Prevalencia de deficiencia de vitamina K y factores asociados en pacientes con fibrosis quística sin aporte suplementario / Prevalence of vitamin K deficiency and associated factors in non-supplemented cystic fibrosis patients

Introducción. La deficiencia de vitamina K es prevalente en pacientes con fibrosis quística (FQ) aun con aporte suplementario. Se desconocen factores de riesgo fiables para determinar su ocurrencia. Nuestro objetivo fue evaluar la prevalencia de deficiencia de vitamina K y factores asociados en los pacientes con FQ que no recibían aporte suplementario. Métodos. Se determinaron protrombina inducida por ausencia de vitamina K (PIVKA-II) y osteocalcina infracarboxilada (OCic). Se evaluó el estado clínico y su relación con la deficiencia de vitamina K. El análisis estadístico incluyó prueba de Mann-Whitney, ANOVA o Kruskal-Wallis, prueba χ² o prueba de Fisher-Freeman-Halton y regresión logística múltiple lineal y escalonada hacia adelante. Resultados. Se incluyeron 79 pacientes con FQ de entre 0,4-25,3 años. Se observaron valores anómalos de PIVKA-II y OCic en 56 (70,9%) y 45 (57,0%) pacientes. Los pacientes con PIVKA-II elevada eran significativamente mayores (p = 0,0184) y tenían puntajes Z de peso corporal (p= 0,0297) inferiores a los pacientes que tenían concentraciones normales. No se hallaron diferencias entre los pacientes con OCic normal o patológica. Se notificaron valores anómalos de PIVKA-II y OCic más frecuentemente en pacientes con dos mutaciones graves en el gen CFTR y con un estado nutricional malo/deficiente. Los análisis de regresión múltiple lineal y de regresión múltiple escalonada hacia adelante no revelaron factores predictivos sólidos para determinar la deficiencia de vitamina K. Conclusión. La deficiencia de vitamina K es altamente prevalente durante la evolución natural de la fibrosis quística. No se hallaron determinantes clínicos fiables para precisar su ocurrencia.

Introduction. Vitamin K deficiency is highly prevalent in cystic fibrosis (CF) patients despite supplementation. Moreover, no reliable risk factors for its occurrence are known. The aim was to assess the prevalence of vitamin K deficiency and associated factors in non-supplemented CF patients. Methods. Prothrombin concentration induced by vitamin K absence (PIVKA-II) and the undercarboxylated osteocalcin percentage (u-OC) were determined. In all patients clinical status was assessed and its relation to vitamin K deficiency determined. The following tests were used for statistical analysis: Mann-Whitney test, ANOVA test or the Kruskal Wallis test, the chi-squared test or the Fisher-Freeman-Halton test, and multiple linear and multiple forward stepwise logistic regression analysis. Results. The study group comprised 79 CF patients aged 0.4-25.3 years. PIVKA-II and u-OC were abnormal in 56 (70.9%) and 45 (57.0%) patients. Patients with elevated PIVKA-II were significantly older (p= 0.0184) and had lower Z-score values for body weight (p= 0.0297) than those with normal concentrations. Patients with normal or pathological u-OC percentage did not differ. Abnormal PIVKA-II and u-OC were reported more frequently in subjects with two severe CFTR mutations and with worse/poor nutritional status. Multiple linear and forward stepwise regression analyses did not reveal strong predictive factors of vitamin K deficiency. Conclusion. Vitamin K deficiency is highly prevalent in the natural course of cystic fibrosis. There are no reliable clinical determinants of its occurrence.

Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation

BACKGROUND/AIMS: The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated. METHODS: Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 +/- 1.3 ng/mL (mean +/- SD). RESULTS: The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive 18fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05). CONCLUSIONS: Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients.

