I wished for a calm call after a hectic day but that was not the order, as barely an hour into the call, child A; an 11 month old child was rushed into the emergency room.

He was very hot( febrile), crying uncontrollably (irritable) with swollen hands and feet (dactylitis). "What is your hemoglobin genotype" I asked the mother. She looked confused and didn't say anything. "Have you heard of "hemoglobin or genotype" I asked again. She said no. I sent for hemoglobin genotype among other laboratory tests and it came out HbSS.

After the rest of the history, examination and stabilizing of the child, I was still counseling the mother about the result and the condition when child B was brought in

Child B is a 9yr old boy, in severe painful distress, very pale and looking wasted. "What is his hemoglobin genotype" I asked the mother. "HbSS" she replied. "Why do you have to marry AS? Didn't you know your genotype?" I asked again. "I have always known that I'm AS. My husband deceived me that he is AA because he said he could not afford living without me. We have four children, 3 are affected. No single week passes without one being hospitalized" she said, sobbing in between.
Child B's blood level (PCV) came out 9%. Worse still, he could not get blood transfusion for religious reasons.

Lots of medics must have heard different stories and reasons that gave rise to having a child with Sickle Cell disease, ranging from ignorance to emotions and religious convictions. In as much as some might have very few and subtle symptoms, others might experience frequent, severe and life threatening crisis even with the best care. And each time i see one in such Agony, i can't but wonder if anything worths being the excuse.

Sickle Cell Disease

Sickle Cell Disease is a group of illnesses transferable from parents to their children, caused by a problem in the substance that binds and transports oxygen in the body called hemoglobin.

Source : wikipediacommons.com

The cause

Red blood cells contain hemoglobin, a protein that binds and transports oxygen in the body. The hemoglobin has four submits and each subunit contains iron(heam) and protein(globin). Differences in the composition and arrangement of amino acids in the globin chain gives rise to the different types of hemoglobins. The adult hemoglobin (HbA); the type predominant few months after birth and all through life is made up of two alpha and two beta submits.

Sickle Cell Disease is caused by a point mutation in the beta submit that results in replacement of the amino acid glutamic acid with another, valine, resulting in the formation of sickle hemoglobin (HbS).

This single mutation and substitution changes the entire behavior and characteristics of the hemoglobin molecule and such include :

• Decreased solubility of the molecule
• Increased molecular instability
• Increased polymer formation.

Conditions favouring the above include low oxygen tension, infections, dehydration, extremes of temperature(fever and cold), emotional upset and physical exertion.

How it is inherited

Expression of genetic materials is dependent on the presence of two alleles. Those that require the presence of only one allele to manifest are said to be dominant while those requiring both to express are said to be recessive. Sickle Cell Disease is an autosomal recessive disorder. This means that both allele must carry the mutated or Sickle hemoglobin before it can manifest.

There are other variants of sickle cell diseases. They must have at least one Sickle hemoglobin and other forms of mutated hemoglobin. Such include HbSC, HbSD, HbSO and Hb beta thalasaemia. All these other variants have asymptomatic or subtle clinical manifestations. The only one mostly of clinical importance is HbSS and is usually referred to as sickle cell anemia.

source : wikipediacommons.com

Normal individuals have HbAA. The carries of this disorder have one normal and one Sickle hemoglobin( HbAS) and so do not manifest the disease. A normal person( HbAA) can marry a carrier (HbAS) without any problem as they can only give birth to normal and carrier children.

Sickle Cell Disease occurs when a carrier of the disorder marries another carrier. For every pregnancy, they have 25% chance of normal, 50% chance of carriers and 25% chance of sickle cell diseases in their children.

source : wikipediacommons.com

A quick look at the above diagram might make one to conclude that only one out of four children of the carriers will be affected. This is not so as it follows mendelian law of independent assortment. In every pregnancy, each allele(of the gene) separate and combine independent of the other and independent of what happened in previous pregnancies. Thus the diagram only represents probabilities in each pregnancy. A woman might be unlucky and have all her children inheriting both the Sickle gene(HbSS).

Pathophysiology

It has already been stated that Sickle hemoglobin has increased risk of polymer formation, decreased solubility and increased instability and fragility.
When exposed to to unfavorable conditions like low oxygen tension, the hemoglobins in the cytoplasm of red blood cells(RBC) begin to join together and form polymers, there is increased viscosity of the cytosol, hence the red blood cells becomes more stiff. While passing through small vessels, unlike the normal cells that are flexible and can easily Squeeze through tiny capillaries without harm, these rigid cells get deformed structurally. They loose the normal biconcave nature of the RBC, assume a Sickle shape, hence the name. Although this Sickling can be reversible, repeated episodes can cause permanent cellular damage.

There is associated damage in cell membrane of the RBC with repeated episodes of reversible sickling which results in change in its permeability, favoring calcium influx and potassium and water efflux. The overall effect of this is cellular dehydration, increased viscosity and more Sickling. Hence hydration is crucial to these patients.

Sickle RBC under normal conditions have shorter life span(20 to 30 days) compared to normal RBC(90 to 120 days). This increases the concentration of free hemoglobin in their circulation(break down product of RBC).
Free hemoglobin has a strong affinity for, and mops up nitric oxide(NO); a substance produced by the endothelium of blood vessels that dilate and keeps it patent as well as suppressing expression of adhesion factors by the vascular endothelium.
Sickle Cell also have increased expression of adhesion molecules on their surface which attracts them to the lining of the blood vessel and even macrophages that will destroy them.
The overall effect is vasoconstriction and increased binding to blood vessels resulting in narrowing and blockage of blood vessels, and ischaemia of the affected organ supplied by such vessels.

source :Wikipediacommons.com

Types of crisis

Sickle Cell Disease patients are always having chronic mild pain, anemia and jaundice which characterize the illness. But these individuals occasionally have Acute and severe exacerbation of their symptoms, termed crisis. The severity, frequency and nature of the crisis is individual based, though might be modified by care.

The various crisis include:

• vaso-occlussive crisis - Typically manifest as pain, caused by ischaemia from blockage of blood vessels by Sickled cells. Any organ can be affected but typically affects long bones. This is the commonest type.
• Aplastic crisis - Here, the marrow erythropoetic function shuts down. It is believed to be caused by parvo virus B19 infection and it is self limiting.
• Acute sequestration crisis - A large pull of patient's blood is sequestered in the spleen, characterized by severe anemia, acute massive splenic enlargement and increased reticulocyte count.
• Hyper-heamolytic crisis - characterized by acute and severe breakdown of RBC. Infection and presence of other haemolytic conditions like thalasaemia and G6PD deficiency are predisposing factors.

complications

Individuals suffering from Sickle Cell anemia are not just faced with the acute symptoms (crisis), they also suffer chronic problems from complications of the illness. Such complications include delayed sexual maturation, priapism and sexual dysfunction, pulmonary hypertension, stroke, bone infarction and necrosis, growth abnormalities, gallstones, decreased immunity, autospleenectomy and recurrent infection, underweight. Pathophysiology of these complications will be left out to make this work readable.

Treatment

The summary of treatment includes analgesics, supplemental oxygen, hydration, antibiotics and other infections treatment, +/- transfusion, hydroxyurea, heamatinics, immunization, Stem cells transplant and counseling.

References

Medscape: Sickle Cell Anemia, Practical Essentials, Background and Genetics

PATHOPHYS. ORG: Sickle Cell Disease

Healthline: Sickle Cell Anemia, Types, Symptoms and Treatment

MedicineNet: Sickle Cell Anaemia, learn about SCD, symptoms and treatment