Glucose -6-Phosphate Dehydrogenase Deficiency is an inherited genetic enzyme disorder. It was first discovered in 1956 as the cause of hemolytic anemia that developed in some individuals after the administration of the antimalarial drug primaquine. It was then recognized as also being the cause of the disorder called Favism, known for centuries as the reaction some people have to eat fava beans. The common factor between the antimalarial drugs and fava beans is their propensity to cause oxidative stress.
The genetic variants that cause G6PD deficiency to affect the functioning of the enzyme called glucose-6-phosphate dehydrogenase. The majority of carriers of the deficiency have no obvious clinical symptoms in the absence of “triggers”(such as primaquine or fava beans) and are often unaware that they have this deficiency. G6PD deficiency has, however, the potential to cause attacks of acute hemolytic anemia, severe neonatal jaundice that can lead to kernicterus, and, more rarely, chronic anemia called Chronic Non-Spherocytic Hemolytic Anemia (CNSHA).
What is Glucose-6-Phosphate Dehydrogenase
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme found in every cell of the body. It is part of the chemical mechanism by which the body is able to process glucose. Although we are most familiar with the concept of using glucose as a fuel to provide energy, the function of G6PD is different; it is needed to produce a substance called NADPH which is very important both for cells’ ability to make other compounds and also to protect against oxidative stress. Although every cell contains G6PD, it plays a special role in the red blood cell (RBC). In the RBC, the only source of NADPH is the pentose phosphate pathway, the first step of which is controlled by G6PD. At the same time, since the main function of the RBC is to transport oxygen from the lungs to the rest of the body, it is uniquely susceptible to oxidative stress. It is not surprising, therefore, that the most common clinical manifestation of an inherited deficiency in G6PD is the accelerated breakdown of the RBCs leading to something called Acute Hemolytic Anemia. Hemolytic anemia in adults is usually not life-threatening in developed countries but newborn infants with G6PD deficiency are also at risk for a severe form of jaundice that can lead to irreversible brain damage.
Is the Deficiency Common?
G6PD deficiency is actually the most common inherited enzyme deficiency in the world. A statistical analysis of 280 studies in the medical literature derived a number equivalent to about 5% of the world’s population as being affected. In a way, however, this number is not very useful because G6PD deficiency is not evenly distributed around the world. This seems to be because, countering the negative health effects of G6PD deficiency, the deficiency gives some protection against malaria. As a result, in regions of the world where malaria has been endemic since prehistoric times, there has been positive selection for G6PD. Thus even within the same country, the prevalence of G6PD deficiency can vary greatly between different ethnic or geographical populations, from near zero to perhaps as high as 70%.
Malaria was not present in the Americas before the arrival of the Europeans and Native American populations do not have a significant incidence of G6PD deficiency. Since then, of course, there has been extensive migration to the Americas and significant numbers of the present-day population of the United States originate from or have ancestors who originate from, the areas of the world where the frequency of G6PD deficiency is high. These include sub-Saharan Africa, the shores of the Mediterranean, and Southeast Asia. Thus, the overall frequency of G6PD deficiency in the USA is probably between 4 and 7% but in African-American males, the prevalence is about 12%.
Approximately 130 – 160 mutations of the G6PD gene have been identified, although it seems that not all of the individually named variants are in fact unique. Four or five distinct variants seem to account for the majority of people affected, with distinct geographical ranges associated with them. These mutations differ in the kind and severity of impairment they cause in G6PD activity; most seem to primarily affect the stability of the enzyme — which causes the red cell to age more quickly in the circulation — as well as the actual level of enzymatic activity. A total absence of G6PD activity appears to be incompatible with life.
The gene for G6PD is on the X chromosome, which has important consequences. Since males have only one X chromosome and thus only one copy of the gene (hemizygous), they will certainly be symptomatic if that copy contains a deleterious mutation. Females can be normal, have two affected genes (homozygous) or one normal, and one affected gene (heterozygous). Although heterozygous females have two copies of the gene, in any cell only one copy is active. Thus, a heterozygous female is a genetic mosaic and a proportion of her red cells will have the mutated form of G6PD. It is explained in greater detail in the “Did I inherit G6PD deficiency?” section.
Cases of G6PD deficiency are assigned to one of 5 classes based on a combination of clinical manifestations and actual measured levels of G6PD activity. Classes IV and V have normal or greater than normal activity and are not associated with any clinical symptoms.
- Class I is a severe form of G6PD deficiency. The residual enzyme activity is less than 20% of normal and is associated with Chronic Non-Spherocytic Hemolytic Anemia. The mutations leading to Class I G6PD deficiency are always sporadic mutations rather than one of the known inherited variants.
