Sorafenib for non-selected patient population with advanced hepatocellular carcinoma: efficacy and safety data according to liver function

OBJECTIVE: Sorafenib is the standard treatment of patients with advanced hepatocellular carcinoma, regardless of the liver functional reserve. We present a single institutional series of Child-Pugh A and Child-Pugh B patients treated with sorafenib with the aim to establish the efficacy and safety of sorafenib in patients of daily clinical conditions and to compare these results between Child-Pugh A and Child-Pugh B patients. MATERIALS AND METHODS: A total of 51 patients were treated with sorafenib 400 mg/12 h until disease progression or unacceptable toxicity. RESULTS: The median progression-free survival and overall survival for the overall population were 3.5 and 8.2 months, respectively, with a 1-year survival rate of 27 %. Overall survival was significantly longer for patients Child-Pugh A compared with those with Child-Pugh B liver function (8.7 vs. 4.7 months, respectively). The most common adverse events were fatigue (62.7 %), diarrhea (58 %), hypertension (31.3 %), and hand-foot syndrome (31.3 %), and in most cases grade 1 or 2 according to the NCI-CTC 3.0. Grade 4 liver-related events occurred mainly in Child-Pugh B patients with decompensated cirrhosis at the time of sorafenib initiation (54.5 % of that group). DISCUSSION: The benefit of sorafenib in Child-Pugh B patients, if exist, may be limited by frequent liver-related events, especially in decompensated patients, and then, toxicity and impact in quality of life should be carefully monitored (AU)

Predictive baseline criteria of primary therapeutic failure in chronic hepatitis C genotype 1.

BACKGROUND AND AIMS: more than half of patients with genotype 1 chronic hepatitis C (CHC) do not achieve a sustained viral response (SVR) to current antiviral therapy due to primary non-response, relapse or intolerance. Factors related to each of these unfavorable outcomes are different and the last two may be partially prevented. Our aim was to identify basal criteria to predict the risk of primary failure. PATIENTS AND METHODS: we included 251 consecutive patients (152 males) from a single centre, infected with HCV genotype 1 and not previously treated. SVR was achieved in 141 patients and primary failure in 110. RESULTS: high vs. low viral load (> 400,000 IU/mL, OR = 6.17; 95% CI: 2.50-15.23), high serum GGT (> 60 IU/mL, OR = 4.25; 95% CI: 2.49-7.24), low serum cholesterol ( < 178 mg/dL, OR = 2.93; 95% CI: 1.75-4.92) and older age (> 47 yrs., OR = 1.79; 95% CI: 1.08-2.96) were associated to the risk of primary failure in the lineal logistic regression analysis. From the 58 patients carrying all the first three negative criteria, 46 (79.3%) were primary non-responders. CONCLUSIONS: the negative basal profile identified in this study is based on easily available data and provides information about the risk of primary therapeutic failure, and may help to decide whether antiviral therapy should be offered to a single patient.

Predictive baseline criteria of primary therapeutic failure in chronic hepatitis C genotype 1

Background and aims: more than half of patients with genotype 1 chronic hepatitis C (CHC) do not achieve a sustained viral response (SVR) to current antiviral therapy due to primary non-response, relapse or intolerance. Factors related to each of these unfavorable outcomes are different and the last two may be partially prevented. Our aim was to identify basal criteria to predict the risk of primary failure. Patients and methods: we included 251 consecutive patients (152 males) from a single centre, infected with HCV genotype 1 and not previously treated. SVR was achieved in 141 patients and primary failure in 110. Results: high vs. low viral load (> 400,000 IU/mL, OR = 6.17; 95% CI: 2.50-15.23), high serum GGT (> 60 IU/mL, OR = 4.25; 95% CI: 2.49-7.24), low serum cholesterol (< 178 mg/dL, OR = 2.93; 95% CI: 1.75-4.92) and older age (> 47 yrs., OR = 1.79; 95% CI: 1.08-2.96) were associated to the risk of primary failure in the lineal logistic regression analysis. From the 58 patients carrying all the first three negative criteria, 46 (79.3%) were primary non-responders. Conclusions: the negative basal profile identified in this study is based on easily available data and provides information about the risk of primary therapeutic failure, and may help to decide whether antiviral therapy should be offered to a single patient(AU)

Oscillations in serum ferritin associated with antiviral therapy in chronic hepatitis C.

