Información del artículo
Resumen
El ácido ursodesoxicólico, empleado en el tratamiento de colestasis intrahepática que se da en la cirrosis biliar primaria, colangitis esclerosante primaria, y hepatitis crónica, no tiene aprobación en el mercado para su prescripción durante el embarazo debido a lafalta de información.
En dos casos de colestasis gravídica, nosotros administramos ácido ursodesoxicólico oral 1 g al día a apartir de la 34 semana de amenorrea hasta el parto. En ambos casos, en 3 días de tratamiento hubo regresión completa del prurito y descendieron los niveles plasmáticos del ácido biliar y de las transaminasas. Los niños, nacidos entre las 37 y 38 semanas de amenorrea, no presentaron ningún problema.
Cincuenta y un casos de colestasis gravídica tratados con ursodesoxicólico (0,4 a 1 g por día) han sidodescritos en la bibliografía 18 casos pertenecientes a2 estudios randomizados. En 49 casos el prurito desapareció generalmente a los 3 días de establecer el tratamiento, y los niveles de ácido biliar en plasma y transaminasas descendieron en una semana. Sólo 2 pacientes experimentaron prurito persistente a pesar de la mejora en el aspecto biológico. No se han descrito efectos adversos.
El ácido ursodexoxicólico parece ser un tratamiento eficaz para la colestasis gravídica. Es necesaria una observación a largo plazo de los fetos expuestos en el útero a este tratamiento para valorar su seguridad.
Summary
Ursodeoxycholic acid, used in the treatment of in-trahepatic cholestasis present in the chronic liver diseases such as, primary biliary cirrhosis, primary sclerosing cholangitis or chronic hepatitis, is contra-indicated in pregnant women as there are no studies of its use in pregnancy.
In 2 cases of gravid cholestasis we administered a dose of 1mg/day from the 34th week of amenorrhoea until delivery. In both cases, pruritus regressed completely after 3 days of treatment and plasma levels of biliary acid and transaminases began to decrease. Both infants, born between the 37th and 38th weeks, were normal.
In the literature we found 51 cases of gravid cho-lestasis treated with Ursodeoxycholic acid in doses varying from 400mg to 1g/day. Of these 18 cases were in 2 randomised studies. In 49 cases pruritus had generally disappeared 3 days after the start of treatment and plasma levels of biliary acids and transami-nases decreased in one week. Only two patients experienced persistent pruritus, although the biological criteria of cholestasis had decreased. No foetal teratogenicity or toxicity was observed.
Ursodeoxycholic acid seems to be an efficient treatment of gravid cholestasis. Long term observation of children exposed to this treatment in utero are required to confirm its apparent foetal safety.
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Bibliografía
[1.]
U.P. Haemmerli.
Jaundice during pregnancy.
Acta Med Scand, 444 (1966), pp. 1-111
[2.]
P.S. Lathan.
Hepatopatías del embarazo.
Medicina clínica en obstetricia, pp. 951-961
[3.]
H.J. Fallon, C.A. Riely.
Enfermedades hepáticas.
pp. 307-341
[4.]
F.G. Cunningham, P.C. MacDonald, N.F. Gant, K.J. Leveno, III LC Gilstrap, GDV Hankins, et al.
Enfermedades gas-trointestinales.
Williams obstetricia, 20, pp. 1063-1089
[5.]
T.F. Ferris.
Enfermedades médicas durante el embarazo.
Harrison. Principios de medicina interna (I, 14, pp. 28-34
[6.]
K.J. Isselbacher.
Metabolismo de la bilirrubina e hiperbilirru-binemia.
Harrison. Principios de medicina interna (II, 14, pp. 1899-1904
[7.]
L. Thorling.
Jaundice during pregnancy: A clinical study.
Acta Med Scand, 302 (1955), pp. 131-192
[8.]
S.P. Mistiles.
Liver disease in pregnancy, with particular emphasis on the colestatic syndromes.
Aust Ann Med, 17 (1968), pp. 248-255
[9.]
H. Reyes, N.C. González, J. Ribalta, H. Aburto, C. Matus, G. Sch-ramm, et al.
Prevalence of intrahepatic cholestasis of pregnancy in Chile.
Ann Intern Med, 88 (1978), pp. 487-493
[10.]
