Información del artículo
Diversos estudios farmacogenéticos han analizado la influencia de determinados polimorfismos genéticos en la toxicidad del tratamiento antirretroviral. En esta revisión se describen algunos de los efectos adversos de los fármacos antirretrovirales en los que se ha documentado que puede existir una predisposición genética: la toxicidad neurológica en pacientes en tratamiento con efavirenz, por lo general asociada al polimorfismo 516G>T de la isoenzima hepática 2B6 del sistema del citocromo P450 (CYP2B6); las reacciones de hipersensibilidad a nevirapina asociadas con alelos específicos del complejo mayor de histocompatibilidad (HLA), principalmente el alelo HLA-DRB1* 0101 que, en combinación con un recuento elevado de linfocitos CD4, se ha asociado a reacciones sistémicas y hepatitis en pacientes de raza caucásica, y el alelo HLA-Cw8 asociado con las reacciones de hipersensibilidad en personas de la isla italiana de Cerdeña y de Japón; la hepatotoxidad con nevirapina (NVP) asociada al polimorfismo C>T en la posición 3435T del gen ABCB1 (MDR-1) que codifica la glucoproteína P (gp- P) (protector); la hiperbilirrubinemia en pacientes expuestos a atazanavir o indinavir portadores del polimorfismo UGT1A1*28; la neuropatía periférica con análogos de nucleósidos asociada al haplogrupo T del genoma mitocondrial (mayor riesgo) y al genotipo HFE C282Y del gen de la hemocromatosis (protector); la mutación en el codón 964 (R964C) del gen POLG que codifica la ADN polimerasa mitocondrial gamma descrita en un paciente tailandés con acidosis láctica; los haplotipos ABCC2 asociados con la tubulopatía proximal inducida por tenofovir, y el riesgo de pancreatitis en las personas con mutaciones en los genes CFTR y SPINK-1.
Palabras clave:
Farmacogenética
VIH
Sida
Tratamiento antirretroviral
Toxicidad
Efectos adversos
Several pharmacogenetics studies have analyzed the influence of specific genetic polymorphisms on the toxicity of antiretroviral treatment.
The present review describes some of the adverse effects of antiretroviral drugs in which a genetic predisposition may be involved: efavirenz-induced neurological toxicity, generally associated with the 516G>T polymorphism of liver enzyme cytochrome P450 2B6 (CYP2B6); hypersensitivity reactions to nevirapine, associated with specific alleles of major histocompatibility complex, mainly the HLA-DRB1* 0101 allele, which, in combination with a high CD4 lymphocyte count, has been associated with systemic reactions and hepatitis in Caucasians, and the HLA-Cw8 allele, which is associated with hypersensitivity reactions in persons from the Italian island of Sardinia and from Japan; nevirapine-induced hepatotoxicity associated with the C>T polymorphism in position 3435T of the ABCB1 (MDR-1) gene codifying for glycoprotein P (lower risk); hyperbilirubinemia in patients exposed to atazanavir or indinavir carrying the UGT1A1*28 polymorphism; peripheral neuropathy with nucleoside analogues associated with haplogroup T of the mitochondrial genome (higher risk) and with the HFE C282Y genotype of the hemochromatosis gene (lower risk); the mutation in codon 964 (R964C) of the POLG gene that codifies the mitochondrial polymerase DNA gamma described in a Thai patient with lactic acidosis; the ABCC2 gene haplotypes associated with tenofovir-induced proximal tubulopathy, and the risk of pancreatitis in persons with mutations in the CFTR and SPINK-1 genes.
Key words:
Pharmacogenetics
HIV
AIDS
Antiretroviral treatment
Toxicity
Adverse effects
El Texto completo está disponible en PDF
Bibliografía
[1.]
A. Telenti, U.M. Zanger.
Pharmacogenetics of anti-HIV Drugs.
Annu Rev Pharmacol Toxicol, 48 (2008), pp. 9.1-9.30
[2.]
M.T. Huisman, J.W. Smit, A.H. Schinkel.
Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors.
AIDS, 14 (2000), pp. 237-242
[3.]
J.D. Schuetz, M.C. Connelly, D. Sun, S.G. Paibir, P.M. Flynn, R.V. Srinivas, et al.
MRP4: A previously unidentified factor in resistance to nucleoside-based antiretroviral drugs.
Nat Med, 5 (1999), pp. 1048-1051
[4.]