- Class II G6PD deficiency is characterized by very low measured enzyme activity (<10% normal) and is associated with episodes of Acute Hemolytic Anemia. The common Mediterranean and Asian variants are included in Class II.
- Class III G6PD deficiency is characterized by enzyme levels of 10-60% of normal and includes the A- variant common in Africa and in the US among African-Americans. It too is associated with hemolytic anemia but the RBCs seem to be more resistant to oxidative stress.
All three classes are associated with a risk of neonatal jaundice that is more severe than the so-called physiologic jaundice.
Chronic Non-Spherocytic Hemolytic Anemia is a complicated and very variable syndrome. It is almost always found in males without any family history of G6PD deficiency. There is a wide range of severity, apparently because many different mutations affecting the G6PD molecule have differing effects on the activity and stability of the enzyme. In many cases, there is a history of neonatal jaundice and ongoing anemia as well as enlarged spleen (splenomegaly) and gallstones. To make things worse, the triggers that cause Acute Hemolytic Anemia can also affect these individuals exacerbating their symptoms and causing attacks of acute anemia that may require transfusion.
Acute Hemolytic Anemia is usually characterized by malaise, fatigue or weakness, abdominal or back pain and after a day or so, jaundice and dark urine appear and anemia develops.
An attack of Acute Hemolytic Anemia is usually triggered by one of three stimuli that have led to different names for G6PD deficiency. Primaquine sensitivity and Favism are both terms that have been used to describe the occurrence of hemolytic anemia in patients whom we now know to have G6PD deficiency. Although the antimalarial Primaquine was the first drug associated with the development of hemolysis in G6PD deficient subjects, a number of drugs are now known to be risk factors as well as some chemicals, most notably naphthalene used in mothballs. Favism appears to have been recognized since ancient times; it refers to the illness seen in G6PD deficient individuals after eating Fava Beans (although not every G6PD deficient person will react every time they consume the beans). Despite these well-known observations, there is reason to believe that the most common precipitating factor of hemolytic anemia is in fact infection and both viral and bacterial infections have been implicated.
Neonatal Jaundice is detected with many newborn babies. More than 80% of newborns develop a mild jaundice in their first week or two. In most cases, this resolves without harm and the total serum bilirubin does not rise to harmful levels. In some cases, however, newborns develop more severe forms of jaundice as a consequence of severe hyperbilirubinemia (a high concentration of bilirubin in the blood). Untreated or insufficiently treated infants are at risk of a condition called kernicterus, which occurs when the serum bilirubin crosses the blood-brain barrier and affects the developing brain, leading to lifelong disability.
There are multiple disorders known to cause or contribute to neonatal jaundice but the association of hyperbilirubinemia with G6PD deficiency is clear: of the infants who develop the syndrome or go on to develop kernicterus, there is a disproportionate number with G6PD deficiency, several times the percentage in the general population and rising in some studies to 20 or 30% of readmissions. Nevertheless, it should be emphasized that not all infants with G6PD deficiency develop severe jaundice (the incidence is about 30%) and not all, or even the majority, of cases of neonatal hyperbilirubinemia are the result of G6PD deficiency.
The topic of neonatal jaundice is an extremely important one since though rare; the consequences can be so devastating. Thus it is explained in greater detail in the Jaundice & Kernicterus section.
KNOW the signs of hemolytic anemia!
A hemolytic episode in those with G6PD Deficiency may present itself with any of the following non-specific symptoms:
In the Adult
- Yellowing of Skin and Eyes (Jaundice)
- Darker than Usual Urine
- Fever, Fatigue
- Rapid Heart Rate – Shortness of Breath
- Confusion, Lightheadedness, or Dizziness
- Back or Abdominal Pain
- Heart Murmur
- Enlarged Spleen or Liver
- Blue/Grey Fingernail Color, Pale Skin
In the Newborn
- Yellowing of Skin and Eyes (Jaundice). Severe if Below the Abdomen. Jaundice Toxins May Cause Brain Damage/Death.
- Darker than usual urine
- Fever, Lethargy – Very Sleepy, Loss of Appetite
- Rapid Heart Rate – Shortness of Breath
- Arching Back Movements
- Seizures or Convulsions
- Change of Normal Muscle Tone – Loose or Rigid
- Enlarged Spleen or Liver
- High-Pitched Cries
Brody’s Battle happened in the first ten days of his life and nearly ended it, leaving him with terrible brain damage caused by a condition called Kernicterus. Our foundation was started to spare other newborns such life-threatening events by raising awareness of how undiagnosed G6PD deficiency can cause Jaundice. A Kernicterus event can occur if neonatal Jaundice is not properly managed.
This story does not have to happen to another family...