Acute Liver Failure Induced by Menopausal Supplement

ABSTRACT

Drug-induced liver injury is one of the most common causes of acute liver failure in the Western world. Despite discontinuation of the offending agent, it can still tax a grim prognosis. We describe a case of a menopausal woman taking a herbal supplement to relieve hot flashes and bloating. This is the first case report of liver injury from this supplement. She initially presented with mild jaundice and elevated transaminases. Unfortunately, she rapidly progressed to encephalopathy, experienced multiorgan failure, and then died.

INTRODUCTION

Drug-induced liver injury (DILI) is one of the most common causes of acute liver failure (ALF) in the Western world.¹ ALF is the development of severe acute liver injury with encephalopathy and diminished synthetic function (international normalized ratio [INR] ≥1.5) in a patient without preexisting liver disease.² In the United States, the most common causes of ALF have been acetaminophen overdose (46%), indeterminate (14%), idiosyncratic drug reactions (12%), hepatitis B virus (7%), and hepatitis A virus (3%).³ The use of non–Food and Drug Administration regulated supplements over the past 3 decades has increased with about 80% of people worldwide using them for a portion of primary health care.⁴ The agents associated with DILI are prescription medications, illicit or recreational substances, and herbal and dietary supplements (HDS).

A herbal supplement has been gaining traction among menopausal women who hope to alleviate hot flashes, bloating, and weight gain. The supplement consists of a probiotic blend of Bifidobacterium breve, Lactobacillus gasseri, Bifidobacterium lactis, turmeric root extract, moringa leaf, curry leaf, lecithin, and black pepper fruit extract.

There is no published data on liver injury from the use of this supplement as it had not been reported on LiverTox.⁵ We present an unfortunate case of ALF in a middle-aged woman shortly after starting the HDS.

CASE REPORT

A 49-year-old White woman with a history of asthma on no chronic medications except for a newly started herbal supplement presented to the hospital after her primary care physician sent her due to abnormal liver function tests. She experienced new-onset jaundice, nausea, and decreased appetite. She drank alcohol socially and denied tobacco or illicit drug use.

One month before admission, she began consuming 1 capsule of the HDS daily. She consumed it for a total of about 30 days. She had been taking the supplement in hopes of alleviating menopausal symptoms of hot flashes, bloating, and weight gain.

Upon hospital arrival, she was hemodynamically stable. Initial blood work revealed alanine transaminase of 3,008 U/L, aspartate transaminase of 2,861 U/L, alkaline phosphatase 195 U/L, total bilirubin of 8.8 mg/dL, and direct bilirubin of 5.7 mg/dL. She had a platelet count of 201,000 µL, INR of 2. Her urine drug screen, acetaminophen levels, and salicylate levels were unremarkable. She was started on 7.7 g of N-acetyl cysteine (NAC) for a duration of 5 days due to her severely elevated hepatic enzymes.

Initial computed tomography scan of the abdomen and pelvis showed a contracted gallbladder with a slightly thickened wall. Magnetic resonance imaging of the abdomen showed mild heterogeneous abnormalities seen in the liver with a right lobe smaller in size compared to the left without any focal liver lesions and no evidence of biliary obstruction. The peritoneal cavity showed moderate abdominal ascites.

She underwent extensive hepatitis workup (viral hepatitis panel, Epstein–Barr virus, herpes simplex virus, cytomegalovirus, chlamydia–gonorrhea serologies, antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, ceruloplasmin, and alpha-1 antitrypsin), which was unremarkable. Despite the use of NAC, her total, direct bilirubin, and INR continued to rise while her transaminases remained elevated (Figure 1, Table 1 with complete lab values). Liver biopsy (Figure 2) showed significant hepatocyte necrosis with hepatic plate collapse around the central veins with focal bridging necrosis due to DILI.

Figure 1.

(A) AST/ALT/ALP, (B) bilirubin, & (C) INR trend throughout patient's entire hospitalization. AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; INR, international normalized ratio.

Table 1.

Liver function trend throughout patient's entire hospitalization

	Day 0	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8	Day 9	Day 10	Day 11	Day 12	Day 13	Day 14
Total protein (g/dL)	6.7	5.4	5.1	5	5	4.6	4.6	4.7	4.4	4.2	4.1	4	4	3.8	3
Albumin (g/dL)	4.3	3.5	3.3	3.2	3.2	3.1	3.1	3.1	3	2.9	2.9	2.9	2.7	3.2	2.6
ALP (U/L)	195	166	154	177	186	165	158	210	169	225	218	174	192	211	140
ALT (U/L)	3,008	2,518	2,115	2,101	2,139	2,063	1,919	1,787	1,514	1,358	1,227	1,029	928	654	728
AST (U/L)	2,861	2,442	1,903	1,705	1,740	1,766	1,484	1,156	906	724	651	593	530	728	1,721
Total bilirubin (mg/dL)	8.8	8.1	9.5	11.7	13.6	14.8	17.6	20.3	21.1	22.6	24	24.6	25.2	18.8	12.8
Direct bilirubin (mg/dL)	5.7	5	5.1	5.9	7.1	7.8	8.1	9.4	9.4	13.7	14.1	14.1	13.6	8.7	4.9
INR	2	2.3	2.4	2.6	3.1	3.7	4.8	4.9	6.5	6.6	6.8	7.2	7.8	>10	9.3

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.

