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Toxicology

Tincture of Immunity

Andrew Ferrara, D.O.

Hartford Hospital Department of Emergency Medicine

Emergency Critical Care Fellow

 

Matthew Griswold, M.D

Hartford Hospital Department of Emergency Medicine

University of Connecticut Department of Toxicology

 

A 36-year-old, otherwise healthy, African American male presented to the local emergency room with complaints of dark colored urine, weakness and flank pain. He recently returned from Ghana after a two-week vacation. Two days prior to presentation, he consumed 10mL of a reported “Tincture of Immunity”. He reported the tincture to have a strong odor. The next day he developed abdominal pain, vomiting, malaise, darker colored urine, and jaundiced eyes. He had no antimalarial prophylaxis prior to his travel.

Vital Signs:

Temp 98 °F  | Pulse 85  |  BP 130/88 |  RR 16  | SpO2 95% RA

Exam was significant for scleral icterus and mild diffuse abdominal pain.

Emergency Department Work-up:

CBC: WBC 17.2, Hgb 9.0, HCT 27.5, MCV 102, Platelets 188

Chemistry: Na 139, K 4.0, Cl 97, CO2 28, BUN 25, Cr 1.7, Glu 135. AG 14

TBili 8.9, DBili: 0.3, AST 220, ALT 28, Alk Phos 52, Lipase 46, Tylenol <5, Salicylate: 1,  CK 714, Haptoglobin 17, LDH 2808, Reticulocyte Count: 8.8, Peripheral Smear: No blood parasite, Positive Bite cells, Howell Jolly bodies,  and Schistocytes. Coombs Test: Negative,

Urinalysis: Brown color, >25 WBC, >25 RBC, unable to perform further analysis due to color

Background:

Naphthalene is an aromatic compound, traditionally found in crystalline form. The substance gives off a distinct odor as it degrades. It is most widely known for its use in mothballs. It is irritating to the eyes and lungs and may cause cataracts in chronic ocular exposures. Naphthalene will likely result in hemolysis, especially in the G6PD deficient patient, with as little as 250-500mg of naphthalene. Confusion and potential seizures may result with as few as 4-8 mothballs (1-2 grams of naphthalene). Keep in mind, mothballs come in three various forms; naphthalene, paradichlorobenzene and camphor. If you have access to the crystalline substance you may differentiate the active ingredients via a simple water test.  Naphthalene will float in a salt saturated solution but sink in plain water. Camphor will float in water and paradichlorobenzene will sink in both. Paradichlorobenzene is also more radiopaque and may be seen on plain x-ray after ingestion. In comparison to naphthalene, ingestions of up to 20 grams of paradichlorobenzene have resulted in minimal health effects in adults.

Expected Clinical Course:

Exposure to naphthalene can occur by inhalation, ingestion, or dermal exposure. After acute ingestion with naphthalene, patients will begin to have symptoms of general abdominal pain, nausea, vomiting, weakness, and headaches. As mentioned above, patients may complain of irritation to their eyes, coughing and dyspnea during the exposure. Shortly after ingestion of the benzene containing, aromatic compound, it begins to cause oxidative damage to red blood cells, and results in hemolytic anemia. Levels of methemoglobin may rise.

Hemolytic anemia can be confirmed by laboratory analysis. Aside from acutely low levels of hemoglobin, one would see elevated levels of LDH and low levels of haptoglobin. Lactate dehydrogenase (LDH) is used as an indicator for cellular damage. Haptoglobin is a protein that will bind free hemoglobin that has been lysed from red blood cells.  Other biomarkers would include elevated indirect (unconjugated) bilirubin, a byproduct of lysed RBCs, and elevated reticulocyte counts, an indicator of RBC production from the marrow. Care must be taken to differentiate the drug induced oxidative hemolysis secondary to naphthalene from many other causes of hemolytic anemia.

Differentiation from other causes of hemolytic anemia can be done by history as well as laboratory evaluations. Direct autoimmune hemolytic anemia may be caused by medications, blood transfusions, cold agglutinins, lupus, malignancy or various other entities. This can be assessed via a direct coombs antibody test. This test will be positive if antibodies are present that are causing red blood cell destruction. Antibiotics (cephalosporins, quinolones), non-steroidal anti-inflammatories, and anti-neoplastic treatments are common causes for autoimmune drug induced hemolytic anemia. A family history of prior hemolytic anemia may clue one into G6PD deficiency, sickle cell/thalassemia or various membrane abnormalities including spherocytosis, elliptocytosis. G6PD deficiency creates a deficiency in NADPH, which is required for use by glutathione reductase to reduce oxidized glutathione within the hexose monophosphate shunt. This deficiency will effectively cause increased oxidative stress on red blood cells, leading to potential methemoglobinemia as well as hemolysis. Lastly, a peripheral smear showing schistocytes may indicate microangiopathic hemolytic anemia, commonly seen in hemolytic uremic syndrome (HUS), disseminated intravascular coagulopathy (DIC) and thrombotic thrombocytopenic purpura (TTP). Schistocytes are created as RBCs travel through damaged endothelium and become fragmented.

Management:

The major complications from naphthalene toxicity include coombs negative hemolytic anemia, methemoglobinemia (particularly in patients with G6PD deficiency), acute kidney injury and renal tubular acidosis. Patients may require repeat transfusions of PRBCs throughout their hospitalization. Treatment of their methemoglobinemia must be done cautiously, especially in G6PD deficient patients. Commonly, methylene blue is given to act as an electron acceptor to help facilitate reduction of methemoglobin to hemoglobin. In cases of G6PD deficiency, exchange transfusion is preferred over methylene blue. In this situation, methylene blue may induce significant hemolysis. N-acetylcysteine may also be considered to help with reduction process secondary to oxidative stress by increasing glutathione stores. Confirmatory testing for naphthalene poisoning may be obtained via urinary naphthol metabolites (1- and 2-naphthol).

Case Summary:

The 36-year-old male with hemolytic anemia was found to have a negative coombs antibody test, no family history of G6PD deficiency or other prior hemolytic event, and he had mild to moderate schistocytes on peripheral smear. Given the strong aroma from the compound he ingested, concern was for naphthalene, nitrites or aniline dye as these are known to cause oxidative stress. Naphthalene has the distinct odor of mothballs. Nitrites are often described as a cleaner/chemical odor, and aniline dyes may be described as fish odor. The patient was admitted and required transfusion of packed red blood cells. His methemoglobin levels were mildly elevated. He also tested negative for G6PD deficiency. He made a complete recovery and was discharged on hospital day six.  Confirmatory testing for urine naphthol was unable to be obtained however he confirmed the odor was similar to that of mothballs.

References:

Galbo, Mark. Naphthalene and Paradichlorobenzene. Poisoning & Drug Overdose 3/e. 1999. pp230-231

Shick, et al. Hemolytic Anemia. Medscape. 20 Dec 2017

Schrier, et al. Approach to Adult with Anemia. UptoDate. 15 Feb 2018

Schrier, et al. Hemolytic anemia due to drugs and toxins. UptoDate.02 Oct 2017

Schrier, et al. Diagnosis of hemolytic anemia in the adult. UptoDate. 15 Feb 2018

 

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