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Home , Hemolytic anemia, Methemoglobinemia, Phenazopyridine

Disease/Medical Condition

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY Date of Publication: October 14, 2020

(also known as “G6PD deficiency” and “erythrocyte glucose-6-phosphate dehydrogenase deficiency”; includes “favism”)

Note: For more detail on the general manifestations of , and those of in particular, please refer to the Anemia Fact Sheet.

Is the initiation of non-invasive dental hygiene procedures* contra-indicated? No

 Is medical consult advised? ...... Yes, if G6PD deficiency is newly suspected.1  Yes, if a patient/client with known G6PD deficiency has been recently exposed to a trigger that could potentially trigger acute hemolytic anemia (AHA).  Yes, if an episode of acute hemolytic anemia is suspected. This should be considered a medical emergency with immediate referral to an appropriate facility for management.  Yes, if the patient/client has chronic hemolytic anemia, in which case liaison with the patient/client’s hematologist (blood specialist) or experienced internist, paediatrician, or family physician is advisable regarding the severity and management of the patient/client’s disorder before undertaking dental hygiene treatment for the first time.

Is the initiation of invasive dental hygiene procedures contra-indicated?** Yes. This metabolic condition entails blood disorders (hemolytic anemia2 and ) that may affect appropriateness or safety, and scaling and root planing, including curetting surrounding tissue, are contraindicated until the patient/client is medically cleared (as per Ontario Regulation 510/07 pursuant to the Dental Hygiene Act, 1991). Another potential contraindication is hypersplenism, which can cause (i.e., low platelet count, and hence increased risk of bleeding) and/or neutropenia (i.e., low neutrophil count, and hence compromised immunity and increased risk of infection).

 Is medical consult advised?...... See above.  Is medical clearance required? ...... Yes, if G6PD deficiency and/or hemolytic anemia have been diagnosed or are suspected. (Note: Most patients/clients with G6PD deficiency, in the absence of a trigger, are merely at elevated risk of hemolytic anemia rather than actually having it or exhibiting clinically relevant signs/symptoms. – Yes, if significant thrombocytopenia exists or is suspected. – Yes, if significant neutropenia exists or is suspected .  Is prophylaxis required? ...... No, in most cases.  Potentially, if significant neutropenia exists.3  Is postponing treatment advised? ...... Yes, pending medical clearance (and potential preventive measures or treatment for hemolytic anemia, as indicated). – Yes, if patient/client has recently been exposed to a trigger for hemolytic anemia, including certain drugs, infections (including uncontrolled oral infections), and metabolic conditions, as well as fava beans.  Yes, if an episode of acute hemolytic anemia is suspected.  Yes, if chronic hemolytic anemia is suspected to be severe and the patient/client has attendant signs/symptoms. Patients/ clients who are short of breath and in whom (Hb) levels are < 110 g/L [also expressed as 11.0 g/dL], have an abnormal heart rate, or have an oxygen saturation < 91% (as determined by pulse oximetry) are considered medically unstable, and routine dental/dental hygiene treatment should be deferred until health status improves.

1 Diagnosis is confirmed by measuring levels of the G6PD . 2 While most patients/clients with G6PD deficiency do not exhibit significant of red blood cells in the absence of a trigger, a minority experience ongoing, chronic hemolytic anemia even in the absence of an oxidative trigger. 3 Because certain can trigger acute hemolytic anemia in patients/clients with G6PD deficiency, careful selection of antibiotic prophylaxis is warranted.

cont’d on next page... Disease/Medical Condition GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

(also known as “G6PD deficiency” and “erythrocyte glucose-6-phosphate dehydrogenase deficiency”; includes “favism”)

