Archives of Academic Emergency Medicine. 2020; 8(1): e82 OR I G I N A L RE S E A RC H Henna-induced Hemolysis and Acute Kidney Injury in an 85-year-old Man; a Case Report Sahel Asgari1, Mohsen Esfandbod2, Maryam Haghshomar3∗ 1. Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2. Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. 3. Faculty of Medicine, Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. Received: August 2020; Accepted: September 2020; Published online: 14 October 2020 Abstract: Henna is a commonly used traditional cosmetic agent, which also holds medical potentials and is used to treat skin lesions including seborrheic dermatitis or fungal infections and also has possible anti-inflammatory ef- fects. It contains lawsone (2-hydroxy-1,4-naphthoquinone) and, therefore, has the potential to induce oxidative hemolysis. Henna-induced hemolysis has been previously reported in children with Glucose 6-Phosphate Dehy- drogenase Deficiency. Here, we report an 85-year-old man who developed hemolytic anemia and acute kidney injury following oral consumption of henna to help his dyspnea. He was treated with hydration, bicarbonate, and dexamethasone. Over the course of hospitalization, the patient developed ventilator-associated pneumo- nia and was treated with antibiotic. He was discharged after one month. This finding is of high importance due to common use of henna, especially among people with false beliefs regarding traditional and herbal medicine, and highlights the role of a full history taking. Keywords: Case reports; hemolysis; Lawsonia plant; toxicity; herbal medicine; anemia, hemolytic; acute kidney injury Cite this article as: Asgari S, Esfandbod M, Haghshomar M. Henna-induced Hemolysis and Acute Kidney Injury in an 85-year-old Man; a Case Report. Arch Acad Emerg Med. 2020; 8(1): e82. 1. Introduction Hemolytic anemia is a situation in which disruption of red blood cells (RBCs) happens with a faster speed than their reproduction and is accompanied with a decrease in hemoglobin. Its etiology is divided into inherited and ac- quired. Certain medications, chemicals, toxins, and herbal medicines can cause hemolytic anemia (1). Drug-induced immune hemolytic anemia (DIIHA) is an uncommon phe- nomenon caused by an immune response to a drug fol- lowing its administration (2). This reaction is caused ei- ther by antibody-mediated complement activation, which results in an intravascular hemolysis, or antibody-mediated phagocytosis, which results in an extravascular hemolysis. Since the first discovery of DIIHA, a large number of drugs have been reported to cause positive Direct Anti-globulin Test (DAT) (3). Penicillin and its derivates, cephalosporins, Κ-lactamase inhibitors, and quinidine are the most com- ∗Corresponding Author: Maryam Haghshomar; Students’ Scientific Research Center, Mirzaye Shirazi Avenue, Tehran, Iran. Postal code: 1586615113, Tel: +989226039842, Email: Maryam_haghshomar@yahoo.com. mon causes of this uncommon complication (4). Chemi- cals like phenylhydrazine-HCL can induce hemolytic anemia (5). This phenomenon is most likely a side effect of oxida- tive stress. Henna has been reported to lead to this problem in previous case reports (6, 7). Here, we report an 85-year- old man who developed hemolytic anemia and acute kidney injury following oral consumption of henna to help his dys- pnea. Recognizing this rare complication caused by a com- mon traditional cosmetic agent is of high importance due to common use of henna, especially among people with false beliefs regarding traditional and herbal medicine, and high- lights the role of a full history taking. 2. Case presentation 85-year-old men presented to emergency department (ED) with chief complain of abdominal pain and constipation from 3 days prior to admission. He hadn’t passed any gas during those days. Pain was not related to eating. On admis- sion, his general examination and vital signs showed restless- ness, icteric sclera, generalized wheezing in lung ausculta- tion, peri-umbilical tenderness, mild tachycardia (heart rate 100 bpm), tachypnea (respiratory rate 32), decreased O2 sat- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Asgari et al. 2 uration (78% in room air) and wide pulse pressure (150/70 mmHg). The patient was admitted to general surgery service in ED. Abdominal ultrasonography and computed tomogra- phy (CT) scan were normal and chest X-ray showed some lev- els of increased air. Medical history of the patient revealed nothing significant, except for some unclear respiratory sys- tem problems, dyspnea