Sickle Cell Disease

Definition

HämoglobinSickle Cell Disease is a disorder of the “haemoglobin” protein. Haemoglobin occurs in red blood cells and determines their red colour. Sickle Cell Disease is a genetic disorder which is passed on through generations. A homozygote patient is distinctively sick, while the heterozygote is mostly healthy and merely the carrier.

“Compound haemoglobinopathies” also exist. The concerned patients have Sickle Cell Disease, plus another disease in which the haemoglobinFor example, haemoglobin S and thalassaemia, or Haemoglobin S and Haemoglobin C is abnormal. 

In general, homozygote patients or compound haemoglobinopathy patients are referred to as “Sickle Cell Disease patients”, and heterozygote patients are referred to as “carriers”.

In Sickle Cell Disease the haemoglobinHaemoglobin is the carrier protein for oxygen in the blood is altered in such a way, that it leads to a change in shape of the erythrocytesred blood cells.This sickled shape gives the disease its name. The sickled erythrocytes clog small blood vessels, and consequently a lack of oxygen supply occurs. This leads to organ-specific symptoms and the so called "sickle-cell-crisis". Furthermore an increased destruction of red blood cells occurs, leading to anaemiapoorness of red blood cells. 

Cause

The cause of Sickle Cell Disease is a mutationgenetic fault in the DNA. This mutation is passed on over generations. Every human has 2 different copies of all genes (one from the mother, the other from the father). Heterozygotes have only one mutation, the other gene functions normally. This is why heterozygotes can live normally and healthy and are called “carriers”.

Homozygotes have the Sickle Cell Disease mutation on both genes; from the father and from the mother. This presents itself seriously with symptoms already occurring during childhood. These patients distinctively have Sickle Cell Disease and are not merely carriers.

Occurrence and Frequency

International

The frequency of SCD is very variable. The occurence depends on different regions. Many SCD patients are of African origin. However SCD also often occurs in the Middle East, in India, the Mediterranean Region and in Eastern Europe. These are regions in which Malaria existed formerly or still exists. SCD-carriers heterozygoteshave a minimal evolutional advantage against Malaria infection.

National – Switzerland

By means of immigration of SCD carriers and patients, but also because of the geographic proximity to the Mediterranean Region, SCD also exists in Switzerland.

Approximately 200-500 people in Switzerland sufferhomozygotes and sick from SCD. Additionally 5’000-10’000 SCD carriersheterozygotes live in Switzerland.

In 2008, almost 100 SCD patients were treated in the Children’s Hospitals Zurich and Geneva. These are 5 times more patients than treated in 1994. 

Symptoms 

Sickle Cell Disease presents itself with numerous symptoms. The later the stage of the disease and the longer no treatment is given, the more serious the symptoms.

If serious symptoms occur, call your general practitioner, go to an emergency unit or call the Swiss Emergency Number 144.

If milder symptoms occur and you suspect a Sickle Cell Disease contact us freely.

A few of the most important symptoms are enlisted below:

- Sudden loss of strength in the case of anaemia; loss of red blood cells.

-  The skin appears paler than usual; especially the mucosa of the mouth and the conjunctiva of the eye. Fatigue and exhaustion are also typical. A blood test in the laboratory confirms the diagnosis.

- Vaso-occlusive crisis: occurs with strain (heavy work load or sport), stress for the body (illness or infection) or without any apparent reason.

- Occlusion of the smallest blood vessels, capillaries, in different organs of the body through “clumping” of the blood.

- Life-threatening occlusion of blood vessels

- Lung: occlusion of blood vessels of the lung (respiratory problems and/or breathing dependent piercing sensation, shortage of breath.)
- Spleen: splenic sequestration (enlargement of the spleen, occurs with abdominal pain symptoms)
- Brain: Occlusion of brain artery -> stroke (often: sudden one-sided paralysis, epileptic fit or other neurological changes)

- Severe Pain

- Abdominal Crisis: (Abdomen = stomach) severe abdominal pain

- Acute Chest Syndrome: (Chest = Thorax; Syndrome = certain symptoms which occur within a group of symptoms) often triggered by pulmonary infection (pathologic infestation with viruses or bacteria) with the following symptoms:

- Acute chest pain
- Coughing
- Fever
- Tachypnea – fast breathing rate (normal: 15-20 breaths per minute) and hypoxia (= not enough oxygen), often causes shortage of breath

-Bone crisis: Less blood flow in bones often leads to severe bone pain

- Priapism

- Painful prolonged erection of the penis, which is needed to be treated urgently. If not treated, continuous erection problems may occur.

- Retinopathy: (Retina = the “seeing” part of the eye.)

- Occlusion of the blood vessels which supply the retina, lead to partial or complete blindness. 

- Severe infections

- The immune system is weakened in Sickle Cell Disease patients, because the spleen cannot sustain the defence functions of the body. Virus- or bacteria-infections can thus often lead to complications. Affected patients with pneumonia have a risk 400 times higher to develop complications. In these cases vaccination and prophylactic antibiotics play an important role. These have to be controlled and monitored by doctors. 

- Neurologic Symptoms

- During a stroke, a decreased blood supply to the brain or to the nerves, following symptoms can occur: Paralysis, numbness or even a decrease of intelligence.

- Renal Disease

- Due to a decreased blood supply of the kidneys, an impaired elimination of urine occurs especially in adults (not so often in children). An early symptom is a higher protein excretion in the urine. A urine test is one of the standard tests your doctor should always perform. If the urine is abnormal, a drug therapy is commenced.

