Hematological Abnormalities In Abetalipoproteinemia

The effective management of abetalipoproteinemia is significantly associated with a thorough understanding of the condition and its related abnormalities. This considerably improves patients' health outcomes. 

Especially in rare conditions like abetalipoproteinemia, where gaining insight into the variable changes is crucial. Such knowledge equips patients and their families with the tools necessary to manage the condition effectively and enhance the quality of life.¹ 

Abetalipoproteinemia is a hereditary metabolic disorder manifested by malabsorption of fats, leading to a lack of certain fats and fat-soluble vitamins in the body, and failure to gain weight.² 

Lipids are essential components of cellular membrane structure and also act as a solvent or environment for the transportation and storage of fat-soluble vitamins and nutrients. A lack of lipids is associated with functional, biological, and structural abnormalities.³ On the haematological level, the abnormalities arise from changes in the red blood cell membrane and vitamin deficiencies.⁴ 

Pathophysiology

Abetalipoproteinemia is an inherited autosomal recessive (passing a copy of the defective gene from both parents) disorder caused by various mutations in the gene coding for microsomal triglyceride transfer protein (MTTP),⁵ leading to the absence of the MTTP protein. The protein is present in mucosal cells of the intestine and liver cells and is essential for chylomicrons and very low-density lipoprotein (VLDL) formation.⁶ 

VLDL and chylomicrons are molecules formed from a combination of protein and fats, functioning in the transportation of different forms of fats in the bloodstream. As lipids are hydrophobic molecules( cannot be dissolved in water), they need special carriers to be transported in plasma.^{7, 8} Consequently, the lack of MTTP protein disrupts the secretion of these carriers, which prevents fat absorption from the intestine and transportation,⁶ followed by impaired absorption of fat-soluble vitamins and subsequent vitamin deficiencies.⁹ This leads to a range of symptoms, including haematological abnormalities, neurological defects, muscle weakness, and gastrointestinal, hepatic, and ophthalmic symptoms.¹⁰ 

Hematological abnormalities

Acanthocytosis

The presence of acanthocytes is one of the most distinctive features in abetalipoproteinemia. Acanthocytes a red blood cell (RBCS) that exhibits membrane structural abnormalities. The membrane develops crenation or spur-like projections due to lipids irregular distribution. The suffix "osis" indicates a significant number of acanthocytes, which can account for up to 50% of patients' RBCs.^{10, 11} 

Low erythrocyte sedimentation rate (ESR) 

A measurement of the  RBC settling down due to the effect of gravity per unit of time. Rouleaux formation (RBCs stack partially over each other like coins) is the principle of sedimentation processing; a smooth membrane structure is required to form a rouleaux shape. Acanthocytosis prevents this process, leading to slow RBCs settling in the blood test tube and a low ESR test result.⁹ 

Anemia

Attributed to malabsorption, patients experience anaemia due to a lack of essential nutrients, minerals, and vitamins, such as iron, folic acid, and vitamin B12. Hemolysis (destruction of Red blood cells) is another factor contributing to anaemia development. This results from vitamin E deficiency, which acts as an antioxidant agent; its deficiency makes RBCs susceptible to destruction by oxidative stress.^{2, 12}  

Reticulocytosis

Reticulocytes are immature red blood cells. The presence of high reticulocyte counts in peripheral blood is known as reticulocytosis, and its Presence indicates bone marrow compensation for the drop  in RBCs.^{13, 14} 

Hyperbilirubinemia

Bilirubin is a yellow pigment released from red blood cells after destruction. An increase in bilirubin causes skin and mucous membrane yellowish discolouration.^{13, 15}  

High INR and low coagulation factors

This explains the bleeding tendency in patients with abetalipoproteinemia. Coagulation factors, such as factors X, IX, VII, and II, are vitamin K-dependent and require activation by vitamin K to perform their biological function. Vitamin K, being a lipid-soluble vitamin, relies on lipids for absorption and transport. Lipid deficiency disrupts this process, leading to coagulation issues.^{2, 12} 

Others abnormalities 

Neurological defects

The manifestations include ataxia, which is a defect in controlling muscular movement, neuropathy, and failure to thrive due to vitamin E deficiency. These symptoms affect the patient's quality of life and their ability to practice daily activities.¹⁶ 

Muscle weakness

This prevalent symptom occurs due to the malabsorption of fats and fat-soluble vitamins, affecting the body's movement and strength.^{17, 18} 