suggestive of possible smoking his- tory, and chronic obstructive pulmonary disease (COPD). Due to presence of jaundice, an initial lab examination was performed with the aim of evaluating liver and gallblad- der function, which found reduced hemoglobin (HB) (9.5 g/dL) and RBC count (3000000 number/ml) (Table 1). More- over, lab results showed increase in Lactate dehydrogenase (LDH)(3273 U/L), C-Reactive Protein (CRP) (139.6 mg/L), Ferritin (>2000 µg/L), Aspartate aminotransferase (AST U/L) (78), prothrombin time (PT) (14.7 seconds), international normalized ratio (INR) (1.17 seconds), potassium (K) (5.93 mmol/L), urea (94 mg/dL), white blood cell (WBC) (36000 number/ml), bilirubin total (9.93 mg/dL), and bilirubin di- rect (1.02 mg/dL) (Table 1). Urine analysis (UA), manifested a 4+ proteinuria and 1+ glycosuria (Table 2). Morphine was present in urine toxicology (Table 2). On the third day of admission, lab tests were ordered follow- ing consultation with an internal medicine specialist due to patient’s fever and loss of consciousness. On that day, the patient arrested but fortunately successful cardiopulmonary resuscitation (CPR) was performed. Emergency service intu- bated the patient and started full cardiac monitoring. Lab results showed hemolysis with a severe loss of RBC count (1030000 number/ml) and HB level (3.5 g/dL) along with sus- tained increased ferritin (>2000 µg/L), urea(130), bilirubin total (6.68 mg/dL), and bilirubin direct (1.8 mg/dL). Further- more, direct and indirect Coombs test appeared negative and Glucose 6 Phosphate Dehydrogenase (G6PD) levels were in normal range (12.0 units/g). Moreover, the patient had de- veloped acute kidney injury (AKI) marked by an elevated cre- atinine (2.23 mg/dL). Peripheral blood smear showed schistocytes and other frag- mented RBCs. Elevated serum bilirubin, alanine amino- transferase (ALT), lactate dehydrogenase (LDH), and periph- eral blood smear results led us to hemolytic anemia diagno- sis. Following the diagnosis of hemolytic anemia, the patient’s diet was reinvestigated through his family members and his wife, which revealed oral consumption of henna. Henna was prescribed by a traditional medicine physician to help the patient’s dyspnea. Henna powder was dissolved in a glass of water and the patient had drank a glass a day, for 2 consec- utive days prior to admission. Hematology consultant made a DIIHA diagnosis based on the history of Henna consump- tion, clinical findings, and laboratory results of hemolysis. Following this diagnosis, 4 mg dexamethasone three times a day (TDS) was prescribed for the patient. Hydration and bi- carbonate therapy were performed to treat the AKI. The patient’s condition was improved; however, after a few days he developed fever and a ventilator-associated pneu- monia (VAP) was diagnosed, and an infectious disease spe- cialist started antibiotic therapy. The patient was discharged after one month. Two weeks later, the patient referred to the hospital with CBC, Cr level, and G6PD level results. G6PD level was rechecked as the enzyme levels might not be low in the acute hemolysis phase. All test appeared within normal range. 3. Discussion Henna is a traditional cosmetic agent applied over skin, hair, or nails as a dye. It is derived from Lawsonia Alba shrub and it contains Lawsone (2hydroxy–1,4 napthoquinon). Black henna contains Paraphenylenediamine (PPD). In some countries in Africa, south east Asia, and middle east, henna is commonly used in ceremonies to create patterns on the skin. In addition to cosmetic uses, it has anti-inflammatory affects, which makes it suitable for seborrheic dermatitis or fungal infections therapy. Studies have suggested anti- inflammatory, antipyretic, and analgesic effects for henna (8). Lawsone has a structure and redox potential similar to ortho- substituted 1, 4-naphthoquinones, which is an oxidant of G6PD and normal RBCs, and henna absorption may lead to oxidative injury (9). PPD is also an oxidative chemical aller- gen that can cause adverse systemic effects such as laryngeal edema and respiratory distress, often demanding emergency tracheostomy and leading to AKI, rhabdomyolysis, and mul- tiple organ failure (10). The patient had obstruction symp- toms like abdominal pain and constipation, and also suffered from AKI and acute respiratory distress, which led to his intu- bation, and taken together, they seem highly compatible with henna toxicity. Although henna absorption has a high risk of hemolytic ane- mia, merely a few reports of DIIHA due to henna applica- tion