A Rare Cause of Acute on Chronic Liver Failure (ACLF): Bakuchi-Induced Liver Injury

Abstract

Psoralea corylifolia Linn (Bakuchi or Babchi), commonly known as purple fleabane, is a popular herb used in Ayurvedic traditional medicine. Its seeds, called Fructus Psoraleae, are traditionally used for treating leprosy, vitiligo, and psoriasis in the absence of empirical evidence. We report the first case of acute on chronic liver failure (ACLF) caused by Bakuchi, a well-documented hepatotoxic agent, in a middle-aged female. Her liver function deteriorated progressively which prompted us to go for a liver biopsy which was consistent with diagnosis of herb-induced liver injury after excluding all competing causes. Fortunately, the patient improved gradually after herb withdrawal and supportive care. Patients with underlying chronic liver disease (CLD) should be aware of risks in using untested herbal formulations. This case emphasizes the need for increased surveillance to formulate guidelines regarding the regulation and informed use of herbal supplements in patients with chronic liver disease.

The use of Bakuchi seeds (Psoralea corylifolia Linn, also known as purple fleabane) is described in Ayurvedic and other alternative forms of medical system for non-empirical treatment of vitiligo and reducing the symptoms of leucoderma and psoriasis. It is also used in other conditions like osteoporosis, postmenopausal symptoms, depression, impotence, and leprosy in the absence of clinical evidence as well as a “safe and natural cure” for depigmentation of skin.^{1, 2, 3} The most important phytochemical component is monoterpenoid phenol called bakuchiol. Other bioactive compounds include psoralens, benzofuran derivatives, and flavonoids.⁴ Psoralen causes inhibition of the mTOR signaling pathway, mitochondrial injury, and impairment in liver regeneration with deleterious effects on liver lipid metabolism. The dose and frequency-related accumulation of psoralen has been shown to promote hepatotoxicity in small animal and in vitro studies.^{5, 6, 7} Herbal medications are implicated in asymptomatic anicteric acute hepatitis to full-blown cirrhosis with portal hypertension. Here, we present a rare case of acute on chronic liver failure (ACLF) in a 44-year-old woman who consumed Bakuchi seeds for vitiligo.

Case report

A 44-years-old lady presented to the outpatient clinic with a history of generalized weakness, jaundice, generalized itching for one month, and ascites for five days. Ascites was insidious in onset, gradually progressive, painless, and not associated with bilateral lower limb swelling. There was no associated history of fever, prodromal symptoms, loss of appetite, loss of weight, gastrointestinal (GI) blood loss, oliguria, and altered sensorium. She was diagnosed with rheumatoid arthritis five years back and was taking oral hydroxychloroquine (400 mg once a day). She was also diagnosed with vitiligo during the same time and gave a history of using Ayurvedic herbal formulation in the form of single ingredient Bakuchi seeds (twice a day) for the last six months. She stopped taking those Ayurvedic medications eight days back before her symptoms worsened. She denied any recreational drug use or over-the-counter medications and was a teetotaler. There was no history of liver disease in the family. On general examination, there was icterus and patches of vitiligo involving the left frontal region, bilateral upper and lower extremities, and right lower abdomen. Her BMI was 25.7 kg/m². Ascites was evident without other peripheral features of chronic liver failure. A syndromic provisional diagnosis of ACLF was made (APASL definition).⁸

Blood investigations revealed hemoglobin 10.9 g/dl, total leucocyte count – 29200/cu.mm, platelet count – 198000/cu.mm, international normalized ratio – 2.48, total bilirubin – 23.7 mg/dl, aspartate aminotransferase (SGOT) – 316 U/L, alanine aminotransferase (SGPT) – 141 U/L, alkaline phosphatase (ALP) – 302 U/L, total protein −5.7 g/dl, and serum albumin – 2.3 g/dl. Ultrasound of the abdomen with hepatoportal Doppler showed liver size of 12.9 cm, heterogenous, coarse echotexture, irregular, nodular margins with moderate ascites with normal sized (11.7 cm) spleen, and patent vasculature. Upper GI endoscopy showed three small esophageal varices with mild portal hypertensive gastropathy. Ascitic fluid examination showed high serum ascitic albumin gradient and low protein ascites without evidence of spontaneous bacterial peritonitis. There was no evidence of urinary tract infection, and blood cultures were sterile. Serum lactate and procalcitonin levels were normal. Her human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), anti-hepatitis C virus (HCV), hepatitis B virus (HBV) DNA, and hepatitis C virus (HCV) RNA were negative. Serum anti-nuclear antibody (ANA) was 1:100, anti- smooth muscle antibody (SMA) was weakly positive, anti- mitochondrial antibody (AMA) was negative, and serum immunoglobulin G (IgG) was 2.175 g/l (1.5 times elevation).