J. Wijnholds, C.A. Mol, L. Van Deemter, M. De Haas, G.L. Scheffer, F. Baas, et al.
Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleoside analogs.
Proc Natl Acad Sci USA, 97 (2000), pp. 7476-7481
[5.]
H. Izzedine, V. Launaty-Vacher, G. Deray.
Renal tubular transporter and antiretroviral drugs: an update.
AIDS, 19 (2005), pp. 455-462
[6.]
S. Staszewski, J. Morales-Ramírez, K. Tashima, A. Rachlis, D. Skiest, J. Stanford, et al.
Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults.
N Engl J Med, 341 (1999), pp. 1865-1873
[7.]
C. Marzolini, A. Telenti, L. Decosterd, J. Biollaz, T. Buclin.
Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients.
AIDS, 15 (2001), pp. 1193-1194
[8.]
F. Gutiérrez, A. Navarro, S. Padilla, R. Antón, M. Masiá, J. Borrás, et al.
Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring.
Clin Infect Dis, 41 (2005), pp. 1648-1653
[9.]
C. Csajka, C. Marzolini, K. Fattinger, L.A. Décosterd, J. Fellay, A. Telenti, et al.
Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection.
Clin Pharmacol Ther, 73 (2003), pp. 20-30
[10.]
B. Hasse, H. Gunthard, G. Bleiber, M. Krause.
Efavirenz intoxication due to slow hepatic metabolism.
Clin Infect Dis, 40 (2005), pp. e22-e23
[11.]
E. Lowenhaupt, K. Matson, B. Qureishi, A. Saitoh, D. Pugatch.
Psycosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz.
Clin Infect Dis, 45 (2007),
[12.]
L. Stahle, L. Moberg, J.O. Svensson, A. Sonnerborg.
Efavirenz plasma concentrations in HIV-infected patients:inter-and intraindividual variability and clinical effects.
Ther Drug Monit, 26 (2004), pp. 267-270
[13.]
B.A. Ward, J.C. Gorski, D.R. Jones, S.D. Hall, D.A. Flockhart, Z. Desta.
Thecytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primaryand secondary metabolism: implication for HIV/AIDS therapy and utility ofefavirenz as a substrate marker of CYP2B6 catalytic activity.
J Pharmacol Exp Ther, 306 (2003), pp. 287-300
[14.]
K. Klein, T. Lang, T. Saussele, E. Barbosa-Sicard, W.H. Schunck, et al.
Genetic variability of CYP2B6 in populations of African and Asian origin: allelefrequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz.
Pharmacogenet. Genomics, 15 (2005), pp. 861-873
[15.]
T. Lang, K. Klein, J. Fischer, A.K. Nüssler, P. Neuhaus, U. Hofmann, et al.
Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver.
Pharmacogenetics, 11 (2001), pp. 399-415
[16.]
D.W. Haas, H. Ribaudo, R. Kim, C. Tierney, G. Wilkinson, R. Gulick, et al.
Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Group study.
AIDS, 18 (2004), pp. 2391-2400
[17.]
K. Tsuchiya, H. Gatanaga, N. Tachikawa, K. Teruya, Y. Kikuchi, M. Yoshino, et al.
Homozygous CYP2B6*6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens.
Biochem Biophys Res Comm, 319 (2004), pp. 1322-1326
[18.]
S. Rodriguez-Novoa, P. Barreiro, A. Rendón, I. Jiménez-Nacher, J. Gonzalez-Lahoz, V. Soriano.
Influence of 516 G>T polymorphisms at the gen encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects.
Clin Infect Dis, 40 (2005), pp. 1358-1361
[19.]
M. Rotger, S. Colombo, H. Furrer, G. Bleiber, T. Buclin, B.L. Lee, et al.
Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapina in HIV-infected patients.
Pharmacogenet Genomics, 15 (2005), pp. 1-5
[20.]
D.W. Haas, L.M. Smeaton, R.W. Shafer, G.K. Robbins, G.D. Morse, et al.
Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult Aids Clinical Trials Group Study.
J Infect Dis, 192 (2005), pp. 1931-1942
[21.]
H.J. Ribaudo, D.W. Haas, C. Tierney, R.B. Kim, G.R. Wilkinson, et al.
Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group study.
Clin Infect Dis, 42 (2006), pp. 401-407
[22.]
J. Wang, A. Sonnerborg, A. Rane, F. Josephson, S. Lundgren, L. Stahle, et al.
Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz.
Pharmacogenet Genomics, 16 (2006), pp. 191-198
[23.]
