Beta-thalassemia - causes, symptoms, diagnosis, treatment, pathology

Summary

Beta thalassemia is an autosomal recessive genetic disorder characterized by a deficiency in the production of beta-globin chains of hemoglobin, which are crucial for oxygen transport in red blood cells (RBCs). It predominantly affects populations from Mediterranean, African, and Southeast Asian regions. The disorder can be classified into three types: minor, intermedia, and major, with varying degrees of severity and symptoms. Symptoms include anemia, jaundice, hepatosplenomegaly, and growth retardation, while severe cases can lead to secondary hemochromatosis. Diagnosis is typically made through blood tests, peripheral blood smear, and hemoglobin electrophoresis. Treatment may involve blood transfusions and iron chelation therapy to manage iron overload. Regular transfusions are required for transfusion-dependent patients, while non-transfusion-dependent cases may not need them. The condition is caused by mutations in the beta-globin gene on chromosome 11, leading to reduced or absent beta-globin chain synthesis.

Takeaways

• 🩸 Beta thalassemia is a genetic disorder affecting the production of beta-globin chains in hemoglobin, leading to various forms of the disease.
• 🌍 It is most commonly seen in Mediterranean, African, and Southeast Asian populations.
• 🧬 Hemoglobin is composed of four globin chains, with different types (alpha, beta, gamma, delta) combining to form various hemoglobins like HbF, HbA, and HbA2.
• 🧬🧬 Beta-thalassemia results from a point mutation in the beta-globin gene on chromosome 11, affecting mRNA reading and beta globin synthesis.
• 👪 It is an autosomal recessive disease, requiring two mutated copies of the gene to manifest fully.
• 📉 Beta-thalassemia minor is often asymptomatic, while major requires two beta zero mutations, leading to no beta-globin chain production.
• 🚫 The deficiency causes free alpha chains to accumulate and damage red blood cells, leading to hemolysis and anemia.
• 🤒 Symptoms of beta-thalassemia major include anemia, jaundice, hepatosplenomegaly, and growth retardation.
• 🩺 Diagnosis typically starts with a blood test showing low hemoglobin, decreased MCV, and high RDW, followed by hemoglobin electrophoresis.
• 💉 Treatment may involve blood transfusions for severe cases, with iron chelation therapy to manage iron overload from transfusions.
• ⚠️ Complications of untreated or poorly managed beta-thalassemia include hemochromatosis, arrhythmias, and organ damage.
• 🧵 The hair-on-end appearance on a skull X-ray and chipmunk facies are characteristic physical findings in beta-thalassemia major.

Q & A

What is beta thalassemia?

Beta thalassemia is a genetic disorder characterized by a deficiency in the production of beta-globin chains of hemoglobin, which are the oxygen-carrying proteins in red blood cells.

Which populations are most commonly affected by beta thalassemia?

Beta thalassemia is most commonly seen in Mediterranean, African, and Southeast Asian populations.

What are the four major globin chain types that make up hemoglobin?

The four major globin chain types are alpha, beta, gamma, and delta.

What is the composition of hemoglobin A (HbA), the major adult form of hemoglobin?

Hemoglobin A is composed of two alpha globin chains and two beta-globin chains.

What is the genetic cause of beta thalassemia?

Beta thalassemia is caused by a point mutation in the beta-globin gene present on chromosome 11, which results in a partial or complete deficiency of beta globin chain production.

How is beta thalassemia inherited?

Beta thalassemia is an autosomal recessive disease, meaning two mutated copies of the gene, one from each parent, are needed to develop the disease.

What are the three types of beta thalassemia?

The three types of beta thalassemia are minor, intermedia, and major, which differ in the severity of symptoms and the level of beta-globin chain synthesis.

What is the consequence of free alpha chains accumulating within red blood cells in beta thalassemia?

The accumulation of free alpha chains within red blood cells leads to the formation of intracellular inclusions that damage the red blood cell membrane, causing hemolysis.

