History

Fact Explanation
Yellowing of skin and eyes Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common disease caused by an enzyme deficiency in human. It is X- linked recessive genetic disorder. G6PD is an metabolic enzyme that is involved in pentose phosphate pathway (PPP). PPP is specially important in red blood cell metabolism as it is the only source of NADPH in them. NADPH is important for RBC in many ways. It protects red blood cells from the effects of potentially harmful reactive oxygen species by reduction of oxidized glutathione to reduced glutathione. Reduction of amounts of NADPH in RBCs in G6PD deficiency therefore causes red cell damage and hemolysis. [1,2,3,4,5] This excessive hemolysis results in increased amount of bilirubin in the blood. They get deposited in the skin and mucous membrane causing yellowish discoloration of it. This is marked in neonates who present with jaundice within 24 hours after birth. The marked presentation in neonates is thought to be as a result of the imbalance between the bilirubin production and conjugation combined with an inefficient bilirubin conjugation. Others are usually asymptomatic except for in severe flare ups when severe hemolysis may result in jaundice. [2,3,5,6]
Fatigue Chronic or flares of hemolysis results in anemia in some cases. Patient usually presents with anemic symptoms such as extremely tiredness and fatigue. Patient may further complains of weakness, shortness of breath, chest pain, lightheadedness or dizziness. [3,5,6,7]
Dark colored urine Excessive bilirubin products in the blood are excreted in the urine causing the urine to become a dark brown color. [1,2,3]
Past history of similar events Usually there are similar events in patients who are already diagnosed with G6PD deficiency. Past flare up are common findings in the history. [1,2,7,8]
Family history The most important finding in the family history is a positive history in maternal uncles. But sometimes carrier females may also be symptomatic. This is as a result of lyonization (random X chromosomal inactivation/homozygous form) in females. [1,2,8,9]
Triggering factors Hemolytic crises may occur in response to illness, specially infections, certain oxidant drugs such as antibiotics (eg - sulfamethoxazole), antimalarial (eg- primaquine), antipyretics (eg - acetanilide), certain foods, most notably broad beans, certain chemicals and diabetic ketoacidosis. Favism is defined as hemolytic response to the consumption of broad beans. All individual with favism show G6PD deficiency. However not all individuals with G6PD deficiency show favism. [1,2,3,5,8,10]
Complications Hemolysis and hyperniliribinemia pose an risk of particular long-term complications, such as gallstones and pulmonary hypertension. If a severe hemolytic event occurs and is not treated, kidney failure or death can occur. But this is very rare. Kernicterus is a dreaded complications of the neonates who have prolonged jaundice. [2,3,8,9]
At risk population Glucose-6-Phosphate Dehydrogenase Deficiency occurs worldwide with higher prevalence in regions of tropical Africa, middle East, tropical and subtropical Asia and some areas of the Mediterranean. [1,2,3,10]
References
  1. BEUTLER E. G6PD deficiency. Blood [online] 1994 Dec 1, 84(11):3613-36 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7949118
  2. CLARK M, ROOT RK. Glucose-6-phosphate dehydrogenase deficiency and infection: a study of hospitalized patients in Iran. Yale J Biol Med [online] 1979 Mar-Apr, 52(2):169-79 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/377826
  3. Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ [online] 1989, 67(6):601-611 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491315
  4. FRANK JE. Diagnosis and management of G6PD deficiency. Am Fam Physician [online] 2005 Oct 1, 72(7):1277-82 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16225031
  5. WILLIAMS O, GBADERO D, EDOWHORHU G, BREARLEY A, SLUSHER T, LUND TC. Glucose-6-phosphate dehydrogenase deficiency in Nigerian children. PLoS One [online] 2013, 8(7):e68800 [viewed 30 August 2014] Available from: doi:10.1371/journal.pone.0068800
  6. GUPTE SC, PATEL PU, RANAT JM. G6PD deficiency in Vataliya Prajapati community settled in Surat. Indian J Med Sci [online] 2005 Feb, 59(2):51-6 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15738610
  7. STANTON RC. Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life [online] 2012 May, 64(5):362-9 [viewed 30 August 2014] Available from: doi:10.1002/iub.1017
  8. CHHABRA A, RAJ D, CHOUDHARY PN, GROVER A. Interesting case of G6PD deficiency anemia with severe hemolysis. Asian J Transfus Sci [online] 2013 Jul, 7(2):147-8 [viewed 30 August 2014] Available from: doi:10.4103/0973-6247.115574
  9. MOIZ B, NASIR A, KHAN SA, KHERANI SA, QADIR M. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr [online] 2012 Aug 20:126 [viewed 30 August 2014] Available from: doi:10.1186/1471-2431-12-126
  10. LAI HC, LAI MP, LEUNG KS. Glucose-6-phosphate dehydrogenase deficiency in Chinese. J Clin Pathol [online] 1968 Jan, 21(1):44-7 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/5697334

