Clinical Utility of Protein Induced by Vitamin K Absence-II in Patients with Hepatocellular Carcinoma

Objective: Despite moderate sensitivity, alpha fetoprotein (AFP) is widely used in screening and prognostication for hepatocellular carcinoma (HCC). The objective of the current study was to assess clinical utility of Prothrombin induced by Vitamin K absence-II (PIVKAII) in addition to AFP in patients with HCC. Methods: We retrospectively reviewed 244 patients with documented AFP, PIVKA II and dynamic imaging of the liver. Using ROC curves, cutoff values for AFP and PIVKAII for HCC detection, tumor grade and microvascular invasion (MVI) were assessed. In patients who underwent liver transplantation (LT) for HCC, survival was determined using Kaplan Meier curves. Results: The median PIVKAII in healthy living donors was 28.6mAU/ml (15.9-55). In cirrhotics, the sensitivity of an AFP cutoff of 7.6 ng/ml or PIVKAII  cutoff of 250 mAU/ml for HCC detection was 91.7% (176/192) and specificity was 62.9%(68/108) (p <0.0001). In patients with HCC, PIVKAII values were significantly elevated with tumor size > 5 cm (P < 0.0001), tumor nodules > 3(P=0.01), and macrovascular invasion(p <0.0001).  The high risk group (patients with AFP ≥ 40 ng/ml + PIVKAII ≥ 350 mAU/ml), had a sensitivity of (23/33) 69.6% and specificity of (22/22)100% for MVI (P <0.001). The estimated 3 year RFS after LT in the low risk group (AFP     

Comparing Prothrombin induced by vitamin K absence-II (PIVKA-II) with the oncofetal proteins Glypican-3, Alpha feto protein and Carcinoembryonic antigen in diagnosing hepatocellular carcinoma among Egyptian patients

BackgroundHepatocellular carcinoma (HCC) is usually asymptomatic in the early stage and does not show elevated alpha-feto protein (AFP). AFP shows 60–80% sensitivity in diagnosing HCC.Glypican3 (GPC-3) is an oncofetal protein that is only detected in HCC cells but not in benign liver tissues, while Carcinoembryonic antigen (CEA) is expressed in various neoplasms including HCC. Although, it is not specific for HCC.Prothrombin induced by vitamin K absence-II (PIVKA-II) is an abnormal prothrombin protein that is increased in the serum of HCC patients. It has higher sensitivity and specificity compared to AFP.The aim of this study is to compare the clinical utility of PIVKA-II with GPC-3, AFP and CEA in diagnosing HCC.Patients and methodsThis study included 40 patients with HCC, 10 patients with cirrhosis as a benign control group, and 10 apparently healthy volunteers as normal controls.Serum samples were subjected to routine laboratory investigations, measurement of CEA, AFP using MEIA technique (Axsym), glypican3, and PIVKA-II using ELISA technique in the sera of all patients and controls.ResultsAll markers showed the highest results in the HCC group. Higher concentrations of PIVKA-II were detected in patients with splenomegaly, and in tumors with size (>3 cm). Combination of Glypican-3 and PIVKA-II showed the highest sensitivity, while GPC-3 alone and combination of GPC-3 and AFP showed the highest specificity to differentiate HCC from liver cirrhosis and normal controls. GPC-3, PIVKAII, and combination of both showed the highest sensitivity, while GPC-3 alone showed the highest specificity to differentiate HCC from liver cirrhosis.ConclusionGlypican-3 is the only oncofetal antigen that showed comparable high diagnostic accuracy as PIVKA-II in diagnosing HCC among Egyptian patients.     

血清GP73联合AFP在肝细胞癌诊断中的价值

目的 探讨血清高尔基体蛋白73（GP73）与甲胎蛋白（AFP）联合检测在肝细胞癌（HCC）诊断中的价值。方法 收集2011年2月至2012年1月30例HCC患者（HCC组）、30例肝硬化患者（肝硬化组）和20例健康人（健康对照组）的血清,分别用酶联免疫吸附法（ELISA）和电化学发光免疫法（ECLIA）检测各组血清中GP73和AFP水平。结果 HCC组、肝硬化组和健康对照组血清GP73水平分别为（251.9±130.2）ng／ml、（74.7±40.6）ng／ml和（12.2±4.0）ng／ml,AFP水平分别为（141.6±158.3）ng／ml、（36.0±35.0）ng／ml和（2.2±1.5）ng／ml。GP73 检测HCC的敏感度为76.7％,特异度82.0％,约登指数58.7％,准确度80.0％。AFP检测HCC的敏感度为63.3％,特异度80.0％,约登指数43.3％,准确度68.8％。两者联合检测的敏感度为86.7％,特异度78.0％,约登指数64.7％,准确度81.3％。结论 HCC患者血清中GP73和AFP水平较高,两者联合检测可以显著提高HCC的诊断能力。     

