Acute liver failure caused by alkaloids from traditional Chinese medicine: A case report

Abstract

BACKGROUND

Case reports of traditional Chinese medicine (TCM)-related liver injury have been relatively limited in the past decade. In more than 1200 cases of drug-induced liver injury, TCM accounted for 20.6% of the cases. Among the chemical components that cause important liver injury, alkaloids (such as chrysanthemum, notoginseng) are typical, mainly causing veno-occlusive disease, and progressing to liver failure in severe cases. Other alkaloids, such as aristolochic acid, have also been associated with liver cancer risk.

CASE SUMMARY

In this case report, we present a unique case of a 35-year-old female patient with progressive jaundice within one month after intake of alkaloid-containing TCM, followed by a rapid development of liver injury that progressed to liver failure, and finally, receiving liver transplantation. The clinical diagnosis of TCM-related liver injury is usually an exclusion diagnosis, with a lack of characteristic imaging signs or specific clinical symptoms, resulting in a delay in diagnosis.

CONCLUSION

This case shows that the patient received liver transplantation due to progressive liver failure after multiple conservative treatment modalities, thus, with a good prognosis and survival. It provides valuable guidance for the clinical diagnosis of liver injury and the timing of liver transplantation treatment caused by alkaloid hepatotoxic drugs.

Key Words: Liver transplantation; Veno-occlusive disease; Traditional Chinese medicine-related liver injury; Liver failure; Case report

Core Tip: This case report presents a patient who suffered from liver damage due to the intake of alkaloid-containing traditional Chinese medicine and eventually achieved good therapeutic outcomes through liver transplantation. It explores the clinical diagnosis of liver damage caused by alkaloid hepatotoxic drugs and the appropriate timing for liver transplantation treatment, providing valuable guidance for clinical treatment.

INTRODUCTION

Traditional Chinese medicine (TCM)-related liver injury (TCM-LI) includes both acute and chronic liver injury. Pathological types[1] include hepatocellular type, cholestatic type, and mixed type. It is characterized by complex components, diverse mechanisms, and significant individual differences[2]. In terms of prevalence, the proportion of women is slightly higher (about 55%), and middle-aged and older people and those with preexisting liver disease are at greater risk[3]. Studies show that TCM-LI accounts for 20% to 30% of all drug-induced liver injury (DILI) cases[4], but published case reports of alkaloid-induced liver injury in TCM-LI are rare[5]. Here, we present a case report of acute liver injury caused by the administration of TCM containing alkaloids, which was successfully treated with liver transplantation. This intervention achieved successful recovery of liver function and became the ultimate life-saving treatment modality for patients. This case report is of great significance for clinicians to make the diagnosis of TCM-LI and timely control the timing of liver transplantation for irreversible liver injury.

CASE PRESENTATION

Chief complaints

A 35-year-old female presented with progressive jaundice for over one month.

History of present illness

One month previously, she had presented to a local TCM hospital for treatment of facial acne. She developed jaundice 7 days after initiating TCM therapy. From July 16 to August 22, 2024, she consumed 30 doses of a TCM decoction containing: Panax ginseng leaves, Usnea diffracta, Schizonepeta tenuifolia, Saposhnikovia divaricata, Angelica dahurica, Glycyrrhiza uralensis, Zanthoxylum bungeanum, and Sophora flavescens (specific dosages unspecified; prepared by boiling in 200 mL water). The patient stated that for the three months prior to the onset of the illness, she had not taken any other medications except TCM. She had received artificial liver plasma exchange combined with hemofiltration treatment four times.

History of past illness

The patient did not have a history of diabetes, hypertension, heart disease, tuberculosis, chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, or any other diseases.

Personal and family history

The patient did not have a history of smoking or alcohol consumption, and there was no family history of similar diseases.

Physical examination

Physical examination revealed an altered mental status, restlessness, uncooperative behavior, stable respiration, sallow complexion, severe jaundice, mild abdominal distension, and traces of lower limb edema. No hepatomegaly, splenomegaly, or significant ascites was detected.

Laboratory examinations

On the day of admission, the emergency blood tests of the patient were as follows: Total bilirubin (527.10 μmol/L), direct bilirubin (166.40 μmol/L), serum alanine aminotransferase (ALT, 62.00 IU/L), serum aspartate aminotransferase (AST, 116.00 IU/L), albumin (36.30), platelet (51 × 10⁹/L), red blood cell (1.89 × 10⁹/L), hemoglobin (65 g/L). The detailed test results and the changes in the regular postoperative re-examination tests are shown in Tables 1 and 2. The laboratory findings supported the diagnosis of TCM-LI. Laboratory findings supported the diagnosis of TCM-LI.