H. Reyes.
The enigma of intrahepatic cholestasis of pregnancy: lessons from Chile.
Hepathology, 2 (1982), pp. 87-96
[11.]
H. Reyes.
The spectrum of liver and gastrointestinal disease seen in cholestasis in pregnancy.
Gastroenterol Clin North Am, 21 (1992), pp. 905-918
[12.]
M.H. Davies, Silva RC Da, S.R. Jones, J.B. Weaver, E. Elias.
Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid.
Gut, 37 (1995), pp. 580-584
[13.]
J. Ribalta, H. Reyes, M.C. González, J. Iglesias, M. Arrese, J. Po-niachik, et al.
S-adenosyl-L-methionine in the traitment of patients of intrahepatic cholestasis of pregnancy: a randomi-sed double-bling, placebo-controlled study with negative results.
Hepatology, 13 (1991), pp. 1084-1090
[14.]
Y. Bacq.
La cholestase intra-hépatique gravidique. Le point de vue de l’hépatologue.
J Gynecol Obstet Biol Reprod, 22 (1993), pp. 553-558
[15.]
G. Rennevik, S. Jeppsson, S. Kullander.
Effect of oral contraceptives on the liver in women with recurrent cholestasis (hepatosis) during previous pregnancies.
J Obstet Gynaecol Br Commonw, 79 (1972), pp. 1128-1136
[16.]
P. Calmelet, D. Coumaros, B. Viville, J. Raiga, J.J. Favreau, A. Treisser.
L’acide ursodésoxycholique: perspective de traitment de la cholestase gravidique? A propos de 3 observations.
J Gynecol Obstet Biol Reprod, 27 (1998), pp. 617-621
[17.]
N.M. Fisk, W.B. Bye, GNB. Storey.
Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital.
Aust NZ J Obstet Gynecol, 28 (1988), pp. 172-176
[18.]
B. Schorr-Leswick, E. Lebovics, B. Dworkin, W.S. Rosenthal.
Liver diseases unique to pregnancy.
Am J Gastroenterol, 86 (1991), pp. 659-670
[19.]
M.C. González, H. Reyer, M. Arrese, D. Figueroa, B. Lorca, M. Andressen, et al.
Intrahepatic cholestasis of pregnancy in twin pregnancies.
J Hepatol, 9 (1989), pp. 84-90
[20.]
U.P. Haemmerli.
Jaundice during pregnancy.
pp. 1023-1036
[21.]
A.K. Furthoff, K. Jaundice in pregnancy. Hellstrom.
A follow-up study of the series of women originally reported by L. Thor-ling. I. The pregnancies.
Acta Med Scand, 193 (1973), pp. 259-266
[22.]
R.T. Holzbach.
Familial recurrent intrahepatic cholestasis of pregnancy: evidence for a dominant, possibly autosomal trait.
Hepatology, 2 (1982), pp. 149
[23.]
R.T. Holzbach.
Familiar recurrent intrahepatic cholestasis of pregnancy: concomitant occurrence of a shared HLA ha-plotype in effected members.
Hepatology, 2 (1982), pp. 149
[24.]
R.T. Holzbach, D.A. Sivak, W.E. Braun.
Familial recurrent in-trahepatic cholestasis of pregnancy: a genetic study providing evidence for transmission of a sex-limited, dominant trait.
Gastroenterology, 85 (1983), pp. 175-179
[25.]
D. Larrey, B. Rueff, G. Feldmann, C. Degott, G. Dannan, J.P. Ben-hamou.
Recurrent jaundice caused by recurrent hypere-mesis gravidarum.
Gut, 25 (1984), pp. 1414-1415
[26.]
AFG De Patger, Henegouwen GP Van Berge, Bokkel Huinink JA Ten, K.H. Brandt.
Familial bening recurrent intrahe-patic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?.
Gastroentero-logy, 71 (1976), pp. 202-207
[27.]
Y. Bacq, et grossesse. Foie.
Encycl Méd Chir Gynécolo-gie/Obstétrique.
[28.]
M.J. Kreek, E. Weser, M.H. Sleisenger, G.H. Jeffires.
Idiopathic cholestasis of pregnancy. The response to challerge with the synthetic estrogen, ethynil estradiol.
N Engl J Med, 177 (1967), pp. 1391-1395
[29.]
