Acute liver failure temporally associated with intensive consumption of Plantago major tea: A case report

Abstract

BACKGROUND

Herb-induced liver injury is an increasingly recognized cause of acute liver injury, but severe hepatotoxicity associated with Plantago major (P. major) has not been well characterized in humans. We report a case of acute liver failure temporally associated with intensive consumption of P. major tea requiring urgent liver transplantation.

CASE SUMMARY

A previously healthy 44-year-old woman developed worsening abdominal pain, jaundice, dark urine, and acholic stools after consuming approximately 2 L/day of prepared P. major tea for 15 consecutive days. Her clinical condition rapidly progressed to grade III hepatic encephalopathy. At the first complete laboratory assessment available for retrospective review, alanine aminotransferase was 338 U/L, aspartate aminotransferase was 370 U/L, alkaline phosphatase was 194 U/L, and total bilirubin was 14.41 mg/dL, corresponding to an R factor of 6.27 and a hepatocellular pattern of injury. The international normalized ratio reached 2.27, serum ammonia was 146 μmol/L, and arterial lactate reached 4.52 mmol/L, while renal function remained preserved. The contemporaneous medical record documented negative investigations for viral hepatitis and autoimmune liver disease and documented that Wilson disease and hemochromatosis had been investigated and excluded. She received enteral N-acetylcysteine and corticosteroid therapy without reversal of the progressive clinical course. Given the rapidly progressive acute liver failure with grade III hepatic encephalopathy and worsening hepatic dysfunction, urgent liver transplantation was performed on July 4, 2024. Histopathological examination of the explanted liver demonstrated massive hepatic necrosis, marked cholestasis, and regenerative changes without fibrosis or steatosis; these findings were nonspecific and did not establish the etiology of the liver injury. The post-transplant course was subsequently complicated by persistent/recurrent biopsy-proven acute cellular rejection requiring corticosteroid pulses and thymoglobulin. At more than two years of follow-up, the patient remained alive with preserved graft synthetic and renal function.

CONCLUSION

This case describes severe acute liver failure temporally associated with intensive P. major tea consumption. Although the medical record documented negative investigations for viral hepatitis and autoimmune liver disease and exclusion of Wilson disease and hemochromatosis during the etiologic investigation, a definitive causal relationship with P. major cannot be established because the herbal preparation was not botanically authenticated or chemically analyzed and a complete structured causality assessment was not possible. Clinicians should systematically investigate herbal-product exposure in patients with otherwise unexplained acute liver injury.

Key Words: Plantago major; Herb-induced liver injury; Acute liver failure; Liver transplantation; Case report

Core Tip: This case describes acute liver failure temporally associated with intensive consumption of Plantago major tea in a previously healthy 44-year-old woman. After consuming approximately 2 L/day of prepared infusion for 15 consecutive days, she developed progressive hepatic dysfunction and grade III hepatic encephalopathy, ultimately requiring urgent liver transplantation. Explant histology demonstrated nonspecific massive hepatic necrosis and marked cholestasis. Although the temporal relationship raises suspicion for herb-induced liver injury, causality cannot be definitively established because the herbal preparation was not botanically authenticated or chemically analyzed.

INTRODUCTION

Acute liver failure (ALF) is a potentially fatal condition characterized by acute liver injury, coagulopathy [international normalized ratio (INR) > 1.5], and hepatic encephalopathy in individuals without preexisting chronic liver disease. ALF has multiple etiologies, among which acute viral hepatitis and drug-induced liver injury (DILI) are important causes[1].

DILI encompasses a broad spectrum of hepatic injury, ranging from asymptomatic biochemical abnormalities to severe hepatitis and ALF. Herb-induced liver injury (HILI), a form of liver injury associated with herbal and plant-based products, has also become increasingly recognized[2,3]. Herbal preparations may contain multiple biologically active compounds, and their composition, concentration, and purity may vary considerably.

Plantago major (P. major) is widely used in traditional medicine and has predominantly been associated with beneficial and hepatoprotective effects in experimental studies. However, severe human liver injury temporally associated with its consumption has been poorly characterized. We report a case of ALF requiring urgent liver transplantation after intensive consumption of P. major tea, in which HILI was considered as a possible etiology.