BACKGROUND: Hyperferritinemia is often found in patients with chronic hepatitis C (CHC) and is predictive of poorer response to antiviral therapy. OBJECTIVE: To investigate changes in ferritinemia during and after antiviral therapy. PATIENTS AND METHODS: serum ferritin levels were measured in 262 CHC patients (163 males, mean age 48.5 years +/- 10.1) before and during antiviral therapy, and six months post-treatment in all 154 patients with undetectable serum HCV-RNA after therapy completion. RESULTS: Baseline serum ferritin was higher in patients with primary therapeutic failure than in those reaching sustained viral response (330 +/- 291 ng/mL vs. 211 +/- 192 ng/mL, p = 0.002). Serum ferritin transiently increased during therapy from baseline (257 +/- 242 ng/mL vs. 875 +/- 630 ng/mL, p < 0.001). Six months after finishing therapy, serum ferritin decreased under baseline values both in sustained responders (117 +/- 102 ng/mL vs. 211+/- 192 ng/mL, p < 0.001) and, to a lesser extent, in relapsers (217 +/- 174 ng/mL vs. 257 +/- 221 ng/mL, p = 0.047). CONCLUSIONS: Baseline serum ferritin may predict response to antiviral treatment in chronic hepatitis C. Combined antiviral therapy induces a marked increase in serum ferritin that falls below baseline values after sustained viral response, suggesting that the cause of hyperferritinemia in many patients is HCV infection itself rather than iron overload.

Oscilaciones de la ferritina sérica asociadas al tratamiento antiviral en la hepatitis crónica por virus C / Oscillations in serum ferritin associated with antiviral therapy in chronic hepatitis C

Antecedentes: la hiperferritinemia es frecuente en los enfermoscon hepatitis crónica C (HCC) y reduce las probabilidades derespuesta al tratamiento antiviral.Objetivo: investigar las variaciones de la ferritina sérica durantey después del tratamiento y su relación con la respuesta al mismo.Pacientes y métodos: la ferritina sérica se ha medido en262 enfermos con HCC (163 hombres, edad media 48,5 años ±10,1) antes y durante el tratamiento antiviral, y a los 6 meses definalizado en los 154 enfermos con viremia indetectable al finaldel tratamiento.Resultados: la ferritina sérica basal era más alta en enfermoscon fracaso terapéutico primario que en los que consiguieron respuestaviral sostenida (RVS) (330 ± 291 ng/ml vs. 211 ± 192ng/ml, p = 0,002). La ferritina sérica aumentó transitoriamentedurante el tratamiento (257 ± 242 ng/ml vs. 875 ± 630 ng/ml, p< 0,001). La ferritina sérica descendió a valores inferiores a losbasales seis meses después de finalizado el tratamiento en los pacientescon RVS (117 ± 102 ng/ml vs. 211± 192 ng/ml, p <0,001) y, en menor grado, en los que sufrieron recidiva viral (217± 174 ng/ml vs. 257 ± 221 ng/m, p = 0,047).Conclusiones: una ferritina sérica basal elevada se asocia conmayor riesgo de fracaso terapéutico en la HCC. El tratamientoantiviral induce un marcado incremento de la ferritina sérica quevuelve a valores por debajo de los basales en los enfermos que obtienenRVS. Esto sugiere que la causa de hiperferritinemia en lamayoría de los enfermos es la propia infección por VHC y no lasobrecarga de hierro(AU)

Background: hyperferritinemia is often found in patients with chronic hepatitis C (CHC) and is predictive of poorer response to antiviral therapy. Objective: to investigate changes in ferritinemia during and after antiviral therapy. Patients and methods: serum ferritin levels were measured in 262 CHC patients (163 males, mean age 48.5 years ± 10.1) before and during antiviral therapy, and six months post-treatment in all 154 patients whit undetectable serum HCV-RNA after therapy completion. Results: baseline serum ferritin was higher in patients with primary therapeutic failure than in those reaching sustained viral response (330 ± 291 ng/mL vs. 211 ± 192 ng/mL, p = 0.002). Serum ferritin transiently increased during therapy from baseline (257 ± 242 ng/mL vs. 875 ± 630 ng/mL, p < 0.001). Six months after finishing therapy, serum ferritin decreased under baseline values both in sustained responders (117 ± 102 ng/mL vs. 211± 192 ng/mL, p < 0.001) and, to a lesser extent, in relapsers (217 ± 174 ng/mL vs. 257 ± 221 ng/mL, p = 0.047). Conclusions: baseline serum ferritin may predict response to antiviral treatment in chronic hepatitis C. Combined antiviral therapy induces a marked increase in serum ferritin that falls below baseline values after sustained viral response, suggesting that the cause of hyperferritinemia in many patients is HCV infection itself rather than iron overload(AU)

Influence of polymorphic N-acetyltransferases on non-malignant spontaneous disorders and on response to drugs.

