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

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.

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.