Examination

Fact Explanation
Pallor Severe hemolysis can make the patient anemic. This shows as pallor of the conjunctiva. [1,2,3]
Jaundice Severe hemolysis results in hyperbilirubinemia that gets deposits in the skin and mucous membranes causing yellowish discolorations. [2,3,4]
Rapid shallow breathing Patient with severe anemia may present with difficulty in breathing. [1,2,4]
Tachycardia Occurs due to severe anemia during flare ups. [3,5]
Abdominal tenderness Right upper quadrant tenderness may appear due to the mild hepatomegaly secondary to hyperbilirubinemia and cholelithiasis. [1,3,5]
Splenomegaly Excessive hemolysis results in enlargement of the spleen. [1,2,3]
References
  1. Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ [online] 1989, 67(6):601-611 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491315
  2. CLARK M, ROOT RK. Glucose-6-phosphate dehydrogenase deficiency and infection: a study of hospitalized patients in Iran. Yale J Biol Med [online] 1979 Mar-Apr, 52(2):169-79 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/377826
  3. LAI HC, LAI MP, LEUNG KS. Glucose-6-phosphate dehydrogenase deficiency in Chinese. J Clin Pathol [online] 1968 Jan, 21(1):44-7 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/5697334
  4. FRANK JE. Diagnosis and management of G6PD deficiency. Am Fam Physician [online] 2005 Oct 1, 72(7):1277-82 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16225031
  5. BEUTLER E. G6PD deficiency. Blood [online] 1994 Dec 1, 84(11):3613-36 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7949118

Differential Diagnoses

Fact Explanation
Hemolytic Anemia Hemolytic anemia is a form of anemia due to hemolysis. This RBC breakdown can occur intravascularly or extravascularly. Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension. [1]
Sickle Cell Anemia It is a special hemoglobinopathy with abnormal forms of hemoglobin called HbS. It is an inherited blood disorder, an autosomal recessive disease. Sickle cell disease (SCD) usually seen in early childhood. Complaints may include acute and chronic pain in any body part, bone pain, anemia, aplastic crisis, infections, growth retardation, delayed sexual maturation and Hand-foot syndrome. [2]
Hemolytic Disease of Newborn (HDN) Hemolytic Disease of Newborn is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta. HDN ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. [3]
Hereditary Spherocytosis Hereditary Spherocytosis is a non immune-mediated hemolytic anemia characterized by the production of red blood cells that are sphere-shaped. The disorder is inherited in an autosomal dominant manner and exhibits incomplete penetrance in its expression. The signs and symptoms include intermittent jaundice, with mild pallor and splenomegaly. However, these are highly variable. [4]
References
  1. ALAARG A, SCHIFFELERS RM, VAN SOLINGE WW, VAN WIJK R. Red blood cell vesiculation in hereditary hemolytic anemia. Front Physiol [online] 2013 Dec 13:365 [viewed 30 August 2014] Available from: doi:10.3389/fphys.2013.00365
  2. CôBO VDE A, CHAPADEIRO CA, RIBEIRO JB, MORAES-SOUZA H, MARTINS PR. Sexuality and sickle cell anemia. Rev Bras Hematol Hemoter [online] 2013, 35(2):89-93 [viewed 30 August 2014] Available from: doi:10.5581/1516-8484.20130027
  3. DUTTA S. Intravenous immunoglobulin in Rh hemolytic disease of newborn. Indian Pediatr [online] 2009 Jan, 46(1):80-1; author reply 81 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19179727
  4. DAS A, BANSAL D, DAS R, TREHAN A, MARWAHA RK. Hereditary spherocytosis in children: profile and post-splenectomy outcome. Indian Pediatr [online] 2014 Feb, 51(2):139-41 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24632695