H. Reyes, J. Ribalta, M.C. González, N. Segovia, E. Oberhauser.
Sulfobromophthalein clearance tests before and after ethynil estradiol administration, in women and men with familial history of intrahepatic cholestasis in pregnancy.
Gas-troenterology, 81 (1981), pp. 226-231
[30.]
K.K. Leslie, L. Reznikov.
Intrahepatic cholestasis of pregnancy is associated with abnormal estrogen excretion.
Am J Obstet Gynecol, 174 (1996), pp. 368-373
[31.]
P. Monin, P. Vert, J.M. Petry.
Cholostase récidivante de la grossesse.
Maladie autosomique dominante. Nouv Press Med, 9 (1980), pp. 1779
[32.]
D.K. Podolsky, K.J. Isselbacher.
Alteraciones del metabolis-mo hepático.
Harrison. Principios de medicina interna (II, 14, pp. 1893-1898
[33.]
M.J. Kreek, E. Weser, M.H. Sleinsenger, G.H. Jeffries.
Idiopathic cholestasis of pregnancy. The response to challenge with the synthetic estrogen, ethynil estradiol.
N Engl J Med, 277 (1967), pp. 1391-1395
[34.]
V.A. Drill.
Benign cholestatic jaundice of pregnancy and be-ning cholestatic jaundice from oral contraceptive.
Am J Obstet Gynecol, 119 (1974), pp. 165-174
[35.]
J. Heikkinen, O. Maentausta, P. Ylostalo, O. Jaén.
Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching.
Br J Obstet Gynaecol, 88 (1981), pp. 240-245
[36.]
J. Heikkinen, O. Maentausta, P. Ylostalo, O. Janne.
Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital of cholestyramine. Eur.
J Obstet Gynecol Reprod Biol, 14 (1982), pp. 153-162
[37.]
J. Heikkinen.
Serum Bile acids in the early diagnosis of in-trahepatic cholestasis of pregnancy.
Obstet Gynecol, 61 (1983), pp. 581-587
[38.]
T. Laatkainen.
Effect of cholestyramine and Phenobarbital on pruritus and serum bile acid levels in cholestasis of pregnancy.
Am J Obstet Gynecol, 132 (1978), pp. 501-506
[39.]
M. Lunzer, P. Barnes, K. Byth, M. O’Halloran.
Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis.
Gastroenterology, 91 (1986), pp. 825-829
[40.]
D. Shaw, J. Frohlick, B.A. Witmann, M. Willms.
A prospective study of 18 patients with cholestasis or pregnancy.
Am J Obstet Gynecol, 142 (1982), pp. 621-625
[41.]
F.L. Iber.
Jaundice in pregnancy.
A review. Am J Obstet Gy-necol, 91 (1965), pp. 721-753
[42.]
B. Frokman, P.D. Gannt, G. Gennser, G. Rannevik.
Plasma protein pattern in recurrent cholestasis of pregnancy.
Scand J Clin Lab Invest, 29 (1972), pp. 89-96
[43.]
P. Johnson, G. Samioe, A. Gustafson.
Studies in cholestasis of pregnancy with special reference to lipids and lipopro-teins.
Acta Obstet Gynecol Scand, 27 (1973), pp. 1-80
[44.]
D.B. Rolfes, K.G. Isaac.
Liver disease in pregnancy.
Histopathology, 10 (1986), pp. 555-570
[45.]
P. Kirkinen, M. Ryynänen.
First-trimester manifestation of intrahepatic cholestasis of pregnancy and high fetoplacental hormone production in a triploid fetus.
J Reprod Med, 40 (1995), pp. 471-473
[46.]
D. Brites, CMP Rodrigues, N. Oliveira, Conceiçao Car-dosa M Da, L.M. Graça.
Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy.
J Hepatol, 28 (1998), pp. 91-98
[47.]
U.P. Haemmerli, H.I. Wyss.
Recurrent intrahepatic cholestasis of pregnancy. Report of six cases and review of the literature.
Medicine, 46 (1967), pp. 299-321
[48.]
R. Reid, K.J. Ivey, R.H. Rencoret, B. Storey.
Fetal complications of obstetric cholestasis.
Br Med J, 1 (1976), pp. 870-872
[49.]
