Tetracycline is an oral, broad-spectrum antibiotic used to treat mild-to-moderate infections due to susceptible microbial organisms. High doses of several forms of tetracycline given intravenously have been associated with acute fatty liver that can be severe and result in liver failure and death. Oral tetracycline use has been rarely and not very convincingly linked to acute hepatic injury.


Tetracycline is an oral, broad-spectrum antibiotic and semisynthetic derivative of Streptomyces actinobacteria. Tetracycline acts by inhibition of protein synthesis by binding to the 30S subunit of microbial ribosomes. Human cells are less susceptible to this inhibition. Tetracycline was first approved for use in the United States in 1957 and was one of several oral tetracyclines used at that time (oxytetracycline, chlortetracycline), many of which are no longer available or are used in veterinary medicine only. More modern forms of tetracycline include doxycycline and minocycline which are much more commonly used and have similar indications. Currently, tetracycline is most frequently used for upper respiratory and skin and soft tissue infection and more than 2 million prescriptions are filled yearly. Chronic therapy with tetracycline is effective in ameliorating acne, but because of their better absorption and tissue penetration, minocycline and doxycycline have largely replaced tetracycline for this indication. Tetracycline is also active against infections with several rickettsial, spirochetal, chlamydial and mycoplasmas infections and are often used for therapy of nonspecific urethritis and several Rickettsia diseases, such as Rocky Mountain spotted fever and Lyme disease. Tetracycline is available in multiple generic forms as capsules or tablets of 250 and 500 mg and generally recommended in doses of 250 to 500 mg three to four times daily for 7 to 30 days. Chronic therapy is typical for therapy of acne. Pediatric formulations as oral suspension are also available. Parenteral tetracycline is no longer used. Common side effects include gastrointestinal upset, nausea, poor appetitle, diarrhea, glossitis, rash and hypersensitivity reactions. Tetracycline can cause staining of developing teeth (in children or when taken by a pregnant mother).


High doses of intravenous tetracycline can induce fatty liver disease and may result in severe hepatic dysfunction, acute liver failure and death. This syndrome is more common among pregnant women, largely during the last trimester or early postpartum period. However, instances of acute fatty liver attributed to intravenous tetracycline have been reported in nonpregnant women and in men and even in children. The injury is characterized by onset of weakness, fever, fatigue, nausea and abdominal pain after 3 to 10 days of therapy. Laboratory tests show minimal-to-moderate elevations in serum aminotransferase and alkaline phosphatase levels with mild jaundice, but presence of hyperammonemia and coagulopathy. Pancreatitis, renal dysfunction and lactic acidosis are also common, although not always specifically sought. The syndrome may be reversible if tetracycline is stopped promptly, but it is usually recognized late and can progress to multiorgan failure and death despite stopping the agent. This syndrome also occurs with high doses of intravenous doxycycline and minocycline, but quite rarely. This syndrome is rarely seen currently as tetracycline is no longer available in parenteral form and the use of intravenous tetracyclines has been superseded by availability of safer, better tolerated and more effective broad spectrum antibiotics.

Oral tetracycline has been associated with rare instances of acute liver injury, but the association with tetracycline use as opposed to other agents being taken has not always been very well shown. Despite frequency of its use, oral tetracycline remains a very rare cause of liver injury. In contrast, cases of doxycycline and minocycline induced liver disease are well described. Rare instances of acute fatty liver have been attributed to oral tetracycline, particularly when given to pregnant women in high doses. Currently, tetracycline is considered contraindicated in pregnant women, particularly during the last trimester.

Likelihood score: A[HD] (well known cause of clinically apparent liver injury but usually when given in high doses intravenously).

Mechanism of Injury

The hepatic injury from intravenous forms of tetracycline was likely due to mitochondrial injury due to inhibition of mitochondrial protein synthesis, although another possibility is that tetracycline interferes with fat metabolism in hepatocytes. The injury is less idiosyncratic than direct, varying in frequency and severity based upon pharmacokinetics and host metabolic factors (age, pregnancy, drug accumulation, and other factors affecting mitochondrial function). The rare idiosyncratic forms of liver injury from tetracycline are of unknown cause, but are likely to be immunoallergic.

Outcome and Management

Acute fatty liver due to tetracycline has a high fatality rate and is best managed with intensive care and attention to multiorgan support. Lactic acidosis should be treated with intravenous glucose (20% infusions) and bicarbonate. Idiosyncratic acute liver injury from tetracycline is rare and usually resolves rapidly once the agent is withdrawn. An instance of chronic cholestasis with vanishing bile duct syndrome has been reported, although the patient had received several medications that might have accounted for the hepatic injury.