Evaluation of a Modified Enzyme Linked Immunosorbent Assay for Serum PIVKA-II Measurement

BACKGROUND: The serum des-gamma-carboxyprothrombin (protein induced by vitamin K antagonist-II, PIVKA-II) is a useful tumor marker in addition to alpha-fetoprotein for diagnosing primary hepatocellular carcinoma (HCC). In this study, we evaluated the laboratory performance of a modified ELISA method for PIVKA-II measurement adopting an automated ELISA processor in comparison with conventional manual method and investigated its diagnostic performance in patients with HCC. METHODS: The laboratory performance of modified ELISA using PIVKA-II ELISA kit (Sanko Junyaku Co., Japan) was evaluated using control materials (10, 25, 500, 1,000 mAU/mL) and 208 patient samples according to the CLSI guidelines. In 93 HCC patients and 88 disease controls (30 chronic hepatitis and 58 liver cirrhosis), ROC curve, sensitivity, specificity, and positive and negative predictive values were analyzed. RESULTS: Total and within-run CVs for middle, high and very high level samples were less than 10%, while those of low level samples were over 10% (12.6% and 11.7%, respectively). The modified ELISA showed an excellent linearity (r>0.99) and low carryover rate (-0.14%). Although the correlation between the conventional and modified ELISAs was excellent (r=0.982), there was a proportional deviation of PIVKA-II levels (y intercept: 0.621). With a cut-off of 30 mAU/mL, the sensitivity and specificity of PIVKA-II for the diagnosis of HCC were 58% and 92%, respectively. CONCLUSIONS: PIVKA-II measurement by modified ELISA using an automated ELISA processor can improve the efficiency of laboratory in terms of turnaround time and labor intensiveness while maintaining reasonable sensitivity and specificity for the diagnosis of HCC.

PIVKA-II as a Serological Marker of Hepatocellular Carcinoma / 대한간학회지

No abstract available.

Optimal Cut-off Value of PIVKA-II for Diagnosis of Hepatocellular Carcinoma: Using ROC Curve / 대한간학회지

BACKGROUND/AIMS: Protein induced by vitamin K absence or antagonist-II (PIVKA-II), also known as des-carboxyprothrombin (DCP), can be used as an alternative tool to alpha-fetoprotein (AFP) for surveillance of hepatocellular carcinoma (HCC). The aims of the present study were to compare PIVKA-II levels between the patients with HCC and patients with non-HCC chronic liver disease, to evaluate the correlation of PIVKA-II and AFP in HCC patients, and finally to estimate the optimal cut-off value for PIVKA-II for the diagnosis of HCC with using the receiver operating characteristic (ROC) curve. METHODS: A total of 227 consecutive patients with HCC (n=42) or chronic liver disease (n=185) were enrolled in this study. HCC was diagnosed histologically or by imaging such as computed tomography, magnetic resonance imaging or angiography. The serum PIVKA-II and AFP levels were measured by electrochemiluminoimmunoassay with using the Haicatch PIVKA-II kit and by immunoradiometric assay, respectively. RESULTS: The PIVKA-II level in the HCC patients was significantly higher than the non-HCC chronic liver disease patients (903.0+/-1156.7 vs. 111.7+/-211.0 mAU/ mL, respectively, P<0.01). PIVKA-II and AFP showed a statistical correlation in HCC patients (r=0.46, P<0.01). The sensitivity and specificity of PIVKA-II for the diagnosis of HCC were 66.7% and 74.1%, respectively, and when tasted together with AFP, the sensitivity was increased by 85.7%. For the ROC curve of PIVKA-II in HCC patients, the specificity of a 250 mAU/mL level of PIVKA-II was 95%. CONCLUSIONS: PIVKA-II was as useful surveillance tool for differentiating HCC from chronic liver disease, and a PIVKA-II value of 250 mAU/ mL was proposed as a significant cut-off value for diagnosis of hepatocellular carcinoma.