CASE PRESENTATION

Chief complaints

A 44-year-old woman presented with worsening abdominal pain, jaundice, dark urine, and acholic stools.

History of present illness

The patient initially developed epigastric pain approximately two months before hospitalization. Upper gastrointestinal endoscopy demonstrated moderate erosive gastritis, and omeprazole therapy was initiated. Because the abdominal symptoms persisted, she subsequently began self-medicating with a prepared infusion of P. major (tanchagem), consuming approximately 2 L/day for 15 consecutive days. The reported volume refers to the prepared infusion rather than to a quantified botanical dose; the amount of plant material, infusion concentration, and exact preparation method could not be reconstructed retrospectively.

After this period of herbal consumption, the abdominal pain worsened and was followed by jaundice, dark urine, and acholic stools. She was admitted to a local hospital, where acute liver injury with hyperbilirubinemia and coagulopathy was identified. The contemporaneous medical record documented negative investigations for viral hepatitis and autoimmune liver disease and documented that Wilson disease and hemochromatosis had been investigated and excluded.

Despite medical treatment, her clinical condition progressively deteriorated, with worsening hepatic dysfunction and progression to grade III hepatic encephalopathy according to the West Haven criteria. She was subsequently transferred to the University Hospital of the Federal University of Minas Gerais for specialized management and evaluation for urgent liver transplantation. The chronology of the clinical course is summarized in Table 1.

Table 1 Clinical timeline of the case.

Period/date	Clinical event
Approximately 2 months before hospitalization	Epigastric pain developed. Upper gastrointestinal endoscopy showed moderate erosive gastritis, and omeprazole was initiated; the exact dose and treatment dates were unavailable
Subsequent 15 days	Because abdominal pain did not improve, the patient self-administered approximately 2 L/day of a prepared P. major infusion. The preparation was not botanically authenticated or chemically analyzed
After herbal exposure	Abdominal pain worsened, followed by jaundice, dark urine, and acholic stools
June 17-20, 2024	Enteral N-acetylcysteine was administered using a 72-hour regimen consisting of a 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 maintenance doses
June 21-July 1, 2024	Prednisolone 40 mg/day was administered; the clinical course nevertheless progressed
July 2, 2024	The first complete laboratory panel available for retrospective review showed severe liver injury and dysfunction. INR reached 2.27, serum ammonia was 146 μmol/L, and hepatic encephalopathy progressed to West Haven grade III
July 3, 2024	Non-contrast head CT showed no significant acute intracranial abnormality, including no acute hemorrhage, mass lesion, midline shift, or herniation
July 4, 2024	Urgent orthotopic liver transplantation was performed because of rapidly progressive acute liver failure with grade III hepatic encephalopathy and worsening hepatic dysfunction
July-August 2024	Initial graft recovery was documented by rapid normalization of INR, progressive reductions in bilirubin and aminotransferases, and preserved renal function. Early post-transplant CMV DNAemia subsequently became undetectable
March 20, 2025	Liver biopsy demonstrated acute cellular rejection, Banff Rejection Activity Index 5
March 25-27, 2025	First course of high-dose intravenous methylprednisolone (1 g/day for 3 days), with partial biochemical improvement
April 7, 2025	Repeat liver biopsy demonstrated persistent/recurrent acute cellular rejection, Banff Rejection Activity Index 6
April 11-13, 2025	Second course of high-dose intravenous methylprednisolone (1 g/day for 3 days); graft dysfunction and marked cholestasis persisted
May 15, 2025	A third liver biopsy again demonstrated acute cellular rejection, Banff Rejection Activity Index 6. Complementary C4d immunohistochemistry showed no vascular endothelial staining, arguing against chronic rejection
May 30-June 6, 2025	Thymoglobulin was administered for steroid-refractory rejection
June-July 2025	The period of intensified immunosuppression was complicated by CMV DNAemia (176 IU/mL on June 3, 2025 and 15338 IU/mL on June 17, 2025), which was undetectable by July 29, 2025. Liver biochemical tests subsequently improved
September 1, 2026	At the most recent follow-up, the patient was alive with preserved graft synthetic and renal function: AST 31 U/L, ALT 35 U/L, ALP 95 U/L, GGT 88 U/L, total bilirubin 0.39 mg/dL, albumin 4.5 g/dL, INR 1.08, and creatinine 0.72 mg/dL

ALF: Acute liver failure; CT: Computed tomography; CMV: Cytomegalovirus; INR: International normalized ratio; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: γ-glutamyl transferase; P. major: Plantago major.