At this stage of illness, patient's Child-Turcotte-Pugh (CTP) score was 13, model for end-stage liver disease (MELD) score was 30, AARC score was 8, pre-biopsy revised autoimmune hepatitis score was 11, and simplified autoimmune hepatitis score was 6. She underwent transjugular liver biopsy and was empirically started on oral steroids (0.75 mg/kg), diuretics, and non-selective beta blockers.⁹

Liver biopsy showed marked intrahepatic cholestasis with ballooning and feathery degeneration, focal interface activity, broad fibrous septa with fibrosis, marked ductular reaction, dense lymphoplasmacytic inflammatory infiltrate admixed with eosinophils, and neutrophils with areas of collapse of liver parenchyma (Figure 1). This was highly suggestive of herb-induced cholestatic hepatitis in the background of cirrhosis possibly related to Bakuchi seed consumption in the absence of classical features of AIH. RUCAM score was 4, the revised autoimmune hepatitis score post-biopsy was 12, and simplified autoimmune hepatitis score was 6. The final diagnosis of the patient was ACLF, secondary to Bakuchi herb seeds. During hospitalization, she clinically deteriorated with the advent of overt hepatic encephalopathy secondary to sepsis. Broad-spectrum antibiotics and anti-encephalopathy measures were upgraded, and steroids were withheld. She was listed for liver transplantation. However, she eventually recovered from sepsis and was restarted on low-dose steroids and immunosuppression (azathioprine, 50 mg/day) in view of herb-induced autoimmune-like liver injury features on biopsy. Presently, after more than a month of follow-up, the patient remains well. Her investigations on follow-up are shown in Table 1.

Figure 1.

HPE at (a) 40x: Thick arrow showing focal interface activity and (b) 10x: Thick arrow showing lymphoplasmacytic infiltrate admixed with eosinophils and neutrophils, thin arrows showing fibrous septae.

Table 1.

Laboratory parameters.

Laboratory parameters	Outside		In hospital			Follow-up
						7 weeks	10 weeks	20 weeks	30 weeks
Hemoglobin	12	12	10.9	10.8	9.5	9.8	11.3	11.5	12.4
Total white blood cell (WBC) count	8100	8600	29,200	21,300	26,300	9470	4140	4290	6150
Platelet count	319,000	291,000	198,000	193,000	139,000	199,000	219,000	205,000	244,000
T.bili/D.bili	7/4.3	10.4/6.4	23.7/14.7	25.3/14.7	21/12.9	7.4/3.5	3.9/1.8	1.7/0.6	0.7/0.4
SGOT/SGPT	551/486	720/565	316/141	152/71	123/74	105/54	81/77	83/45	48/24
ALP (0–310)	156	158	302	162	355	121	179	122	137
T.Prot/S.alb	7.1/4.2	6.2/3.1	5.7/2.3	6.6/2.3	6/2.5	6.1/2.4	6.6/2.7	6.8/3.1	6.9/4.1
INR	1.11	1.7	2.48	2.81	2.54	1.58	1.43	1.25	1.18
S. sodium	136	136	136	131	132	135	–	–	–
S. potassium	3.6	3.6	3	4.5	3.7	3.9	–	–	–
S. creat	0.7	–	0.8	0.6	0.7	0.6	0.6	0.6	–
RBS	–	110	103	96	90	96	–	–	–

Abbreviations: SGOT – aspartate aminotransferase; SGPT – alanine aminotransferase; ALP – alkaline phosphatase; INR – international normalized ratio; HIV – human immunodeficiency virus; HBV – hepatitis B virus; HCV – hepatitis C virus; ANA – anti-nuclear antibody; ASMA – anti-smooth muscle antibody; AMA – anti-mitochondrial antibody; IgG – immunoglobulin G.

The Bakuchi supplement was retrieved from the patient, and a detailed chemical and toxicology analysis was performed using inductively coupled plasma mass spectrometry, triple quadrupole gas chromatography, and mass spectrometry. The detailed analysis is shown in Table 2. Analysis revealed the presence of diazine-dimethyl phenylephrine, and other phytochemicals along with lead contamination.

Table 2.

Chemical and toxicology analysis.

