What is G6PD Deficiency?

Biochemical aspects of G-6-PD deficiency?

Glucose-6-Phosphate dehydrogenase is the first enzyme required by the Hexose Monophosphate Shunt (also called the pentose phosphate pathway). Details about the pathway are not important, what is important is the fact that a very important by-product is produced in the first 2 steps of this pathway called NADPH, the first of which is catalyzed by the enzyme G-6-PD as seen in the following image.

(For the more interested reader, the pathway operates in steroid-predominant sites of the body, notably the liver, adrenal cortex, mammary glands, and also in erythrocytes. Why this is so, we shall see in a few moments).

Role of NADPH in the body

NADPH is a very special molecule. It acts as a reductant in the body. What this means is that it is used in all those reactions in the body where substrates are to be reduced. Like what, you might ask? Well, here’s a list of a few of them

• Reductive biosynthetic reactions in the body. The best example being fatty acid synthesis in the body (now you realize the utility of the hmp shunt in the steroid predominant sites of the body!!)
• Detoxification by the cytochrome p450 system. This branch is called xenobiotics
• Respiratory burst reactions, required for defense mechanisms of the body.
• Oxidative defense: the branch which we are particularly interested in this article and will see in greater detail.

Oxidative defense

This is the most crucial component of the entire article. You understand this and every boring detail that you had to endure till now will get linked.

As you can see, NADPH is required to reduce harmful molecules such as H2O2 into non-hazardous substances (water).

There are many events which in technical terms are called “triggers” that increase the production of these harmful oxidizing molecules. A few of them are:

• Infections
• Drugs:
• a) Primaquine- Antimalarial
• b) Sulfa Drugs- Anti-microbial, Diuretics, and more.

3) Fava Beans (the condition is specifically called favism)

4) Naphthalene mothballs

Under normal circumstances, this surge in oxidative stress is countered by the glutathione reductase system shown above.

However, what if the enzyme G-6-PD is deficient? NADPH is not produced. When this happens, oxidative stress accumulates in the red blood cells (NOTE: RBCs are devoid of the nucleus. Therefore, they are unable to replenish the already malfunctioning or deficient enzyme. Hence, they are most susceptible to this illness.)

Red blood cells burst and a picture of hemolytic anemia is seen. Viola, this is a G-6-PD deficiency disease.

The actual disorder

G-6-PD deficiency is an X-linked recessive disorder. What this means in principle is that men are affected much more than females. It is predominant in the Mediterranean, Asian, African, and Middle East regions. Also, it is the most common genetically inherited enzyme-linked deficiency disorder.

So if you’re a teenage guy with a history of recurrent attacks of anemia, fatigue, jaundice, and many other symptoms which we shall discuss shortly which are precipitated by the list of triggers mentioned earlier and live in India, then yes, you may be suffering from this disease.

Symptoms of G-6-PD deficiency

• Neonatal jaundice leading to brain involvement (kernicterus), arguably the most serious complication of the disorder.
• Dark or muddy urine (due to hemoglobin in the urine)
• Acute kidney failure (also in severe cases)
• Breathlessness
• Palpitations
• Increased heart rate and breathing rate.

Note that many times; patients may remain asymptomatic throughout their lives because of 2 main reasons

• The enzyme is not severely deficient or defective and;
• The patient is never exposed to a significant trigger

Moreover, the above symptoms are only seen during a crisis or the phase of “triggers”, effectively meaning that the patient is normal during intermittent periods of the disease and does not normally suffer from the effects of chronic hemolysis, such as an enlarged spleen or the like.

Diagnosis of G-6-PD deficiency:

The diagnosis is made in a 2 step manner, the preliminary and the confirmatory diagnosis.

The preliminary diagnosis is essentially a complete blood panel testing. A typical report would be suggestive in the manner shown below:

• Complete blood count– Anemia, reticulocytosis, Heinz bodies (on methylene blue staining) and bite cells are typical. (The last two are formed due to oxidative damage to hemoglobin and its subsequent clumping just under the membrane of the RBC)
• Lactate Dehydrogenase- Increased in hemolytic anemia.
• Serum haptoglobin- decreased in hemolytic anemia
• Liver enzymes( SGPT, SGOT, GGT)- to eliminate jaundice from other causes
• Coomb’s test- Negative because the condition is not autoimmune in origin.

Once preliminary tests are suspicious of the disorder, more targeted tests such as sodium nitrite test, osmotic fragility test, high-performance liquid chromatography, and the gold standard: spectrophotometric analysis are made and the condition is diagnosed.

Treatment

No specific treatment exists. Once diagnosed, care is taken to avoid any triggers. However, during a hemolytic crisis, efforts are directed to remove the trigger itself. The body recovers by itself. A blood transfusion may at times become necessary.

A curious episode from the past

It is very tough to find fun episodes in the monotony that is medicine. However, fortune favors us in this regard for this particular topic.

Favism was known since ancient times. The priests of the Greco-Roman empire were forbidden to even mention beans, let alone eat them.

Moreover, Pythagoras had imposed a strict rule for all of his followers to renounce beans, probably because they resembled male genitalia. However, who knows, whether he secretly knew about the disorder!!