are present. Cases report acute renal failure associ- ated with henna use along with hemolytic anemia. Previ- ously, most cases of henna-induced hemolysis had been re- ported in newborns and infants. Deveciglu et al. reported hemolytic anemia and acute renal failure after cutaneous ap- plication of henna to abdomen, intertriginous region, and legs for treating diaper rash, developed in a 27-day-old boy (6). Seyedzadeh et al. found severe acute hemolysis in a 42-day old infant followed by topical application of henna for treating his napkin dermatitis (11). Ilkhanipur et al. de- scribed a 35-day old, G6PD-deficient boy who had advanced jaundice, hemogluinuria, and kernicterus symptoms after cutaneous intake of henna (12). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2020; 8(1): e82 Table 1: Laboratory findings of the patient Measures Day 1 Day 3 Normal Range pH 7.40 - 7.35-7.45 PCO2 (torr) 38.7 - 35-45 Lactate dehydrogenase (U/L) 3273 5010 <480 C-reactive protein (mg/L) 139.6 - <3.0 Ferritin (µg/L) >2000 >2000 35-300 Folic Acid (ng/mL) 13.3 - 2-20 Vitamin B12 (ng/mL) 548 - 138-652 Blood Sugar (mmol/L) 200 180 <200 Urea (mg/dL) 94 130 18-55 Creatinine (mg/dL) 1.13 2.23 0.6-1.2 Natrium (mmol/L) 135 149.8 135-145 Potassium (mmol/L) 5.93 5.12 3.5-5 Calcium (mmol/L) - 8.3 8.2-10.3 Magnesium (mmol/L) - 2.7 1.8-2.6 Aspartate Aminotransferase (U/L) 78 - 10-40 Alanine Aminotransferase (U/L) 52 - 7-56 Alkaline Phosphatase (U/L) 293 - 44-147 Bilirubin Total (mg/dL) 9.93 6.68 0.1-1.2 Bilirubin Direct (mg/dL) 1.02 1.8 <0.4 Prothrombin Time (seconds) 14.7 - 11-13.5 Partial Thromboplastin Time (seconds) 31 - 30-40 International Normalized Ratio (seconds) 1.17 - <1.1 Amylase (U/L) 45 - 30-110 White Blood Cell (number/mm3 ) 36000 39900 4500-11000 Red Blood Cell, million (number/mm3 ) 3.0 1.03 4.32-5.72 Hemoglobin (g/dL) 9.5 3.5 13.5-17.5 Hematocrit (%) - 11 41-52 Mean corpuscular volume (femtoliters) 95.72 106.8 80-96 MCH∗ (picograms/cell) 31.25 33.98 27-33 MCHC∗∗ (g/dL) 32.65 31.28 33-36 Platelets (mm3 ) 285000 207000 150000-450000 Red cell distribution (width %) 18.8 23 11.5-14.5 Mean platelet volume (femtoliters) - 11.3 8-12 Platelet Distribution (width %) - 15.5 10.0-17.9 Neutrophil (%) - 70.7 40-60 Lymphocyte (%) - 27.7 20-40 Mixed (%) - 1.6 4-8 ∗: Mean corpuscular hemoglobin; ∗∗: mean corpuscular hemoglobin concentration. Table 2: Urine analysis and urine toxicology findings of the patient Urine Toxicology Result Urine Analysis Result Nitrite Negative pH 6.5 Morphine Positive Specific Gravity 1.01 Amphetamine Negative Color Yellow Benzodiazepines Negative White Blood Cell 4-5 Buprenorphine Negative Red Blood Cell 0-1 Cocaine Negative Glucose 1+ Methadone Negative Protein 4+ Tricyclic Antidepressant Negative - - Cases with older age, are also present. Through investigat- ing venous blood exposure with different levels of lawsone in 15 healthy and 4 G6PD-deficient adults, Zinkham et al. found that henna is capable of causing oxidative hemolysis, which is more severe and more probable in G6PD-deficient patients (8). Kheir et al. reported a case of life-threatening henna-induced hemolytic anemia after application of henna to skin in Sudan. This case was a 6-year-old boy who was This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Asgari et al. 4 diagnosed with G6PD deficiency after workup for hemolysis (13). Raupp et al. found 4 cases of hemolytic crisis following topical application of henna, all diagnosed with G6PD de- ficiency. One male and one female neonate, and two boys aged three and 4 years made up the cases (7). Qurashi et al. reported a young Saudi male who developed AKI and intravascular hemolysis following ingestion of henna mixed with para-phenylenediamine (14). Moreover, a case of severe hemolytic anemia was reported after voluntary ingestion of henna to induce abortion. The 17-year-old girl year was later diagnosed with G6PD deficiency (15). We are the first to report henna-induced hemolytic anemia in a non-G6PD-deficient patient after oral consumption of henna at an old age. It can be assumed that oral intake of henna will be more potent in causing hemolysis compared to cutaneous absorption. 4. Conclusion In conclusion, henna-induced hemolytic anemia is rare and most cases occur in G6PD-deficient individuals during their first months of life or at a young age; however, the chance of hemolysis occurrence in healthy or old individuals cannot be ruled out. Since henna is a commonly used herbal agent, clinical suspicion toward henna-induced hemolysis after un- explained hyperbilirubinemia in patients with a history of henna intake is of high importance. More observations and further investigation into the mechanism of this hemolytic reaction seems necessary. It should be highlighted that ob- taining a full history of herbal medicines remains critical due to patients’ false beliefs. 