Polymorphic N-acetyl transferases (NAT) 1 and 2 are involved in detoxification of xenobiotic arylamines and hydralazines. These common environmental chemicals may be related to the pathogenesis of many spontaneous disorders, mainly malignancies, but also disimmune or degenerative diseases, for which a polygenic predisposition has been suggested. Hence, polymorphic NAT genes (NAT2 has been the most studied one) may be low-penetrance risk genes for some of these disorders. Although a relation of risk may be definitely discarded for systemic lupus erythematosus (SLE), inflammatory bowel disease and endometriosis, more research is needed for rheumatoid arthritis, Parkinson's, Alzheimer's, Behçet's and periodontal diseases , as current results are inconclusive but suggest a possible relation with NAT2 polymorphism. In diabetes mellitus the possible relation with the rapid phenotype may be due to acquired metabolic changes and more genotyping studies are needed. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides. Future research should be based on well-designed studies, with adequate sample sizes and homogeneous recruitment criteria, to obviate the proliferation of small studies that are time- and resource-consuming without offering definite answers.

[Results of the treatment of chronic hepatitis C genotype 4--a comparative analysis with genotype 1]. / Resultados del tratamiento de la hepatitis crónica por VHC genotipo 4. Un análisis comparativo con el genotipo 1.

INTRODUCTION: nearly all the data on the efficacy of combined antiviral therapy on chronic hepatitis C genotype 4 have been obtained in countries of Middle East. Genotype 4 is quite unusual in Spain. We report our experience in a group of Spanish patients treated with homogeneous criteria. PATIENTS AND METHODS: between 2001 and 2007 we have treated 30 patients with chronic hepatitis C genotype 4 (20 males) with pegylated Interferon alpha-2b (26 cases) or alpha-2a (4 cases) combined with ribavirin at a weight-adjusted dose. Results of therapy are known in all patients and liver biopsy is available in 24 cases. RESULTS: ten patients (33.3%) obtained sustained viral response (SVR: HCV-RNA undetectable in blood 6 months after the end of therapy), 12 were primary non-responders, 4 relapsed after reaching undetectable HCV-RNA at the end of therapy and 4 interrupted the treatment due to severe adverse events. These results are very close to those obtained in 355 patients infected with HCV genotype 1. CONCLUSION: HCV genotype 4 should be considered as "difficult to treat". The better results of therapy in other geographical areas (Middle East) may be due to a different distribution of the subtypes of HCV genotype 4.

[The H63D mutation in the HFE gene is related to the risk of hepatocellular carcinoma]. / La mutacion H63D del gen HFE se asocia con un riesgo aumentado de carcinoma hepatocelular .

AIM: To disclose whether mutations in the HFE gene inducing liver iron overload are related to the risk of hepatocellular carcinoma (HCC) in otherwise predisposed patients. PATIENTS AND METHODS: One hundred and ninety-six patients (161 males) diagnosed with HCC and 181 healthy controls were included in the study. All subjects were white Spaniards.C282Y and H63D mutations in the HFE gene were identified in leucocyte genomic DNA using a polymerase chain reaction (PCR) and specific restriction enzymes. RESULTS (CASES/CONTROLS): 1. Genotype distribution: a) C282Y mutation: homozygotes 1/0, heterozygotes 12/23, wild type 183/158 (p = 0.07, non significant); b) H63D mutation: homozygotes 9/5, heterozygotes 85/52, wild type 102/124 (0dds ratio 2.00, 95% C.I. 1.29-3.12, p = 0.002. Four cases and 6 controls were carriers of heterozygous mixed genotypes. 2. Allele frequencies: a) C282Y mutation: wild type allele 378/339, mutated allele 14/23 (p = 0.11, non significant); b) H63D mutation: wild type allele 289/300, mutated allele 103/62 (0dds ratio 1.72, 95% C.I. 1.19-2.50, p = 0.004). Age at diagnosis, gender and etiology of the underlying liver disease do not influence these findings. CONCLUSION: The C282Y mutation in the HFE gene is not related to the risk of HCC in non-hemochromatosis patients. The H63D mutation is associated with a higher risk of HCC in cirrhotic patients irrespective of their underlying liver disease.

