Tara Flour

Introduction

Tara flour is a protein-rich flour made from the seeds of the Caesalpinia spinosa tree that was found to cause acute gastrointestinal and liver injury when used in a commercial food product called “Daily Harvest’s French Lentil and Leek Crumbles”. Chemical analysis of the product demonstrated the presence of a non-protein amino acid baikiain which caused liver injury when given orally in an animal model and was therefore the likely cause of the liver injury seen in humans who consumed the product.

Background

Tara flour is a protein-rich flour made from the seeds of the Caesalpinia spinosa tree which is native to Peru and found in several regions in South America. When introduced into a commercial food product called “Daily Harvest’s French Lentil and Leek Crumbles” in April 2022, it caused an outbreak of acute gastrointestinal and liver disease that affected at least 393 people before it was removed from the market in late-June 2022. Chemical analysis of the product demonstrated more than 27 ingredients, none of which were known to cause liver injury. The product was free of evidence of contamination with toxic compounds including microbial or viral pathogens, mycotoxins, allergens, heavy metals, and pesticides. However, among products identified in the crumbles was tara flour which on further analysis was found to be rich in the 3 non-protein amino acids, baikiain (3% dry weight), L-3-hydroxymethyltyrosine (3HMT: 1.5%), and L-3-hydroxymethylphenylalanine (3HMP: 0.5%). Analysis of baikiain in toxicology studies demonstrated that it caused liver injury in mice after oral ingestion with serum ALT levels rising from 31 to 230 U/L within 6 hours. After removal of the tara flour from the commercial product, no further human cases of liver injury were seen. While tara flour had not been known to cause liver injury, similar acute toxic reactions to foods have been seen in the past in grazing animals exposed to plants that synthesize non-protein amino acids, which are analogues of amino acids and result in absent or diminished function of the protein enzymes with the substituted amino acid.

Hepatotoxicity

The typical clinical onset of tara flour toxicity was with indigestion and variable degrees of abdominal pain, nausea and vomiting within 4 to 12 hours of ingestion, which was sometimes severe enough to result in an emergency room visit or even hospitalization and cholecystectomy. In some patients, symptoms persisted and were followed by fatigue, dark urine, and jaundice two to eight days later. Laboratory testing demonstrated a hepatocellular pattern of serum enzyme elevations with ALT and AST levels in the range of 3 to 20 times the upper limit of normal (ULN) and only mild or no increases in alkaline phosphatase levels. Total serum bilirubin levels were elevated in more severe cases, but generally were rather modest with peak levels of 2.0 to 10.0 mg/dL and rapid improvement within days. In long term follow up of patients, all values returned to the normal or baseline levels. Liver biopsy in one case showed a mild acute hepatitis with lobular inflammation, mild lymphocytic infiltration and no steatosis, fibrosis, or cholestasis. Virtually all cases arose in May and June of 2022 with none appearing after the withdrawal of the food product. However, cases of acute liver injury have also been reported after ingestion of other food products that included tara flour as an ingredient.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of liver injury

Tara flour appears to be a direct hepatotoxin, although its toxicity may depend upon an initial metabolism to a more toxic intermediate or substitution of the non-protein amino acid baikiain into a functional and important enzyme. Baikiain does not harm mammalian or human cells in culture but does cause liver injury and depletion of glutathione is rodent models. The pathways involved in the cell injury have not been fully defined but may be similar to those of acetaminophen which also depletes glutathione which plays a major role in detoxifying injurious substances in the liver. The depletion of glutathione leaves hepatocytes and other cells vulnerable to toxic molecular intermediates of normal cellular metabolism.

Outcome and Management

Tara flour hepatotoxicity is generally self-limited and only mild-to-moderate in severity. Most important is to identify the cause as being due to ingestion of a food that is responsible and discontinuation of further use as well as avoiding possibly harmful interventions for diagnosis such as liver biopsy, cholecystectomy and even invasive forms of cholangiography. Most appropriate is symptomatic therapy and withdrawal of further possible exposure as the liver injury is self-limited and ultimately resolves completely. While unproven, administration of NAC or a glutathione repleting agent might be appropriate in an attempt to shorten and ameliorate the injury, but currently it must be considered experimental. Such an approach is certainly worthy of laboratory and clinical investigation.

