Case of cholestatic drug-induced liver injury (DILI) associated with black cohosh
- Himmat Singh Brar and
- Rachana Marathi
- Internal Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Correspondence to Dr Himmat Singh Brar; himmatbrar91@gmail.com
Abstract
Drug-induced liver injury is an uncommon yet fatal cause of liver injury. Black cohosh is a herbal supplement that is derived from Actaea racemosa. It has been used for vasomotor symptoms in postmenopausal women, but it can cause liver injury. A 50-year-old Afro-American woman presented with a 2-month history of malaise, itching and severe jaundice. The labs showed elevation of bilirubin and alkaline phosphatase. The patient had a history of black cohosh use for postmenopausal symptoms before she developed her current symptoms. The extensive workup for infective and autoimmune pathology was negative. Black cohosh was discontinued. The patient improved clinically, and her liver enzymes normalised 6 months after the discontinuation of black cohosh. This report emphasises the need to recognise black cohosh as a potential hepatotoxic agent and to monitor the liver enzymes for a patient on black cohosh.
Background
Drug-induced liver injury (DILI) is defined as liver injury caused by medications, herbal products or other agents leading to abnormalities in liver biochemistries due to damage to liver parenchyma and the resultant liver dysfunction.1 2 Liver injury can be caused by almost all classes of drugs.3 The spectrum of liver injury ranges from being asymptomatic to a mild elevation of liver biochemistries to fulminant hepatic failure resulting in death or liver transplantation. Among the significant areas of public health concern in the USA, liver injury has been a frontrunner.4
The annual worldwide incidence of DILI has been reported at 0.014%–0.024%. DILI has been the most reported cause of adverse drug reactions.5 6 The exact measurement of the incidence of DILI has been a challenge. The factors posing this challenge involve DILI being a relatively uncommon entity and under-reporting and under-recognition of this injury. Nearly half the cases of acute liver failure in the USA alone are due to DILI. The case fatality rate has been about 10%–50%.7
DILI can be both idiosyncratic or dose-dependent.8–10 Due to the rapidly expanding market of non-prescription drugs in the USA, DILI has become a vital aetiology of acute liver injury. Non-prescription drugs do not undergo testing and escape the Food and Drug Administration (FDA) trials as these are considered supplements.11 However, due to rising concerns, the FDA has begun taking regulatory actions to implement guidelines involved with the use of these supplements. The studies emphasise the timely and accurate reporting of DILI, which is essential for spreading awareness and early detection of DILI.
Black cohosh is a herbal product that is used for the treatment of vasomotor symptoms of menopause. The product is associated with common side effects, including nausea, vomiting, weight gain, rash and headache (table 1). We present a case of black cohosh-associated cholestatic liver injury.
Common side effects of black cohosh
| General | Weight gain, tiredness, loss of appetite |
|---|---|
| CNS | Headache, dizziness |
| Cardiovascular | Bradycardia, tachycardia |
| Respiratory | Difficulty breathing |
| Gastrointestinal | Nausea, vomiting, dark urine, clay-coloured stools, jaundice |
| Endocrine | Vaginal spotting, breast pain/enlargement |
| Musculoskeletal | Muscle pain, muscle weakness |
| Skin | Skin rash, itching |
Case presentation
A 50-year-old Afro-American woman was referred to our centre to evaluate worsening jaundice, malaise, itching and significantly elevated liver enzymes. These symptoms started developing about 2 months before the presentation. The patient’s medical history was significant for asthma/chronic obstructive pulmonary disease, type 2 diabetes mellitus and iron deficiency anaemia. There was no history of liver disease before these symptoms. Her medications included carvedilol 12.5 mg two times per day, famotidine 20 mg/day, albuterol and formometrol–budesonide inhalers. She had a history of black cohosh use 2 months before the onset of the symptoms, for a total duration of 2 months. She denied any history of smoking, alcohol use, substance abuse, blood transfusion, tattooing or travel history. There was no history of any liver disease in the family.
The patient was feeling well and was in her usual state of health 2 months back when she started developing fatigue, nausea and yellowing of the skin.
Investigations
She was seen at an outside hospital. Liver chemistries performed at the outside hospital revealed the following: total bilirubin (TBili)=27.9 mg/dL, alkaline phosphatase (ALP)=201 U/L, aspartate aminotransferase (AST)=24 U/L, alanine aminotransferase (ALT)=33 U/L and serum creatinine=1.04 mg/dL. Her international normalized ratio (INR) was 1.06, and serum albumin was normal at 4.0 g/dL. Haemoglobin was 960 g/L; white blood cell count was 6.0/L; and platelet count of 468×106 cells/mL. Her immune workup at the outside hospital was positive for antimitochondrial antibody, and she was started on ursodeoxycholic acid 250 mg two times per day. The patient had no relief in her symptoms. Magnetic resonance cholangiopancreatography (MRCP) revealed narrowing of intrahepatic bile duct radicals. The patient’s family noticed the worsening of the yellowing of her eyes and itching.