History of past illness

The patient had no known history of chronic liver disease or other relevant pre-existing medical conditions. Shortly before the acute hepatic event, she had been diagnosed with moderate erosive gastritis and treated with omeprazole. Because the exact dose, treatment duration, and discontinuation date could not be reliably reconstructed, omeprazole was considered a competing medication exposure in the causality assessment.

Personal and family history

The patient reported self-administration of P. major infusion as described above. The patient denied acetaminophen use, alcohol consumption, and illicit or recreational drug use. No additional prescription medications, over-the-counter medications, or dietary supplements were reported beyond the previously documented omeprazole and P. major infusion. No known history of chronic liver disease was reported. No relevant family history contributing to the acute hepatic presentation was identified in the available clinical records.

Physical examination

The patient was jaundiced and developed progressive alteration in mental status, culminating in grade III hepatic encephalopathy according to the West Haven criteria. Despite neurological deterioration, she remained hemodynamically stable, without clinically significant circulatory instability during the documented pre-transplant course.

Laboratory examinations

At the first complete laboratory assessment available for retrospective review on July 2, 2024, aspartate aminotransferase was 370 U/L, alanine aminotransferase was 338 U/L [upper limit of normal (ULN), 35 U/L], alkaline phosphatase was 194 U/L (ULN, 126 U/L), gamma-glutamyl transferase was 322 U/L, total bilirubin was 14.41 mg/dL, direct bilirubin was 11.83 mg/dL, albumin was 2.6 g/dL, and INR was 2.11. The calculated R factor was 6.27, consistent with a hepatocellular pattern of liver injury. These values represent the first complete laboratory panel available for retrospective review and should not necessarily be interpreted as the absolute biochemical peak of the initial injury.

During the subsequent pre-transplant course, INR reached 2.27, total bilirubin reached 15.10 mg/dL, serum ammonia was 146 μmol/L (reference range, 9-30 μmol/L), and arterial lactate reached 4.52 mmol/L. Renal function remained preserved, with serum creatinine ranging from approximately 0.30 mg/dL to 0.40 mg/dL.

The contemporaneous medical record documented viral hepatitis serologies and autoimmune liver-disease investigations as negative and documented that Wilson disease and hemochromatosis had been investigated and excluded. However, the individual assays, numerical results, testing methods, and exact dates of these investigations were not available for independent retrospective verification. Serial biochemical findings before and after liver transplantation are summarized in Table 2, and the available etiologic evaluation is summarized in Table 3.

Table 2 Serial laboratory findings before and after liver transplantation.

Date/clinical phase	AST (U/L)	ALT (U/L)	ALP (U/L)	GGT (U/L)	Total bilirubin (mg/dL)	INR	Creatinine (mg/dL)	Ammonia or lactate, when relevant
July 2, 2024/first complete pre-LT panel	370	338	194	322	14.41	2.111	0.30	Ammonia 146 μmol/L
July 3, 2024/pre-LT	300	307	228	317	14.10	1.92	0.39	Lactate 4.52 mmol/L
July 4, 2024/pre-LT	284	282	202	301	12.41	1.95	0.40	Lactate 3.40 mmol/L
July 5, 2024/POD1	2044	1325	121	326	10.00	1.75	0.40	Lactate 3.65 mmol/L
July 10, 2024/POD6	101	387	135	358	2.79	1.05	0.43	Lactate 1.60 mmol/L
August 9, 2024/early recovery	40	55	81	132	0.97	0.99	0.70	-
January 21, 2025/stable graft function	23	27	-	23	0.30	1.01	-	-
March 14, 2025/graft dysfunction	731	877	327	428	8.10	-	0.48	-
April 22, 2025/persistent rejection/cholestasis	172	397	258	851	17.20	-	0.62	-
May 13, 2025/persistent graft dysfunction	117	193	192	501	14.90	-	0.57	-
July 29, 2025/recovery after intensified treatment	127	245	-	986	1.63	-	0.54	-
September 1, 2026/most recent follow-up	31	35	95	88	0.39	1.08	0.72	-