What are the common symptoms of beta thalassemia major in infants?

Common symptoms of beta thalassemia major in infants include anemia-like symptoms such as pallor, shortness of breath, easy fatigue, jaundice, hepatosplenomegaly, and growth retardation.

How is the diagnosis of beta thalassemia typically confirmed?

The diagnosis of beta thalassemia is typically confirmed with hemoglobin electrophoresis, which shows low amounts of HbA, but an increase in HbF and HbA2 levels.

What are the two clinically relevant categories of beta thalassemia based on the need for blood transfusions?

The two clinically relevant categories are transfusion-dependent thalassemia, which includes phenotypes requiring recurrent blood transfusions, and non-transfusion-dependent thalassemia, which includes milder cases that do not require regular blood transfusions.

How can iron overload from regular blood transfusions be managed in beta thalassemia patients?

Iron overload from regular blood transfusions can be managed using iron chelating agents like deferoxamine, which help to remove excess iron through feces or urine.

Outlines

00:00

🧬 Understanding Beta Thalassemia

Beta thalassemia is a genetic disorder characterized by a deficiency in the production of beta-globin chains, which are crucial components of hemoglobin—the oxygen-carrying protein in red blood cells (RBCs). This condition is prevalent among Mediterranean, African, and Southeast Asian populations. Hemoglobin is composed of four globin chains, with different types (alpha, beta, gamma, delta) combining to form various hemoglobins. Beta-thalassemia results from a point mutation in the beta-globin gene on chromosome 11, leading to reduced or absent beta-globin chain synthesis. The disease is autosomal recessive, requiring two mutated copies of the gene for manifestation. Symptoms vary based on the severity of the mutation, with beta-thalassemia minor being asymptomatic and major leading to severe anemia, jaundice, hepatosplenomegaly, and growth retardation. Complications include hemochromatosis and organ enlargement due to increased RBC production. Diagnosis involves blood tests revealing low hemoglobin levels, small pale RBCs, and high serum iron, with confirmation through hemoglobin electrophoresis.

05:02

🩸 Diagnosis and Treatment of Beta Thalassemia

The diagnosis of beta thalassemia is confirmed through hemoglobin electrophoresis, which shows reduced levels of hemoglobin A (HbA) and increased levels of hemoglobin F (HbF) and hemoglobin A2 (HbA2) due to the binding of excess alpha chains to gamma and delta chains. There are two main clinical categories of the disease: transfusion-dependent thalassemia, which includes severe cases requiring regular blood transfusions, and non-transfusion-dependent thalassemia, which includes milder forms that do not require regular transfusions. Treatment may involve blood transfusions to correct low hemoglobin levels and manage symptoms. Iron overload from transfusions can be mitigated with chelating agents like deferoxamine. In cases of severe splenomegaly, a splenectomy may be performed. Beta-thalassemia is caused by a mutation in the beta-globin gene on chromosome 11, leading to reduced or absent synthesis of beta-globin chains. The major form of the disease presents with characteristic symptoms such as 'chipmunk face,' 'hair on end' appearance on skull X-ray, hepatosplenomegaly, jaundice, and secondary hemochromatosis.

Keywords

💡Beta Thalassemia

Beta Thalassemia is a genetic disorder characterized by a deficiency in the production of beta-globin chains of hemoglobin, which are essential for oxygen transport in red blood cells. This condition is most prevalent in Mediterranean, African, and Southeast Asian populations. The disorder affects the formation of hemoglobin, leading to various health complications, such as anemia and iron overload, and is central to the video's theme of understanding the genetic and physiological aspects of the disease.

💡Hemoglobin

Hemoglobin is an oxygen-carrying protein found in red blood cells (RBCs). It is composed of four globin chains, each bound to a heme group. The video discusses different types of hemoglobin, including fetal hemoglobin (HbF), adult hemoglobin (HbA), and HbA2, which are affected by the presence or absence of beta-globin chains in beta thalassemia. Hemoglobin plays a crucial role in the disease's pathology, as its abnormal structure and function lead to the clinical manifestations of the disorder.