Oral management implications

 The dental hygienist should be aware that certain (including some antibiotics and ) can precipitate an acute hemolytic anemia episode in some patients/clients with G6PD deficiency.4 These include sulfa drugs (e.g., sulfacetamide, sulfadiazine, sulfamethoxazole, sulfanilamide, sulfapyridine, and ); certain other antibiotics (such as quinolones [e.g., ciprofloxacin, moxifloxacin, nalidixic acid, and norfloxacin], some anti-tuberculosis drugs [e.g., isoniazid and streptomycin], as well as , cotrimoxazole, and furazolidone)5; certain analgesics (including acetylsalicylic acid [i.e., ASA, particularly in high doses] and [a urinary ]); certain antimalarial drugs (e.g., chloroquine, pentaquine, , and ); certain anti-arrhythmic agents (e.g., quinidine); certain chemotherapy drugs (e.g., doxorubicin); certain antihelminthic6 agents (e.g., niridazole); certain chelating agents (e.g., dimercaprol, which is used to treat acute poisoning by arsenic, mercury, gold, and lead); rasburicase (used to lower uric acid levels, particularly in persons undergoing treatment for leukemia, lymphoma, and certain tumours); certain anti-diabetes agents (particularly the first-generation sulfonylurea chlorpropamide); (used to treat methemoglobinemia, and also a component of some urinary tract products); toluidine blue (a dye which has been used in vivo to identify dysplasia and carcinoma of the oral cavity); and ascorbic acid ( C). In addition, camphor (a wood oil commonly used in creams, lotions, and ointments) can be a trigger. The degree of susceptibility varies between persons, with persons with lower degrees of residual G6PD activity being at higher risk and having more limitations with respect to “probably safe” drugs.  Acetaminophen use within recommended therapeutic dosages is generally considered safe for most persons with G6PD deficiency (i.e., those with Class II deficiency or higher, without nonspherocytic hemolytic anemia).7 Similarly, many non- steroidal anti-inflammatory drugs within recommended dosages are probably safe for most persons with G6PD deficiency.8  Local anaesthetic agents (e.g., , , and ), topical , and silver have been reported to induce methemoglobinemia9 in G6PD deficient persons. However, as with analgesics and antibiotics commonly used in the dental setting, there is considerable debate regarding which anaesthetic drugs should be generally or selectively avoided. While inhalation sedation is usually safe, general anaesthesia should generally be given in a hospital environment.  The dental hygienist should be aware that infection — including uncontrolled oral infection — is a trigger for acute hemolytic anemia in patients/clients with G6PD deficiency.10 Dental infections should be avoided, and if they occur, be managed quickly and effectively.

4 Medical references are inconsistent regarding “unsafe” versus “probably safe” drugs in persons with G6PD deficiency. This is a general, non- exhaustive list and may not apply to all G6PD-deficient individuals. According to some authorities, some medications previously thought to be unsafe are probably safe in usual therapeutic doses. Individual characteristics (e.g., degree of G6PD deficiency, dose, presence of infection, etc.) will influence actual safety or injury. 5 Penicillin and amoxicillin have also been rarely implicated in hemolysis in persons with G6PD-deficiency. 6 anti-helminthic agent = anti-parasitic drug for worms 7 The World Health Organization’s classes of G6PD deficiency are: I (congenital nonspherocytic hemolytic anemia and chronic hemolysis without exposure to oxidative stressors; rare, and tends to be in white males of Northern European background); II (severe deficiency, with 1-10% residual activity and intermittent -induced hemolysis; prototype is G6PD-Mediterranean); III (mild deficiency, with 10-60% residual activity and intermittent oxidative stress-induced hemolysis; most common type); IV (60-150% -- normal activity, with no clinical sequelae); and V (> 150% -- increased activity, with no clinical sequelae). 8 Case reports of NSAID-linked hemolytic anemia in G6PD-deficient persons exist in the medical literature. 9 Methemoglobinemia (congenital or acquired) occurs when red blood cells (RBCs) contain at levels higher than 1%. Methemoglobin results from the presence of iron in RBCs in the ferric rather than the usual ferrous form. If the activity of G6PD is low, ferrous to ferric conversion occurs when RBCs are exposed to oxidizing triggers, resulting in methemoglobinemia (oxidized hemoglobin molecules), which impedes availability of oxygen to tissues. 10 According to some authorities, infection is probably the most common trigger inciting hemolysis in children who are G6PD deficient. Microbial triggers include E. coli, Rickettsia, cytomegalovirus, hepatitis A, hepatitis B, typhoid, beta-hemolytic streptococci, pneumonia, and those related to deep carious lesions and maxillofacial infections.

cont’d on next page... 2 Disease/Medical Condition GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

(also known as “G6PD deficiency” and “erythrocyte glucose-6-phosphate dehydrogenase deficiency”; includes “favism”)

Oral manifestations

 In the absence of hemolytic anemia, methemoglobinemia, and hypersplenism, G6PD deficiency typically exhibits no overt or distinctive facial or bucodental signs.  (yellowing) and/or of oral mucous membranes and/or perioral may be present.  Gingival swelling and bleeding may occur, as may palatal petechiae and ecchymoses (i.e., discolouration from bruising).  Progressive spacing between teeth (especially anterior maxillary and mandibular) can occur if gingival swelling is chronic or chronically recurrent.

