Adverse Liver Events and Causal Claims Against Black Cohosh

Liver toxicity in pharmaceutical products liability cases is one of the more difficult categories of cases for judicial gatekeeping because of the possibility of idiosyncratic liver toxicity. Sometimes a plaintiff will exploit this difficulty and try to recover for an acute liver reaction.

Susan Grant began to take a black cohosh herbal remedy in 2002, and within a year, developed autoimmune hepatitis, which required her to undergo a liver transplant. She and her husband sued the seller of black cohosh for substantial damages. Grant v. Pharmavite, LLC, 452 F. Supp 2d 903 (D. Neb. 2006). Granted enlisted two expert witnesses, Michael Corbett, Ph.D, a toxicologist, and her treating gastroenterologist, Michael Sorrell, M.D. The defense relying upon liver expert, Phillip Guzelian, M.D., challenged the admissibility of plaintiffs’ expert witnesses’ opinions under the federal rules.

Struggling with the law, Senior Judge Strom observed that Nebraska law requires expert witness opinion testimony on causation. Id. at 906. Of course, in this diversity action, federal law controlled on the scope and the requirements of expert witness opinion testimony.

And in a similarly offbeat way, Judge Strom suggested that plaintiffs’ expert witnesses need not have opinion supported by evidence:

While it is not necessary that an opinion be backed by scientific research, it is necessary that an expert’s testimony, which contradicts all of the research, at minimum address and distinguish the contradictory research in order to support the expressed opinion.”

Id. at 907 (emphasis added). Senior Judge Strom thus suggests had there been no published research at all, then Dr. Corbett could just make up an opinion, not backed by scientific research. This is, of course, seriously wrong, but fortunately it amounts only to obiter detritus, because Judge Strom believed that given the available studies, the testifying expert witnesses had to do more than simply criticize the studies that disagreed with their subjective opinion.

Michael Corbett, Ph.D, a consultant in “chemical toxicology,” from Omaha, Nebraska, criticized existent studies, which generally failed to identify liver toxicity, but he failed to conduct his own studies. Id. at 907. And Corbett also failed to explain why he rejected the great weight of medical publications that found that black cohosh was not hepatotoxic. Id. Michael Sorrell, M.D., started out as Ms. Grant’s treating gastroenterologist, but became a litigation expert witness. He was generally unaware of the randomized clinical trials of black cohosh, or any study that, or group of scientists who, supported his opinion. Id. at 909.

To Dr. Sorrell’s credit, he did attempt to write up a case report, which was published after the termination of the case. Unfortunately for Dr. Sorrell and his colleagues, Ms. Grant and her lawyers were less than forthcoming about her medical history, which included medications and lifestyle variables that were apparently not shared with Dr. Sorrell. Id. at 909.

You know that the quality of gatekeeping due process is strained when judges fail to cite key studies sufficiently to permit their readers to find the scientific evidence. Between Google Scholar and PubMed, however, you can find Dr. Sorrell’s case report, which was published in 2005, before Judge Strom issued his Rule 702 opinion. Josh Levitsky, Tyron A. Alli, James Wisecarver, and Michael F. Sorrell, “Fulminant liver failure associated with the use of black cohosh,” 50 Digestive Dis. Sci. 538 (2005). If nothing else, Judge Strom provoked an erratum from Dr. Sorrell and colleagues:

“After the article was published, it was brought to the authors’ attention through legal documentation and testimony that the patient admitted to consuming alcohol and had been taking other medications at the time of her initial presentation of liver failure. From these records, she reported drinking no more than six glasses of wine per week. In addition, up until presentation, she was taking valacyclovir 500 mg daily for herpes prophylaxis for 2 years, an occasional pseudoephedrine tablet, calcium carbonate 500 mg three times daily, iron sulfate 325 mg daily and ibuprofen up to three times weekly. She had been taking erythromycin tablets but discontinued those 3 months prior to presentation.

The authors regret the omission of this information from the original case report. While this new information is important to include as a correction to the history, it does not change the authors’ clinical opinion … .”