¹On July 2, 2024, INR was 2.11 in the selected first complete panel and subsequently reached 2.27. The R factor for the July 2, 2024 panel was 6.27, calculated as (alanine aminotransferase/upper limit of normal)/(alkaline phosphatase/upper limit of normal) = (338/35)/(194/126), indicating a hepatocellular pattern. The July 2, 2024 pre-liver transplantation panel is the first complete panel available for retrospective review and may not represent the true biochemical peak of the initial suspected herb-induced injury. Early post-transplant aminotransferase elevations reflect graft-related postoperative changes and are not the peak of the initial suspected herb-induced injury. Em dashes indicate that the variable was not measured or was not available at that time. LT: Liver transplantation; POD: Postoperative day; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: γ-glutamyl transferase; INR: International normalized ratio.

Table 3 Etiologic evaluation of acute liver failure and limitations of retrospective causality assessment.

Etiologic category	Investigation or exposure	Available result/documentation	Interpretation or limitation
Viral hepatitis	Viral hepatitis investigation	Documented as negative in the medical record	The contemporaneous medical record documented negative viral hepatitis testing; individual viral assays, numerical results, methods, and testing dates were unavailable for independent retrospective verification
Autoimmune liver disease	Autoimmune liver-disease investigation	Documented as negative in the medical record	The medical record documented a negative autoimmune liver-disease investigation; individual autoantibodies, immunoglobulin results, methods, and testing dates were unavailable for independent retrospective verification
Wilson disease	Wilson disease evaluation	Documented as investigated and excluded	Wilson disease was documented as investigated and excluded; the individual diagnostic tests, numerical results, methods, and dates were unavailable for independent retrospective verification
Hemochromatosis	Hemochromatosis evaluation	Documented as investigated and excluded	Hemochromatosis was documented as investigated and excluded; the individual diagnostic tests, numerical results, methods, and dates were unavailable for independent retrospective verification
Additional viral testing	HEV, HSV, EBV, and CMV testing	Documented as investigated/negative in the medical record	The original individual assay results, methods, and testing dates were unavailable for independent retrospective verification
Drug or toxin exposure	Acetaminophen, alcohol, illicit/recreational drugs, and other medications or supplements	Patient denied acetaminophen use, alcohol consumption, and illicit/recreational drug use; no additional medications or supplements were reported beyond omeprazole and P. major infusion	No competing exposure was identified from the documented history other than omeprazole. A serum acetaminophen concentration and formal toxicology screening results were not available for retrospective verification
Competing medication	Omeprazole	Documented exposure	The exact dose and exposure dates were unavailable; omeprazole was retained as a competing exposure
Herbal exposure	P. major infusion	Approximately 2 L/day for 15 consecutive days	This represents prepared infusion volume only. Botanical authentication, quantified botanical dose, chemical analysis, and contamination testing were not available
Rechallenge	Re-exposure to P. major	Not performed	No rechallenge occurred
Dechallenge	Biochemical course after cessation	Not interpretable	Liver transplantation occurred before biochemical recovery, preventing interpretation of a conventional dechallenge course

Causality note: A formal Roussel Uclaf Causality Assessment Method score could not be calculated reliably because mandatory elements were missing, despite the negative results from important portions of the etiologic work-up. The association with Plantago major should therefore remain presumptive and temporally based rather than definitive. CMV: Cytomegalovirus; EBV: Epstein–Barr virus; HEV: Hepatitis E virus; HSV: Herpes simplex virus; P. major: Plantago major.

Imaging examinations

A noncontrast head computed tomography scan was performed on July 3, 2024, during evaluation for urgent liver transplantation (Figure 1). The examination showed no significant acute intracranial abnormalities, including no acute intracranial hemorrhage, mass lesion, midline shift, or cerebral or cerebellar tonsillar herniation. The basal cisterns remained patent. Electroencephalography and brain magnetic resonance imaging reports were not available for retrospective review.

Figure 1 Intraoperative appearance of the native liver in situ before explantation during liver transplantation, showing heterogeneous mottled discoloration of the hepatic surface. The falciform ligament provides anatomical orientation between the right and left hepatic lobes.