Due to the worsening of her clinical symptoms, significant hyperbilirubinaemia and MRCP findings, the patient was referred to our hospital. The patient presented with complaints of significant nausea, vomiting, poor appetite, 10 lb weight loss and persistent jaundice. On presentation, the physical examination was significant for jaundiced skin and bilateral scleral icterus. The abdominal examination was unremarkable without tenderness, distension or hepatosplenomegaly. The laboratory studies at presentation revealed the following: AST=26 U/L, ALT=37 U/L, TBili=26.2 mg/dL, INR=1.02, albumin=3.6 g/dL and ALP=207 U/L. Drug levels for alcohol and acetaminophen were undetectable. The workup for viral serologies including hepatitis A, hepatitis B sAg, HBc IgM, hepatitis C Ab, HIV Ag/Ab, herpes simplex 1 and 2, Epstein-Barr virus and cytomegalovirus was negative. The autoimmune workup was negative for antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody and anti-liver-kidney microsomal antibody (anti-LKM) antibody. The lab work was negative for haemochromatosis and Wilson disease. Immunoglobulin and thyroid-stimulating hormone levels were within the normal range.
The CT scan of the abdomen was significant for the findings of multiple foci of hypoattenuation throughout the left and right hepatic lobes representing cysts or haemangiomas without any evidence for cirrhosis or biliary ductal dilation. Endoscopic ultrasound was performed and showed no signs of significant pathology in the pancreatic ducts or the common bile duct. Concerned for the MRCP findings of bile duct narrowing, endoscopic retrograde cholangiopancreatography was performed. It demonstrated that the common bile duct and common hepatic duct were approximately 5 mm, smooth and without stricture (figure 1). The intrahepatic and extrahepatic biliary duct systems were completely normal with no missing secondary duct or ductal irregularities.
Endoscopic retrograde cholangiopancreatography with normal duct morphology.
The percutaneous liver biopsy demonstrated mild lobular and portal inflammation, intrahepatic canalicular cholestasis, ductopenia of the interlobular bile ducts and mild sinusoidal dilation (figures 2–4). It was suggestive of more recent and significant hepatocyte injury, which correlated with the patient’s clinical history.
Mild portal and lobular inflammation.
Bile canaliculi with stasis.
Trichrome stain showing acidophilic bodies, sinusoidal dilation and fibrosis.
Differential diagnosis
There were many differentials, to begin with. In the case of cholestatic liver injury pattern, obstruction of the biliary tree should be suspected. It could be obstruction secondary to stone, choledocholithiasis, cholangitis or compression from any mass lesion from the outside. A malignant lesion of the head of the pancreas could cause a compression. Any malignancy arising from the biliary tree, like cholangiocarcinoma, can cause a similar presentation. Imaging studies, including a CT scan of the abdomen, are useful. However, in the cases where obstruction of the biliary tree is suspected, MRCP is the test of choice. Autoimmune disorders like primary sclerosing cholangitis and primary biliary cholangitis can cause obstructive jaundice. Autoimmune workup including serologies and antibodies should be done to exclude these. Acute conditions, like acute viral hepatitis and ischaemic hepatitis, can also present with similar findings, and thus the viral serologies should be done.
Treatment
The patient was told to abstain from black cohosh. Due to a lower side effect profile, she was started on budesonide for a short course due to concerns of her worsening clinical picture.
Outcome and follow-up
After the drug withdrawal and treatment, the patient’s enzymes started trending downwards. She started improving in her clinical symptoms with the resolution of nausea, fatigue and jaundice. Her liver enzymes showed normalisation of her bilirubin and near normalisation of her alkaline phosphatase over the next 6 months (figures 5 and 6). The patient was counselled to avoid the use of black cohosh in the future. Rechallenge with the suspected agent was not attempted due to ethical reasons and for the patient’s safety.
Graph showing bilirubin trend.
Graph demonstrating alkaline phosphatase trend.
Discussion
DILI is the single most common cause of acute liver failure.1 There has been a database of hundreds of drugs that have been linked to DILI as the suspected agent. The severity of DILI ranges from being asymptomatic to vague symptoms of nausea, vomiting and abdominal pain to severe hepatic injury leading to fulminant hepatic failure requiring liver transplantation and death. DILI can be divided into predictable or dose-dependent and dose-independent idiosyncratic.8–10 There have been extensive data on the dose-dependent liver damage as explained by the acetaminophen-induced liver toxicity.12 The idiosyncratic DILI represents a complex interaction involving the drug morphology and the human genetic framework, and each person’s unique metabolism characteristics.13 14 Therefore, these drug injuries may not be recognised until phase IV of the drug trial. The drug is launched in the market with thousands of patients exposed to it, leading to the recognition of DILI.15
The diagnosis of DILI is challenging. It is usually a diagnosis of exclusion. There are no specific tests that are proven for the diagnosis of DILI. DILI is usually diagnosed when all the other causes have been ruled out. It is essentially a diagnosis of exclusion.16 Many factors further make the diagnosis challenging, including a pre-existing liver pathology or the patient being on multiple potential hepatotoxic agents.