La mutacion H63D del gen HFE se asocia con un riesgo aumentado de carcinoma hepatocelular / The H63D mutation of the HFE gene is related to the risk of hepatocellular carcinoma

Objetivo: comprobar si las mutaciones del gen HFE, que puedeninducir sobrecarga hepática de hierro, guardan relación conel riesgo de desarrollar carcinoma hepatocelular (CHC) en sujetospredispuestos a sufrir este tumor.Material y métodos: se han incluido 196 pacientes (161 varones)diagnosticados de CHC. Ninguno estaba diagnosticado dehemocromatosis. El grupo control estaba constituido por 181 sujetossanos. Todos los sujetos eran españoles de raza blanca.Las mutaciones C282Y y H63D del gen HFE se identificaronmediante reacción en cadena de polimerasa (PCR) sobre ADN genómicoleucocitario utilizando enzimas de restricción específicas.Resultados (casos/controles): 1. Distribución genotípica:a) mutación C282Y: 1/0 homocigotos, 12/23 heterocigotos,183/158 normales (p = 0,07, n.s.); y b) mutación H63D: 9/5homocigotos, 85/52 heterocigotos, 102/124 normales (odds ratio2,00, IC95% 1,29-3,12, p = 0,002). Cuatro casos y seis controleseran heterocigotos compuestos. 2. Frecuencias alélicas: a)mutación C282Y: normales 378/339, mutados 14/23 (p =0,11, n.s.); b) mutación H63D: normales 289/300; mutados103/62 (odds ratio 1,72, IC95% 1,19-2,50, p = 0,004). No seobservaron diferencias en relación con el sexo, la edad o la etiología(VHC, VHB, etílica o mixta) de la hepatopatía previa.Conclusiones: la mutación C282Y no guarda relación con elriesgo de desarrollar CHC en sujetos sin hemocromatosis conocida.La posesión de la mutación H63D se asocia con un riesgo aumentadode desarrollar CHC independientemente de la etiologíade la hepatopatía crónica subyacente

Aim: to disclose whether mutations in the HFE gene inducingliver iron overload are related to the risk of hepatocellular carcinoma(HCC) in otherwise predisposed patients.Patients and methods: one hundred and ninety-six patients(161 males) diagnosed with HCC and 181 healthy controls wereincluded in the study. All subjects were white Spaniards.C282Y and H63D mutations in the HFE gene were identifiedin leucocyte genomic DNA using a polymerase chain reaction(PCR) and specific restriction enzymes.Results (cases/controls): 1. Genotype distribution: a)C282Y mutation: homozygotes 1/0, heterozygotes 12/23, wildtype 183/158 (p = 0.07, non significant); b) H63D mutation: homozygotes9/5, heterozygotes 85/52, wild type 102/124 (0ddsratio 2.00, 95% C.I. 1.29-3.12, p = 0.002. Four cases and 6controls were carriers of heterozygous mixed genotypes. 2. Allelefrequencies: a) C282Y mutation: wild type allele 378/339, mutatedallele 14/23 (p = 0.11, non significant); b) H63D mutation:wild type allele 289/300, mutated allele 103/62 (0dds ratio1.72, 95% C.I. 1.19-2.50, p = 0.004). Age at diagnosis, genderand etiology of the underlying liver disease do not influence thesefindings.Conclusion: the C282Y mutation in the HFE gene is not relatedto the risk of HCC in non-hemochromatosis patients. TheH63D mutation is associated with a higher risk of HCC in cirrhoticpatients irrespective of their underlying liver disease

Hacia una estrategia diagnóstica de las enfermedades hepáticas / Towards a diagnostic strategy of liver disease

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Hereditary hyperferritinemia-cataract syndrome. Study of a new family in Spain.