FINAL DIAGNOSIS

ALF with suspected HILI temporally associated with intensive P. major tea consumption.

TREATMENT

Before transplantation, the patient received enteral N-acetylcysteine using a 72-hour regimen consisting of a loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours for 17 maintenance doses, from June 17, 2024 to June 20, 2024. Prednisolone 40 mg/day was subsequently administered from June 21, 2024 to July 1, 2024. The specific contemporaneous rationale for corticosteroid initiation could not be reconstructed from the available records. Because autoimmune liver-disease investigations were documented as negative, corticosteroid administration is reported here as part of the clinical course and should not be interpreted as standard therapy for suspected HILI. Despite these interventions, hepatic dysfunction and neurological status continued to deteriorate, progressing to grade III hepatic encephalopathy. Plasma exchange and other extracorporeal liver-support or blood-purification modalities were not available at the treating public institution.

Given the rapidly progressive ALF, worsening hepatic dysfunction, and progression to grade III hepatic encephalopathy, the multidisciplinary transplant team proceeded with urgent liver transplantation. The transplant assessment was reported to have incorporated the King’s College Criteria; however, the individual qualifying components could not be completely reconstructed from the records available for this retrospective report. On July 4, 2024, the patient underwent urgent orthotopic liver transplantation using the piggyback technique.

Macroscopic examination of the explanted native liver demonstrated heterogeneous brown discoloration and softened areas of the hepatic parenchyma (Figure 2). Histopathological examination showed massive hepatic necrosis, marked cholestasis, and areas of hepatocellular regeneration, without fibrosis or steatosis (Figure 3). These findings were nonspecific and did not establish the etiology of the acute liver injury.

Figure 2 Gross cut-surface appearance of the explanted native liver, showing heterogeneous brown discoloration of the hepatic parenchyma. Histopathological examination of the explant subsequently demonstrated massive hepatic necrosis, marked intraductal cholestasis, and regenerative changes, without fibrosis or steatosis.

Figure 3 Histopathological examination of the explanted native liver. A: Low-power panoramic view showing extensive confluent areas of hepatic parenchymal necrosis with marked architectural distortion, interspersed with relatively preserved/regenerative parenchyma [hematoxylin and eosin (H&E), digital magnification 0.6×; scale bar = 2000 μm]; B: Intermediate-power view showing extensive hepatocellular necrosis with marked architectural disruption, regenerative changes, focal inflammatory cell aggregates, and bile plugs consistent with cholestasis (H&E, digital magnification 10.9×; scale bar = 100 μm); C: High-power view demonstrating regenerative hepatocellular changes with enlarged hepatocytes and nuclear variability, associated with prominent canalicular and intracellular bile pigment consistent with marked cholestasis (H&E, digital magnification 44.4×; scale bar = 20 μm); D: Reticulin stain demonstrating marked disruption and collapse of the reticulin framework in areas of severe parenchymal injury (digital magnification 8.0×; scale bar = 200 μm). These histopathological findings were nonspecific and did not establish the etiology of the acute liver injury.

OUTCOME AND FOLLOW-UP

Following liver transplantation, the patient initially demonstrated progressive biochemical and synthetic recovery, with rapid improvement in INR and bilirubin levels and preserved renal function. Early post-transplant aminotransferase elevations progressively declined and were considered part of the postoperative graft course rather than persistence of the pre-transplant liver injury.

During subsequent follow-up, graft dysfunction developed and three serial liver biopsies demonstrated persistent/recurrent acute cellular rejection, with Banff Rejection Activity Index scores of 5, 6, and 6. The first episode was treated with intravenous methylprednisolone 1 g/day for 3 days from March 25, 2025 to March 27, 2025. Persistent graft dysfunction prompted a second course of intravenous methylprednisolone 1 g/day for 3 days from April 11, 2025 to April 13, 2025. Because acute cellular rejection persisted despite corticosteroid therapy, thymoglobulin was subsequently administered for steroid-refractory rejection from May 30, 2025 to June 6, 2025. Complementary C4d immunohistochemistry showed no vascular endothelial staining, which argued against chronic rejection.