Figure 2.

Liver biopsy pathology. Central vein (CV). Arrows depict necrosis. (A) 50× magnification. (B) 100× magnification. (C) 200× magnification.

She was listed for liver transplant with a model for end-stage liver disease score >35. She was offered a donor organ; however, before planned surgery, she decompensated with worsening shock, encephalopathy, respiratory failure, renal failure, and disseminated intravascular coagulation. She died before transplant.

DISCUSSION

This case highlighted the severity of DILI in the form of ALF from HDS, which has seldom been reported in the literature. Interestingly, our patient was not taking the supplement as recommended on the package label. She was taking one capsule daily. The manufacturing company recommends taking 2 capsules daily. Despite her underdosed regimen, the outcome was catastrophic.

The combination of the ingredients of the supplement may be novel. There have been isolated case reports of liver injury without liver failure due to high bioavailability forms of turmeric in Italy.⁶ Moringa leaf extract has been shown to cause moderate hepato-nephrotoxicity in mice with significant increases in aspartate transaminase, creatinine kinase, hepatic degeneration, and necrosis.⁷ While this supplement contains concentrations of tumeric (curcumin) and/or black pepper (pererine) which may be contained within commonly used dietary formulations, these ingredients have been reported in some studies to be associated with liver failure. Piperine is the major active component of black pepper. When piperine is combined with curcumin in a complex, the bioavailability has been shown to increase 2,000%.⁸ Curry leaf has not been studied in the literature as a contributor of DILI. The synergistic and/or additive effects of turmeric, piperine, moringa, and curry leaf need to be further studied to observe a mechanism of liver injury as there are no well-defined processes describing it. ALF secondary to turmeric toxicity with this poor outcome has not been seen in the literature.

The company claims that Lactobacillus gasseri is unique due to a 2013 Japanese study showing that individuals who ingested its fermented milk had a reduction in visceral fat areas.⁹ The amalgamation of the herbs alongside bacteria brings forth the concept of gut-liver axis as a DILI mediator. The intestinal microbiome digests the herbal medication components or transports compounds that are not absorbed by the gastrointestinal tract. Furthermore, bacteria yield metabolites that compete with the drugs over the metabolic process, which either decreases the metabolism and accumulates the drug or there is a synergistic toxic phenomenon between the bacteria and supplement.¹⁰

Apart from cessation of the implicated agent, there is no standard therapy for DILI. While NAC is typically used for hepatoxic doses of acetaminophen, it has also been shown to be beneficial in nonacetaminophen liver failure. A 2021 meta-analysis demonstrated that NAC significantly improves overall survival, post-transplant survival, and transplant-free survival while decreasing the overall length of hospital stay.¹¹ On the other hand, corticosteroids in moderate–severe DILI and drug-induced autoimmune hepatitis have demonstrated beneficial effects, but this was not the case in drug-induced ALF.¹² Due to a lack of improvement with supportive care and increase in complications, liver transplant was indicated for our patient.

The supplement is readily available for consumers because HDS are considered to be foods and not drugs by the Food and Drug Administration. Thus, they are not required to go through rigorous testing that pharmaceutical companies go through when introducing a new drug on the market. A 2012 study found contamination with mercury, cadmium, arsenic, lead, and aluminum in various HDS around the world.¹³

This report highlights the importance of a thorough evaluation of abnormal liver function tests alongside a detailed history of home medications. Given the unfortunate outcome on our patient, this HDS was submitted for review to the Food and Drug Administration. It is important to educate the public on the potential risks of taking herbal supplements despite their natural origins.

DISCLOSURES

Author contributions: R. Patel: drafted all versions of the manuscript including the final version and is the article guarantor; A. Hassan: synthesized graphs and tables and assisted with initial draft; H. Scanlan: editor, assisted with initial draft; M. Everwine: editor, provided guidance of case; Z. Ren: provided, labeled, and analyzed liver biopsy pathology images; C. Snyder and H. ElGenaidi: provided primary guidance of case.

Financial disclosure: None to report.

Informed consent was obtained for this case report.