M. Rotger, H. Tegude, S. Colombo, M. Cavassini, H. Furrer, L. Dacosterd, et al.
Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals.
Clin Pharmacol Ther, 81 (2007), pp. 557-566
[24.]
J. Fellay, C. Marzolini, E.R. Meaden, D.J. Back, T. Buclin, J.P. Chave, et al.
Response to antiretroviral treatment in HIV-infected individuals with allelic variants of the multidrug resistant transporter 1: a pharmacogenetics study.
Lancet, 359 (2002), pp. 30-36
[25.]
A.A. Motsinger, M.D. Ritchie, R.W. Shafer, G.K. Robbins, G.D. Morse, L. Labbe, et al.
Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study.
Pharmacogenet Genomics, 16 (2006), pp. 837-845
[26.]
H. Gatanaga, T. Hayashida, K. Tsuchiya, M. Yoshino, T. Kuwahara, H. Tsukada, et al.
Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26.
Clin Infect Dis, 45 (2007), pp. 1230-1237
[27.]
D.T. Dieterich, P.A. Robinson, J. Love, J.O. Stern.
Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors.
Clin Infect Dis, 38 (2004), pp. S80-S89
[28.]
J.O. Stern, P.A. Robinson, J. Love, S. Lanes, M.S. Imperiale, D.L. Mayers.
A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients.
J Acquir Immune Defic Syndr, 34 (2003), pp. S21-S33
[29.]
S.M. Patel, S. Johnson, S.M. Belknap, J. Chan, B.E. Sha, C. Bennett.
Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV infected individuals.
J Acquir Immune Defic Syndr, 35 (2004), pp. 120-125
[30.]
M. Martin, D. Nolan, I. James, P. Cameron, J. Keller, C. Moore, et al.
Predisposition to nevirapine hypersensitivity associated with HLA-DBR1*0101 and abrogated by low CD4 T-cell counts.
AIDS, 5 (2005), pp. 97-99
[31.]
R. Littera, C. Carcassi, A. Masala, P. Piano, P. Serra, F. Ortu, et al.
HLA-dependent hypersensitivity to nevirapina in Sardinian HIV patients.
AIDS, 20 (2006), pp. 1621-1626
[32.]
H. Gatanaga, H. Yazaki, J. Tanuma, M. Honda, I. Genka, K. Teruya, et al.
HLA-Cw8 primarily associated with hypersensitivity to nevirapine.
AIDS, 21 (2007), pp. 264-265
[33.]
E. Stormer, L.L. von Moltke, M.D. Perloff, D.J. Greenblatt.
Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture.
Pharm Res, 19 (2002), pp. 1038-1045
[34.]
L.M. Almond, D. Edirisinghe, M. Dalton, A. Bonington, D.J. Back, S.H. Khoo.
Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals.
Clin Pharmacol Ther, 78 (2005), pp. 132-142
[35.]
M. Ritchie, D.W. Haas, A. Motsinger, J. Donahue, H. Erdem, S. Raffanti, et al.
Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse transcriptase inhibitor hepatotoxicity.
Clin Infect Dis, 43 (2006), pp. 779-782
[36.]
D.W. Haas, J. Barlett, J. Andersen, I. Sanne, G. Wilkinson, J. Hinkle, et al.
Pharmacogenetics of nevirapine associated hepatotoxicity: an adult AIDS Clincal Trials Group collaboration.
Clin Infect Dis, 43 (2006), pp. 783-786
[37.]
G.L. Plosker, S. Noble.
Indinavir: a review of its use in the management of HIV infection.
Drugs, 58 (1999), pp. 1165-1203
[38.]
A.J. Busti, R.G. Hall, D.M. Margolis.
Atazanavir for the treatment of human immunodeficiency virus infection.
Pharmacotherapy, 24 (2004), pp. 1732-1747
[39.]
S. Zucker, X. Qin, S. Rouster, F. Yu, R. Green, P. Keshavan, et al.
Mechanism of indinavir-induced hyperbilirrubinemia.
Proc Natl Acad Sci USA, 98 (2001), pp. 12671-12676
[40.]
C.S. Huang, M.J. Huang, M.S. Lin, S.S. Yang, H.C. Teng, K.S. Tang.
Genetic factors related to unconjugated hyperbilirrubinemia amongst adults.
Pharmacogenet Genom, 15 (2005), pp. 43-50
[41.]