Related

 G6PD deficiency is a genetic metabolic abnormality involving the glucose-6-phosphate dehydrogenase enzyme.11 When the level of this enzyme is too low, hemolysis of red blood cells occurs. When the body cannot compensate for accelerated loss, anemia occurs. However, in most affected persons, deficiency of G6PD in and of itself is insufficient to cause hemolysis — a trigger is required.  G6PD deficiency may occur by a new (sporadic) genetic mutation, or be inherited in an X-chromosome-linked manner.12 There is a range of variants, from near normal to severe deficiency to chronic hemolytic anemia even in the absence of triggers.)  G6PD deficiency is one of the most common enzyme deficiencies, affecting between 400 million and 500 million persons globally. Many authorities assert that it affects males more than females, although this is disputed by others. While individuals of all races and ethnic backgrounds are affected, persons of black African, Middle Eastern (particularly Kurdish and Sephardic Jewish), certain Mediterranean (e.g., Sardinian), certain Asian (e.g., southern Chinese and Southeast Asian), and central and southern Pacific island backgrounds have the highest prevalence rates. Although overall world-wide prevalence is high, the vast majority of persons remain clinically asymptomatic throughout their lives, and therefore overt disease is rare. The severe form of the disorder occurs most often in persons of Mediterranean or Asian background.  G6PD deficiency — in the absence of hemolytic anemia, methemoglobinemia, and hypersplenism — typically exhibits no overt or distinctive physical signs/symptoms.  Triggers that cause hemolytic anemia in G6PD-deficient persons include certain drugs, certain infectious diseases, certain metabolic conditions (e.g., diabetic ketoacidosis, and eating fava beans (i.e., broad beans). In addition, — found in mothballs — is a trigger. Some persons with G6PD deficiency should also avoid red wine, blueberries, all beans, soya products, and tonic water. In the absence of triggering factors, most persons are asymptomatic, and many persons proceed throughout life without any knowledge or noticeable signs/symptoms of the disorder.  Clinical manifestations of G6PD deficiency, which involves intravascular hemolysis, include acute and chronic hemolytic anemia with methemoglobinemia, neonatal bilirubinemia, and .  Onset of signs/symptoms of acute hemolytic anemia is typically within 2 to 3 days after exposure to the trigger, and even less with fava beans.

11 G6PD enables red blood cells to covert carbohydrates into energy. Blockade of this enzymatic pathway in persons with G6PD deficiency results in production of methemoglobin and denatured hemoglobin, which leads to cell membrane alteration and hemolysis. 12 Because a female has two X chromosomes, certain disease traits on the affected X chromosome may be “masked” by a normal gene on the other X chromosome. By contrast, a male has only one X chromosome, and if he inherits an X chromosome that contains a disease gene (such as G6PD deficiency) he will develop (or have a greater likelihood of manifesting) the disease. Daughters of female carriers of an X-linked disorder have a 50% chance of being carriers themselves, whereas boys have a 50% chance of being affected. 13 Acute hemolytic anemia from eating fava beans (favism) can be rapid. While favism can occur at any age, it occurs more often and severely in children. In severe cases, hypovolemic shock, or even , can occur.

cont’d on next page... 3 Disease/Medical Condition GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

(also known as “G6PD deficiency” and “erythrocyte glucose-6-phosphate dehydrogenase deficiency”; includes “favism”)

Related signs and symptoms (cont’d)

 Signs/symptoms of G6PD deficiency related hemolytic anemia include: , pallor, jaundice (yellowing of eyes, skin, and mucous membranes), dyspnea (), , tachycardia (elevated resting heartrate), palpitations, dizziness, cold extremities, lumbar/substernal pain, a sudden rise in body temperature, dark , and (enlarged ). An episode of hemolytic anemia may be preceded by irritability and/or lethargy. While most episodes of G6PD deficiency related acute hemolytic anemia are self-limiting and resolve on their own, AHA is potentially life- threatening.14  Gastrointestinal sign/symptoms may occur with hemolytic anemia, including nausea, diarrhea, and .  Acute kidney injury can result from severe hemolysis.  If a considerable proportion of hemolysis of red blood cells occurs in the spleen, hypersplenism (overactive spleen) may develop, with consequent thrombocytopenia and/or neutropenia.  Signs/symptoms of G6PD deficiency related to methemoglobinemia include: pallor, cyanosis, lightheadedness, headache, palpitations, , and dyspnea. In very severe cases (methemoglobin fraction above 50%), dysrhythmias, , , and even death can occur. At high levels of methemoglobinemia, blood appears to be chocolate brown in colour.  Some persons with G6PD deficiency are elevated risk of (widespread infection of the blood) following severe trauma.