💡Globin Chains

Globin chains are the protein components of hemoglobin that bind to heme groups to form the complete hemoglobin molecule. There are four major types of globin chains: alpha, beta, gamma, and delta. The video emphasizes the importance of beta-globin chains, as their deficiency is the hallmark of beta thalassemia. The different combinations of these chains give rise to various forms of hemoglobin, which are affected by the genetic mutations in beta thalassemia.

💡Autosomal Recessive Disease

An autosomal recessive disease is a genetic condition that requires two copies of the mutated gene, one from each parent, for the disease to manifest. Beta thalassemia is an example of such a disease, where the inheritance pattern is crucial for understanding why some individuals are asymptomatic carriers, while others have the full-blown disease. The video explains that having one mutated gene results in beta thalassemia minor, while two mutated genes lead to beta thalassemia major or intermedia.

💡Point Mutation

A point mutation is a type of genetic mutation where a single nucleotide in the DNA sequence is replaced by another nucleotide. In the context of beta thalassemia, point mutations occur in the beta-globin gene on chromosome 11, leading to either reduced or completely absent beta globin chain synthesis. The video highlights that these mutations often happen in promoter sequences and splice sites, which affect mRNA reading and, consequently, the production of beta globin chains.

💡Hemolysis

Hemolysis refers to the breakdown of red blood cells, which can occur either within the bone marrow (intravascular) or outside of it (extravascular), such as in the spleen by macrophages. The video describes how the accumulation of free alpha chains in beta thalassemia damages the red blood cell membrane, leading to hemolysis. This process releases hemoglobin into the plasma, recycling heme into iron and unconjugated bilirubin, which can cause jaundice and contribute to hemochromatosis.

💡Hypoxia

Hypoxia is a condition where there is a deficiency of oxygen in body tissues. In beta thalassemia, hemolysis leads to a decrease in the number of red blood cells available to transport oxygen, resulting in hypoxia. The video explains that this triggers the bone marrow and extramedullary tissues to increase red blood cell production, which can cause enlargement of the liver and spleen and other organs.

💡Hemochromatosis

Hemochromatosis is a condition characterized by the accumulation of excess iron in the body, which can lead to damage in various organs. The video describes secondary hemochromatosis as a complication of beta thalassemia, where the recycling of heme from hemoglobin released during hemolysis leads to an excess of iron. This can cause serious health issues, such as arrhythmias, pericarditis, cirrhosis, hypothyroidism, and diabetes mellitus.

💡Blood Transfusions

Blood transfusions are medical procedures where blood or its components are given intravenously to a patient. In the context of beta thalassemia, transfusions are used to correct low hemoglobin levels and associated symptoms. The video outlines two categories of the disease based on the need for transfusions: transfusion-dependent thalassemia, which includes major forms of the disease, and non-transfusion-dependent thalassemia, which includes minor and some forms of intermedia thalassemia.

💡Hemoglobin Electrophoresis

Hemoglobin electrophoresis is a laboratory technique used to separate and identify different types of hemoglobin based on their electrical charge. The video explains that this test is used to diagnose beta thalassemia by showing low amounts of HbA, an increase in HbF and HbA2 levels, and the presence of excess alpha chains binding to gamma and delta chains. This diagnostic tool is crucial for confirming the disease and differentiating its various forms.

💡Splenectomy

A splenectomy is the surgical removal of the spleen. The video mentions this procedure as a treatment option for beta thalassemia when splenomegaly, or an enlarged spleen, causes excess hemolysis. By removing the spleen, the rate of red blood cell destruction can be reduced, which may alleviate some of the disease's symptoms and complications.