Usefulness of PIVKA-II for diagnosis and evaluation of recurrence of hepatocellular carcinoma / 대한내과학회지

BACKGROUND: Although alpha-fetoprotein (AFP) is most widely used tumor marker for hepatocellular carcinoma (HCC), the sensitivity is about 60~70% in advanced HCC. Furthermore, the specificity of AFP is relatively low. The aim of this study was to evaluate the usefulness of prothrombin-induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of HCC, and of recurrence after curative surgical resection. METHODS: Between April 2001 and March 2004, a total of 245 patients with pathologically confirmed HCC and a total of 267 patients with non-HCC, chronic liver diseases were enrolled. RESULTS: With cutoff-value 20 ng/mL for AFP and 40 mAU/mL for PIVKA-II, the sensitivity of AFP and PIVKA-II was 48.6% (119/245) and 75.1% (184/245), respectively. The specificity of them was 81.3% (217/267) and 94.8% (253/267), respectively. When AFP and PIVKA-II were combined, the sensitivity and specificity was 83.3% (204/245) and 77.2% (206/267), respectively. For HCC

Clinical Efficacy of Serum PIVKA-II in the Diagnosis and Follow up after Treatment of Hepatocellular Carcinoma / 대한간학회지

BACKGROUND/AIMS: Protein induced by vitamin K absence or antagonist II (PIVKA-II) appears to be a useful tumor marker for the evaluation of patients with hepatocellular carcinoma (HCC). But the usefulness of PIVKA-II was not yet clear in Korea where hepatitis B-virus is endemic. We investigated the usefulness of PIVKA-II in the diagnosis and follow-up after treatment of HCC. METHODS: We studied patients with HCC which was pathologically confirmed. PIVKA-II was measured by enzyme immunoassay. PIVKA-II levels before and after treatment, in correlation with imaging studies, were analyzed for the comparison of treatment responses. Kappa index was obtained. RESULTS: A total of 129 patients were included. 93 patients (72%) were HBsAg positive. 86 patients (67%) were PIVKA-II >40 mAU/mL. 52 patients (40%) were AFP >20 ng/mL and 77 patients (60%) were AFP 40 mAU/mL. 68 of 129 patients were evaluated treatment response. On the basis of radiologic response, CR was 33, PR 17, SD 12, and PD 6. Of the 33 radiologic CR patients, 30 patients were CR and 3 patients were PR by means of PIVKA-II response. Of the 17 radiologic PR patients, 6 patients were CR and 7 patients were PR. Therefore, tumor responses by radiologic and PIVKA-II were well correlated (Kappa index was 0.59). CONCLUSIONS: PIVKA-II can be used as a useful tumor marker for patients with HCC, especially those with low levels of AFP, before and after treatment in Korea.

Clinical Implication of Automatically Analysed AFP-L3 and PIVKA-II in the Diagnosis of Hepatocellular Carcinoma / 대한간학회지

BACKGROUND/AIMS: Prothrombin induced by Vitamin K Antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) subtype reacting with Lens Culinaris Agglutinin (AFP-L3) are known as specific tumor markers for HCC. Recently a more sensitive EIA method for PIVKA-II and an automatic analyzer with Liquid Phase Binding Assay method (LBA method) for AFP-L3 have been developed. The aim of this study was to evaluate the feasibility of PIVKA-II and AFP-L3 measured by newly developed methods as complementary tumor markers to AFP in the diagnosis of HCC. METHODS: The serum concentration of AFP, PIVKA-II, and a fraction of AFP-L3 were determined from 188 patients with HCC and 118 patients with various liver diseases including 46 with liver cirrhosis, 10 with chronic hepatitis, 50 with metastatic liver cancers, and 12 with benign tumors of the liver. AFP was measured by EIA, PIVKA-II by sensitive EIA, and AFP-L3 by the LBA method with LiBASys Auto-analyzer. The cutoff values for AFP, PIVKA-II, and AFP-L3 were 400 ng/mL, 40 mAU/mL, and 15%, respectively. RESULTS: The sensitivity and specificity of serum PIVKA-II were 69.2% and 76.5%, respectively. Sixty-two (51.2%) of 121 patients with HCC, in which AFP was less than 400 ng/mL were PIVKA-II positive. The sensitivity and specificity of serum AFP-L3 were 48.8% and 90.8%, respectively. When AFP-L3 was used in combination with PIVKA-II, 31 (46.3%) of the 67 patients with small less than 3 cm HCC were positive for at least one of these markers. CONCLUSION: PIVKA-II measured by sensitive EIA may be useful for the diagnosis of HCC with low AFP level. AFP-L3 and PIVKA-II may improve the detection rate of small HCCs less than 3 cm.

