Acute liver injury associated with Oxyfluorfen toxicity

Introduction

Oxyfluorfen is a commercially available pesticide which is commonly used for weed control in crop production. The carcinogenic and teratogenic effects are well described in literature among animals.^1,2 The potential toxic effects such as liver cancer, liver failure and haematological effects are recognized in animal models. ³ One case of an oxyfluorfen poisoning is reported in literature in young man. ⁴ Herein, we described an oxyfluorfen toxicity complicated with acute liver injury in a young woman who presented with a deliberate self-harming with an Oxyfluorfen poisoning in Sri Lanka.

Case history

A 20-year-old previously healthy woman was admitted to an emergency unit of district general hospital in Northern Sri Lanka with a history of nausea, vomiting and throat discomfort after an one of oxyfluorfen poisoning. She had ingested 150 mL of an oxyfluorfen following quarrelling with her husband. Poison was identified by medical professional via empty bottle labelled with an Oxyfluorfen which was brought by patient and relatives. On examination, she was conscious with Glasgow coma scale of 14/15 (GCS 14/15). ⁵ Her pupils were equally reacting to light and were 3 mm in size. Her blood pressure was 112/65 mmHg and pulse rate was 86 beats per minute. Her respiratory rate was 12 breaths per minute and core body temperature was 36.8°C. The rest of the systemic examinations were unremarkable. Gastric lavage was performed and single dose of activated charcoal was administrated. Her biochemical investigations were within normal limits (Table 1). She was observed in highly dependency care unit for 24 h. She was counselled and was discharged on day 3 of admission.

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Table 1.

The biochemical profile of patient is shown with clinical progression of disease.

Biochemical investigations	FirstDay 1	AdmissionDay 3	Day 1	SecondDay 2	AdmissionDay 3	Day 4	Day 7	Day 10	Day 14
Full blood count
White cell count (4,000–11,000/mm3)	6,230	7.7	7,460	13,500	8,000	11,790	10,800	8,900	9,000
Neutrophils (50%-70%)	72	74	78	83	68	68	50	54	65
Lymphocytes (20%–40%)	27	14	10	8.9	23	18	29	32	23
Haemoglobin (12–16 g/dL)	12.1	12.9	14	13.2	12.8	12.5	12.5	12.3	11.1
MCV (80–100 fL)	82	83	81	83.6	87	82	83	84	85
Red cell count (400,000–550,00 mm3)	445,000	471,000	420,000	432,000	420,000	408,000	418,000	408,000	467,000
Platelets (150,000–450,000 mm3)	284,000	267,000	428,000	379,000	330,000	258,000	247,000	255,000	287,000
Renal functions tests
Blood urea (18–55 mg/dL)	35	37	26.2	19	25	12.9	20	23	34
Serum Creatinine (0.7–1.5 mg/dL)	1.1	1.0	0.91	0.64	0.78	0.71	0.98	1.0	1.1
Serum electrolytes
Serum sodium (135–145 mmol/L)	135.3	138.1	134.8	134.9	135.6	138.2	134.9	135.0	134.8
Serum potassium (3.5–5.0 mmol/L)	4.3	4.48	3.78	4.1	4.2	4.08	4.1	4.2	4.7
Liver profile
Serum AST (0–45 U/L)	19	24	418.5	1815.6	2201	1366	732	212	47
Serum ALT (0–35 U/L)	15	26	482.4	1658.6	2112	1728	991	347	39
Serum bilirubin (0–2.0 mg/dL)	0.70	0.64	1.0	1.90	2.58	1.23	1.65	1.0	1.1
Direct bilirubin (0–0.2 mg/dL)	0.10	0.14	0.30	0.7	0.60	0.20	0.55	0.2	0.3
Indirect bilirubin (0.2–0.6 mg/dL)	0.6	0.50	0.7	1.2	1.98	1.0	1.10	0.8	0.8
Serum protein (6.4–8.3 g/dL)	7.1	7.0	7.48	6.53	5.22	6.14	6.99	7.1	7.0
Serum albumin	4.5	4.4	4.49	3.98	3.24	3.67	4.02	4.0	4.3
Serum globulin	2.6	2.6	2.99	2.55	1.98	2.47	2.97	3.1	2.7
PT/INR (<1.4)	1.1	1.1	1.4	1.95	2.45	1.83	1.27	1.23	1.1

MCV-Mean Corpuscular Volume; AST-Aspartate Transaminase; UL-Unit/Litre; ALT-Alanine Transaminase; PT/INR-Prothrombin Time/Internationalized Ratio.