Highlights

Beta thalassemia is a genetic disorder characterized by a deficiency in the production of beta-globin chains of hemoglobin.

It is most prevalent in Mediterranean, African, and Southeast Asian populations.

Hemoglobin is composed of four globin chains, with different types (alpha, beta, gamma, delta) combining to form various hemoglobins.

Beta-thalassemia results from a point mutation in the beta-globin gene on chromosome 11, affecting mRNA reading and beta globin chain synthesis.

The disease is autosomal recessive, requiring two mutated gene copies to manifest.

Beta-thalassemia minor is often asymptomatic, while major requires two beta zero mutations leading to no beta-globin chain production.

Deficiency in beta-globin chains causes free alpha chains to accumulate and damage red blood cells, leading to hemolysis.

Hemolysis results in anemia, jaundice, and potential secondary hemochromatosis due to excess iron deposits.

Hypoxia from fewer red blood cells triggers increased red blood cell production, potentially leading to bone and organ enlargement.

Beta-thalassemia major symptoms include anemia, jaundice, hepatosplenomegaly, and growth retardation.

Complications from hemochromatosis can include arrhythmias, pericarditis, cirrhosis, hypothyroidism, and diabetes mellitus.

Diagnostic methods include blood tests for hemoglobin levels, MCV, RDW, and hemoglobin electrophoresis to identify specific hemoglobin types.

Beta-thalassemia minor may show increased HbA2 levels, while major has low HbA but increased HBF and HbA2 levels.

Treatment for beta-thalassemia may involve blood transfusions and iron chelation therapy to manage symptoms and prevent iron overload.

Transfusion-dependent thalassemia includes major and some severe intermediate cases, while non-transfusion-dependent includes minor and milder intermedia forms.

Regular blood transfusions can lead to iron overload, managed with agents like deferoxamine to remove excess iron.

Splenectomy may be performed in cases of severe splenomegaly causing excessive hemolysis.

Beta-thalassemia major is identified by characteristic facial features, hair-on-end skull appearance, and other clinical findings.