Drug Class: Antiinfective Agents, Tetracyclines


Case 1. Liver failure from intravenous tetracycline.

[Modified from: Robinson MJ, Rywlin AM. Tetracycline-associated fatty liver in the male. Report of an autopsied case. Am J Dig Dis 1970; 15: 857-62. PubMed Citation]

A 72 year old man treated for cystitis and diverticulitis with 10 days of iv tetracycline developed lactic acidosis and multiorgan failure. The patient had no previous history of liver disease or risk factors for hepatitis. When initially admitted to the hospital, he had fever, abdominal pain, leukocytosis and an abnormal urinalysis, but liver tests were normal (Table). He was treated with hydration and iv tetracycline in doses of 3 grams daily. His fever improved slowly, but by day 4, liver tests were mildly abnormal and they had worsened by day 8. Colistin was added on day 6, and chloramphenicol was substituted for tetracycline on day 10. The following day, he developed progressive restlessness, stupor and respiratory failure. He had renal failure and severe acidosis and he died within hours of attempting resuscitation and dialysis. Autopsy showed an enlarged fatty liver with minimal inflammation and no obvious hepatocellular necrosis. Fat was also identified in renal tubular cells. There was marked ascites and hemorrhagic pancreatitis.

Key Points

Laboratory Values

* King Armstrong units


Acute fatty liver caused by tetracycline was initially thought to occur only in pregnant women during the last trimester, but was subsequently reported to occur at other times during pregnancy, after delivery, in nonpregnant women, in men and even in children. The syndrome typically occurs after 3 to 10 days of relatively high doses of im or iv tetracycline. The case above is typical in demonstrating that the precipitous onset of symptoms is a late phenomenon and has a grim prognosis; symptoms are preceded by several days of worsening liver injury, although laboratory tests may be only mildly or moderately abnormal. Acute fatty liver is accompanied by minimal hepatic inflammation and liver cell necrosis and is a syndrome of mark mitochondrial failure, early appearance of hepatic synthetic dysfunction and lack of ATP to drive normal metabolism. The injury is not confined to the liver, and renal failure and pancreatitis are common. As in this case, the immediate cause of death is typically multiorgan failure due to lactic acidosis or pancreatitis.



Tetracycline – Generic, Sumycin®


Antiinfective Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 10 June 2017

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    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, minocycline accounted for 3 cases, doxycycline for 3 cases and tetracycline was listed as a secondary possible cause for one).
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    (3 cases of minocycline hepatotoxicity; 16 year olds with onset of jaundice 2, 13 and 24 months after starting minocycline for acne [bilirubin 19.6, 9.1 and 9.5 mg/dL, ALT 1282, 2306 and 2056 U/L, ANA 1:160-1:640], liver biopsies showing hepatitis and fibrosis; all treated with corticosteroids, 2 requiring prolonged therapy).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database containing 9036 hepatic adverse drug reactions in children includes 117 cases attributed to minocycline, but no other tetracycline listed in the top 40 causes).
  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]
    (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; none were due to tetracyclines).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury and 25 to antituberculosis agents, including 15 to isoniazid alone [ranking first], 6 to isoniazid combined with other agents, 3 to rifampin and pyrazinamide, and 1 to dapsone).
  • Leitner JM, Graninger W, Thalhammer F. Hepatotoxicity of antibacterials: Pathomechanisms and clinical. Infection 2010; 38: 3-11. [PubMed: 20107858]
    (Review of hepatotoxicity of antibiotics; mentions that hepatotoxicity from oral tetracycline is rare ~1.5 cases per million prescriptions, whereas minocycline has been associated with either an immediate reaction with eosinophilia, dermatitis and enzyme elevations or a delayed autoimmune hepatitis-like syndrome).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to a tetracyclinel).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, 37 of which were attributed to an antibiotic, but none to a tetracycline).
  • Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, Kreutz R, et al. Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. Br J Clin Pharmacol 2015; 79: 988-99. [PMC free article: PMC4456131] [PubMed: 25444550]
    (Among 76 inpatients with hepatitis of uniknown cause enrolled in a prospective case-cohort surveillance study between 2002 and 2011, one was attributed to doxycycline, but no other tetracycline was implicated).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 323 [36%] were attributed to antibiotics including 28 [3%] to minocycline and 4 [0.4%] to doxycycline).