The erratum omits that Ms. Grant was taking Advil (ibuprofen) at the time of her transplantation, and that she had been taking erythromycin for 2.5 years, stopping just a few months before her acute liver illness. The Valtrex use shows that Ms. Grant had a chronic herpes infection. In the past, plaintiff took such excessive doses of ibuprofen that she developed anemia. Grant v. Pharmavite, LLC, 452 F. Supp 2d at 909 n.1. Hardly an uncomplicated case report to interpret for causality and an interesting case history of confirmation bias. Remarkably, the journal charges $39.95 to download the erratum, as much as the case report itself!

And how has the plaintiff’s claim fared in the face of the evolving scientific record since Judge Strom’s opinion?

Not well.

See, e.g., Peter W Whiting, Andrew Clouston and Paul Kerlin, “Black cohosh and other herbal remedies associated with acute hepatitis,” 177 Med. J. Australia 432 (2002); Cohen SM, O’Connor AM, Hart J, et al. Autoimmune hepatitis associated with the use of black cohosh: a case study. 11 Menopause 575 (2004); Christopher R. Lynch, Milan E. Folkers, and William R. Hutson, “Fulminant hepatic failure associated with the use of black cohosh: A case report,” 12 Liver Transplantation 989 (2006); Elizabeth C-Y Chow, Marcus Teo, John A Ring and John W Chen, “Liver failure associated with the use of black cohosh for menopausal symptoms,” 188 Med. J. Australia 420 (2008); Gail B. Mahady, Tieraona Low Dog, Marilyn L. Barrett, Mary L. Chavez, Paula Gardiner, Richard Ko, Robin J. Marles, Linda S. Pellicore, Gabriel I. Giancaspro, and Dandapantula N. Sarma, “United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity,” 15 Menopause 628 (2008) (toxicity only possible on available evidence); D. Joy, J. Joy, and P. Duane, “Black cohosh: a cause of abnormal postmenopausal liver function tests,” 11 Climacteric 84 (2008); Lily Dara, Jennifer Hewett, and Joseph Kartaik Lim, “Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements,” 14 World J. Gastroenterol. 6999 (2008); F. Borrelli & E. Ernst, “Black cohosh (Cimicifuga racemosa): a systematic review of adverse events,” Am. J. Obstet. & Gyn. 455 (2008); Rolf Teschke & A. Schwarzenboeck, “Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh, root): critical analysis and structured causality assessment,” 16 Phytomedicine 72 (2009); Stacie E. Geller, Lee P. Shulman, Richard B. van Breemen, Suzanne Banuvar, Ying Zhou, Geena Epstein, Samad Hedayat, Dejan Nikolic, Elizabeth C. Krause, Colleen E. Piersen, Judy L. Bolton, Guido F. Pauli, and Norman R. Farnsworth, “Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial,” 16 Menopause 1156 (2009) (89 women randomized to four groups; no hepatic events in trial not powered to detect them); Rolf Teschke, “Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review,” 17 Menopause 426 (2010) (“The presented data do not support the concept of hepatotoxicity in a primarily suspected causal relationship to the use of BC and failure to provide a signal of safety concern, but further efforts have to be undertaken to dismiss or to substantiate the existence of BC hepatotoxicity as a special disease entity. The future strategy should be focused on prospective causality evaluations in patients diagnosed with suspected BC hepatotoxicity, using a structured, quantitative, and hepatotoxicity-specific causality assessment method.”); Fabio Firenzuoli, Luigi Gori, and Paolo Roberti di Sarsina, “Black Cohosh Hepatic Safety: Follow-Up of 107 Patients Consuming a Special Cimicifuga racemosa rhizome Herbal Extract and Review of Literature,” 2011 Evidence-Based Complementary & Alternative Med. 1 (2011); Rolf Teschke, Wolfgang Schmidt-Taenzer and Albrecht Wolff, “Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality?” 20 Pharmacoepidemiol. & Drug Safety 567 (2011) (causation unlikely or excluded); Rolf Teschke, Alexander Schwarzenboeck, Wolfgang Schmidt-Taenzer, Albrecht Wolff, and Karl-Heinz Hennermann, “Herb induced liver injury presumably caused by black cohosh: A survey of initially purported cases and herbal quality specifications,” 11 Ann. Hepatology 249 (2011).

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