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Can tetracycline-induced fatty liver in pregnancy be attributed to choline deficiency?
Medical
Hypotheses
9:
157-162,
CAN TETRACYCLINE-INDUCED CHOLINE DEFICIENCY?
FATTY
1982
LIVER
IN PREGNANCY
of Pharmacology, Department M.C.E. Gwee, National University of Singapore, Kent Ridge,
BE ATTRIBUTED
TO
of Medicine, Faculty SINGAPORE 0511.
ABSTRACT those in their third trimester, Pregnant women, especially to tetracycline-induced fatty liver. are particularly susceptible Experimental evidence obtained in rats suggest that the precipitous fall in maternal liver choline concentration nearing the end of could lead to a severe reduction in the lipotropic pregnancy It is hypothesised that the liver in this activity of the liver. state will be at much greater risk of developing fatty degeneration, agents such as hepatotoxic exposed to especially if it is tetracycline.
INTRODUCTION Tetracycline is known to induce fatty liver in experimental animals(l). A serious and often fatal clinical syndrome resulting from the use of tetracycline has also been well documented in humans, especially if the drug is administered parenterally and in large doses. The syndrome is characterised by fatty liver, hepatic dysfunction, azotemia and pancreatitis(2-6); the liver appears yellow and highly enlarged with the dominant histologic picture of numerous small droplets of fat in parenchyma cells(7-10). The pathogenesis of tetracycline-induced fatty liver remains unclear. Several mechanisms have been suggested including interference with adenosinetriphosphate (ATP) synthesis leading to impairment of fat metabolism(l1, 12) consequent upon structural alterations of mitochondria(l3, 14).
157
Pregnancy:
a predisposing
factor
tetracycline-induced fatty liver A prominent feature of formation in humans is that it occurs most frequently in pregnant women in whom the mortality rate is high(2, 11, 15-17). Moreover, the fatal steatosis due to tetracycline display features that closely resemble those of the fatty liver of pregnancy itself(lg-26) and of Reye's syndrome(27). The question then arises, why does the state of pregnancy predispose an individual to the hepatotoxic effects of tetracycline? tetracycline in normal The disposition of pregnant and non-pregnant women were found to be similar with respect to its plasma concentration-time profile, its uptake by the liver and its renal excretion(28). Even in pregnant women with pyelonephritis the plasma half-life of tetracycline was prolonged in only a few women whose GFR was depressed to less than 60 ml/min(29). Thus, in the effect of tetracycline in the majority of cases hepatotoxic pregnancy cannot be attributed to the occurrence of higher plasma levels of the drug in the women. It seems that somehow the state of pregnancy increases the "sensitivity" of the liver to the toxic effect of tetracycline. What then is the this mechanism responsible for increased sensitivity? So far this question remains largely unresolved, it has been suggested that tetracycline toxicity is although increased in pregnancy or in protein undernutrition due to inhibition of protein synthesis that is already "under stress or impaired", resulting in a reduction of lipoproteins responsible for the removal of triglyceride from the liver(24, 30).
Choline deficiency
of maternal
liver in pregnancy
Experimental results in rats obtained in our laboratory(31, 32) can offer an alternative and convincing explanation for the clinical phenomenon of tetracycline-induced fatty liver formation in pregnant women. In pregnant rats the concentration of free choline (nmol/g maternal liver significant and tissue) in the undergoes a progressive fall from a control value of 130+9 to 93~9 after about 11 days gestation, and then to 38+1 from about 17 days gestation to Thus, pregnancy in rats ultimately leads term (21-22 days)(31, 32). to a relative state of choline deficiency in the liver. If similar changes in maternal liver choline are assumed to occur in human pregnancy, then this can offer an explanation for the greater susceptibility of pregnant women to tetracycline-induced fatty liver.