- Hand-Foot-Syndrome: one of the most common symptoms of Sickle Cell Disease. Symptoms:

- Occur between the 6th and 18th month of life
- Pain and swelling of the hands and feet, especially in the region of the metacarpal bones.
- Tight shiny skin, maybe reddened 

Hand-Foot-Syndrome

Differential diagnosis - what else could it be

It does not mean that sickle cell disease is present if one ore more of these symptoms occur. A doctor will perform various tests to confirm the precise diagnosis. If you have a suspicion of Sickle Cell Disease, contact your general practitioner or one of our doctors.

In case of emergency go to the closest emergency unit or call the Swiss emergency number 144.

Diagnosis

Typical symptoms can be the first clues for the diagnosis Sickle Cell Disease.

To diagnose Sickle Cell Disease the haemoglobin (carrier protein for oxygen in the blood) or the mutation (genetic defect) are examined in one or more blood tests.

Therapy

conservative – precautionary measures (prophylaxis)

(in addition to the pharmacological treatment)

- Protection against the cold (warm jackets, caps, scarves and gloves, especially in winter)

- Avoid oxygen shortage

- Avoid high altitudes (> 3000m above sea level)
- Heterozygote carriers should avoid heavy work load or sport in high altitudes (> 3000m above sea level)
- Heavy work load or sport should be avoided generally if not tolerated by the patient
- Flights are considered as unproblematic (however, during long flights it is advised to move around and to drink enough water)

- Avoid dehydration

- Enough water should be drunken, especially in hot and dry weather, but also in winter.

- Precautionary measures against infections

- Avoid close contact to persons with infectious diseases. Viruses and bacteria lead to fever and loss of water quickly (sweating or diarrhoea). This leads to a worsened general condition in patients with sickle cell disease.

Drug therapy –the main therapy

- Pain relievers

- Quick use of very strong pain relieving drugs (such as opioids)

- Vaccines

- Prevent infections (Pneumococci = pneumonia, and Haemophilus influenzae = flu)

- Antibiotics

- The body’s defences against germs are insufficient in children with sickle cell disease, because the spleen loses its function over the years of the disease.

- Small children up until school age should take an antibiotic dose of penicillin every day.

- Older children and adults with fever >38.5°C should consult a doctor immediately, and start an antibiotic therapy (Augmentin)

- Blood transfusion

- When the haemoglobin drops or when the oxygen supply to the body is decreased in patients with a grave course of the disease, or in Sickle cell crises, blood should be given quickly. In life threatening Crises or in case of a stroke, an exchange transfusion could be necessary. In the exchange transfusion the patient’s blood is exchanged with “healthy blood”, i.e. does not contain sickle cells. This method shows a quick clinical improvement.

- Hydroxyurea (Litalir®, Droxia®)

- Hydroxyurea promotes clinical improvement and reduction of sickle cell crises. It is postulated to prolong survival of sickle cell disease patients.

- ACE-Inhibitors (z.B. Enalapril)

- In sickle cell disease patients with a symptomatic renal disease, the commencement of ACE inhibitors could be necessary.

- Vitamin B12, folic acid, iron

- These essential substrates are important for the haematopoiesis (blood production). A normal erythrocyte (red blood cell) has a life span of 120 days (= 4months) until it is degraded. In sickle cell disease this life span is only 100 days (=less than 3 months). This means that an increased turnover is present, more red blood cells are produced and hence more substrates are needed for the blood cell production (folic acid and iron). In isolated cases a supply of these substrates is necessary.

Causal Therapy (healing of sickle cell disease, treating its cause)

All therapies which exist today have to be taken lifelong. These therapies combat only the symptoms of sickle cell disease, but patients are mostly enabled to live a normal life. In grave courses of the disease, a stem cell transplantation (bone marrow transplantation) is considered possible. The bone marrow is responsible for the blood cell production, ie also the red blood cells, which in sickle cell disease are malformed. This variant is only possible if a matched donor is found (often siblings or unrelated donors from the international donor registry). The match or mismatch is determined by medical doctors in laboratories. If a bone marrow transplantation is performed, the blood producing system in the bone marrow of the sickle cell disease patient is replaced completely by that of the donor. 

Prognosis and life-expectancy

The prognosis for sickle cell disease has improved considerably in the last years. More than 90% of children with sickle cell disease in industrialised countries attain adulthood. When these children are treated optimally however, they still do not have a normal life expectancy compared to healthy individuals. A study conducted in 1994 reports of a life expectancy of 60-65 years. We hope that this life expectancy is further still increasing, especially in industrialised countries. 

Expert information
Sichelzellanämie Vorgang

In sickle cell disease the haemoglobin is mutated. During oxygen deficiency the haemoglobin polymerises. This polymerised haemoglobin leads to the sickling of erythrocytes (red blood cells), forming a sickled shape. This process gave the disease its name.

Haemoglobin is a protein of the erythrocyte (red blood cell). It is responsible for the oxygen uptake in the lung, and the oxygen release in the body (in tissues such as muscles). 

Haemoglobin (Hb = normal haemoglobin, HbS = sickle cell haemoglobin) has 4 protein subunits: 2 α-chains and 2 β-chains. In sickle cell disease the β-subunit is mutated. In heterozygotes only 1 subunit is affected, whereas in homozygotes both subunits are affected. The β-subunit has a mutation in the 6th amino acid: Valin substitutes glutamic acid.

Each of the 4 subunits of Hb has one haem group affiliated to itself. This haem group contains one iron atom. The iron is responsible for the red colour and the oxygen affinity of red blood cells. 

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