S. Rodríguez-Nóvoa, L. Martín-Carbonero, P. Barreiro, G. González-Pardo, I. Jiménez-Nácher, J. González-Lahoz, et al.
Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia.
AIDS, 21 (2007), pp. 41-46
[42.]
M.A. Boyd, P. Srasuebkul, K. Ruxrungtham, P.I. Mackenzie, V. Uchaipichat, M. Stek, et al.
Relationship between hyperbilirubinaemia and UDP-glucuronosyltransferase 1A1(UGT1A1) polymorphism in adult HIV-infected Thai patients treated with indinavir.
Pharmacogenet Genomics, 16 (2006), pp. 321-329
[43.]
M. Rotger, P. Taffé, G. Bleiber, H.F. Günthard, H. Furrer, P. Vernazza, et al.
Gilbert Syndrome and the development of antiretroviral therapy-associated hyperbilirrubinemia.
J Infect Dis, 192 (2005), pp. 1381-1386
[44.]
S. Rodríguez Nóvoa, P. Barreiro, A. Rendón, A. Barrios, A. Corral, I. Jiménez-Nacher, et al.
Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C—>T polymorphism at the multidrug resistance gene 1.
Clin Infect Dis, 42 (2006), pp. 291-295
[45.]
W. Lewis, W.C. Copeland, B.J. Day.
Mitochondrial DNA depletion, oxidative stress, and mutation: mechanisms of dysfunction from nucleoside reverse transcriptase inhibitors.
Lab Invest, 81 (2001), pp. 777-790
[46.]
S.C. Keswani, C.A. Pardo, C.L. Cherry, A. Hoke, J.C. McArthur.
HIV-associated sensory neuropathies.
AIDS, 16 (2002), pp. 2105-2117
[47.]
M.J. Browne, K.H. Mayer, S.B. Chafee, M.N. Dudley, M.R. Posner, S.M. Steinberg, et al.
2’, 3’-didehydro-3’-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial.
J Infect Dis, 167 (1993), pp. 21-29
[48.]
T. Kelleher, A. Cross, L. Dunkle.
Relation of peripheral neuropathy to HIV treatment in four randomized clinical trials including didanosine.
Clin Ther, 21 (1999), pp. 1182-1192
[49.]
T. Hulgan, D.W. Haas, J. Haines, M. Ritchie, G. Robbins, R. Shafer, et al.
Mitocondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS Clinical Trial Group study.
AIDS, 19 (2005), pp. 1341-1349
[50.]
J. Canter, D. Haas, A. Kallianpur, M. Ritchie, G. Robbins, R. Shafer, et al.
The mitochondrial phramacogenomics of haplogroup T: MTND2 (*) LHON4 917G and antiretroviral therapy-associated peripheral neuropathy.
Pharmacogenomics J, 8 (2008), pp. 71-77
[51.]
A. Kallianpur, T. Hulgan, J. Canter, M. Ritchie, J. Haines, G. Robbins, et al.
Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.
AIDS, 20 (2006), pp. 1503-1513
[52.]
Lactic Acidosis International Study Group.
Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy.
AIDS, 21 (2007), pp. 2455-2464
[53.]
H. Yamanaka, H. Gatanaga, P. Kosalaraksa, S. Matsuoka-Aizawa, T. Takahashi, S. Kimura, et al.
Novel mutation of human DNA polymerase c associated with mitocondrial toxicity induced by anti-HIV treatment.
J Infect Dis, 195 (2007), pp. 1419-1425
[54.]
S. Coca, M.A. Parazella.
Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity.
Am J Med Sci, 324 (2002), pp. 342-344
[55.]
A. Karras, M. Lafaurie, A. Furco, A. Bourgarit, D. Droz, D. Sereni, et al.
Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus.
Clin Infect Dis, 36 (2003), pp. 1070-1073
[56.]
B.S. Rifkin, M.A. Perazella.
Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure.
Am J Med, 117 (2004), pp. 282-284
[57.]
S. Padilla, F. Gutiérrez, M. Masiá, V. Cánovas, C. Orozco.
Low frequency of renal function impairment during one-year of therapy with tenofovir-containing regimens in the real-world: a case-control study.
AIDS Patient Care STDS, 19 (2005), pp. 421-424
[58.]
M. Saumoy, F. Vidal, J. Peraire, S. Sauleda, A.M. Vea, C. Viladés, et al.
Proximal tubular kidney damage and tenofovir: a role for mitochondrial toxicity?.
AIDS, 18 (2004), pp. 1741-1742
[59.]