Combined measurement of preoperative α-fetoprotein and des-γ-carboxy prothrombin predicts recurrence after curative resection in patients with hepatitis-B-related hepatocellular carcinoma

Alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) are widely used complementary tumor markers for hepatocellular carcinoma (HCC). In this study, we investigated whether preoperative AFP and DCP levels predict recurrence after curative resection in patients with hepatitis B virus (HBV)-related HCC. Records for 267 patients who were diagnosed with HBV-related HCC and who underwent curative resection for HCC were retrospectively reviewed. Patients were divided into two preoperative groups: pre-op I (AFP ≥20 ng/dL and DCP ≥40 mAU/mL) and pre-op II (AFP ≥20 ng/dL and DCP <40 mAU/mL; AFP <20 ng/dL and DCP ≥40 mAU/mL; or AFP <20 ng/dL and DCP <40 mAU/mL). Among 267 patients, 102 (38.2%) patients were classified as pre-op I, whereas the other 165 (61.8%) belonged to pre-op II. During the post-resection follow-up [69.0 (3.0-136.0) months] period, 154 (57.7%) patients developed recurrences [68 (66.7%) patients in pre-op I vs. 86 (52.1%) in pre-op II, p = 0.029]. A multivariate analysis revealed that multiple tumors [hazard ratio (HR), 2.210; 95% confidence interval (CI), 1.185-4.121] and pre-op I (HR: 1.890; 95% CI; 1.080-3.289) were significant predictors for recurrence. Disease-free survival (DFS) was significantly shorter in pre-op I compared to that in pre-op II (20.0 vs. 46.8 months, p = 0.006). Elevated preoperative AFP and DCP levels were associated with a higher recurrence rate and shorter DFS in patients with HBV-related HCC after curative resection. The combined measurement of preoperative AFP and DCP may be a prognostic factor for future recurrence.     

Alpha-fetoprotein synthesis in human hepatocellular carcinoma: correlation with hepatitis B surface antigen expression.

We analyzed the pattern of alpha-fetoprotein (AFP) synthesis in 40 consecutive human hepatocarcinomas (HCC) in relation to hepatitis B viral (HBV) infection. In addition, histopathological characteristics of liver parenchyma and the tumor itself were examined. Elevated AFP (> 20 ng/ml) were found in 90% of HCC patients and in none of the controls. In 35% of HCC cases, serum AFP was above 100,000 ng/ml. AFP levels were significantly higher in patients seropositive for hepatitis B surface antigen (HBsAg) compared with their negative counterparts (mean log[AFP]: 4.28 +/- 1.67 vs. 3.28 +/- 1.96, respectively; geometric mean (GM): 19,322.6 ng/ml and 1939.5 ng/ml, respectively; p < 0.05). Furthermore, serum AFP levels were higher in HCC patients with liver cirrhosis than in those without (log[AFP]: 4.43 +/- 1.58 vs. 3.23 +/- 1.98, respectively; p < 0.05). However, the relationship of cirrhosis with AFP was confounded by the high prevalence of HBsAg in cirrhotic HCC patients. There was no correlation of AFP with either liver necrosis (abnormal AFP in 45% of cases; mean log[AFP]: 3.99 +/- 1.91 vs. 3.75 +/- 1.85 for HCC with and without necrosis, respectively; 0.05 < p < 0.68, not significant (NS)), or inflammation (abnormal AFP in 25%; mean log[AFP]: 4.33 +/- 1.62 vs. 3.70 +/- 1.93 for HCC with and without inflammation, respectively; 0.05 < p < 0.39, NS). A vast majority of HCC (75%) were moderately (grade 2-3) or poorly differentiated tumors (grade 3, grade 4, or combined grade 3-4). Serum AFP did not correlate with tumor grade. Immunohistochemical analysis of HBsAg and AFP confirmed the serological findings, and confirmed earlier observations of elevated AFP in HBsAg-positive patients. These results may reflect pathogenic and biological differences between HBsAG-secreting and nonsecreting HCC.     