References and sources of more detailed information

 College of Dental of Hygienists of Ontario https://www.cdho.org/Advisories/CDHO_Factsheet_Anemia.pdf http://www.cdho.org/Advisories/CDHO_Advisory_Anemia.pdf  Hernández-Pérez, D, Butrón-Téllez Girón, C, Ruiz-Rodríguez, S, Garrocho-Rangel, A, & Pozos-Guillén, A. Dental considerations in children with glucose-6-phosphate dehydrogenase deficiency (favism): A review of the literature and case report. Case Reports in Dentistry. 2015. https://doi.org/10.1155/2015/506459  Bubp J, Jen M, Matuszewski K. Caring for Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Patients: Implications for Pharmacy. P T. 2015;40(9):572-574. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571844/  Gupta H, Arora R, Kamboj M. Periodontal considerations in a patient with glucose-6-phosphate dehydrogenase deficiency with associated pancytopenia: A rare case report. J Indian Soc Periodontol. 2014;18(2):229-231. doi:10.4103/0972-124X.131334 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033892/  Greenwood M, Meecham JG. General medicine and for dental practitioners. Part 2 – metabolic disorders. British Dental Journal. 2010;208(9):389-392. https://www.nature.com/articles/sj.bdj.2010.397.pdf?proof=true19

14 G6PD deficiency is usually best managed by preventive measures. Individuals at elevated risk should be screened for the G6PD defect before being treated with oxidative drugs such as certain antibiotics, antimalarials, and other medications known to trigger hemolysis. In individuals who are G6PD-deficient, hemolytic anemia from known drugs or fava beans can be prevented, because exposure can be avoided. If hemolytic anemia is due to the use of a certain , its use should be discontinued under medical supervision. Similarly, if hemolytic anemia is caused by an underlying infection, the infection should be treated. Persons with hemolytic anemia may need short-term treatment with fluids to prevent hemodynamic shock, or, in severe cases where the rate of hemolysis is rapid, even blood transfusions. Blood transfusions are more likely to be required in children, particularly for favism, which can be life-threatening.

cont’d on next page... 4 Disease/Medical Condition GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

(also known as “G6PD deficiency” and “erythrocyte glucose-6-phosphate dehydrogenase deficiency”; includes “favism”)

References and sources of more detailed information (cont’d)

 Elyassi AR, Rowsham HH. Perioperative Management of the Glucose-6-Phosphate Dehydrogenase Deficient Patient: Review of the Literature. Anesth Prog. 2009:56:86-91. https://www.oralsurgerycenter.net/files/2014/05/G6PD_deficiency.pdf  Blanquicett CJ, Raavi T, Robert SM. A Severe Episode of Hemolytic Anemia After Amoxicillin Exposure in A G6PD Deficient Patient. Arch Clin Med Case Rep. 2019;3(3):104-112. doi:10.26502/acmcr.96550068 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637955/  Kumar RA, Venkatesh B, Karumaran CS, Rajasekaran MS, Shankar P. Protocol for Dental Management in a Patient with Glucose-6-Phosphate Dehydrogenase Deficiency. Journal of Clinical and Diagnostic Research. 2017;11(10):ZD09-ZD11. https://www.jcdr.net/articles/PDF/10747/31222_CE(RA1)_F(AP)_PF1(PG_SS)_PFAPG_AP).pdf  About Sick Kids (The Hospital for Sick Children) https://www.aboutkidshealth.ca/Article?contentid=870&language=English (G6PD deficiency)  McMaster Physiology Review http://www.pathophys.org/g6pd/ (Glucose 6-Phosphate Dehydrogenase Deficiency)  Medline Plus https://medlineplus.gov/ency/article/000528.htm (G6PD deficiency)  National Organization of Rare Disorders https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/  Medscape https://emedicine.medscape.com/article/204178-overview (Methemoglobinemia)  5-Minute Clinical Consult https://www.unboundmedicine.com/5minute/view/Select-5-Minute-Pediatric-Consult/14180/all/ Glucose_6_Phosphate_Dehydrogenase_Deficiency  UpToDate https://www.uptodate.com/contents/image/print?imageKey=HEME%2F74254&topicKey=PEDS%2F5927&source=see_link (Unsafe and Probably Safe Medicines and Substances in G6PD deficiency)  Little JW, Miller CS and Rhodus NL. Dental Management of the Medically Compromised Patient (9th edition). St. Louis: Elsevier; 2018.

* Includes oral hygiene instruction, fitting a mouth guard, taking an impression, etc.

** Ontario Regulation 501/07 made under Dental Hygiene Act, 1991. Invasive dental hygiene procedures are scaling teeth and root planing, including curetting surrounding tissue.

Date: July 23, 2020

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