DILI has been classified, taking into account the different factors. One of the most commonly used markers is the R factor. The R factor was introduced in 1989 at an international consensus meeting. The R factor is calculated considering the patient’s lab values of alanine transaminase and alkaline phosphatase and comparing them to the normal values. There are three main classifications of DILI: (1) hepatocellular damage, (2) cholestatic damage and (3) mixed liver damage.17 Hepatocellular injury is characterised by significant damage to the hepatocytes. The R factor is >5, and AST, ALT is more elevated than the ALP levels. Cholestatic injury is due to direct injury to the biliary tract. The R factor is <2, and ALP and bilirubin are significantly elevated. Mixed injury is a combination of the hepatocellular and cholestatic pattern. The R factor is 2–5. A disproportionately elevated total bilirubin is characteristic of a more severe liver injury.
The biggest challenge in DILI is to establish a relationship with the causative agent. There have been different scales that are used for the assessment of the causative agent in DILI. These are the Roussel Uclaf Causality Assessment Model (RUCAM) Scale and the Maria and Victorino (M&V) Scale. However, these are not the perfect scales to guide a patient’s assessment with suspicion of DILI.18 19 Depending on the grading on the RUCAM scale, a score between −9 and +14 is obtained. The offending agent is classified as excluded, unlikely, possible, probable and highly probable. On this scale, our patient had black cohosh as the ‘probable’ cause of DILI. The M&V is the simplified version of the RUCAM scale.20 Depending on the grading on the M&V scale, a score of −8 to 20 is obtained. The offending agent is then categorised as unlikely, possible, probable and definite. Using this scale, our patient had black cohosh as a ‘possible’ cause of DILI. The major drawback to the RUCAM and the M&V scale is the great emphasis on rechallenging with an offending agent resulting in DILI.21 The rechallenge with black cohosh was not attempted due to ethical reasons and for concerns for patient safety.
Black cohosh has been cited in multiple case reports. The published data have reported cases ranging from mild self-limited injury to fulminant hepatic failure. The spectrum ranges from mild hepatitis, hepatitis with cholestasis and hepatic failure requiring transplant.22 The mechanism of action is unknown. However, it is suspected to be due to oxidative damage from the accumulation of by-products in cells and the migration of inflammatory mediators.23 The time duration between the first dose and the onset of symptoms has ranged from 1 to 48 weeks, but usually, it has been within 2–12 weeks.24
There has been controversy regarding the relationship between black cohosh and liver injury. There have been multiple reports of black cohosh-induced liver injury, but there have been multiple discrepancies. There has been limited data on the dosing, purity of the product, source and preparation of the compound, and temporal relation. Most of the black cohosh products available over the counter have multiple ingredients and unknown compounds.25 The review of the articles on black cohosh was done by Teschke et al 26 It was found that most of the cases had confounding variables, including pre-existing liver pathologies, herbal products with multiple ingredients and the lack of chronological relation. Only one case was found to be true of black cohosh-induced hepatotoxicity. Therefore, the conclusion was reached that there have not been enough data to suggest a causal relationship.26
Patient’s perspective
I had symptoms of severe itching, jaundice, and malaise. I was distressed as the doctors could not figure out what was going wrong with my body. I underwent multiple blood tests at various hospitals with lab abnormalities. I continued experiencing the symptoms despite being started on medication. I was told that it could be cancer in my body. That was a massive shock for me.
At this facility, specific blood labs were drawn. Imaging studies, including Ultrasound, CT scan, and MRIs, were done. I was recommended to the Interventional Radiologist, and they explained the risks and benefits of the procedure. They took further biopsies and ran further pathological tests. They told me that it was a drug induced injury to my liver secondary to the Black Cohosh, which I had used a couple of months back due to my menopausal symptoms. I was told to abstain from using this drug and was started on a short course of steroids. I started improving with my itching and jaundice of my skin getting improved. I felt back to normal and was living a normal life within a couple of months.
I had follow-up appointments with my Gastroenterologist, and they were outstanding and explained things very well. I had fantastic support from all my doctors, who have been following up with me regularly and scheduling my appointments frequently to monitor my progress. I was very aware of the doctors all working together throughout and still now. They would send me all the notes from the appointments, and I always felt involved in all the decisions. Before this diagnosis, I was only seeing my PCP and thought that I was in good health. However, in a couple of months, I had to be in 3 hospitals and undergo multiple scans and biopsies. The care I have had was great and appreciable.
Learning points
-
This case emphasizes recognising herbal products as a potential cause of Drug-induced Liver Injury. Our patient had no known hepatic history, no potential hepatotoxic usage, and a negative workup for any pathology.
-
Biopsy is useful in cases where no conclusive diagnosis is reached. It helps in excluding other causes of liver injury.
-
It hereby emphasizes the importance of recognising herbal black cohosh as a cause of liver injury and close monitoring of hepatic function with patients on black cohosh.
Footnotes
-
Contributors All listed authors' contributions include the conception and design, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version published. Conceptualisation, project administration, resources, visualisation, writing—review and editing: HSB and RM; data curation, formal analysis and writing—original draft: HSB; supervision: RM. All authors read and agreed on the published version of the manuscript. Regarding responsibility for overall content, the lead author, HSB, is the guarantor.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Competing interests None declared.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer