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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Caffeine

Last Update: June 18, 2020.

OVERVIEW

Introduction

Caffeine is xanthine alkaloid that occurs naturally in seeds, leaves and fruit of several plants and trees that acts as a natural pesticide. Caffeine is a major component of coffee, tea and chocolate and in humans acts as a central nervous system (CNS) stimulant. Consumption of caffeine, even in high doses, has not been associated with elevations in serum enzyme elevations or instances of clinically apparent liver injury.

Background

Caffeine is a psychoactive xanthine alkaloid that is a major component of coffee, tea and some foods (chocolate) and is the most frequently used psychoactive agent. At least 90% of adults in the United States consume caffeine daily. Caffeine is also found in several herbs including yerba mate, green coffee beans, guarana berries and yaupon holly. Caffeine is a frequent component of multiingredient dietary supplements, particularly those used for weight loss, improving athletic performance, increasing alertness and decreasing sleepiness. Finally, caffeine is available over-the-counter in tablets generally of 100 or 200 mg for improving alertness and decreasing sleepiness. Caffeine acts as a CNS stimulant, probably by displacing adenosine from A1 or A2 receptors in the brain. Adenosine in the circulation suppresses neural activity and is believed to be responsible for the feeling of sleepiness via activation of sleep promoting neurons. Reversal of the actions of adenosine may account for the psychoactive characteristics of caffeine containing products. Caffeine has many other actions including inhibition of other neurotransmitters as well as antiinflammatory and immunomodulatory actions. Nevertheless, caffeine is not formally approved as a medication for any condition or disorder. Caffeine is, however, the most commonly used psychoactive drug in the world, largely because of its presence in coffee and tea. The concentration of caffeine in coffee varies greatly by method of preparation and source, but typically ranges from 80 to 175 mg per cup of coffee, and from 20 to 80 mg per cup of tea. The amount in chocolate generally ranges from 10 to 30 mg per bar. Soft drinks also contain caffeine usually in amounts similar to tea. Recently, energy drinks have become popular (Red Bull, Jolt, Monster, and others) which may contain added caffeine in concentrations of 80 to more than 200 mg per can or bottle. Caffeine is a frequent component of multiingredient dietary supplements which may not provide the actual concentrations but are often in the range of 50 to 250 mg per serving. Caffeine in typical amounts is well tolerated and not associated with long term adverse outcomes. In high doses however, generally in excess of 1000 mg daily, caffeine can be toxic. Symptoms include nervousness, irritability, insomnia, headaches, rapid heartbeat, tremor, and gastrointestinal discomfort. Severe toxicity is marked by confusion, excessive anxiety, mania, hallucinations, seizures, rhabdomyolysis, cardiorespiratory arrest and death.

Hepatotoxicity

Some degree of caffeine intake is almost universal in modern society and an estimated 90% of adults in the United States consume caffeine daily, the average amount being 200 mg daily. Yet despite its widescale use, there is no evidence that regular consumption of caffeine or coffee has adverse effects on the liver. Indeed, epidemiological studies suggest that regular coffee intake may have modest protective effects against the progression of chronic liver disease and development of liver cancer. In high, toxic doses, caffeine can have severe effects on brain, heart and muscle function but has not been linked to clinically apparent liver injury. In contrast, there have been several reports of liver injury linked to use of caffeine rich energy drinks. These reports have not been very convincing and most were not well documented. In many instances, the hepatic injury resembled acute hepatic necrosis or ischemic hepatitis (Case 1). In other cases, other diagnoses were more likely than liver injury from the energy drinks (Case 2). Furthermore, it remains unclear whether the hepatic effects were caused by caffeine per se or to other components in typical energy drinks, such as vitamins, herbs or other botanical products. In reports of caffeine overdose including cases with autopsies, hepatic injury has been absent or not mentioned. Thus, caffeine is unlikely to cause liver injury, but the various high caffeine energy drinks which are widely used may possibly cause liver injury when used to excess.

Likelihood score for caffeine: E (unlikely cause of clinically apparent liver injury).

Likelihood score for energy drinks: C[H] (probable rare cause of clinically apparent liver injury when used in high amounts).

Mechanism of Injury

Caffeine is metabolized by the microsomal P450 drug metabolizing enzymes, predominantly CYP 1A2. Patients with advanced cirrhosis may have delayed metabolism of caffeine and experience caffeine side effects (nervousness, insomnia, headache) at levels of intake that are well tolerated by patients without liver disease.

Energy drinks typically have high concentrations of caffeine but also a myriad of other components including vitamins, minerals, amino acids, sugar and various herbal products, the concentration and purity of which are usually unknown.