A. Diaferia, P.L. Nicastri, M. Tartagni, P. Loizzi, C. Iacovizzi, Leo A. Di.
Ursodeoxycholic acid therapy in pregnant women with cholestasis.
Int J Gynecol Obstet, 52 (1996), pp. 133-140
[50.]
A.J. Rioseco, B. Ivankovic, A. Manzur, F. Harmed, S.R. Kato, J.T. Parer, et al.
Intrahepatic cholestais of pregnancy: A retrospective case control study.
Am J Obstet Gynecol, 170 (1994), pp. 890-895
[51.]
O.M. Alsulyman, J.G. Ouzonian, M. Ames-Castro, R. Paul, T.M. Go-olwin.
Intrahepatic cholestasis in pregnancy: perinatal outcome associated with expectant management.
Am J Obs-tet Gynecol, 174 (1996), pp. 957-960
[52.]
P. Frieldlander, M. Osler.
Icterus and pregnancy.
Am J Obs-tet Gynecol, 97 (1967), pp. 894-900
[54.]
T. Laatikainen, E. Ikonen.
Fetal prognosis in obstetric hepa-tosis.
Ann Chir Gynaecol, 64 (1975), pp. 155-164
[55.]
T. Laatikainen, A. Tulenheimo.
Maternal serum bile acid levels fetal distress in cholestasis of pregnancy.
Int J Gynae-col Obstet, 22 (1984), pp. 91-94
[56.]
B. Berg, G. Helm, L. Petersohn, N. Tryding.
Cholestasis of pregnancy. Clinical and laboratory studies.
Acta Obstet Gy-necol Scand, 65 (1986), pp. 107-113
[57.]
N.M. Fisk, G.N. Storey.
Fetal outcome in obstetric cholestasis.
Br J Obstet Gynaecol, 95 (1988), pp. 1137-1143
[58.]
E. Ikonen.
Jaundice in late pregnancy.
Acta Obstet Gynecol Scan, 43 (1964), pp. 1-180
[59.]
G. Dorta.
Cholestase et grossesse: hépatopathies spécifiques à la grossesse.
Arch Gynecol Obstet, 225 (1994), pp. 237-244
[60.]
E.J. Israel, M.L. Guzman, G.A. Campos.
Maximal response to ocytocine of the isolated myometrium from pregnant patients with intrahepatic cholestasis.
Acta Obstet Gynecol Scand, 65 (1986), pp. 23-26
[61.]
C.A. Seymour, V.S. Chadwick.
Liver and gastrointestinal function in pregnancy.
Postgrad Med J, 55 (1979), pp. 343-352
[62.]
L.C. Sadler, M. Lane, R. North.
Severe fetal intracraneal haemorrhage during treatment with cholestyramine for intrahe-patic cholestasis of pregnancy.
Br J Obstet Gynaecol, 102 (1995), pp. 169-170
[63.]
T. Sapey, D. Guyader, P. Brissot.
Traitment symptomatique de la cholestase.
Gastroenterol Clin Biol, 21 (1997), pp. 472-480
[64.]
T. Laatikainen.
Effect of cholestyramine and phenobarbital on pruritus an serum bile acid levels in cholestasis of pregnancy.
Am J Obstet Gynecol, 132 (1978), pp. 501-506
[65.]
M.L. Hirvioja, R. Tuimala, J. Vuon.
The treatment of intrahe-patic cholestasis of pregnancy by dexamethasone.
Br J Obs-tet Gynaecol, 99 (1992), pp. 109-111
[66.]
G.D. Stramentinoli, C. Padova, M. Gualano, D. Rovagnati, M. Ga-lli-Kienle.
Ethynilestradiol induced impairment of bile secretion in the rat: protective effects of S- adenosyl-L-met-hionine and its implications in estrogen metabolism.
Gastro-enterology, 80 (1981), pp. 154-158
[67.]
M. Frezza, G. Pozzato, L. Chiesa, G. Stramentinoli, Padova C. Di.
Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosy-L-methionine administration.
Hepatology, 4 (1984), pp. 274-278
[68.]
P. Almasio, M. Bortolini, L. Pagliaro.
Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis (of pregnancy.
Drugs, 40 (1990), pp. 111-117
[69.]
M. Frezza, G. Centini, G. Cammareri, Grazie C Le, Padova C. Di.
S-adenosyl-L-methionine for the treatment of intrahepatic cholestasis of pregnancy.