Clinical evaluation of urinary transforming growth factor-beta1 and serum alpha-fetoprotein as tumour markers of hepatocellular carcinoma.

To evaluate the diagnostic application of urinary transforming growth factor-beta1 (TGF-beta1) and serum alpha-fetoprotein (AFP) levels in hepatocellular carcinoma (HCC), TGF-beta1 and AFP were determined in 94 patients with cirrhotic HCC and in 94 sex- and age-matched patients with cirrhosis alone. TGF-beta1 and AFP levels in HCC were higher than in cirrhosis alone (P = 0.0001). There is an inverse correlation between TGF-beta1 and log AFP (r = -0.292, P = 0.004). Multivariate analysis indicated that TGF-beta1 and AFP were closely associated, in a dose-related fashion, with the development of HCC. Receiver-operating characteristic (ROC) curves were used to determine the optimal cut-off values of TGF-beta1 (50 microg g(-1) creatinine) and AFP (100 ng ml(-1)). Both TGF-beta1 and AFP showed a high specificity (99%) and positive likelihood ratio. The sensitivity was 53.1% for TGF-beta1 and 55.3% for AFP. The determination of both markers in parallel significantly increased the diagnostic accuracy (90.1%) and sensitivity (84%), with a high specificity (98%) and positive likelihood ratio (40.0). In conclusion, TGF-beta1 and AFP are independent tumour markers of HCC and may be used as complementary tumour markers to discriminate HCC from cirrhosis.     

原发性肝癌患者肿瘤组织生长抑素受体表达与血AFP水平的相关性

背景与目的:生长抑素类似物(somatostatin analogue,SSTA)对部分原发性肝癌(hepatocellular carcinoma,HCC)患者具有一定疗效,但HCC患者肿瘤组织中生长抑素受体(somatostatin receptor,SSTR)表达状况不详,其与血甲胎蛋白(alphafetoprotein,AFP)的相关性也未见探讨.本研究拟了解肝癌组织中SSTR1、SSTR2、SSTR3、SSTR4及SSTR5亚型的表达状况及其与血AFP的相关性.方法:逆转录-聚合酶链反应及免疫组织化学法分别检测人肝癌及肝硬化组织(各40例)SSTR1、SSTR2、SSTR3、SSTR4及SSTR5亚型的mRNA及蛋白表达:酶联免疫吸附试验检测HCC患者肿瘤组织及外周血AFP水平.结果:肝癌组织中SSTR1、SSTR2、SSTR3、SSTR4及SSTR5蛋白阳性率(分别为47.5%、70.0%、50.0%、65.0%及67.5%)显著高于肝硬化组织(分别为55.0%、67.5%、52.5%、60.0%及47.5%).肝癌组织中SSTR1、SSTR2、SSTR3、SSTR4及SSTR5表达与患者血AFP水平呈二次曲线正相关(r依次为0.882、0.901、0.877、0.854、0.903,P＜0.05).血AFP水平在200～800 μg/L范围时,伴有肝癌组织SSTRs的高表达,过低或过高的血AFP水平伴有SSTR低表达.结论:约60%HCC患者的肿瘤组织表达了SSTRs,其表达量明显高于肝硬化组织;15 AFP水平在200-800μg/L的HCC患者伴有肝癌组织SSTRs的高表达,提示为SSTA治疗的适宜候选者.     

Measurement of serum levels of des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma by a revised enzyme immunoassay kit with increased sensitivity

BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a useful tumor marker for hepatocellular carcinoma (HCC). The conventional enzyme immunoassay (EIA) kit for DCP lacks adequate sensitivity to detect small HCC. Thus, a revised EIA kit for DCP has been developed. In this revised DCP kit, the blank value has been reduced, making it now possible to obtain a normal value. The authors used this revised EIA kit for DCP with increased sensitivity and evaluated its usefulness as a tumor marker for HCC. METHODS: Serum DCP and alpha-fetoprotein (AFP) levels were determined in 60 patients with HCC, 60 with cirrhosis, 57 with chronic hepatitis, and 273 normal subjects. The cutoff value for the revised DCP kit was determined to be 40 mAU/mL, and the values for the conventional DCP kit and AFP were 100 mAU/mL (0.1 AU/mL) and 20 ng/mL, respectively. RESULTS: The mean DCP value was 17.5 mAU/mL in the normal subjects, and the detection limit was 10 mAU/mL for this revised DCP kit. The positivity rate for DCP in patients with HCC was 60% by the revised DCP kit, in contrast to 40% by the conventional DCP kit. The sensitivity, specificity, and accuracy of the revised kit were 60%, 92.3%, and 81.4%, respectively, whereas those of the conventional kit were 40%, 98.3%, and 78.5%. Thirty-five percent of HCC tumors smaller than 2 cm and 78.1% of those larger than 3 cm were positive for DCP by the revised kit. The corresponding figures were 20% and 56.3% with the conventional kit. Twelve (33.3%) of the 36 HCC patients who were negative for DCP by the conventional kit were positive by the revised kit. When the revised DCP kit was used in combination with AFP, 86.7% of the HCC patients and 78.3% of the patients with solitary HCC were positive for at least 1 of these markers. CONCLUSIONS: The revised DCP kit is more useful than the conventional DCP kit as a tumor marker for HCC and should be used in combination with AFP.     

Spontaneous Regression of Hepatocellular Carcinoma due to Disruption of the Feeding Artery

We present an unusual case of spontaneous regression of hepatocellular carcinoma (HCC). A 77-year-old man with alcoholic liver cirrhosis presented with a 50-mm tumor in the Couinaud''s segment 8 (S8) of the liver, a 15-mm tumor in the S8-7 and 10-mm tumors in the other segments (S4, S6). The tumors were diagnosed as HCC by typical imaging findings and elevated serum alpha-fetoprotein (AFP, 1,825.0 ng/ml) and protein induced by vitamin K absence II (PIVKA II, 3,043 mAU/ml). One month later, AFP and PIVKA II decreased to 51.1 ng/ml and 411 mAU/ml, respectively, and the 50-mm tumor in the S8 became small and completely necrotic on angiography and computed tomography arteriography without any treatment. On the other hand, the 15-mm tumor in the S8-7 decreased in size to 10 mm and received blood supply from the right posterior superior arteries (A7). The other 10-mm tumors remained. Ischemia of the tumors due to disruption of the feeding artery (A8) might have induced tumor regression in the present case.Key words: Spontaneous regression, Hepatocellular carcinoma, Ischemia, Feeding artery     

血清高尔基体糖蛋白73在肝细胞癌诊断中的作用

目的 探讨血清高尔基体糖蛋白73(GP73)在肝细胞癌(HCC)早期诊断中的作用.方法 采用酶联免疫吸附试验(ELISA)定量检测43例体检正常者(正常对照)、110例慢性肝炎或肝硬化(CH/LC)患者和219例HCC患者血清中GP73水平,计算ROC曲线下面积及GP73对HCC诊断的敏感性与特异性.结果 正常对照组、CH/LC组和HCC组GP73分别为(22.1±8.5)ng/ml、(81.4±57.2)ng/ml和(271.5±202.3)ng/ml,HCC组GP73水平明显高于CH/LC组(P＜0.001).GP73的ROC曲线下面积是0.857,以100 ng/ml作为cut-off值,GP73诊断HCC的敏感性为76.7%,特异性为73.2%.在149例甲胎蛋白(AFP)＜400 ng/ml的HCC样本中,有108例(72.5%)GP73＞100 ng/ml.对4例AFP＜400ng/ml的HCC患者连续检测表明,GP73与治疗效果及预后有一定的相关性.结论 GP73可作为HCC早期诊断及治疗效果监测的指标,尤其对AFP＜400 ng/ml的HCC患者有较好临床意义.     