158
Hypothesis: tetracycline
lipotropic reduced hepatotoxicity?
activity
and
susceptibility
to
Choline is well recognised as one of the most important In choline deficiency states the liver is lipotropic agents(33). rats fed a choline weanling organ: tht primary target young deficient diet rapidly develop fatty degeneration of the liver(34, In rats the precipitous fall in maternal liver choline during 35). pregnancy can be expected to lead to a significant reduction in the lipotropic activity of the liver. It is possible, then, that such a will liver to the development of state predispose the fatty degeneration and, possibly, to the action of hepatotoxic agents such as tetracycline. This tentative hypothesis extrapolates from our experimental observations in rats(31, 32) to the clinical situation. It receives further support from the chronological sequence of events occurring in pregnant women and in pregnant rats which appear to coincide well It has been reported that tetracycline-induced with each other. fatty liver occurs most frequently in the third-trimester of pregnancy(36). In pregnant rats the fall in liver choline concentration is most marked (70%) at about the "third-trimester" as of pregnancy possibly represents well. Thus, the third-trimester the stage of "least resistance" of the liver to the action of hepatotoxic agents, perhaps consequent upon a severe reduction in its lipotropic activity. It is also useful to note that, in rats, the foetal liver choline already attained adult levels before birth probably to ensure optimum lipotropic activity in the early neonatal period, during which time the neonatal liver would not have the capacity to synthesize choline at adult rates(32).
CONCLUSION On the basis of experimental evidence obtained in rats, a tentative hypothesis is made to account for the greater susceptibility of pregnant women, especially in their third-trimester, to tetracycline-induced fatty liver. It is hypothesised that a precipitous fall in maternal liver choline concentration nearing the end of pregnancy could lead to a severe reduction in the lipotropic activity of the liver. In this state liver will be at much the greater risk of developing fatty degeneration, especially if it is exposed to hepatotoxic agents such as tetracycline.
159
REFERENCES
1.
Seto JT, Lepper NH: The effect of chlortetracycline, oxytetracycline, and tetracycline administered intravenously on hepatic fat content: A quantitative method of study including failure of some vitamins and other drugs to mitigate the effect. Antibiot. Chemother. 4: 666, 1954.
2.
Schultz JC, Adamson JS, Workman WW, and Norman TD: Fatal liver disease after intravenous administration of tetracycline in high dosage. New Engl. J. Med. 269: 999, 1963.
3.
Peters RL, Edmondson HA, Tatter D: Mikkelsen WP, Tetracycline- induced fatty liver in nonpregnant patients: A report of six patients. Amer. J. Surg. 113: 622, 1967.
4.
Schiffer MA: Fatty liver associated with administeration of tetracycline in pregnant and nonpregnant women. Amer. J. Obstet. Gynec. 96: 326, 1966.
5.
Robinson MJ, Rywlin AM: Tetracycline-associated fatty liver in the male. Report of an autopsied case. Amer. J. Dig. Dis. 15: 857, 1970.
6.
Winterling AN, Goldman RL: Hepatic and renal lesions in a case of tetracycline toxicity during long term estrogen therapy after orchiectomy. Calif. Med. 102: 314, 1965.
7.
Faloon WW, No11 JW, Prior JT: Nitrogen metabolism and liver histology during aureomycin administration in patients with hepatic disease. J. Lab. Clin. Med. 41: 596, 1953.
8.
Faloon WW: Metabolic and histologic studies in patients with and without liver disease receiving chloramphenicol and oxytetracycline. J. Lab. Clin. Med. 44: 75, 1954.
9.
Shils ME: Some metabolic aspects of Pharmacol. Ther. 3: 321, 1962.
10.
Lepper NH, Zimmerman HJ, Carroll G, Caldwell ER Jr, Spies HW, Wolfe CK, Dowling HF: Effect of large doses of aureomycin, terramycin and chloramphenicol on livers of mice and dogs. Arch. Intern. Med. (Chicago) 88: 284, 1951.
11.
Wruble LD, Ladman AJ, Britt LG, Armmins AJ: Hepatotoxicity produced by tetracycline overdosage. J. Amer. Med. Assoc. 192: 92, 1965.
12.
Hyams, DE and Isselbacher KJ: Prevention of fatty liver by administration of adenosine triphosphate. Nature 204: 1196, 1964.
160
tetracyclines.
Clin.
Showacre JL: and in mitochondria of
localization of Selective Science 133: living cells.
13.
Buy HG Du tetracycline 196, 1961.
14.
The effect of Journey LJ, Goldstein MN: fine structure of HeLa cell mitochondria. 551, 1963.
15.