Gastrointestinal symptoms

Gastrointestinal abnormalities include diarrhoea, steatorrhea (fatty stools), general malabsorption, nutritional defects and weight loss. ^{16, 19} 

Ophthalmic symptoms

As a result of vitamin A and E deficiencies, patients may experience vision problems. Appropriate management is required to prevent the progression of these symptoms to more persistent damage, like vision loss.¹⁸ 

Diagnostic methods 

Lipid profile 

Levels of triglycerides, chylomicrons, and VLDL are low or absent in patients with abetalipoproteinemia, in addition to low total cholesterol levels.⁹ 

Complete blood count (CBC)

This routine blood test aims to detect the presence of anaemia. It aims to calculate different blood cells (RBCs, white blood cells, and platelets) and measure cell size. Also measures the haemoglobin levels (a protein inside red blood cells, giving the red pigment to blood, responsible for oxygen and carbon dioxide transportation). Low levels of haemoglobin are found in anaemia.²⁰  

Peripheral blood smear

Microscopic examination of blood cell morphology indicates the presence of acanthocytosis and fragments of RBCs, which are features of hemolysis.¹⁰  

Molecular genetic testing

This test identifies biallelic (both inherited copies of the mutated gene) pathogenic variants in the MTTP gene.²¹ 

Vitamin A, D, E, K levels

 Complete deficiency of these fat-soluble vitamins is found in patients with abetalipoproteinemia.^{2, 12}  

Coagulation studies

Prothrombin time and INR tests evaluate patients' bleeding tendencies. Patients with abetalipoproteinemia show prolonged clotting times due to vitamin K-dependent coagulation factors.^2,12 

Effective management of haematological abnormalities involves:

Supplementary vitamin intake

To compensate for vitamin deficiencies, regular supplementation with fat-soluble vitamins (A, D, E, and K) is essential. This can help prevent and manage symptoms related to vitamin deficiencies. 

Dietary management

Patients should follow a low-fat restricted diet, supplemented with essential fatty acids, which are easier to absorb. This helps ensure that they receive the necessary nutrients without exacerbating malabsorption issues.

Periodic testing and follow-up

Regular laboratory tests, including complete blood counts and INR tests, are crucial for monitoring the patient's condition and adjusting treatment as needed.¹² 

Prognosis and complications

Early diagnosis is vital, patients are diagnosed in early childhood (1-6 years). The severity of the disease and the age of onset rely on the mutation phenotype. Most patients experience symptoms after the cessation of breastfeeding. The late presentation may lead to more complications as a consequence of vitamin deficiencies, which are essential for growth and development.¹² Also, regular follow-up and adherence to the treatment protocol assigned by the physician are critical to prevent complications and ensure effective disease management.

Current research and future direction

The development of research processes in disease modelling using stem cells facilitates the understanding of disease pathophysiology,²² as well as the innovation and testing of drug effectiveness without potential harm to patients. This approach may also favour the production of safe and clinically tested replacement lipid transportation molecules.²³ 

Gene therapy is one of the most revolutionary treatment approaches, carrying great promise for the treatment of genetic defects by targeting defective genes and replacing them with normal, healthy genes. Although clinical trials and research are currently limited to specific diseases, gene therapy potentially provides long-term treatment for patients with genetic defects, such as those with abetalipoproteinemia.²⁴  

Summary

In summary, understanding the haematological abnormalities associated with abetalipoproteinemia is crucial for effective management.

Abetalipoproteinemia is a rare inherited fat metabolism disorder that leads to deficiencies in essential lipids, nutrients and fat-soluble vitamins.² These deficiencies bring about several complications, including haematological changes like acanthocytosis, anaemia, low erythrocyte sedimentation rate, and bleeding risk.¹⁰  

Early diagnosis and management are indispensable to lowering the risk of these complications. Prompt identification through diagnostic methods, such as lipid profiles, complete blood counts, and molecular genetic testing, enables timely intervention.^{2, 12} 

Effective management involves supplementary vitamin intake, dietary adjustments, and regular monitoring of blood parameters.¹² 

Given the biological functions of lipids and the associated defects, patients and their families must understand the abnormalities related to this condition. This aids in the management and follow-up of the disease. Moreover, awareness about abnormalities and clinical symptoms helps ensure timely medical care and lowers the risk of developing complications