Other Names: Spiny Holdback, Tara spinosa, Tara, Taya, Quechua

Drug Class: Herbal and Dietary Supplements

Case 1. 37 year old woman with pain and jaundice after eating Daily Harvest’s French Lentil and Leek Crumbles [107-0127].(1)

A 37 year old woman, who had been receiving monthly Daily Harvest frozen food preparations for more than a year, consumed a new product called “French Lentil and Leek Crumbles” for dinner and noted feeling ill with transient stomach pain afterwards. Three days later she consumed more of the product and developed severe stomach pains and nausea followed by constipation the next day which she attributed to stress at work. Six days later she prepared tacos for lunch to which she added the lentil and leek crumbles and again developed severe abdominal pain 4 to 6 hours later. That evening she had body aches and the following morning still felt ill and developed nausea and vomiting. That same day she received notification from Daily Harvest about the potential of the crumbles product to cause liver injury. The following day, she noted that her urine had turned dark, and she sought medical care. Laboratory testing revealed a total bilirubin of 4.3 mg/dL, ALT 810 U/L, AST 226 U/L, alkaline phosphatase 178 U/L (R=14), albumin 4.9 g/dL, and INR 1.1. She enjoyed general good health, had no major medical illnesses, and had no history of liver disease, drug allergies, alcohol use, recent travel, or risk factors for viral hepatitis. Her only medications were cyclobenzaprine and vitamin B12, both of which she had taken for more than a year. Serologic testing revealed no evidence of acute hepatitis A, B, C, or E nor of acute EBV infection. The ANA was positive (1:320), but SMA and AMA were negative and total globulins (2.9 g/L) and IgG levels (1011 mg/dL) were normal. An abdominal ultrasound showed no evidence of biliary obstruction and a normal gall bladder without stones. The ultrasound also showed hyperechogenicity suggestive of hepatic steatosis, even though her BMI was 21.4 kg/m², and cholesterol, triglycerides, and fasting blood sugar were normal. Over the next 2 to 3 weeks both her symptoms and liver test abnormalities resolved (Table). In follow up 1, 4, and 7 months later, her liver test results were normal, although ANA remained positive (1:160) and repeat ultrasound showed echogenicity suggestive of steatosis.

Key Points

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Laboratory Values

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Case 2. 55 year old woman with pain and jaundice after eating Daily Harvest’s French Lentil and Leek Crumbles [110-0199].(1)

A 55 year old woman developed abdominal pain, fatigue, and jaundice the day after her second use of Daily Harvest’s new frozen food product called “French Lentil and Leek Crumbles” for dinner. The first use had been 4 days earlier. Laboratory testing revealed a total bilirubin of 3.3 mg/dL, ALT 485 U/L, AST 518 U/L, alkaline phosphatase 138 U/L (R=16.7), and albumin 4.2 g/dL. She was generally healthy, had no history of medical illnesses, drug allergies, alcohol use, recent travel, or risk factors for viral hepatitis. She was taking no prescription medications or other herbal or dietary supplements. Tests for acute hepatitis A, B and C were negative. She was not hospitalized and did not undergo liver imaging or biopsy. Her symptoms improved rapidly, and when seen 12 days later, her serum total bilirubin was normal and liver enzymes were much improved (Table). In further follow up 1 and 3 months later, she was asymptomatic, and her liver tests were normal. Tests for ANA and SMA were negative, and IgG levels were normal. An abdominal ultrasound was normal without evidence of hepatic steatosis, biliary obstruction, or gall stones. Ultrasound elastography showed normal liver stiffness. At 10 months after onset, her liver tests remained normal, despite having started several over-the-counter supplements including garlic and resveratrol. Interestingly, both her husband and son also ate some of the crumbles with her, and both were found to have similar symptoms and liver test abnormalities (see Case 3).

Key Points

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Laboratory Values

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Case 3. 55 year old husband of Case 2 developed mild acute hepatitis after eating daily Harvest’s French Lentil and Leek Crumbles [110-0198].(1)

The 55 year old man whose wife developed acute, symptomatic hepatitis after Daily Harvest’s new frozen food product called “French Lentil and Leek Crumbles” (Case 2) ate the same meals with her and had similar but milder symptoms, feeling ill with a low grade fever, and then jaundice after the second meal. The first meal with the crumbles had been 4 days earlier. His initial laboratory test results included a total bilirubin of 5.5 mg/dL, ALT 369 U/L, AST 117 U/L, alkaline phosphatase 183 U/L (R=7.7). Tests for hepatitis A, B and C were negative. Like his wife, he was generally healthy, had no major medical illnesses except kidney stones and no history of liver disease, alcohol use, recent travel, or risk factors for viral hepatitis. He was not taking any prescription medications but took fish oil, multivitamins, and a probiotic. He had a history of allergic reactions to doxycycline and levofloxacin. Tests for acute hepatitis A, B and C were negative. He was not hospitalized and did not undergo liver imaging or biopsy. His symptoms improved rapidly, and when seen 12 day later serum total bilirubin was normal and liver enzymes were much improved (Table). In further follow up 1 and 3 months later, he was asymptomatic and liver tests were normal. The ANA was weakly positive (1:80), but SMA was negative, and IgG levels were normal. An abdominal ultrasound and transient elastography were normal without evidence of hepatic stiffness or steatosis, biliary obstruction, or gall stones. At 10 months after onset, his liver tests remained normal but transient elastography now showed evidence of mild hepatic steatosis (CAP 244). His BMI was 26.7. He had started several over-the-counter supplements including multivitamins and resveratrol.

Key Points

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Laboratory Values

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