Tetracycline Whalley PJ, Adams RH, Combes B: J. Amer. Med. Assoc. 189: 357, 1964. pregnancy.
16.
Fatty Constantine T, Kunelis CT, Peters LJ, Edmondson HA: its tetracycline liver of pregnancy and relationship to therapy. Amer. J. Med. 38: 359, 1965.
17.
A Davis JS, Kaufman RH: Tetracycline toxicity: clinicopathologic study with special reference to liver damage and its relationship to pregnancy. Amer. J. Obstet. 95: 523, 1966.
18.
Stander JH, Cadden JF: Acute yellow atrophy of the pregnancy. Amer. J. Obstet. Gynec. 28: 61, 1963.
19.
Whitacre FE, Fang pregnancy. Report histologic studies.
20.
Dill LV: Acute yellow atrophy of the liver associated with A review of the literature and six cases. pregnancy: Obstet. Gynec. Survey 5: 139, 1950.
21.
Ober WB, LeCompte PM: Acute fatty metamorphosis of the associated with pregnancy. Amer. J. Med. 19: 743, 1955.
22.
Lewis PL, Takeda M, Warren WJ: Obstetric acute yellow atrophy: Report of a case. Obstet. Gynec. 22: 121, 1963.
23.
Czernobilsky B, Bergnes MA: Acute fatty metamorphosis of the liver in pregnancy with associated liver cell necrosis. Obstet. Gynec. 26: 792, 1965.
24.
Duma RJ, Dowling EA, Alexander HC, Sibrans D, Dempsey H: Acute fatty liver of pregnancy: Report of a surviving patient studied with serial liver biopsies. Ann. Intern. Med. 63: 851, 1965.
25.
Joske RA, pregnancy.
26.
Breen KJ, Perkins KW, Mistilis SP, Shearman R: acute fatty liver of pregnancy. Gut. 11: 822, 1970.
terramycin on Cancer Res.
toxicity
liver
the 23:
in
in
LY: Fatty degeneration of the liver in of a case with recovery: Chemical and J. Amer. Med. Assoc. 118: 1358, 1942.
McCully DJ, Mastaglia Gut 9: 489, 1968.
161
FL:
Acute
fatty
liver
liver
of
Idiopathic
27.
Spectrum Drug Hepatotoxicity: Zimmerman HJ: p. 35 in Drug Reactions and the Liver Lesions. Tredger, R Williams, eds) Pitman, London, 1981.
28.
Whalley PJ, Martin FG, Adams disposition in normal pregnancy.
29.
Whalley PJ, Martin FG, Adams RH, Combes B: tetracycline by pregnant women with acute Obstet. Gynec. 36: 821, 1970.
30.
Drugs and Sherlock Sheila: Biliary Liver and the Publications, Oxford, 1981.
31.
Free choline concentration and cephalin-NGwee MCE, Sim MK: methyltransferase activity in the maternal and foetal liver and placenta of pregnant rats. Clin. Exper. Pharmac. Physiol. 5: 649, 1978.
32.
Gwee MCE, Sim, MK: of free Changes in the concentration choline and cephalin-N-methyltransferase activity of the rat maternal and foetal liver and placenta during gestation and of and neonatal liver in the early the maternal postpartum period. Clin. Exper. Pharmac. Physiol. 6: 259, 1979.
33.
Ridout JH: Fatty livers Lucas CC , and lipotropic phenomena. p. 5. in Progress in the Chemistry of Fats and Other Lipids (RT Holman, ed), Vol. 10 Pergamon Press, Oxford, 1967.
34.
Best CH, Huntsman, Elinor M: deposition of fat in the liver.
35.
Lombardi B: Effects of choline hepatocytes. Fed. Proc. 30: 139, 1971.
36.
Combes B, Whalley PJ, Adams RH: Tetracycline and the Liver. p. 589 in Progress in Liver Disease (H Popper, F. Schaffner, ed), Vol. IV . Grune 6 Stratton Inc., New York, 1972.
RH, Combes B: Tetracycline Obstet. Gynec. 28: 103, 1966.
the Liver. System,
162
of Clinical (M Davis, JM
Disposition of pyelonephritis.
p. 295 in Diseases of Blackwell Scientific
The effects of lecithin upon J. Physiol. 73: 405, 1932. deficiency
on
rat
Hypotheses
9:
157-162,
CAN TETRACYCLINE-INDUCED CHOLINE DEFICIENCY?