Table 1 Laboratory values and immunosuppression (operation date: October 30, 2024).

Laboratory tests	Item	POD 0	POD 1	POD 7	POD 14
Blood test	WBC (109/L)	14.23	10.51	7.71	8.00
	RBC (109/L)	1.89	3.20	2.80	2.63
	Hb (g/L)	65.00	101.00	90.00	117.00
	PLT (109/L)	51.00	28.00	53.00	125.00
Biochemistry	ALT (IU/L)	62.00	545.00	61.30	76.80
	AST (IU/L)	116.00	642.20	108.70	82.70
	ALP (IU/L)	96.00	156.00	270.00	202.00
	γ-GT (IU/L)	25.00	211.00	253.20	213.8
	TBIL (μmol/L)	527.10	183.60	314.20	107.1
	DBIL (μmol/L)	166.40	136.10	303.80	85.00
	ALB (g/L)	36.30	36.20	43.00	46.9
	BUN (mmol/L)	8.20	54.00	52.00	53.00
	CREA (μmol/L)	43.00	69.67	29.42	31.66
	Na (mmol/L)	138.00	136.00	138.00	136.00
Coagulation	PT (seconds)	45.28	13.10	14.70	13.30
	INR	4.13	1.13	1.18	1.03
	APTT (seconds)	86.01	27.90	29.90	35.70
	FIB (g/L)	0.47	2.30	3.40	3.57
	TT (seconds)	32.31	18.00	15.10	15.50
Immunosuppressants	Tacrolimus (mg)	-	-	7.26	4.99

POD: Postoperation day; WBC: White blood cell; RBC: Red blood cell; Hb: Hemoglobin; PLT: Platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; γ-GT: Gamma-glutamyltransferase; TBIL: Total bilirubin; DBIL: Direct bilirubin; ALB: Albumin; BUN: Blood urea nitrogen; CREA: Creatinine; Na: Sodium; PT: Prothrombin time; INR: International normalized ratio; APTT: Activated partial thromboplastin time; FIB: Fibrinogen; TT: Thrombin time.

Table 2 Major components of the traditional Chinese medicine prescription and their primary effects/adverse reactions.

Herb/Ref.	Primary chemical constituents	Main effects/adverse reactions
Ginseng leaf, Piao et al[11], 2020	Ginsenoside	Reduces fasting blood glucose, regulates lipid metabolism, lowers inflammation and oxidative stress; adverse effects: Reproductive and developmental toxicity, CNS overexcitation, skin rashes
Usnea, Sepahvand et al[12], 2021	Usnic acid	Hepatocyte toxicity (the specific mechanism is yet to be confirmed)
Saposhnikovia, Yang et al[13], 2020	Chromones	Antipyretic, analgesic, anti-inflammatory, antioxidant, and antiplatelet effects
Schizonepeta, Zhao and Zhou[14], 2022	Volatile oils	Antiviral, anti-inflammatory, antitumor, antibacterial, immunomodulatory, and hemostatic effects
Angelica root, Bae et al[15], 2022	Volatile oils	Anti-inflammatory, analgesic, antitumor, antioxidant, antibacterial, and skin-whitening properties
Licorice, Shang et al[16], 2022	Dihydroflavones, glycyrrhizin, glycyrrhiza polysaccharides	Antitumor, anti-inflammatory, antiviral, and hepatoprotective effects
Sophora root, Huang et al[17], 2021	Alkaloids, flavonoids	Lipid accumulation, hepatotoxicity, inducing hepatic cytochrome P450 enzymes and accelerating drug metabolism may lead to the accumulation of metabolic intermediates and damage to liver cells. Some patients are allergic to flavonoid components, which triggers immune hepatitis, manifested as elevated ALT and jaundice. High concentrations of oxymatrine interfere with the mitochondrial respiratory chain, resulting in reduced ATP synthesis and accumulation of ROS
Zanthoxylum bungeanum, Bhambhani et al[18], 2021	Alkaloids, volatile oil	Hepatotoxicity, affects the blood supply of the liver. The metabolite epoxymelitticin has strong hepatotoxicity, causing liver cell necrosis and DNA alkylation. Long-term intake increases the risk of liver cancer. Oxidative stress: High-dose volatile oil depletes glutathione, inducing oxidative damage. Metabolic burden: Long-term and large intake aggravates the metabolic burden on the liver, especially for patients with alcoholic liver disease or hepatitis

CNS: Central nervous system; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; ROS: Reactive oxygen species.

