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This is the defect found in Gilbert's syndrome, causing benign jaundice.
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Inherited defect in UDP glucuronyltransferase levels
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This is the defect found in Wilson's disease, which usually presents with hepatic impairment and neuropsychiatric features.
10017283
c
Inherited defect of ATP7B gene
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The features are those of iron overload which can be inherited as in the case of haemochromatosis, but the patient's medical history makes an iatrogenic cause more likely.
10017282
b
Inherited defect of the HFE gene
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This causes Lynch syndrome, causing colorectal, ovarian, gastric and endometrial cancers.
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Inherited defect of MSH2 gene
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This patient is likely to be suffering from iatrogenic iron overload from repeated blood transfusions for his thalassemia major. This causes symptoms similar to hereditary haemochromatosis, such as cardiac failure, liver impairment, and endocrine issues like diabetes.
10017281
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Blood transfusions
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# Summary

Thalassaemia is an inherited disorder characterized by abnormal haemoglobin production, with alpha and beta thalassaemia caused by defects in the alpha and beta globin genes, respectively. Key signs and symptoms include jaundice, fatigue, facial bone deformities, and severe anaemia. Diagnosis is made primarily through genetic testing and a full blood count. Management strategies include blood transfusions, stem cell transplantation, and splenectomy for alpha thalassaemia, and blood transfusions and iron chelating agents for beta thalassaemia.


# Definition

Thalassaemia is a group of inherited disorders characterised by abnormal haemoglobin production. 

Defects in the four genes for α-globin result in α-thalassaemia in the two genes for β-globin result in β-thalassaemia

The absence/abnormality of the α- or β-globin genes leads to quantitative abnormality in globin chain production and an imbalance of the globin-chain synthesis

The clinical severity of the syndrome is proportional to the number of absent or abnormal genes

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# Epidemiology

Geographically, thalassaemias are prevalent in populations originating from Mediterranean Europe, Central Africa, the Middle East, the Indian subcontinent and Southeast Asia – having thalassaemia trait is believed to confer some protection against falciparum malaria.

# Alpha-thalassaemia 

## Inheritance 

- Autosomal recessive inheritance


## Pathophysiology 

α-thalassemia describes the spectrum of diseases caused by nonfunctioning copies of the four α-globin genes on chromosome 16.

Symptomatic disease results when two or more copies of the gene are lost

- Patients with **two** defective copies have a mild asymptomatic anaemia – so-called **α-thalassaemia trait** 
- Those with **three** defective copies have symptomatic **haemoglobin H disease** 
  - Microcytic anaemia (Hb approximately 70 g/l)
  - Haemolysis 
  - Splenomegaly
  - Normal survival is to be expected 

- inheritance of **four** defective copies (**hydrops fetalis**) is incompatible with life 

  - The lack of α-globin chains results in excess γ-chains (creating Hb Barts), which are poor carriers of oxygen owing to their high affinity for oxygen

  - It may affect the fetus in utero


## Signs and Symptoms 

- Jaundice
- Fatigue
- Facial bone deformities

## Investigations 

- FBC will reveal a microcytic anaemia.
- Hb electrophoresis – can be normal, so DNA analysis is required to make the diagnosis


## Management 

Current treatment options for symptomatic thalassaemia include:

- Blood transfusions 
- Stem cell transplantation

A splenectomy is an option, particularly in patients with HbH disease.

Regular folic acid can also be given, especially in those who are pregnant.

# Beta-thalassaemia 

## Inheritance

- Autosomal recessive inheritance


## Pathophysiology 

β-thalassemia describes the spectrum of diseases caused by nonfunctioning copies of the two β-globin genes

- The mildest variant of β-thalassaemia is **β-thalassaemia minor** (also known as **thalassaemia trait**)
  - Patients typically have one functioning and one dysfunctional copy of the β-globin gene

- The most severe form of β-thalassaemia (known as **β-thalassaemia major**) is caused by a complete absence of β-globin synthesis (null mutations in both copies of the β-globin gene)


## Signs and Symptoms

- **β-thalassaemia minor** - patients are typically asymptomatic
- **β-thalassaemia major:**
	- **Severe symptomatic anaemia** at 3–9 months of age 
  - Becomes evident when levels of HbF, which does not contain β-globin, fall and should be replaced by HbA (made up of two α- and two β-globin chains), which is lacking in β-thalassaemia major
- Ineffective haematopoiesis results in extramedullary haematopoesis, which results in
	- Frontal bossing (hair-on-end appearance on Skull XR)
	- Maxillary overgrowth and prominent frontal/parietal bones (hypertrophy of ineffective marrow) - "Chipmunk facies"
	- Hepatosplenomegaly
- Failure to thrive in infancy


## Investigations 

**β-thalassaemia minor**

- **Isolated microcytosis** (MCV approximately 63–77 fl) and mild anaemia (Hb typically not <100 g/l)
  - The degree of anaemia is often less severe than would be expected for the degree of microcytosis