J.E. Gallant, M.A. Parish, J.C. Keruly, R.D. Moore.
Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment.
Clin Infect Dis, 40 (2005), pp. 1194-1198
[60.]
A. Mocroft, O. Kirk, J. Gatell, P. Reiss, P. Gargalianos, K. Zilmer, et al.
Chronic renal failure among HIV-1-infected patients.
AIDS, 21 (2007), pp. 1119-1127
[61.]
M.R. Nelson, C. Katlama, J.S. Montaner, D.A. Cooper, B. Gazzard, B. Clotet, et al.
The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years.
AIDS, 21 (2007), pp. 1273-1281
[62.]
A.E. Zimmermann, T. Pizzoferrato, J. Bedford, A. Morris, R. Hoffman, G. Braden.
Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions.
Clin Infect Dis, 42 (2006), pp. 283-290
[63.]
M.D. Murphy, M. O’Hearn, S. Chou.
Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine.
Clin Infect Dis, 36 (2003), pp. 1082-1085
[64.]
H.M. Crane, B. Kestenbaum, R.D. Harrington, M.M. Kitahata.
Amprenavir and didanosine are associated with declining kidney function among patients receiving tenofovir.
AIDS, 21 (2007), pp. 1431-1439
[65.]
M. Masiá, F. Gutiérrez, S. Padilla, J.M. Ramos, J. Pascual.
Didanosine-associated toxicity: a predictable complication of therapy with tenofovir and didanosine?.
J Acquir Immune Defic Syndr, 35 (2004), pp. 427-428
[66.]
M. Masiá, F. Gutiérrez, S. Padilla, J.M. Ramos, J. Pascual.
Severe toxicity associated with the combination of tenofovir and didanosine: case report and review.
Int J STD AIDS, 16 (2005), pp. 646-648
[67.]
F. Vidal, J.C. Domingo, J. Guallar, M. Saumoy, B. Cordobilla, R. Sánchez de la Rosa, et al.
In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells.
Antimicro Agents Chemother, 50 (2006), pp. 3824-3832
[68.]
N. Venhoff, B. Setzer, K. Melkaoui, U.A. Walker.
Mitochondrial toxicity of tenofovir, emtricitabine and abacavir alone and in combination with additional nucleoside reverse transcriptase inhibitors.
Antivir Ther, 12 (2007), pp. 1075-1085
[69.]
T. Cihlar, A.S. Ray, G. Laflamme, J.E. Vela, L. Tong, M.D. Fuller, et al.
Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors.
Antivir Ther, 12 (2007), pp. 267-272
[70.]
H. Motohashi, Y. Sakurai, H. Saito, S. Masuda, Y. Urakami, M. Goto, et al.
Gene expression levels and immunolocalization of organic ion transporters in the human kidney.
J Am Soc Nephrol, 13 (2002), pp. 866-874
[71.]
D.S. Miller.
Nucleoside phosphonate interactions with multiple organic anion transporters in renal proximal tubule.
J Pharmacol Exp Ther, 299 (2001), pp. 567-574
[72.]
A. Ray, T. Cihlar, K. Robinson, L. Tong, J. Vela, M. Fuller, et al.
Mechanism of active renal tubular efflux of tenofovir.
Antimicrob Agents Chemother, 50 (2006), pp. 3297-3304
[73.]
H. Izzedine, J.S. Hulton, E. Villard, C. Goyenvalle, S. Dominguez, J. Ghosn, et al.
Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy.
J Infec Dis, 194 (2006), pp. 1481-1491
[74.]
A. Argiris, U. Mathur-Wagh, I. Wilets, D. Mildvan.
Abnormalities of serum amylase and lipase in HIV-positive patients.
Am J Gastroenterol, 94 (1999), pp. 1248-1252
[75.]
M.S. Cappell, M. Marks.
Acute pancreatitis in HIV-seronegative patients: a case control study of 44 patients.
Am J Med, 98 (1995), pp. 243-248
[76.]
J.A. Cohn, K.J. Friedman, P.G. Noone, M.R. Knowles, L.M. Silverman, P.S. Jowell.
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.
N Engl J Med, 339 (1998), pp. 653-658
[77.]
R.H. Pfützer, M.M. Barmada, A.P. Brunskill, R. Finch, P.S. Hart, J. Neoptolemos, et al.
SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.
Gastroenterology, 119 (2000), pp. 615-623
Copyright © 2008. Elsevier España S.L.. Todos los derechos reservados