Imaging examinations

Preoperative abdominal computed tomography (CT) (Figure 1) demonstrated diffuse hepatic lesions, veno-occlusive disease (VOD), cirrhosis, splenomegaly, ascites, portal hypertension with collateral circulation, and pancreatic enlargement.

Figure 1 Abdominal computed tomography findings were diffuse hepatic lesions, veno-occlusive disease, cirrhosis, splenomegaly, ascites, and portal hypertension with collateral circulation.

FINAL DIAGNOSIS

The final diagnosis was drug-induced hepatitis with liver failure, hepatic encephalopathy, ascites, hypoalbuminemia, electrolyte imbalance, severe anemia, and thrombocytopenia. Child-Pugh score was 11 (grade C), and the model for end-stage liver disease score was 35.

TREATMENT

On October 30, 2024, she underwent orthotopic liver transplantation in a standard procedure (cross-clamp). Postoperative treatment followed standard procedures as previously reported. Briefly, immunosuppressive therapy was initiated with tacrolimus (3 mg q 12 hours), along with anti-infection treatment. Routine tests included liver function tests, inflammatory markers, and hepatic vascular Doppler studies, as well as enhanced CT to evaluate donor liver structure and blood supply.

On November 8, 2024, based on elevated liver enzymes, a lack of triphasic hepatic vein signal in Doppler ultrasound, and a consecutive angiography. She underwent inferior vena cava (IVC) angiography + hepatic venography + angioplasty under anesthesia consultation due to severe stenosis at the hepatic right vein-IVC junction and IVC hepatic segment stenosis with extensive collateral circulation. Post-procedure, lower limb edema significantly resolved, and bilirubin levels declined markedly (explaining the transient postoperative bilirubin elevation). Tacrolimus dosage was adjusted to 4 mg q 12 hours, with stable therapeutic levels thereafter.

OUTCOME AND FOLLOW-UP

The patient recovered well with normalization of liver function and coagulation, stable tacrolimus concentration, and normal hepatic artery and portal flow confirmed by Doppler ultrasound (Figure 2). There was no ascites or pleural effusion. She was discharged on November 29, 2024. Since discharge from the hospital, there has been no occurrence of jaundice, abdominal pain, or ascites.

Figure 2 Laboratory values and Roussel Uclaf Causality Assessment Method calculations retained in original format with units standardized (μmol/L, U/L). A: The changes in R value before and after surgery; B: The change in tacrolimus concentration after surgery; C: Changes in various liver function indicators after surgery. POD: Postoperation day; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; TBIL: Total bilirubin; DBIL: Direct bilirubin.

DISCUSSION

The causes of TCM-LI mainly include four categories: (1) Direct liver injury due to components in TCM[6,7]: Alkaloids (such as pyrrolixine alkaloids in notoginseng) lead to hepatic sinus obstruction syndrome (VOD); diterpene lactones (such as Diosbulbin B in yellow) activate reactive metabolites and cause oxidative stress; anthraquinones (such as 2,3,5,4’-tetrahydroxystilbene-2-O-beta-D-glucopyranoside in Polygonum multiflorum) induce cytochrome P450 2E1, cytochrome P450 3A4 and other enzymes, and aggravate the hepatotoxicity of acetaminophen and other drugs; (2) Genetic polymorphisms[8] (e.g., HLA-B*35:01 associated with hepatotoxicity), age (metabolic immaturity in children), sex (estrogen may increase the risk of liver injury); (3) Overdose or long-term use[9] (such as bupleurum daily dose > 19 g), processing defects (such as Polygonum multiflorum without steaming), combination of Chinese and Western medicine (such as the combination of tanned Chinese medicine and chemotherapy drugs); and (4) Name confusion (such as soil notoginseng as field notoginseng), heavy metal pollution (mercury in cinnabar), adulteration (illegal addition of health care products)[10]. In this case, the patient’s TCM prescription comprised: Panax ginseng leaves, Usnea diffracta, Schizonepeta tenuifolia, Saposhnikovia divaricata, Angelica dahurica, Glycyrrhiza uralensis, Zanthoxylum bungeanum, and Sophora flavescens. We systematically reviewed the primary chemical constituents and hepatotoxic mechanisms of each herb[11-18] (Table 2). We found that the chemical composition of Sophora flavescens and Zanthoxylum bungeanum contains alkaloids, and alkaloids are known to have toxic effects on the liver[19].