FATTY
1982
LIVER
IN PREGNANCY
of Pharmacology, Department M.C.E. Gwee, National University of Singapore, Kent Ridge,
BE ATTRIBUTED
TO
of Medicine, Faculty SINGAPORE 0511.
ABSTRACT those in their third trimester, Pregnant women, especially to tetracycline-induced fatty liver. are particularly susceptible Experimental evidence obtained in rats suggest that the precipitous fall in maternal liver choline concentration nearing the end of could lead to a severe reduction in the lipotropic pregnancy It is hypothesised that the liver in this activity of the liver. state will be at much greater risk of developing fatty degeneration, agents such as hepatotoxic exposed to especially if it is tetracycline.
INTRODUCTION Tetracycline is known to induce fatty liver in experimental animals(l). A serious and often fatal clinical syndrome resulting from the use of tetracycline has also been well documented in humans, especially if the drug is administered parenterally and in large doses. The syndrome is characterised by fatty liver, hepatic dysfunction, azotemia and pancreatitis(2-6); the liver appears yellow and highly enlarged with the dominant histologic picture of numerous small droplets of fat in parenchyma cells(7-10). The pathogenesis of tetracycline-induced fatty liver remains unclear. Several mechanisms have been suggested including interference with adenosinetriphosphate (ATP) synthesis leading to impairment of fat metabolism(l1, 12) consequent upon structural alterations of mitochondria(l3, 14).
157
Pregnancy:
a predisposing
factor
tetracycline-induced fatty liver A prominent feature of formation in humans is that it occurs most frequently in pregnant women in whom the mortality rate is high(2, 11, 15-17). Moreover, the fatal steatosis due to tetracycline display features that closely resemble those of the fatty liver of pregnancy itself(lg-26) and of Reye's syndrome(27). The question then arises, why does the state of pregnancy predispose an individual to the hepatotoxic effects of tetracycline? tetracycline in normal The disposition of pregnant and non-pregnant women were found to be similar with respect to its plasma concentration-time profile, its uptake by the liver and its renal excretion(28). Even in pregnant women with pyelonephritis the plasma half-life of tetracycline was prolonged in only a few women whose GFR was depressed to less than 60 ml/min(29). Thus, in the effect of tetracycline in the majority of cases hepatotoxic pregnancy cannot be attributed to the occurrence of higher plasma levels of the drug in the women. It seems that somehow the state of pregnancy increases the "sensitivity" of the liver to the toxic effect of tetracycline. What then is the this mechanism responsible for increased sensitivity? So far this question remains largely unresolved, it has been suggested that tetracycline toxicity is although increased in pregnancy or in protein undernutrition due to inhibition of protein synthesis that is already "under stress or impaired", resulting in a reduction of lipoproteins responsible for the removal of triglyceride from the liver(24, 30).
Choline deficiency
of maternal
liver in pregnancy
Experimental results in rats obtained in our laboratory(31, 32) can offer an alternative and convincing explanation for the clinical phenomenon of tetracycline-induced fatty liver formation in pregnant women. In pregnant rats the concentration of free choline (nmol/g maternal liver significant and tissue) in the undergoes a progressive fall from a control value of 130+9 to 93~9 after about 11 days gestation, and then to 38+1 from about 17 days gestation to Thus, pregnancy in rats ultimately leads term (21-22 days)(31, 32). to a relative state of choline deficiency in the liver. If similar changes in maternal liver choline are assumed to occur in human pregnancy, then this can offer an explanation for the greater susceptibility of pregnant women to tetracycline-induced fatty liver.