Drug Class: CNS Stimulants, Xanthine Derivatives

Other Drugs in the Class: Theophylline

See also Energy Drinks

CASE REPORT

Case 1. Acute liver injury attributed to use of energy drinks.(1)

A 22 year old woman developed low grade fever, abdominal pain, nausea and vomiting and was found to have abnormal liver tests having been consuming 10 cans of energy drinks daily for 2 weeks. On examination in the emergency room, she had epigastric tenderness but no other findings and was sent home. The following day she developed jaundice and was seen again and admitted to the hospital. She denied alcohol or drug abuse and was not taking other medications. Laboratory tests showed marked elevations in ALT and AST (Table) but normal levels of bilirubin, alkaline phosphatase and GGT. The INR was 1.6. Acetaminophen levels were undetectable. There was no serologic evidence of acute hepatis A, B, C or E and tests for Epstein Barr virus and cytomegalovirus infection were negative. She was managed conservatively. She did not undergo liver biopsy or imaging studies. Serum aminotransferase levels decreased rapidly and she was discharged four days later. In follow up one month later, she was asymptomatic and serum ALT levels were normal.

Key Points

Medication:Energy drinks (10 cans daily for 2 weeks)
Pattern:Hepatocellular (R=~172)
Severity:3+ (jaundice and hospitalization)
Latency:2 weeks
Recovery:Within 1 month
Other medications:None

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		AST
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
2 weeks02161711.7Nausea, abdominal pain
1 day75337709Normal3.5GGT 29, INR 1.6
5 days19472381.7Discharged
1 month2226
Normal Values Not given <1.2

Comment

This short report described a young woman who presented with acute hepatic necrosis that was attributed to consumption of energy drinks for two weeks. The marked ALT and AST levels, the R ratio above 100, the abnormality of INR with minimal elevation in bilirubin and the rapid improvement within a week of onset are typical features of acute hepatic necrosis and not typical at all of the acute hepatitis seen with idiosyncratic drug induced liver injury. The clinical presentation was similar to that of acute acetaminophen overdose or acute ischemic hepatitis, both of which might be considered more likely than acute injury from a commercial energy drink. The components of the energy drink that were responsible for the severe acute liver injury were not clear. The product name of the energy drink was not provided but the ingredients listed in the report included vitamins, minerals and an “energy blend” which was likely to include caffeine, but other herbal components were not given.

Case 2. Acute hepatitis attributed to use of energy drinks.(2)

A 50 year old previously healthy man developed nausea, anorexia, epigastric pain and fatigue followed by dark urine and jaundice and was found to have markedly abnormal liver tests. He reported that he had been drinking 4 to 5 cans of an energy drink for the previous 3 weeks. He denied a history of liver disease, drug allergies, alcohol abuse, injection drug use or risk factors for viral hepatitis. He was not taking other medications or over-the-counter products. Initially, total serum bilirubin was 10.3 mg/dL (direct 7.7), ALT 1203 U/L, AST 1802 U/L, alkaline phosphatase 206 U/L, and INR 1.0. Tests for acute hepatitis A, B and E were negative, but he was positive for both anti-HCV and HCV RNA (5.6 million IU/mL). Antinuclear and smooth muscle antibodies were negative. Ultrasound of the abdomen showed no gallstones or evidence of biliary obstruction. A liver biopsy showed acute hepatitis with bridging necrosis and cholestasis but no fibrosis. Despite the HCV serology, he was diagnosed as having liver injury due to consumption of energy drinks, the suspected ingredient being niacin. After worsening for a few days, he began to improve spontaneously (Table) and in follow up serum weeks later he was asymptomatic and serum aminotransferase levels were normal. Follow up HCV RNA results were not reported.

Key Points

Medication:Energy drinks (4-5 cans daily for 3 weeks)
Pattern:Hepatocellular (R=~18.8)
Severity:3+ (jaundice and hospitalization)
Latency:3 weeks
Recovery:Unclear in timing
Other medications:None

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		AST
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
3 weeks1 day1203180220610.3Hospitalized
2 days1112171011.5Anti-HCV and HCV RNA positive
3 days1368243513.4Liver biopsy
4 days2073405119.3
5 days1629267415.7
6 days1224169512.0Discharged, asymptomatic
5 weeks14 days90352.7
18 days23362.2
Normal Values <38 <42 <130 <1.2