According to PubMed database search results (as of March 22, 2025), approximately 120-150 alkaloid-related liver injuries, of which case reports accounted for about 30%-40% (about 36-60). Following the analysis and summary of these documents and case reports, alkaloids were mainly divided into two types[20]: Pyronaridine alkaloid and isoquinoline alkaloid, of which pyrrolizidine alkaloids accounted for 50%-70% of alkaloid-related liver injury. The mechanism of damage lies in pyroriridine alkaloids metabolites through the formation of DNA adducts and oxidative stress, leading to hepatic sinusoidal endothelial cell injury and microthrombosis, manifesting as VOD[21]; while the mechanism of damage due to isoquinoline alkaloids lies in the generation of toxic metabolites through cytochrome P450 3A4 metabolic activation, to induce mitochondrial dysfunction, and patients generally present with cholestasis or mixed liver injury[22]. Histopathological examination (Figure 3) showed that the submitted liver tissue revealed bridging necrosis and confluent necrosis of hepatocytes, accompanied by nodular regeneration of surrounding hepatocytes, ductular proliferation at the lobular periphery with marked lymphocytic infiltration, focal fibrosis, and prominent cholestasis. These findings were consistent with the pathological findings of VOD. This proved that the liver injury was characteristic of injury due to pyrrolizidine alkaloid in bitter ginseng. The R value is a critical parameter used to assess the type of liver injury caused by drugs[23]. It is defined as the ratio of ALT level to AST level, normalized to the upper limit of normal for both enzymes. The R value plays a crucial role in differentiating between hepatocellular injury, cholestatic injury, and mixed injury. R < 2 suggests a predominantly cholestatic injury, where there is a significant elevation in alkaline phosphatase relative to ALT and AST. A R ≥ 5 indicates hepatocellular injury, where ALT and AST are markedly elevated, and alkaline phosphatase may not show significant elevation. A value of 2 ≤ R < 5 suggests a mixed type of injury. In this case, the calculated R-value (Figure 2) classified the injury as cholestatic type. Thus, characteristic liver damage due to isoquinoline alkaloids was proved. With regard to interactions between alkaloid drugs and their compatibility with other drugs, no adverse reactions have been reported.

Figure 3 Postoperative pathology. A: Severe interface hepatitis: Massive lymphocytic infiltration, hematoxylin and eosin (HE) stained, 4 ×; B: Portal inflammation: Lymphocytic infiltration in the portal area, with markedly dilated portal vein branches (arrow indicates dilated portal branches), HE, 4 ×; C: Inflammatory infiltrate: Predominantly lymphocytes, HE, 4 ×; D: Bile thrombus formation (circled area shows bile thrombi), HE, 10 ×; E: Sinusoidal dilatation (Disse space), HE, 10 ×; F: Dense bile ductular proliferation (circled area shows clustered proliferating bile ductules), HE, 10 ×.