158
Hypothesis: tetracycline
lipotropic reduced hepatotoxicity?
activity
and
susceptibility
to
Choline is well recognised as one of the most important In choline deficiency states the liver is lipotropic agents(33). rats fed a choline weanling organ: tht primary target young deficient diet rapidly develop fatty degeneration of the liver(34, In rats the precipitous fall in maternal liver choline during 35). pregnancy can be expected to lead to a significant reduction in the lipotropic activity of the liver. It is possible, then, that such a will liver to the development of state predispose the fatty degeneration and, possibly, to the action of hepatotoxic agents such as tetracycline. This tentative hypothesis extrapolates from our experimental observations in rats(31, 32) to the clinical situation. It receives further support from the chronological sequence of events occurring in pregnant women and in pregnant rats which appear to coincide well It has been reported that tetracycline-induced with each other. fatty liver occurs most frequently in the third-trimester of pregnancy(36). In pregnant rats the fall in liver choline concentration is most marked (70%) at about the "third-trimester" as of pregnancy possibly represents well. Thus, the third-trimester the stage of "least resistance" of the liver to the action of hepatotoxic agents, perhaps consequent upon a severe reduction in its lipotropic activity. It is also useful to note that, in rats, the foetal liver choline already attained adult levels before birth probably to ensure optimum lipotropic activity in the early neonatal period, during which time the neonatal liver would not have the capacity to synthesize choline at adult rates(32).
CONCLUSION On the basis of experimental evidence obtained in rats, a tentative hypothesis is made to account for the greater susceptibility of pregnant women, especially in their third-trimester, to tetracycline-induced fatty liver. It is hypothesised that a precipitous fall in maternal liver choline concentration nearing the end of pregnancy could lead to a severe reduction in the lipotropic activity of the liver. In this state liver will be at much the greater risk of developing fatty degeneration, especially if it is exposed to hepatotoxic agents such as tetracycline.
159
REFERENCES
1.
Seto JT, Lepper NH: The effect of chlortetracycline, oxytetracycline, and tetracycline administered intravenously on hepatic fat content: A quantitative method of study including failure of some vitamins and other drugs to mitigate the effect. Antibiot. Chemother. 4: 666, 1954.
2.
Schultz JC, Adamson JS, Workman WW, and Norman TD: Fatal liver disease after intravenous administration of tetracycline in high dosage. New Engl. J. Med. 269: 999, 1963.
3.
Peters RL, Edmondson HA, Tatter D: Mikkelsen WP, Tetracycline- induced fatty liver in nonpregnant patients: A report of six patients. Amer. J. Surg. 113: 622, 1967.
4.
Schiffer MA: Fatty liver associated with administeration of tetracycline in pregnant and nonpregnant women. Amer. J. Obstet. Gynec. 96: 326, 1966.
5.
Robinson MJ, Rywlin AM: Tetracycline-associated fatty liver in the male. Report of an autopsied case. Amer. J. Dig. Dis. 15: 857, 1970.
6.
Winterling AN, Goldman RL: Hepatic and renal lesions in a case of tetracycline toxicity during long term estrogen therapy after orchiectomy. Calif. Med. 102: 314, 1965.
7.
Faloon WW, No11 JW, Prior JT: Nitrogen metabolism and liver histology during aureomycin administration in patients with hepatic disease. J. Lab. Clin. Med. 41: 596, 1953.
8.
Faloon WW: Metabolic and histologic studies in patients with and without liver disease receiving chloramphenicol and oxytetracycline. J. Lab. Clin. Med. 44: 75, 1954.
9.
Shils ME: Some metabolic aspects of Pharmacol. Ther. 3: 321, 1962.
10.
Lepper NH, Zimmerman HJ, Carroll G, Caldwell ER Jr, Spies HW, Wolfe CK, Dowling HF: Effect of large doses of aureomycin, terramycin and chloramphenicol on livers of mice and dogs. Arch. Intern. Med. (Chicago) 88: 284, 1951.
11.
Wruble LD, Ladman AJ, Britt LG, Armmins AJ: Hepatotoxicity produced by tetracycline overdosage. J. Amer. Med. Assoc. 192: 92, 1965.
12.
Hyams, DE and Isselbacher KJ: Prevention of fatty liver by administration of adenosine triphosphate. Nature 204: 1196, 1964.
160
tetracyclines.
Clin.
Showacre JL: and in mitochondria of
localization of Selective Science 133: living cells.
13.
Buy HG Du tetracycline 196, 1961.
14.
The effect of Journey LJ, Goldstein MN: fine structure of HeLa cell mitochondria. 551, 1963.
15.
Tetracycline Whalley PJ, Adams RH, Combes B: J. Amer. Med. Assoc. 189: 357, 1964. pregnancy.