The hyperferritinemia-cataract syndrome, inherited as a Mendelian dominant trait, is due to mutations in the 5' non-coding region of the ferritin light chain gene that modifies the shape of the IRE (iron responsive element) region, which loses its normal function of regulating the synthesis of ferritin light chains. Excess of light chains results in complexes that accumulate into the lens giving rise to early cataracts. We present a Spanish family with seven affected members through three generations. A genetic study reveals a substitution of a single base (C-->T) at position 33 in the IRE sequence in the index case and in one affected brother, whereas a non-affected sister shows the normal sequence. The hyperferritinemia-cataract syndrome was identified in 1995 and is still poorly understood. Clinicians should suspect it when treating any subject with early cataracts, even more if they are familial, or in patients with very high levels of ferritinemia without evidence of iron overload. There are no known consequences of the syndrome other than cataracts, and its proper diagnosis carries a favorable prognosis and eliminates the risk of unnecessary phlebotomies.

Leflunomide-induced acute hepatitis.

Leflunomide, a new immunomodulatory agent, was prescribed to a 67-year-old female patient with rheumatoid arthritis. Fifteen days later she developed diarrhoea and elevated liver enzymes. A liver biopsy showed a pattern of acute hepatitis. The patient was homozygous for the rare CYP2C9*3 allele, which determines the slowest metabolic rate for CYP2C9 enzymatic activity, that is probably involved in the metabolism of leflunomide. Liver damage subsided in few weeks. This case illustrates the risk of hepatotoxicity by leflunomide and suggests that it is possibly related to CYP2C9 polymorphism.

[HFE gene mutations, hepatic iron content, and histological severity in hepatitis C virus-induced chronic hepatitis].

OBJECTIVE: To study whether any relationship exists between the C282Y and H63D mutations of the HFE gene, iron liver content, and the severity of histological damage in patients with hepatitis C virus (HCV)-induced chronic hepatitis. MATERIAL AND METHODS: In 72 patients diagnosed with HCV-chronic infection, naïve for antiviral therapy, and undergoing liver biopsy, the Knodell index was established, a morphometric evaluation of hepatic hemosiderin deposits was performed by using a semiautomatic method of image analysis, and mutations of the HFE gene were identified through a polymerase chain reaction on leukocyte genomic DNA by using specific restriction enzymes. The control group for the distribution of HFE genetic variants was composed of 181 healthy individuals with the same ethnic and geographical (white Spaniards) origin. RESULTS: (Cases/controls): 1. Genotype distribution: a) mutation C282Y: no homozygotes, 6/23 heterozygotes, 66/158 without the mutation (not significant, n.s.); b) mutation H63D: 2/5 homozygotes, 26/52 heterozygotes, 44/124 without the mutation (n.s.). compound heterozygotes 2/6. 2. Allele frequencies: a) mutation C282Y: 0.042/0.064 (n.s.); b) mutation H63D: 0.208/0.171 (n.s.). Four C282Y heterozygous patients had stainable liver iron (p=0.015 vs patients without mutations). Sixty-six patients were not carriers of the C282Y mutation; among them, 26.9% of 26 carriers and 15% of 40 non-carriers of the H63D mutation had liver stainable iron (n.s.). Knodell index score, gender, age at diagnosis, mode of transmission, and serum and liver iron values were not related to the HFE genotype. CONCLUSIONS: our results suggest that the C282Y mutation, but not the H63D mutation, of the HFE gene is frequently associated with stainable iron in the liver in HCV-related chronic hepatitis. The HFE genotype is not related to the histological severity of the disease.

N-acetyltransferase 2 polymorphism is not related to the risk of advanced alcoholic liver disease.

BACKGROUND: Ethanol abuse is the most prevalent cause of liver cirrhosis in Spain. Genetic polymorphisms affect the activity of the enzymes involved in ethanol metabolism and in processing the toxic by-products generated in the liver. N-acetyltransferase 2 (NAT2) is a polymorphic phase 2 enzyme not involved in these processes, but recent data suggest that the most prevalent slow acetylator genotype protects against the risk of advanced alcoholic liver disease (ALD). We have identified six single nucleotide polymorphisms (SNP) at the NAT2 gene locus in order to disclose whether such an association exists. METHODS: Genomic DNA from 95 ALD patients (15 with superimposed hepatocellular carcinoma (HCC)) and from 258 healthy individuals was analysed for SNPs at the coding region of the NAT2 gene by means of allele-specific polymerase chain reaction. RESULTS: There are no differences in the relative frequencies of the eight identified NAT2 alleles (including the wild-type allele) nor in the distribution of predicted phenotypes (54% of slow acetylators in each group). Twelve patients with HCC (80%) were slow acetylators (P < 0.05). CONCLUSIONS: There is no relationship between the NAT2 genotype and the risk of ALD. Slow acetylator genotype may predispose to the development of HCC in severe ALD patients not infected by the hepatitis C virus.