Combination Assay of Serum PIVKA-II and Alpha-fetoprotein in Primary Hepatocellular Carcinoma / 대한임상병리학회지

BACKGROUND: The serum des-gamma-carboxy prothrombin (PIVKA-II) is a tumor marker complementary to alpha-fetoprotein (AFP) for diagnosing primary hepatocellular carcinoma (HCC). A combination assay of the tumor markers was found to be useful for early diagnosis of HCC. So we investigated the clinical relevance of the measurement of serum PIVKA-II and AFP levels in patients with HCC. METHODS: The serum PIVKA-II levels were measured in 64 cases of HCC, 16 cases of cirrhosis, 32 cases of chronic hepatitis, and 23 healthy controls with a revised PIVKA-II ELISA Kit (Eisai, Tokyo, Japan), with the simultaneous determination of the serum AFP value using the AFP immunoassay kit (Elecsys, Roche, Germany). RESULTS: The positive rates of PIVKA-II and the AFP value in HCC were 53.1% and 68.8%, respectively, and were significantly higher than 17.6% and 29.4% in liver cirrhosis, and 3.1% and 0% in chronic hepatitis. No signficant correlation between the two tumor markers was found. The correlation between PIVKA-II levels and the size of tumor in HCC was found. No relation of the clinical characteristics to positive rates of PIVKA-II and AFP was found. The sensitivity, specificity and accuracy of PIVKA-II were 53.1%, 94.4% and 73.8%, and those of AFP were 68.8%, 93.1% and 80.9%, respectively. The sensitivity and accuracy in the combination assay for detection of HCC were higher than those in each assay, especially in HCC with the diameter of the tumor mass at less than 3 cm. CONCLUSIONS: It was demonstrated that the combination assay of PIVKA-II and AFP could increase the diagnostic value for HCC and could be useful in early diagnosis of HCC.

Serum Concentration of Intercellular Adhesion Molecule-1 (ICAM-1) in Patients with Hepatocellular Carcinoma (HCC) with Low AFP / 대한간학회지

BACKGROUND/AIMS: In HCC with low AFP. we have to use repeated imaging study to evaluate residual viable rumor or recurrence after TACE ( transarterial chemoembolization). We performed the study to know that sICAM-1 in HCC can be a tumor marker of diagnosis and has cor relation with tumor size or clinical staging. The results were compared with PIVKA- , an another tumor marker of HCC. METHODS: Previously untreat ed 39 pat ients with HCC were evaluated. Serum sICAM- 1, AFP and PIVKA-II were measured by EIA, immunoradiometric assay and EIA, respectively. Tumor size were meas ured by abdominal CT and angiogr aphy. RESULTS: Range of sICAM- 1 levels with HCC patients were 189.0 to 983.6 ng/ mL, and mean value was 668.3+- 254.4 ng/ mL. Thirty four of the 39 patients (87.2%) with HCC showed sICAM- 1 levels higher than 306.4 ng/ mL (mean of 131 healt hy controls + 2SD level). Range of PIVKA-II level with HCC patients were 25.3 to 2,779.3mAU/nL, and mean value was 1,340.1+-1,091.1mAU/mL. seven of the 39 patients(94.9%) with HCC showde PIVKA-II levels higher than 40mAU/mL. Range of AFP levels with HCC patients were 4.2 to 57,520ng/mL, and mean value was 4,215.6+-10,807.2ng/mL. 10 patients (26%) showed AFP lower than 20ng/mL, and 17 patients(44%) were AFP lower than 100ng/mL. All of the 17 patients with alphaFP lower than 100ng/mL had s ICAM-1 levels more than reference range (mean of 131 healt hy cont r ols + 2 SD level), and PIVKA-II levels also more than reference range. Positive correlation was observed between PIVKA-II level and tumor size in 18 patients without vascular invasion. Accor ding t o HCC clinical staging, 10 patients (25.6%) belonged clinical stage II. 5 pat ients (12.8%) III, 24 pat ients (61.5%) IV. Both of PIVKA-II and sICAM-1 levels of stage showed significantly higher than stage II. PIVKA-II showed more positive correlation with tumor size and clinical stage than sICAM- 1. No correlation was found between AFP and sICAM-1, and positive correlation was AFP and PIVKA-II. CONCLUSION: In HCC patients with low AFP, sICAM-1 and PIVKA-II correlated with tumor size and clinical stage. sICAM-1 and PIVKA-II may be a useful marker of diagnosis. So, we need to further study to evaluate whether sICAM- 1 and PIVKA-II can be used as a marker of disease progression or prognosis.