Hepatobiliary imaging performed during the period of graft dysfunction demonstrated preserved graft morphology, patent hepatic vasculature, and no evidence of biliary obstruction. The period of intensified immunosuppression was also complicated by CMV DNAemia, which subsequently became undetectable. These post-transplant complications were considered transplant-related events and not persistence or recurrence of the suspected pre-transplant HILI.

Liver biochemical tests subsequently improved. At the most recent follow-up on September 1, 2026, more than two years after transplantation, the patient was alive with preserved graft synthetic and renal function. Laboratory results showed aspartate aminotransferase 31 U/L, alanine aminotransferase 35 U/L, alkaline phosphatase 95 U/L, γ-glutamyl transferase 88 U/L, total bilirubin 0.39 mg/dL, albumin 4.5 g/dL, INR 1.08, and serum creatinine 0.72 mg/dL. The longitudinal clinical and biochemical course is summarized in Tables 1 and 2.

Quantitative CMV DNAemia results are summarized in Table 1. Details of the specific antiviral regimen used for CMV DNAemia, the current maintenance immunosuppressive regimen, and a formal assessment of medication adherence were not available for retrospective verification.

DISCUSSION

P. major, commonly known in Brazil as tanchagem, is widely used in traditional medicine. Its leaves contain several biologically active compounds, including flavonoids, polyphenols, alkaloids, and polysaccharides, and experimental studies have described potential anti-inflammatory, antioxidant, anti-ulcer, and hepatoprotective properties[4]. These experimental findings, however, do not establish the safety of all preparations or exclude the possibility of uncommon adverse reactions in susceptible individuals.

Herbal remedies are often used because of perceived therapeutic benefits[5]. More broadly, users of complementary and alternative medicine may perceive these approaches as less harmful than conventional treatments[6]. Nevertheless, HILI is a recognized cause of clinically significant hepatic injury. Causality assessment can be particularly challenging because herbal products may contain multiple constituents and may vary in composition, concentration, preparation, and purity[2,3,7].

Published human data on P. major remain limited and have primarily addressed therapeutic use rather than hepatotoxicity. A randomized double-blind clinical trial of P. major seed supplementation in patients with nonalcoholic fatty liver disease reported reductions in serum aminotransferase levels, whereas a narrative review of traditional and modern phytotherapy described mainly gastrointestinal, hypersensitivity, and dermatologic adverse reactions rather than severe liver injury[8,9]. A focused literature search did not identify well-documented published human cases of severe hepatotoxicity specifically attributed to P. major. These observations do not establish the safety of concentrated or nonstandardized preparations and do not exclude rare idiosyncratic injury. Accordingly, the present case should be interpreted as a potential pharmacovigilance signal rather than evidence of an established hepatotoxic profile of P. major.

In the present case, the temporal relationship between intensive P. major tea consumption and the subsequent development of ALF raised suspicion of HILI. At the first complete laboratory assessment available for retrospective review, the R factor was 6.27, indicating a hepatocellular pattern of injury. However, the reported intake of approximately 2 L/day for 15 consecutive days represents the volume of prepared infusion rather than a quantified botanical dose. The amount of plant material used, the concentration of the infusion, and the exact preparation method were unavailable. Therefore, neither a cumulative-dose effect nor a dose-response relationship can be established.

The mechanism underlying the hepatic injury also remains uncertain. Possible explanations include an idiosyncratic reaction to the herbal preparation, variability in infusion concentration, contamination or adulteration, or botanical misidentification. These possibilities should be regarded as hypotheses rather than demonstrated mechanisms because the consumed preparation was not botanically authenticated and no residual plant material or infusion was available for chemical or toxicological analysis. Consequently, this case cannot establish whether the hepatic injury was directly attributable to P. major itself or to another characteristic of the consumed preparation.

Green tea represents a distinct and more extensively studied example of herbal-product-associated hepatotoxicity. Clinical and experimental studies have described predominantly hepatocellular injury associated with green tea preparations and extracts[10-12]. These reports demonstrate that herbal products with perceived health benefits may, in some circumstances, be associated with clinically important liver injury. However, the chemical composition and proposed mechanisms of green tea-associated hepatotoxicity are distinct from those of P. major; therefore, evidence derived from green tea should not be extrapolated to establish a mechanism of liver injury in the present case.