Hidrotórax hepático recidivante: un difícil reto terapéutico / Recurring hepatic hydrothorax: a difficult therapeutic challenge

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Functionally active duplications of the CYP2D6 gene are more prevalent among larynx and lung cancer patients.

The cytochrome P450 CYP2D6 is a polymorphic drug-metabolizing enzyme that is involved in the metabolism of several drugs and xenobiotics. Several independent studies indicate that the CYP2D6 metabolic status is a secondary factor in the risk of developing lung cancer, with individuals with high activity being at increased risk. The occurrence of functionally active duplications of the CYP2D6 gene is a phenomenon that affects 3-8% of Caucasians and up to 30% in some ethnic groups. These duplications cause ultrarapid metabolism of CYP2D6 substrates. In order to establish whether the highest CYP2D6 enzyme activity is associated with an increased risk of cancer, we analyzed the frequency of CYP2D6 gene duplications and enzyme-inactivating mutations in 199 Caucasian patients with lung or larynx cancer and in 335 healthy controls. A significantly increased frequency of carriers of the CYP2D6 gene duplication were found among lung and larynx cancer patients (13%), as compared with healthy controls (6.9%; p < 0.02). The frequency of the mutated active CYP2D6*9 allele was increased in lung cancer patients (p < 0.01) but not in larynx cancer patients. Global findings indicate that over 20% patients with lung or larynx cancer show CYP2D6 genotypes leading to ultrarapid metabolism or to the expression of an enzyme with altered kinetics (p < 0.01 vs. healthy controls). This may influence the metabolism of CYP2D6 substrates, including antineoplastic drugs and opioid derivatives used for pain relief in cancer patients. These patients would require higher doses than those considered as standard. We conclude that dosages for CYP2D6 substrates should be adapted to lung and larynx cancer patients.

Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk.

CYP2C9 enzyme activity is involved in the metabolism of substances related to colorectal cancer, and it is functionally linked to a genetic polymorphism. Two allelic variants of the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, differ from wild-type CYP2C9*1 by single amino acid substitutions. These mutated alleles encode enzymes with altered properties that are associated with impaired metabolism. The present study evaluates the impact of CYP2C9 genotypes leading to high enzyme activity on colorectal cancer risk. For this, the frequency of allelic variants of the CYP2C9 gene was analysed in genomic DNA from 129 patients with colorectal cancer and in 150 healthy controls. Patients with colorectal cancer showed a statistically significant increase in the frequency of genotypes homozygous for the active CYP2C9*1 gene, as compared with healthy individuals. Such a high frequency is more significant among patients with cancer in proximal segments of the colon (P < 0.025; odds ratio 2.36 95% CI 1.18-4.72), and decreases in more distal tumour locations. We conclude that CYP2C9 polymorphism can be considered as a secondary risk factor for colorectal cancer in the studied population: those individuals with genotypes leading to high enzyme activity were at increased risk. The association of the CYP2C9 polymorphism to colorectal cancer risk could be related to CYP2C9-mediated metabolic activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. In addition, the key role of CYP2C9 in the metabolic inactivation of non-steroidal anti- inflammatory drugs could diminish the protective effect of these drugs against colorectal cancer.

High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population.

OBJECTIVE: To search for ethnic variability in the impact of cytochrome P450 2C9 (CYP2C9) polymorphism. METHODS: CYP2C9 allelic variants related to impaired CYP2C9 metabolism were analysed in genomic DNA from 157 Spanish healthy subjects using amplification-restriction and sequencing procedures. RESULTS: The frequency for CYP2C9 mutated alleles is higher among the Spanish subjects analysed than that reported for other Caucasian individuals: CYP2C9*2, 0.143 and CYP2C9*3, 0.162 (P = 0.0001). Nearly 10% of the individuals studied are expected to metabolise deficiently CYP2C9 substrates. CONCLUSION: In some Caucasian populations the impact of the CYP2C9 polymorphism may be much higher than that estimated from genotyping studies published to date.