Results of a controlled clinical trial. Hepatogastroenterology, 37 (1990), pp. 122-125
[70.]
Pogamp C Le, P. Brissot, Berre C. Le.
Cholestase gravidi-que.
Une nouvelle indication des échanges plasmatiques.Nouv Presse Med, 11 (1982), pp. 4571
[71.]
A.F. Hoffmann.
The enterohepatic circulation of bile acids in health and disease.
5, pp. 127-150
[72.]
L.L. Brunton.
Fármacos que afectan al flujo de agua y la mo-tilidad gastrointestinales; emesis y antieméticos; ácidos bi-liares y enzimas pancreáticas.
Gooldman and Gilman. Las bases farmacológicas de la terapéutica (I, pp. 981-1002
[73.]
N.J. Greenberger, K.J. Isselbacher.
Enfermedades de la vesí-cula biliar y de las vías biliares.
Harrison. Principios de medicina interna (II, 14, pp. 1960-1973
[74.]
G. Paumgartner.
Nonoperative management of gallstone disease.
Gastrointestinal disease, 5, pp. 1844-1857
[75.]
G.S. Tint, G. Salen, S. Shefer.
Effect of ursodeoxycholic acid and chenodeoxycholic acid on cholesterol and bile acid metabolism.
Gastroenterology, 91 (1986), pp. 1007-1018
[76.]
O. Chazouilleres, R. Poupon, J.P. Capron, E.H. Metman, D. Dhu-meaux, M. Amouretti, et al.
Ursodeoxycholic acid for primary sclerosing cholangitis.
J Hepatol, 11 (1990), pp. 120-123
[77.]
H. Beuers, U. Spengler, W. Kruis, U. Aydemir, B. Wiebecke, W. Heldwein, et al.
Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo controlled trial.
Hepatology, 16 (1992), pp. 707-714
[78.]
C.L. Berg, J.L. Gollan.
Pharmacotheraphy of hepatobiliary disease.
pp. 245-264
[79.]
K.D. Lindor, E.R. Dickson, W.P. Bardus, R.A. Jorgensen, J. Lud-wing, P.A. Murtaugh, et al.
Ursodeoxycholic acid in the treatment of primary biliary cirrhoris.
Gastroenterology, 106 (1994), pp. 1284-1290
[80.]
R.E. Poupon, R. Poupon, E. Balkan, UDCA-PBC Study Group. the.
Ursodiol for the long term treatment of primary biliary cirrhosis.
N Engl J Med, 330 (1994), pp. 1342-1344
[81.]
A.F. Attai, A.G. Rusticali, E. Varriali, L. Carli, A.M. Repick, F. Callga.
The effect of ursodeoxycholic acid on serum enzymes and liver biology in patients with chronic hepatitis.
J Hepatol, 20 (1994), pp. 315-323
[82.]
A. Floreani, D. Paternoster, A. Melis, P.V. Grella.
S-adenosyl-methionine versus ursodeoxycolic acid in the treatment of intrahepatic cholestasis of pregnany: preliminary results of a controlled trial.
Eur J Obstet Gynecol Reprod Biol, 67 (1996), pp. 109-113
[83.]
J. Palma, H. Reyes, J. Ribalta, J. Iglesias, M.C. Gonzales, I. Her-nández, et al.
Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis in pregnancy.
Hepatology, 15 (1992), pp. 1043-1047
[84.]
L. Marpeau, O. Chazouilliére, Z. Rhimi, R. Poupon, A. Pigne, J. Barrat.
Pregnancy-associated idiopathic cholestasis. of physiopathology: a therapeutic case report.
Fetal Diagn Ther, 6 (1991), pp. 120-125
[85.]
A. Floreani, D. Paternoster, P.V. Grella, S. Sacco, M. Gangemi, M. Chiaramonte.
Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy.
Br J Obstet Gynaecol, 101 (1994), pp. 64-65
[86.]
A.F. Hoffman.
Acide ursodesocycholique: transport intestinal et métabolisme.
pp. 29-40
[87.]
H. Dobner, H. From.
Effects of ursodeoxycholic acid treatment of intrahepatic cholestasis of pregnancy: observations on efficacy and safety.
Gastroenterology, 104 (1993), pp. 660-661
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