16.
Fatty Constantine T, Kunelis CT, Peters LJ, Edmondson HA: its tetracycline liver of pregnancy and relationship to therapy. Amer. J. Med. 38: 359, 1965.
17.
A Davis JS, Kaufman RH: Tetracycline toxicity: clinicopathologic study with special reference to liver damage and its relationship to pregnancy. Amer. J. Obstet. 95: 523, 1966.
18.
Stander JH, Cadden JF: Acute yellow atrophy of the pregnancy. Amer. J. Obstet. Gynec. 28: 61, 1963.
19.
Whitacre FE, Fang pregnancy. Report histologic studies.
20.
Dill LV: Acute yellow atrophy of the liver associated with A review of the literature and six cases. pregnancy: Obstet. Gynec. Survey 5: 139, 1950.
21.
Ober WB, LeCompte PM: Acute fatty metamorphosis of the associated with pregnancy. Amer. J. Med. 19: 743, 1955.
22.
Lewis PL, Takeda M, Warren WJ: Obstetric acute yellow atrophy: Report of a case. Obstet. Gynec. 22: 121, 1963.
23.
Czernobilsky B, Bergnes MA: Acute fatty metamorphosis of the liver in pregnancy with associated liver cell necrosis. Obstet. Gynec. 26: 792, 1965.
24.
Duma RJ, Dowling EA, Alexander HC, Sibrans D, Dempsey H: Acute fatty liver of pregnancy: Report of a surviving patient studied with serial liver biopsies. Ann. Intern. Med. 63: 851, 1965.
25.
Joske RA, pregnancy.
26.
Breen KJ, Perkins KW, Mistilis SP, Shearman R: acute fatty liver of pregnancy. Gut. 11: 822, 1970.
terramycin on Cancer Res.
toxicity
liver
the 23:
in
in
LY: Fatty degeneration of the liver in of a case with recovery: Chemical and J. Amer. Med. Assoc. 118: 1358, 1942.
McCully DJ, Mastaglia Gut 9: 489, 1968.
161
FL:
Acute
fatty
liver
liver
of
Idiopathic
27.
Spectrum Drug Hepatotoxicity: Zimmerman HJ: p. 35 in Drug Reactions and the Liver Lesions. Tredger, R Williams, eds) Pitman, London, 1981.
28.
Whalley PJ, Martin FG, Adams disposition in normal pregnancy.
29.
Whalley PJ, Martin FG, Adams RH, Combes B: tetracycline by pregnant women with acute Obstet. Gynec. 36: 821, 1970.
30.
Drugs and Sherlock Sheila: Biliary Liver and the Publications, Oxford, 1981.
31.
Free choline concentration and cephalin-NGwee MCE, Sim MK: methyltransferase activity in the maternal and foetal liver and placenta of pregnant rats. Clin. Exper. Pharmac. Physiol. 5: 649, 1978.
32.
Gwee MCE, Sim, MK: of free Changes in the concentration choline and cephalin-N-methyltransferase activity of the rat maternal and foetal liver and placenta during gestation and of and neonatal liver in the early the maternal postpartum period. Clin. Exper. Pharmac. Physiol. 6: 259, 1979.
33.
Ridout JH: Fatty livers Lucas CC , and lipotropic phenomena. p. 5. in Progress in the Chemistry of Fats and Other Lipids (RT Holman, ed), Vol. 10 Pergamon Press, Oxford, 1967.
34.
Best CH, Huntsman, Elinor M: deposition of fat in the liver.
35.
Lombardi B: Effects of choline hepatocytes. Fed. Proc. 30: 139, 1971.
36.
Combes B, Whalley PJ, Adams RH: Tetracycline and the Liver. p. 589 in Progress in Liver Disease (H Popper, F. Schaffner, ed), Vol. IV . Grune 6 Stratton Inc., New York, 1972.
RH, Combes B: Tetracycline Obstet. Gynec. 28: 103, 1966.
the Liver. System,
162
of Clinical (M Davis, JM
Disposition of pyelonephritis.
p. 295 in Diseases of Blackwell Scientific
The effects of lecithin upon J. Physiol. 73: 405, 1932. deficiency
on
rat