Investigations - for Diagnosis

Fact Explanation
Full blood count Full blood count may reveal anemia with increased reticulocyte count which indicates increased bone marrow response to anemia. [1,2,3]
Blood picture Reduction of production of reduced glutathione results in denaturation of protein forming insoluble masses (Heinz bodies). Heinz bodies attach to red cell membranes. Heinz bodies are visualized by using supravital stain. [1,2,3]
Lactate dehydrogenase (LDH) level Rise in serum LDH indicates increased RBC destruction. [2,4]
Serum bilirubin level increased indirect bilirubin level is high due to hemolysis. [3,5]
Liver profile Liver enzymes within normal range is helpful in excluding other causes of jaundice. [1,2,3]
Abdominal ultrasound This may be useful in severe chronic hemolysis, for assessing splenomegaly and gallstones. [3,4,5]
Beutler test The Beutler test, also known as the fluorescent spot test, is a screening test used to identify enzyme defects. This should be dine during the remission as it can be falsely negative in patients who are actively hemolysing. It is a semi-quantitative test that detect the conversion of NADP to NADPH. If the blood spot fails to fluoresce under UV light, the test is considered positive. In patients with acute hemolysis, testing for G6PD deficiency may be falsely negative because older erythrocytes with a higher enzyme deficiency have been hemolyzed. Young erythrocytes and reticulocytes have normal or near-normal enzyme activity. Female heterozygotes may be hard to diagnose because of X-chromosome mosaicism leading to a partial deficiency that will not be detected reliably with screening tests. [1,2,3,4,5]
cytofluorometric assay This novel test is also performed during remission and gives the definitive diagnosis of G6PD deficiency. It quantitatively analysis the G6PD activity in cellular level and gives the diagnosis. [1,3,5,6]
References
  1. BEUTLER E. G6PD deficiency. Blood [online] 1994 Dec 1, 84(11):3613-36 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7949118
  2. Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ [online] 1989, 67(6):601-611 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491315
  3. CLARK M, ROOT RK. Glucose-6-phosphate dehydrogenase deficiency and infection: a study of hospitalized patients in Iran. Yale J Biol Med [online] 1979 Mar-Apr, 52(2):169-79 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/377826
  4. FRANK JE. Diagnosis and management of G6PD deficiency. Am Fam Physician [online] 2005 Oct 1, 72(7):1277-82 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16225031
  5. LAI HC, LAI MP, LEUNG KS. Glucose-6-phosphate dehydrogenase deficiency in Chinese. J Clin Pathol [online] 1968 Jan, 21(1):44-7 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/5697334
  6. SHAH SS, DIAKITE SA, TRAORE K, DIAKITE M, KWIATKOWSKI DP, ROCKETT KA, WELLEMS TE, FAIRHURST RM. A novel cytofluorometric assay for the detection and quantification of glucose-6-phosphate dehydrogenase deficiency Sci Rep [online] :299 [viewed 30 August 2014] Available from: doi:10.1038/srep00299

Investigations - Screening/Staging

Fact Explanation
Quantitative analysis of G6PD activity This should be done for the family members of the patients, specially males who might have the disease. All patients should be screened for G6PD deficiency before starting triggering drugs such as dapsone in leprosy, premaquine in malaria and sulfa drugs in other infections. [1,2]
Brewer's test Even though quantitative G6PD enzyme assay is indicated for diagnosis and screening purposes of G6PD deficiency, Methaemoglobin reduction test (Brewer’s test) is used in some settings. [2,3,4]
References
  1. GUPTE SC, PATEL PU, RANAT JM. G6PD deficiency in Vataliya Prajapati community settled in Surat. Indian J Med Sci [online] 2005 Feb, 59(2):51-6 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15738610
  2. SHAH SS, DIAKITE SA, TRAORE K, DIAKITE M, KWIATKOWSKI DP, ROCKETT KA, WELLEMS TE, FAIRHURST RM. A novel cytofluorometric assay for the detection and quantification of glucose-6-phosphate dehydrogenase deficiency Sci Rep [online] :299 [viewed 30 August 2014] Available from: doi:10.1038/srep00299
  3. WILLIAMS O, GBADERO D, EDOWHORHU G, BREARLEY A, SLUSHER T, LUND TC. Glucose-6-phosphate dehydrogenase deficiency in Nigerian children. PLoS One [online] 2013, 8(7):e68800 [viewed 30 August 2014] Available from: doi:10.1371/journal.pone.0068800
  4. MOIZ B, NASIR A, KHAN SA, KHERANI SA, QADIR M. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr [online] 2012 Aug 20:126 [viewed 30 August 2014] Available from: doi:10.1186/1471-2431-12-126

