retardation 4
• Diabetes mellitus strongly associated with cardiac iron deposition, with insulin resistance and type 2 diabetes creating a shift in cardiac metabolism from glucose to fatty acid oxidation 4
• Hypothyroidism and hypoparathyroidism that can mimic or exacerbate heart failure 4
• Decreased adrenal reserve, requiring treatment as though patients have adrenal insufficiency during heart failure until proven otherwise 4

Hepatic Complications

• Cirrhosis prevalence of 10-20% in thalassemia patients, with male sex, high serum ALT, positive HCV-RNA, and high liver iron concentration as significant risk factors 4
• Hepatocellular carcinoma (HCC) risk approximately 6 times higher than general population, with 2% annual incidence in adults with thalassemia major 4
• Chronic viral hepatitis (HBV and HCV) from transfusion exposure, particularly in patients transfused before 1992 4

Other Complications

• Metabolic deficiencies including thiamine, B6, folate, fat-soluble vitamins, zinc, copper, selenium, and carnitine from hypermetabolic state 4
• Thrombotic complications particularly in thalassemia intermedia 1
• Leg ulcers from chronic hemolysis 1
• Sepsis as the second-leading cause of death, with increased risk in splenectomized patients from encapsulated organisms and unusual pathogens like Yersinia enterocolitica with deferoxamine use 4

Management Approach

Transfusion Therapy

• Initiate regular transfusions immediately to raise hemoglobin above 9 g/dL 6
• Maintain pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion hemoglobin at 13-14 g/dL to suppress ineffective erythropoiesis 6
• Transfuse every 3-4 weeks on a regular schedule 6
• Monitor hemoglobin every 2 weeks during periods requiring closer surveillance 6

Iron Chelation Therapy

Start iron chelation therapy immediately upon diagnosis to prevent life-threatening complications from iron overload. 6

Chelation Regimens Based on Cardiac Status

For patients with cardiac T2 <6 ms or acute decompensated heart failure:*

• Continuous intravenous deferoxamine at 50 mg/kg/day PLUS deferiprone 75 mg/kg/day for combined chelation therapy 6
• Transfer to specialized thalassemia center with integrated cardiology expertise, as this is a medical emergency where delay can be life-threatening 6
• Maintain continuous electrocardiographic and hemodynamic monitoring 6

For patients with cardiac T2 6-10 ms:*

• Intensified but not necessarily maximal chelation therapy 4

For patients with cardiac T2 10-20 ms:*

• Conservative management with dose modifications, compliance improvement, or alternative chelators 4

Chelation Monitoring

• Monitor liver iron concentration via MRI to guide chelation intensity 6
• Cardiac MRI T2 annually* to detect early iron-related cardiomyopathy 6
• Monitor plasma zinc annually and supplement if deficient, as deferiprone therapy causes zinc deficiency 7
• Avoid UGT1A6 inhibitors (diclofenac, probenecid, silymarin) with deferiprone 7
• Allow 4-hour interval between deferiprone and medications containing polyvalent cations (iron, aluminum, zinc) 7

Critical Chelation Warnings

• Deferiprone carries risk of agranulocytosis (2%) and neutropenia (6%), requiring absolute neutrophil count monitoring 7
• Avoid deferasirox in acute heart failure due to concerns with marginal renal perfusion 4
• Deferiprone is teratogenic: females must use effective contraception during treatment and for 6 months after last dose; males with female partners must use contraception during treatment and for 3 months after 7

Cardiac Management Specifics

For acute decompensated heart failure:

• Avoid aggressive diuretic therapy as thalassemia patients require adequate preload; use minimal diuretics only 6
• Treat as adrenal insufficiency until proven otherwise 4
• Optimize glucose control with insulin infusions, avoiding both hypoglycemia and hyperglycemia 4
• Consider thiamine, carnitine, or vitamin D replacement (if 25-hydroxyvitamin D <10 ng/dL) given benign nature of replacement 4
• Mechanical support devices for biventricular support may be considered, though published evidence is limited 4

Monitoring for Complications

Cardiac Surveillance

• Echocardiography and cardiac MRI T2 annually* for all patients 6
• Immediate bedside echocardiography if any signs of cardiac decompensation 6

Endocrine Surveillance

• Annual screening for diabetes, thyroid dysfunction, and hypogonadism 6
• Evaluate for multiple endocrine deficiencies in any patient with decreased cardiac function 4

Hepatic Surveillance

• Liver function tests every 3 months 6
• Test all patients transfused before 1992 for anti-HCV antibodies 4
• Confirm HCV replication with qualitative HCV-RNA by PCR if anti-HCV positive 4
• Liver ultrasound every 6 months for HCC surveillance in patients with cirrhosis or chronic HBV 4

Management of Viral Hepatitis

For HCV infection:

• Peg-interferon plus ribavirin for 24 weeks (genotypes 2/3) or 48 weeks (genotypes 1/4) 6
• Expect 30-40% increase in transfusion requirements during antiviral treatment 6
• Switch to deferoxamine during antiviral treatment (avoid deferiprone due to neutropenia risk) 6

For HBV infection:

• Peg-interferon or nucleoside/nucleotide analogs based on HBeAg status 6

Definitive Therapy

• Bone marrow transplantation remains the only definitive cure currently available 1, 2

Critical Pitfalls to Avoid

• Do not delay cardiac assessment thinking symptoms are purely from another cause—cardiac iron overload can present with seizures and has 50% one-year mortality if untreated 6
• Do not use valproic acid for seizures due to hepatotoxicity risk in patients with underlying liver disease 6
• Do not ignore ethnicity in diagnostic workup—alpha thalassemia is most common in Southeast Asian, Mediterranean, and Middle Eastern populations 3
• Do not confuse thalassemia trait with thalassemia major—management is completely different, with major requiring intensive chelation and trait being clinically asymptomatic 5
• Do not co-administer deferiprone with other drugs causing neutropenia/agranulocytosis without close ANC monitoring 7