Transcripts

beta thalassemia is a genetic disorder

where there's a deficiency in production

of the beta-globin chains of hemoglobin

which are the oxygen-carrying proteins

in red blood cells or rbcs for short

beta-thalassemia is most commonly seen

in mediterranean african and southeast

asian populations

normally hemoglobin is made up of four

globin chains each bound to a heme group

there are four major globin chain types

alpha beta gamma and delta

these four globin chains combine in

different ways to give rise to the

different kinds of hemoglobin

first there's hemoglobin f or hbf where

f stands for fetal hemoglobin and that's

made up of two alpha globin and two

gamma globin chains

hemoglobin a or hva the major adult

hemoglobin form is made up of two alpha

globin and two beta-globin chains

finally hemoglobin a2 or hba2 accounts

for a small fraction of adult hemoglobin

in the blood and it's made up of two

alphaglobin and two delta globin chains

with beta thalassemia there's either a

partial or complete beta globin chain

deficiency due to a point mutation which

is when a single nucleotide in dna is

replaced by another nucleotide in the

beta-globin gene present on chromosome

11. and most often these mutations occur

in two regions of the gene called the

promoter sequences and splice sites

which affects the way the mrna is read

the result is either reduced or

completely absent beta globin chain

synthesis

and since this is an autosomal recessive

disease two mutated copies of this gene

one from each parent are needed to

develop the disease

if the person has just one mutated gene

that codes for either a reduced

production or absent production of

beta-globin chains then they have beta

thalassemia minor

if the person has two mutated genes that

code for reduced beta globin chain

synthesis then they're said to have beta

thalassemia intermedia

if the person has two beta zero

mutations then no beta-globin chains are

produced and they're said to have beta

thalassemia major

when there's a beta-globin chain

deficiency free alpha chains accumulate

within red blood cells and they clump

together to form intracellular

inclusions which damage the red blood

cell cell membrane

this causes hemolysis or red blood cell

breakdown in the bone marrow or

extravascular hemolysis where red blood

cells are destroyed by macrophages in

the spleen

hemolysis causes hemoglobin to spill out

directly into the plasma where heme is

recycled into iron and unconjugated

bilirubin over time the excess

unconjugated bilirubin leads to jaundice

and excess iron deposits leads to

secondary hemochromatosis

at the same time hemolysis leads to

hypoxia because there are fewer red

blood cells to carry oxygen to organs

and tissues and a consequence of hypoxia

is that it signals the bone marrow and

extra medullary tissues like the liver

and spleen to increase red blood cell

production which may cause bone marrow

containing bones like those in the skull

and face as well as the liver and spleen

to enlarge

okay now beta thalassaemia minor is

usually asymptomatic

on the other hand with beta thalassemia

major symptoms do not develop until the

first three to six months of life

that's because during the first three to

six months of life fetal hemoglobin is

still produced

and that process uses up some of the

free alpha chains

common beta thalassemia major signs and

symptoms include symptoms of anemia like

power shortness of breath and easy

fatigue ability

jaundice swollen abdomen due to an

enlarged liver and spleen

hepatosplenomegaly and growth

retardation

complications due to hemochromatosis

include arrhythmias pericarditis

cirrhosis hypothyroidism and diabetes

mellitus

other beta thalassemia major findings

may include enlarged forehead and

cheekbones which is called chipmunk

faces on a skull x-ray the skull bones

show a radiolucent bone marrow with fine

hair-like projections that look a bit

how the hair on your arms stand up when

you get the goosebumps so it's called

hair on end appearance

alternatively this is also called a crew

cut appearance named after the type of

haircut

diagnosis of beta thalassemia usually

begins with a routine blood test that

shows a low hemoglobin level decreased

mean corpuscular volume or mcv and a

high red blood cell distribution width

or rdw which indicates that the red

blood cells come in a lot of different

sizes

however the rdw is often normal with

beta thalassemia minor

the peripheral blood smear shows

microacidic or small and hypochromic or

pale red blood cells

there are also target cells which are

small red blood cells that look like

bull's eyes due to scrunching up of the

excess cell membrane

lab work may also show high serum iron

high ferritin and a high transfer and

saturation level

finally the diagnosis is confirmed with

hemoglobin electrophoresis which shows

low amounts of hba but an increase in

hbf and hba2 levels which are formed

when excess alpha chains start binding

to gamma and delta chains

in beta thalassaemia minor there's

usually an increased hba2 level greater

than 3.5 percent on gel electrophoresis

beta thalassemia does not always require

treatment but when needed blood

transfusions are given to correct low

hemoglobin levels and associated

symptoms based on the need for blood

transfusion there are two clinically

relevant categories of beta thalassemia

first there's the transfusion dependent

thalassemia category which refers to all

the phenotypes that require recurrent

blood transfusions for survival this

category includes beta thalassemia major

and sometimes intermediate beta

thalassemia with severely reduced beta

chain synthesis

the second category is that of

non-transfusion-dependent thalassemia

which refers to thalassemias that do not

require regular blood transfusions this

category includes beta thalassemia minor

and beta thalassemia intermedia with

milder symptoms

keep in mind that regular blood

transfusions add up to the iron overload

which can worsen hemochromatosis

to prevent this iron key weighting

agents like deforoxamine are given which

trap some of the excess iron and sweep

it away through feces or urine

finally a splenectomy can be done when

splenomegaly causes excess hemolysis

beta thalassemia is an autosomal

recessive disorder caused by a mutation

in the beta-globin gene present on

chromosome 11 which results in reduced

or completely absent beta-globin chain

synthesis there are three types beta

thalassemia minor intermedia and major

beta thalassemia major causes chipmunk

faces hair on end appearance on a skull

x-ray hepatosplenomegaly

jaundice and secondary hemochromatosis