Results of gas chromatography (GC) mass spectrometry (MS) analysis compounds detected
S.No.	Compound name	Retention time	Molecular weight	Match factor	Area %
1	Phenylephrine	3.13	C9H13NO2	64.6	46.30
2	Diazene, dimethyl-	6.67	C2H6N2	90.1	7.01
3	Isopropyl alcohol	6.93	C3H8O	85.2	3.60
4	1-Propanol, 2-methyl-	10.12	C4H10O	88.8	1.61
5	Acetic acid	10.37	C2H4O2	97.1	7.31
6	Cyclopentanol	10.43	C5H10O	72.7	3.15
7	Allyl ethyl ether	10.60	C5H10O	80.9	1.09
8	Oxetane, 3-(1-methylethyl)-	12.19	C6H12O	88.3	1.63
9	Aureonitol	17.05	C13H18O2	81.3	1.78
10	3-Carene	17.18	C10H16	90.4	5.40
11	Caryophyllene	20.89	C15H24	96.9	21.12

Results of inductively coupled plasma (ICP) MS analysis
S.No.	Element name	Unit	Result	Limit of quantification
1	Lead (as Pb)	mg/kg	1.81	0.025
2	Cadmium (as Cd)	mg/kg	0.03	0.025
3	Mercury (as Hg)	mg/kg	BLQ	0.025
4	Arsenic (as As)	mg/kg	0.27	0.025

Total no of determination: 15 (fifteen only).

Discussion

The acute cause of liver failure was most likely due to oral long-standing use of Bakuchi seeds as an Ayurvedic herbal remedy for vitiligo. Prolonged use of Bakuchi seeds is associated with severe cholestatic hepatitis, likely related to hepatotoxic psoralen compounds and bakuchiol. They could even lead to acute liver failure and death in patients with other comorbidities.^6,10

There are a total of seven cases reported till now in the literature.^{1,2,10, 11, 12}

Teschke R et al. documented a case of toxic liver disease in a 64-year-old female patient in temporal and causal relationship associated with the use of Bakuchi which the patient took for 9 months.¹ Nam SW et al. reported a case of acute cholestatic hepatitis in post-menopausal women associated with the use of the seeds of Psoralea corylifolia in ten times the usual dose for treatment of osteoporosis.² Cheung WI et al. reported three cases (two of them treated for vitiligo and one for flu-like symptoms) of acute liver injury related to exposure to Fructus Psoraleae (FP), dried seeds of Psoralea corylifolia.¹¹ Similarly Smith et al. reported a case of drug-induced hepatitis.¹² The overall prognosis of all these patients remained good. A case of a 53-year-old female patient diagnosed with vitiligo who took Qubaibabuqi tablet for 7 months was reported by Li A et al.¹⁰ She developed acute cholestatic hepatitis associated with FP usage. She rapidly deteriorated and succumbed five days later due to acute liver failure and multiorgan dysfunction.¹⁰ However, no case of ACLF has been reported till date. Further studies are required to know the exact mechanism of hepatotoxicity of Bakuchi seeds.

The case highlights the need for detailed drug history including the use of complementary and alternative medication (CAM) (oral and topical both) in the context of hepatitis and liver failure as patients often do not perceive them as medications. Mechanisms of herb-induced liver injury (HILI) vary from direct herb-causing hepatotoxicity to liver injury from secondary metabolites or immune-mediated phenomenon. “Herbal” and “natural” do not mean “safe” is a fact and has been illustrated previously also in the literature.¹³ HILI usually improves with stopping of drugs and rarely requires liver transplantation.¹⁴ However, possible CAM-drug-induced liver injury (DILI)-related ACLF is associated with very high mortality and poor intermediate and long-term transplant-free survival.¹⁵ The dosages are unclear, and patients take them on a long term with widespread availability. The case emphasizes the need for increased surveillance to formulate guidelines regarding regulation, use of herbal supplements, and safe dosage levels which should also be mentioned on packaging. Producers should highlight all potentially serious side effects like jaundice associated with itching and clay-colored stools, symptoms of liver cell failure like ascites, hematemesis, malena, hepatic encephalopathy, etc., and recommend seeking medical attention at the earliest if jaundice or any of these occurs. Proper administrative authorities monitoring the use of CAM should be informed regarding such potentially life-threatening side effects, and further actions should be taken regarding the same.

To conclude, HILI secondary to Bakuchi seeds is rare and can cause worsening of underlying liver diseases. Detailed history of all drugs, stopping of the offending agent, monitoring of liver function tests, and treatment of underlying disease can be lifesaving in such patients with ACLF.

Limitation

The confirmatory evidence of Bakuchi causing liver injury is missing which somewhat lowers the strength of causality, and so the causality is more by attribution than confirmation.

Care should have been taken to preserve samples, and tests done to identify confirmation of ingredient or package insert should have been scrutinized to identify implicated ingredient.

CREDIT AUTHORSHIP CONTRIBUTION STATEMENT

Harsh J. Gandhi: conceptualization, methodology, writing. Sanjay Chandnani: supervision. Anuraag Jena: writing- reviewing and editing. Shubham Jain: supervision. Rishikesh N. Malokar: data collection. Jay Chudasama: data collection. Rima Kamat: data collection. Cyriac Abby Philips: writing- reviewing and editing. Pravin Rathi: Supervision, revision and validation.

Conflicts of interest

None.

Funding

None.

Appendix A. Supplementary data

The following is the supplementary data to this article.