Causality assessment in suspected HILI requires careful consideration of the temporal relationship between exposure and liver injury, competing medications, exclusion of alternative etiologies, the biochemical pattern of injury, and, when possible, characterization of the implicated herbal product[2,3,7,13].

Structured causality assessment tools such as RUCAM have recognized limitations, particularly when applied retrospectively and when key information regarding chronology, dechallenge, competing causes, and herbal-product characterization is incomplete[14].

In this patient, the contemporaneous medical record documented negative investigations for viral hepatitis and autoimmune liver disease and documented that Wilson disease and hemochromatosis had been investigated and excluded. However, the original individual test results were not available for independent retrospective verification. Nevertheless, omeprazole represented a competing medication exposure, and its exact dose and exposure dates could not be reliably reconstructed. Although clinically apparent liver injury associated with omeprazole is rare, hepatocellular injury and fulminant hepatic failure have been reported; therefore, omeprazole was retained as a competing exposure[15].

The patient denied acetaminophen use, alcohol consumption, and illicit or recreational drug use, and no additional medications or dietary supplements were reported beyond omeprazole and P. major infusion. However, serum acetaminophen concentration and formal toxicology screening results were not available for retrospective verification. For these reasons, a reliable formal Roussel Uclaf Causality Assessment Method score could not be calculated.

Histopathological examination of the explanted native liver demonstrated massive hepatic necrosis, marked cholestasis, and regenerative changes without fibrosis or steatosis. These findings confirmed the severity and acute nature of the hepatic injury but were nonspecific and cannot independently establish P. major as the causative agent. The absence of fibrosis supported the diagnosis of ALF rather than acute decompensation of previously established chronic liver disease.

An additional consideration is that the subsequent post-transplant graft dysfunction should not be interpreted as persistence or recurrence of the suspected herbal injury. The patient initially showed biochemical and synthetic recovery after transplantation and later developed biopsy-proven acute cellular rejection, documented on three serial biopsies, with Banff Rejection Activity Index scores of 5, 6, and 6. These episodes responded progressively to intensified immunosuppressive treatment and represented well-characterized transplant-related complications rather than evidence of continued exposure-related hepatotoxicity.

This case has several important limitations. It represents a single retrospective observation, and the herbal preparation was not botanically authenticated. The quantity of plant material, infusion concentration, preparation method, and potential contamination or adulteration could not be determined. Omeprazole constituted a competing exposure. A conventional biochemical dechallenge could not be assessed because urgent liver transplantation interrupted the natural course of the liver injury, and rechallenge was neither performed nor ethically appropriate. Furthermore, some components of the original etiologic and toxicological investigation could not be independently reconstructed, and the histopathological findings were nonspecific. Accordingly, although the temporal association is clinically relevant, a definitive causal relationship between P. major consumption and ALF cannot be established.

Despite these limitations, this case reinforces the importance of systematically investigating herbal-product exposure in patients presenting with otherwise unexplained acute liver injury or ALF. Detailed characterization of the herbal preparation, botanical authentication, product-quality assessment, and structured pharmacovigilance may improve causal assessment in future suspected cases of HILI.

CONCLUSION

HILI represents an important challenge in clinical practice, particularly because herbal products are frequently perceived as inherently safe. P. major (tanchagem) has been widely used in traditional medicine and has predominantly been described in the literature in relation to its therapeutic and biological properties[16].

This case describes severe ALF temporally associated with intensive consumption of P. major tea and requiring urgent liver transplantation. Although the temporal relationship raises suspicion for HILI, a definitive causal relationship cannot be established because the herbal preparation was not botanically authenticated or chemically analyzed, the botanical dose could not be quantified, and competing exposures and limitations of the retrospective causality assessment remain.

The case represents a clinically relevant pharmacovigilance signal and highlights the importance of systematically investigating herbal-product use in patients with otherwise unexplained acute liver injury or ALF. Future reports should prioritize detailed exposure characterization, botanical authentication, product-quality and toxicological assessment, and structured causality evaluation to better define whether P. major may be associated with clinically significant hepatotoxicity.

ACKNOWLEDGEMENTS

The authors would like to thank all colleagues and health professionals who contributed to the clinical management and diagnosis of this case, as well as those who provided support during the preparation of this manuscript.