- Blood film - target cells and basophilic stippling 
- Increased red cell count
- Hb electrophoresis (diagnostic) shows raised HbA<sub>2</sub> (>3.5%) – can be lowered by the presence of iron deficiency
- Can be confused with iron deficiency – ferritin in β-thalassaemia minor is usually normal or high


**β-thalassaemia major**

- **Profound microcytic anaemia**; reduced MCV and reduced MCHC
- Increased reticulocytes
- Blood film – marked anisopoikilocytosis, target cells and nucleated RBCs. Teardrop cells from extramedullary haematopoeisis may also be present
- Methyl blue stains – RBC inclusions with precipitated α-globin
- High-performance liquid chromatography (HPLC) or electrophoresis (diagnostic) – mainly shows HbF
- HbA<sub>2</sub> may be normal or mildly elevated
- Haemolysis




## Management of β-thalassaemia major

- Treatment is with **regular blood transfusions**

- The most important long-term consideration in these patients is to reduce the risk of iron overload toxicity 

  - A condition which primarily affects the heart, joints, liver and endocrine glands
  - Half of patients with β-thalassaemia major die before the age of 35 years, usually from cardiac failure secondary to iron overload

  - Iron overload can be prevented with **iron chelating agents** (eg. desferrioxamine/deferiprone/deferasirox) 

- **Hydroxycarbamide** (previously known as hydroxyurea) can also be used to boost HbF levels

- **Allogeneic bone marrow transplantation** (BMT) from a sibling or matched unrelated donor 

  - A potentially curative option 
  - Should be done before significant organ damage has occurred due to iron overload
  - Risks of transplant include graft rejection, graft vs. host disease, infection and transplant-related mortality 

  - These risks must balanced against the long-term benefits of transfusion independence and 'cure'


**Iron chelation**

- **Desferrioxamine** 

  - Used for decompensated organ dysfunction 

  - Given via subcutaneous pump over 2–5 days each week 

  - Compliance may be an issue

- **Deferiprone** 

  - Oral, given in three divided doses

  - Particularly good for cardiac iron overload

  - **side effects** include: 
    - Nausea
    - Arthralgia
    - Agranulocytosis – weekly FBC needed 
    - LFT disturbance 
    - Zinc deficiency

- **Deferasirox**  

  - A newer oral iron chelator 

  - Removes iron in the bile and faeces

  - Once daily suspension with similar efficacy to desferrioxamine

  - **Side effects** include: 
    - Gastrointestinal upset
      - Cytopenias 
      - Increased creatinine

- **Monitoring required**
  - Ferritin 3 monthly
  - Annual assessment of: 
    - Cardiac/liver T2* MRI
    - Endocrine tests
    - Audiology and ophthalmology 

    
## Complications of β-thalassaemia

- Cardiomyopathy/cardiac arrhythmia/cardiac failure
	- Older patients are prone to atrial fibrillation 
	- Urgent cardiac investigations (eg. ECG, echocardiogram, cardiac monitoring and chest X-ray) may be needed
- Acute sepsis – bacterial sepsis (risk is further increased after splenectomy)
	- Consider central venous catheter infection (particularly with *Klebsiella*, *Yersinia enterocolitica* and encapsulated organisms 
	- Give broad-spectrum antibiotics, and consider high-dependency unit input
- Liver cirrhosis, portal hypertension and acute decompensation
	- Early liver unit input and careful fluid balance are required
- Endocrine dysfunction 
  - Hypocalcaemia with tetany due to hypoparathyroidism
    - Needs cardiac monitoring and IV calcium 
  - Diabetes
- **Iron overload** due to repeated blood transfusions. Presents similarly to Hereditary Haemochromatosis
- Death is usually due to heart failure if it goes undiagnosed.


# Screening

Homozygous and compound heterozygous forms of thalassaemia can have huge clinical significance for which genetic counselling and prenatal testing should be offered.

If a patient proves to have thalassaemia, it is strongly recommended to test their partner too.

The **UK screening programme** uses a combination of the pregnant mothers' family of origin questionnaire (FOQ) and FBC, and if required the FOQ and FBC of the baby's father, to detect significant haemoglobinopathies antenatally

- If the maternal MCH is <27 pg, iron studies and HPLC are performed


- If these tests are negative, DNA studies/analyses are performed to look for α-thalassaemia if the pregnant woman and the baby's father are both from 'at risk' parts of the world


During pregnancy, intrauterine diagnosis of thalassaemia major, ideally by chorionic villous sampling, can allow the option of therapeutic abortion of an affected fetus.

# References

[Patient.info - Thalassaemia](https://patient.info/doctor/thalassaemia-pro)
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A blood film showing beta thalassaemia.
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Thalassaemia
Topic
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Haematology
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Iatrogenic iron overload from repeated blood transfusions can lead to severe complications, including liver dysfunction and diabetes in patients with thalassemia major.
A 50 year old man with type 2 diabetes comes to the GP with scleral icterus. He describes severe pain in his knees and breathlessness on minimal exertion, over the last month. His past medical history is remarkable for beta thalassemia major.

What is the most likely aetiology of his condition?
a