Comment

This case report described a 50 year old construction worker who presented with acute hepatitis three weeks after starting regular consumption of energy drinks (4 to 5 cans of an undeclared product daily). Importantly, he also tested positive for anti-HCV and HCV RNA despite having no risk factors for hepatitis C and no previous knowledge of being infected. The authors attributed the acute hepatitis to consumption of the energy drinks and not to hepatitis C, arguing that he more likely had an asymptomatic chronic HCV infection. However, the clinical presentation, liver biopsy findings and subsequent course are entirely compatible with acute hepatitis C. The challenge in this diagnosis is that serologic tests (including IgM anti-HCV) are unreliable in separating acute from chronic infection, and definitive diagnosis acute vs chronic HCV infection depends upon documentation of seroconversion to anti-HCV positivity. The diagnosis can also be fairly reliably made if the infection resolves as the hepatitis resolves, with disappearance of HCV RNA (and rising titers of anti-HCV) or if there is a recent clear history of exposure. Such documentation, however, is not always available and a high proportion of patients with acute hepatitis C develop de novo chronic infection. In large case series, acute hepatitis C accounts for 1 to 5% of cases initially suspected to be drug induced liver injury. Of the six reported cases of acute liver injury from energy drink consumption published between 2000 and 2020, none were very convincing and most had other possible explanations (ischemic hepatitis, liver injury from other drugs being taken, acetaminophen or other toxic overdose).

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Caffeine – Generic, NoDoz®

DRUG CLASS

CNS Stimulants, Xanthine Derivatives

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY
NUMBER		MOLECULAR
FORMULA		STRUCTURE
Caffeine 58-08-2 C8-H10-N4-O2 image 134971358 in the ncbi pubchem database

CITED REFERENCES

1.
Vivekanandarajah A, Ni S, Waked A. Acute hepatitis in a woman following excessive ingestion of an energy drink: a case report. J Med Case Rep. 2011 Jun 22;5:227. [PMC free article: PMC3141691] [PubMed: 21696583]
2.
Harb JN, Taylor ZA, Khullar V, Sattari M. Rare cause of acute hepatitis: a common energy drink. BMJ Case Rep. 2016;2016:bcr2016216612. [PMC free article: PMC5129143] [PubMed: 27803015]

ANNOTATED BIBLIOGRAPHY

References updated: 18 June 2020

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    (Expert review of hepatotoxicity published in 1999; caffeine is not discussed).
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  • Vivekanandarajah A, Ni S, Waked A. Acute hepatitis in a woman following excessive ingestion of an energy drink: a case report. J Med Case Rep. 2011 Jun 22;5:227. [PMC free article: PMC3141691] [PubMed: 21696583]
    (22 year old woman developed abdominal pain, nausea and vomiting having consumed 10 cans of energy drinks daily for 2 weeks [bilirubin 1.7 rising to 3.5 mg/dL, ALT 216 rising to 7553 U/L, Alk P and GGT normal, INR 1.6], recovering within the next few weeks with no specific therapy: Case 1).
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    (36 year old man developed jaundice having consumed 3 energy drinks [Rockstar] daily for a year and having a 15 year history of binge alcohol drinking [bilirubin 16.1 mg/dL, ALT 2995 U/L, Alk P 231 U/L, INR 1.0], with subsequent worsening [bilirubin rising to 23.1 mg/dL, INR 3.7, hepatic encephalopathy] leading to successful liver transplantation).
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    (50 year old man developed an acute hepatitis 3 weeks after consuming 4-5 energy drinks daily [bilirubin 10.3 rising to 19.3 mg/dL, ALT 1203 U/L, Alk P 206 U/L, anti-HCV and HCV RNA positive], with rapid resolution on stopping the energy drinks but no information on HCV RNA levels in follow up).
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  • Harty PS, Zabriskie HA, Erickson JL, Molling PE, Kerksick CM, Jagim AR. Multi-ingredient pre-workout supplements, safety implications, and performance outcomes: a brief review. J Int Soc Sports Nutr. 2018;15:41. [PMC free article: PMC6083567] [PubMed: 30089501]
    (Review of the efficacy and safety of multiingredient pre-workout supplements which typically contain caffeine, amino acids, nitrates and creatine and are “relatively safe with minimal reported adverse events”, mentions that their use has not been linked to serum enzyme elevations; no discussion of hepatotoxicity or concurrent use of anabolic steroids).
  • Al Yacoub R, Luczkiewicz D, Kerr C. Acute kidney injury and hepatitis associated with energy drink consumption: a case report. J Med Case Rep. 2020;14:23. [PMC free article: PMC6988357] [PubMed: 31992329]
    (62 year old woman with advanced small cell lung cancer in hospice developed nausea, vomiting and confusion and was found to have abnormal liver tests [bilirubin 0.3 mg/dL, ALT 2866 U/L, AST 4333 U/L, Alk P 111 U/L], having had little oral intake for 2 weeks except for 5-6 cans of an energy drink daily).
  • van Dam RM, Hu FB, Willett WC. Coffee, caffeine, and health. N Engl J Med. 2020;383:369–78. [PubMed: 32706535]
    (Review of the metabolism, physiologic and toxic effects of caffeine and coffee consumption including discussion of possible beneficial effects of coffee in chronic liver disease).

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