Management - General Measures

Fact Explanation
Phototherapy Neonates with prolonged jaundice due to G6PD deficiency should undergo single or double phototherapy. And they should be frequently assessed for the serum bilirubin level as most of them may progress in to severe form of serum hyperbilirubinemia that requires exchange transfusion. Meticulous management should be carried out to prevent development of kernicterus. [1,2,3,4]
Transfusion Transfusions are rarely indicated in chronic disease. In the acute phase of hemolysis, blood transfusions might be necessary. In cases ofhemolytic anemia or severe neonatal jaundice, exchange transfusion may be necessary. [2,3,4,5]
Folic acid supplements Chronic hemolytic anemia due to G6PD deficiency may be benefited by daily folic acid supplements as does in any disorder featuring a high red cell turnover. [3,4,5]
Treatment for infection Infections play a key role as a trigger in development of G6PD flare ups. Therefore proper treatment for the infections with relevant antibiotic etc. is essential in prevention and control of the disease. [2,3,5,6]
Splenectomy Some patients may benefit from splenectomy as this is an important site of red cell destruction. [2,6,7]
Patient education and prevention Most of the patients with G6PD deficiency do not need treatment. They must be educated regarding the disease and how to prevent flare ups. Avoidance of drugs and chemical exposures that can cause oxidant stress is very important measure in prevention. They should also avoid broad beans such as fava beans. Patient should maintain good hygiene and prevent over crowded places in order to prevent infections. Vaccination against some common pathogens such as hepatitis A and hepatitis B may prevent infection-induced attacks. [1,2,3,5,7]
Avoidance of precipitating drugs The drugs mentioned below caries a definite risk of hemolysis. Antibiotic classes such as Nitrofurantoin, Quinolones (Ciprofloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin), Sulfonamides (Co-trimoxazole, Sulfacetamide, Sulfadiazine, Sulfadimidine, Sulfamethoxazole), Antimalarials (Mepacrine, Pamaquine, Pentaquine, Primaquine) Antimycobacterials (Dapsone, Para-aminosalicylic acid) Antineoplastic Adjuncts (Doxorubicin, Rasburicase), Genitourinary Analgesics ( Phenazopyridine), Anthelmintics (Niridazole, Stibophen) [1,2,3,5]
References
  1. STANTON RC. Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life [online] 2012 May, 64(5):362-9 [viewed 30 August 2014] Available from: doi:10.1002/iub.1017
  2. GUPTE SC, PATEL PU, RANAT JM. G6PD deficiency in Vataliya Prajapati community settled in Surat. Indian J Med Sci [online] 2005 Feb, 59(2):51-6 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15738610
  3. BEUTLER E. G6PD deficiency. Blood [online] 1994 Dec 1, 84(11):3613-36 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7949118
  4. FRANK JE. Diagnosis and management of G6PD deficiency. Am Fam Physician [online] 2005 Oct 1, 72(7):1277-82 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16225031
  5. LAI HC, LAI MP, LEUNG KS. Glucose-6-phosphate dehydrogenase deficiency in Chinese. J Clin Pathol [online] 1968 Jan, 21(1):44-7 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/5697334
  6. Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ [online] 1989, 67(6):601-611 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491315
  7. CLARK M, ROOT RK. Glucose-6-phosphate dehydrogenase deficiency and infection: a study of hospitalized patients in Iran. Yale J Biol Med [online] 1979 Mar-Apr, 52(2):169-79 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/377826