The diagnosis of TCM-LI should be based on the diagnostic principle of exclusion[24], combined with medical history, clinical manifestations, laboratory and imaging examinations, and pass pathological verification if necessary. The first step is the medical history: The name, composition, dose, course, and withdrawal time of TCM (including compound preparation, single medicine, tea drink), health care products (such as dietary supplements) used in the past 3-6 months should be recorded in detail. After repeated careful questioning, it was clear that the patient had only taken TCM one month ago, and the composition of the prescription was known, but the dosage was unknown. No history of alcohol abuse, viral hepatitis (hepatitis A virus, HBV, HCV, hepatitis E virus), metabolic disease, autoimmune liver disease, or recent use of other hepatotoxic drugs (e.g., acetaminophen, anti-tuberculosis agents) was then confirmed. The second step evaluated clinical status. On admission, the patient’s clinical manifestations were hepatitis with hepatic failure, hepatic encephalopathy, ascites, hypoalbuminemia, electrolyte imbalance, severe anemia, and thrombocytopenia, which were consistent with the clinical manifestations of TCM-LI. In addition, attention should be paid to the patient’s laboratory examination results. When the patient was admitted, ALT was 62 IU/L, and AST was 116 IU/L, which were higher than the normal values, indicating hepatocyte injury. Total bilirubin was 527.1 μmol/L and sharply increased within a short time, indicating hepatocyte injury and a critical condition. Hepatitis A virus-immunoglobulin M, HBV-DNA, HCV-RNA, hepatitis E virus-immunoglobulin M, and other virus antibodies were also determined, and autoimmune hepatitis and viral hepatitis were finally excluded (Table 3). The third step is to view the patient’s imaging findings. In this patient, preoperative abdominal CT demonstrated diffuse hepatic lesions, VOD, cirrhosis, splenomegaly, ascites, portal hypertension with collateral circulation, and pancreatic enlargement. Structural lesions such as biliary obstruction, liver cirrhosis, liver fat infiltration, and liver cancer were excluded. The patient was evaluated using the Roussel Uclaf Causality Assessment Method (RUCAM)[25]. RUCAM, a semi-quantitative scoring tool for assessing the causality of DILI, was designed to determine whether liver injury was associated with drugs or herbal medicines using a standardized process. Since its introduction in 1993, its objectivity and reproducibility have made it a widely used diagnostic aid in clinical and scientific research. RUCAM consists of seven core indicators with a total score ranging from -9 to +14, with > 8 points: Most likely DILI (combined with clinical verification); 6-8 points: Most likely DILI (recommended as the diagnostic basis); 3-5 points: Possibly drug related (further exclusion of other etiologies); 0 points: Drug association can be excluded. Based on the patient’s clinical manifestations, onset occurred within 5-90 days after the first medication or within 15 days after discontinuation of the medication (+2); all 7 types of causes, such as viral hepatitis, were completely ruled out (+2); the drug instructions indicate hepatotoxicity (+2); literature reports (+1). The patient received a final score of 77 points, which showed her condition was most likely DILI. The patient’s postoperative pathological characteristics were consistent with those of liver injury caused by alkaloid drugs, resulting in the diagnosis of TCM-LI.

Table 3 Viral immunity test.

Item	Result
HAV	Negative
HBV	Negative
HCV-IgG	Negative
HEV	Negative
HIV	Negative
TP	Negative
EBV	Negative
TOX	Negative
CMV	Negative
HSV	Negative
HBsAg (IU/mL)	Negative
HBeAg (S/CO)	Negative
HBsAb (mIU/mL)	Negative
HBeAb (S/CO)	Negative
HBcAb (S/CO)	Negative
HBV-DNA (IU/mL)	0 IU/mL

HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV-IgG: Hepatitis C virus-immunoglobulin G; HEV: Hepatitis E virus; HIV: Human immunodeficiency virus; TP: Treponema pallidum; EBV: Epstein-Barr virus; TOX: Toxoplasma; CMV: Cytomegalovirus; HSV: Herpes simplex virus; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; HBsAb: Hepatitis B surface antibody; S/CO: Signal/cut-off; HBeAb: Hepatitis B e antibody; HBcAb: Hepatitis B core antibody; HBV-DNA: Hepatitis B virus-deoxyribonucleic acid.

Based on the relevant indications for liver transplantation due to acute liver failure, we evaluated the King’s College criteria (for non-acetaminophen toxic acute liver failure), which included coagulation dysfunction: Prothrombin time > 35 seconds or international normalized ratio of 2.0 with no trend in improvement. This patient had a prothrombin time of 45.28 seconds and an international normalized ratio of 4.13, and a concurrent model for end-stage liver disease score of 35. Early liver transplantation can significantly improve the prognosis of patients with irreversible and rapidly progressive TCM-LI, but it requires strict screening for indications and timing of surgery. For reversible injury, conservative treatment is preferred. In clinical work, doctors should make a comprehensive judgment according to the specific condition, medical resources, and donor matching when making decisions on liver transplantation. This patient received four artificial liver treatments before admission and was in acute liver failure. Post-transplant follow-up suggests a good prognosis and favorable evidence for early liver transplantation in patients with acute liver failure[26].

CONCLUSION

In summary, this patient developed acute liver injury following the intake of TCM containing high levels of alkaloids, specifically Sophora flavescens and Zanthoxylum bungeanum, which ultimately resolved following liver transplantation. The pathological features and clinical presentation associated with alkaloid-induced hepatotoxicity are well documented in this case, providing valuable evidence for early consideration of liver transplantation in cases with irreversible liver injury. Early intervention may significantly improve patient survival and long-term prognosis. However, this study also highlights certain limitations. A critical limitation in evaluating the toxicity of TCM is the variability of preparation methods and the uncertainty regarding the actual concentration of toxic substances present in the consumed product. Notably, there is a lack of relevant literature detailing adverse interactions in patients taking TCM, and the precise etiology of TCM-LI remains inadequately defined. Further research is needed to investigate the hepatotoxic effects of individual TCM components to enhance safety and guide clinical practice.