Four days later, she was admitted to medical ward with a history of right hypochondrial pain, nausea, vomiting and constitutional symptoms. She denied any history of paracetamol overdose. On examination, she was conscious with GCS 15/15. She had pink conjunctiva and no icterus or no flapping tremor. Her blood pressure was 120/60 mmHg and pulse rate was 80 beats per minute. Her respiratory rate was 16 breaths per minute and core body temperature was 36.8°C. Her abdominal examination showed right hypochondrial tenderness. The rest of the systemic examinations were unremarkable. Her full blood count showed white cell count of 7,460/ mm³, haemoglobin of 14.0 g/dL and platelets of 428,000/mm³. Her inflammatory markers were normal (C-reactive protein (CRP): 0.3 mg/dL, erythrocyte sedimentation rate (ESR): 15 mm/1^st hour). Her septic screening was negative. Her aspartate aminotransferase (AST) was 418.5 U/L and aminotransferase (ALT) was 482.5 U/L. Her serum electrolytes showed sodium of 134.8 mmol/ L and potassium of 3.78 mmol/L . Her blood urea was 26.2 mg/dL and serum creatinine was 0.91 mg/dL . Her PT/INR was 1.0 and APTT was 32 . Her total bilirubin was 1.77 mg/dL with indirect bilirubin of 1.27 mg/dL. Her liver enzymes (AST- 2201 IU/L, ALT-2112 IU/L) and serum bilirubin (Total- 2.58 mg/dL, indirect -1.98 mg/dL), PT/INR (2.45) were gradually elevated. Her investigations were shown in Table 1. Her USS scan of abdomen showed acute hepatic injury. Her hepatitis A antibody, Hepatitis Bs Antigen, Hepatitis C antibody, Hepatitis E antigen, Epstein-Barr virus (EBV) antibody, cytomegalovirus (CMV) antibody, HIV screening, Venereal Disease Research Laboratory (VDRL) screening, dengue antigen and antibody were negative. She was managed with N-acetyl cystenine 6.25 mg/kg/hourly infusion for 72 h, fresh frozen plasma 15 mL/kg for 5 days and intravenous vitamin K 10 mg for 5 days. Her liver enzymes were gradually improved with therapy and were back to normal on her discharge. She was discharged on day 10 and followed up at medical clinic.

Discussion

Oxyfluorfen is a diphenyl-ether herbicide which is used for broad spectrum pre- and post-emergent control of annual broadleaf and grassy weeds in a variety of tree fruit, nut, vine, and field crops. It is structurally related to lactofen and acifluorfen which inhibits protoporphyrinogen oxidase, involved in haeme biosynthesis pathway. ⁶ The toxicity occurs through acute oral, dermal and inhalation methods. The moderate toxicity can occur by ingestion and slightly toxicity can occur by dermal absorption. ⁷ The potential adverse effects are liver cancer, liver injury and bone marrow toxicity. ⁸ Oxyfluorfen inhibits haem production which results in a variety of anaemias. Haem is the part of the haemoglobin molecule that contains iron and binds oxygen. It disrupts protoporphyrinogen oxidase enzyme which is involved in haeme biosynthesis pathway as it primary mechanism of action. The person who has genetic inherited disease; variegate porphyria has high risk to oxyfluorfen exposure due to defect of protoporphyrinogen oxidase enzyme. ⁹ The anaemia was usually mild with varying hematologic abnormalities described in the rat, mouse, and dog studies in literature.^10,11

Several chronic oral toxicity studies showed hepatic toxicity among mice fed diets which includes increased absolute liver weight, necrosis, regeneration, and hyperplastic nodules.^8,12 Furthermore, chronic toxicity includes effects on the nervous system, immune system, endocrine function, development and reproduction and carcinogenicity or mutagenicity as well.^1,13– ¹⁵ It is neurotoxicant that interrupts the function of nerves either interacting with nerves directly or by interacting with supporting cells of nervous system. ¹³ It can trigger an immune system and adversely impact the immunity as well. ¹³ The exposure to high concentrations of oxyfluorfen has been associated with adverse effects on adrenal, thyroid and thymus glands. ¹⁴ However, no further systemic effects were not observed except liver injury in our patient.

Moreover, it is recognized cause for human carcinogen based on combined hepatocellular adenomas/carcinomas in the mouse carcinogenicity study. ¹⁵ The pathophysiology of hepatic injury among animal models were well described. The increase in serum alkaline phosphatase and increase in liver weight in dogs fed were described. ¹ Oxyfluorfen has high affinity and causes inhibition of protoporphyrinogen oxidase in mouse liver mitochondria which causes biochemical changes consistent with those observed in variegate porphyria.^8,9 However, exact pathophysiology of hepatic injury associated with an oxyfluorfen toxicity among human was not well described in literature. ¹

There are isolated case reports of other herbicide injections such as paraquat and glyphosate-surfactant as well.^16–19 There are cases reports of hepatic injury associated with paraquat and glyphosate-surfactant in literature.^20,21 We have found one previous reports on oxyfluorfen injections to the forearm among human in literature in which oxyfluorfen produced a chemical burn to the fascia and subcutaneous tissue of the forearm. ⁴ There are major diagnostic and therapeutic challenges among hepatic injury associated with herbicide-poisoning.^20,22 However, there were no cases reported hepatic injury associated with an oxyfluorfen toxicity among humans. The clinical consequences of oxyfluorfen are not very well described among humans.

The management of oxyfluorfen toxicity is mainly supportive as there is no known antidote. Gastric lavage, adsorbents such as activated charcoal should be initiated as early as possible to prevent the absorption of the poison. ²² The outcome depends on the severity of the poisoning and the time taken to avail medical help. The high mortality rates are due to the toxicity of the compound itself and the lack of a specific antidote. ²²

This case illustrates first case of hepatic injury following oxyfluorfen toxicity among human. Therefore, such information is valuable for clinicians, regulatory authorities and the public at large. Furthermore, clinical outcomes depend on early recognition and aggressive supportive management since there is no antidote available.

Conclusion

In the case of oxyfluorfen toxicity; anaemia and hepatic injury are the most serious but uncommon complications. The clinical consequences of oxyfluorfen are not very well described among humans. Therefore, such information is valuable for clinicians, regulatory authorities and the public at large. Furthermore, clinical outcomes depend on early recognition and aggressive supportive management since there is no antidote available.