Prophylactic Effect of Intramuscular, Oral, and Maternal Administration of Vitamin K on Hemorrhagic Disease of the Newborn

PURPOSE: Vitamin K deficiency is associated with hemorrhagic disease of the newborn. Late hemorrhagic disease is often intracranial and may be fatal. Many countries recommend vitamin K prophylaxis after birth to prevent this hazard of vitamin K deficiency. Nevertheless, there are still controversies concerning the best way of providing effective prophylaxis. A recent article by Golding and colleagues has questioned the safety of the routine use of intramuscular vitamin K for the newborn. These authors reported a significantly increased rate of childhood cancer in infants who received intramuscular prophylaxis. So we compared the prophylactic effect of intramuscular, oral, and maternal administration of vitamin K on hemorrhagic disease of the newborn. METHODS: A total of 60 newborns, delivered spontaneously vaginally, in the Masan Fatima hospital from March to June, 1996, were enrolled. Neonated with intrapartum anoxia, liver disease or hereditary coagulation factor deficiencies, who received antibiotics were excluded. Mothers receiving any medication known to interferes with vitamin K metabolism(such as antiepileptics, antibiotics and anticonvulsions) were excluded. The newborns were randomly allocated to one of the four groups. A group was not supplied. B group received 1mg of vitamin K1 intramusculary, C group received 2mg of vitamin K1 orally. D group was given 20mg of vitamin K1 orally to their mothers at least 2days(range 2 to 7) before birth. Blood samples were collected from 48hrs to 72hrs after birth. PIVKA-II level was measured by enzyme-linked immunosorbent assay (EITEST-MONOP, Eisai Ltd), using a monospecific monoclonal antibody against PIVKA-II. The results obtained are expressed in arbitrary unit (AU) : 1AU corresponds to 1micro gram of purified prothrombin. (healthy adults have less than 0.13AU/ml). PT, PTT were measured simultaneously. RESULTS: 1) PIVKA-II was detected in 4 of 15 infants in group A, who were not supplied. None was detected in other groups. So PIVKA-II detection rate was significantly decreased in other groups compared with group A(p<0.05). 2) PT(sec) values were 12.74+/-0.91, 12.58+/-0.89, 12.36+/-1.04, 12.16+/-0.90 respectively, and there was no significant difference between groups. 3) PTT(sec) values were 52.41+/-13.26, 38.39+/-10.04, 42.67+/-7.01, 39.77+/-10.48 respectively and there was significant shortening in other groups compared with group A (p<0.05). CONCLUSION: Not only intramuscular administration but oral and maternal administration of vitamin K have prophylactic effect on hemorrhagic disease of the newborn. Prophylactic effect on the late hemorragic disease of the newborn requires further extensive study and evaluation.