5. List of abbreviations Drug-induced immune hemolytic anemia (DIIHA); red blood cells (RBC); Direct Antiglobulin Test (DAT); emergency room (ER); hemoglobin (HB); Lactate dehydrogenase (LDH); C- Reactive Protein (CRP), Ferritin; Aspartate aminotransferase (AST); prothrombin time (PT); international normalized ra- tio (INR); potassium (K); white blood cell (WBC); bilirubin to- tal (bili. T); bilirubin direct (bili. D.); Urine analysis (UA); car- diopulmonary resuscitation (CPR); glucose 6 Phosphate De- hydrogenase (G6PD); acute kidney injury (AKI); three times a day (TDS); Ventilator-associated pneumonia (VAP); Para- phenylenediamine (PPD) 6. Declarations 6.1. Ethics consideration This study was approved by department of medical ethics, Tehran University of Medical Sciences with ethic number IR.TUMS.SINAHOSPITAL.REC.1399.045. 6.2. Availability of data and materials The datasets used during the current study are available from the corresponding author on reasonable request. 6.3. Conflict of interests The authors declare that they have no competing interests 6.4. Funding This research was supported by the Tehran University of Medical Sciences. 6.5. Authors’ contributions SA performed the initial examination of the patient and con- tributed in the final diagnosis and was a contributor in writ- ing the manuscript. ME analyzed and interpreted the patient data regarding the hematological disease. MH was a major contributor in writing the manuscript. All authors read and approved the final manuscript. 6.6. Acknowledgements Not applicable. References 1. Dhaliwal G, Cornett PA, Tierney Jr LM. Hemolytic ane- mia. American family physician. 2004;69(11):2599-606. 2. Garratty G. Drug-induced immune hemolytic anemia. Hematology. 2009;2009(1):73-9. 3. SNAPPER I, MARKS D, SCHWARTZ L, HOLLANDER L. Hemolytic anemia secondary to mesantoin. Annals of in- ternal medicine. 1953;39(3):619-23. 4. Sarkar R, Philip J, Mallhi R, Jain N. Drug-induced immune hemolytic anemia (Direct Antiglobulin Test positive). Medical Journal, Armed Forces India. 2013;69(2):190. 5. Lee HW, Kim H, Ryuk JA, Kil K-J, Ko BS. Hemopoi- etic effect of extracts from constituent herbal medicines of Samul-tang on phenylhydrazine-induced hemolytic anemia in rats. International journal of clinical and ex- perimental pathology. 2014;7(9):6179. 6. Devecioglu C, Katar S, Dogru O, Tas M. Henna-induced hemolytic anemia and acute renal failure. The Turkish journal of pediatrics. 2001;43(1):65-6. 7. Raupp P, Hassan JA, Varughese M, Kristiansson B. Henna causes life threatening haemolysis in glucose-6- phosphate dehydrogenase deficiency. Archives of disease in childhood. 2001;85(5):411-2. 8. Zinkham WH, Oski FA. Henna: a potential cause of ox- idative hemolysis and neonatal hyperbilirubinemia. Pe- diatrics. 1996;97(5):707-9. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2020; 8(1): e82 9. McMillan DC, Sarvate SD, Oatis Jr JE, Jollow DJ. Role of oxidant stress in lawsone-induced hemolytic anemia. Toxicological Sciences. 2004;82(2):647-55. 10. Gude D, Bansal DP, Ambegaonkar R, Prajapati J. Para- phenylenediamine: Blackening more than just hair. Jour- nal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2012;17(6):584. 11. Seyedzadeh A, Hemmati M, Gheiny S. Henna-induced severe hemolysis: In glucose 6-phosphate dehydroge- nase deficiency. Pakistan Journal of Medical Sciences. 2007;23(1):119. 12. Ilkhanipur H, Hakimian N. Henna: A cause of life threat- ening hemolysis in G6PD-deficient patient. Pak J Med Sci. 2013;29(1 Suppl):429-31. 13. Kheir A, Gaber I, Gafer S, Ahmed W. Life-threatening haemolysis induced by henna in a Sudanese child with glucose-6-phosphate dehydrogenase deficiency. EMHJ. 2017;23(1). 14. Qurashi HE, Qumqumji AA, Zacharia Y. Acute renal fail- ure and intravascular hemolysis following henna inges- tion. Saudi Journal of Kidney Diseases and Transplanta- tion. 2013;24(3):553. 15. Perinet I, Lioson E, Tichadou L, Glaizal M, de Haro L. Hemolytic anemia after voluntary ingestion of henna (Lawsonia inermis) decoction by a young girl with G6PD deficiency. Medecine tropicale: revue du Corps de sante colonial. 2011;71(3):292-4. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Case presentation Discussion Conclusion List of abbreviations Declarations References