Clinical application of determining serum AFP-IgM complexes for diagnosis of small hepatocellular carcinoma

Diagnosis of primary hepatocellular carcinoma (HCC) at early stages has obviously been improved since determination of serum levels of free alpha-fetoprotein (AFP) was implemented. AFP has been considered as the standard tumor marker of primary HCC, although certain patients have very low serum free AFP levels. In the present study, clinical application of measuring serum AFP-IgM immune complexes compared to the serum free AFP was evaluated for diagnosis of small HCC. One hundred and three healthy controls, 74 patients with primary HCC, 27 patients with liver cirrhosis and 63 patients with chronic hepatitis were included in the present study. Serum levels of AFP-IgM immune complexes and free AFP were determined by ELISA and electrochemiluminescence, respectively. The best cut-off values of AFP-IgM immune complexes and free AFP for the diagnosis of primary HCC were 300 AU/ml and 10 μg/l, respectively, according to the area under the curve (AUC). At these cut-off values, the sensitivities of AFP-IgM and AFP for HCC were 64.9% and 79.7%, respectively, with specificities of 75.6% and 80.3%, respectively. Combining positivity for both tumor markers, the specificity and accuracy of diagnosis of HCC were 89.1% and 79.0%, respectively. Moreover, when the diameter of the tumor was ≤ 3 cm (being considered as small HCC), the sensitivity and specificity were 100.0% and 75.3%, respectively. There was no significant correlation between AFP-IgM level, patient sex or age (p>0.05). The ROC area was significantly different between AFP-IgM and AFP (Z = 2.19, p = 0.0286). In addition, the serum AFP-IgM levels were significantly higher in the patients with tumor diameter ≤ 3 cm (1090.4 ± 571.8 AU/ml) than in the patients with tumor diameter >3 cm (604.9 ± 749.9 AU/ml). It is concluded that determining serum levels of both AFP-IgM immune complex and AFP may have potential benefit for the diagnosis of small HCC.     

Expansion of anti-AFP Th1 and Tc1 responses in hepatocellular carcinoma occur in different stages of disease

Background:

α-Fetoprotein (AFP) is a tumour-associated antigen in hepatocellular carcinoma (HCC) and is a target for immunotherapy. However, there is little information on the pattern of CD4 (Th1) and CD8 (Tc1) T-cell response to AFP in patients with HCC and their association with the clinical characteristics of patients.

Methods:

We therefore analysed CD4 and CD8 T-cell responses to a panel of AFP-derived peptides in a total of 31 HCC patients and 14 controls, using an intracellular cytokine assay for IFN-γ.

Results:

Anti-AFP Tc1 responses were detected in 28.5% of controls, as well as in 25% of HCC patients with Okuda I (early tumour stage) and in 31.6% of HCC patients with stage II or III (late tumour stages). An anti-AFP Th1 response was detected only in HCC patients (58.3% with Okuda stage I tumours and 15.8% with Okuda stage II or III tumours). Anti-AFP Th1 response was mainly detected in HCC patients who had normal or mildly elevated serum AFP concentrations (P=0.00188), whereas there was no significant difference between serum AFP concentrations in these patients and the presence of an anti-AFP Tc1 response. A Th1 response was detected in 44% of HCC patients with a Child–Pugh A score (early stage of cirrhosis), whereas this was detected in only 15% with a B or C score (late-stage cirrhosis). In contrast, a Tc1 response was detected in 17% of HCC patients with a Child–Pugh A score and in 46% with a B or C score.

Conclusion:

These results suggest that anti-AFP Th1 responses are more likely to be present in patients who are in an early stage of disease (for both tumour stage and liver cirrhosis), whereas anti-AFP Tc1 responses are more likely to be present in patients with late-stage liver cirrhosis. Therefore, these data provide valuable information for the design of vaccination strategies against HCC.     

Urinary transforming growth factor α and serum α-fetoprotein as tumor markers of hepatocellular carcinoma

This case–control study aimed to evaluate the diagnostic application of urinary transforming growth factor (TGF) α and serum α-fetoprotein (AFP) in hepatocellular carcinoma (HCC). TGFα and AFP were determined in 90 pairs of age- and gender-matched patients with cirrhotic HCC and patients with cirrhosis alone and 60 healthy controls. The results indicated that TGFα and AFP levels in patients with HCC were higher than in those with cirrhosis alone or healthy controls (each P?=?0.0001). Multivariate analysis indicated that TGFα (odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.05–1.16) and AFP (OR 1.03, 95 % CI 1.01–1.06) were closely associated, in a dose-related fashion, with the development of HCC. The optimal cutoff values, determined with the receiver operating characteristic (ROC) curves, were 29 μg/g creatinine for TGFα and 100 ng/ml for AFP, respectively. The areas under ROC curve (AUC) were 0.74 for TGFα and 0.78 for AFP, respectively. Both biomarkers showed the same sensitivity (52.2 %), high specificity, high positive predictive value, and moderate positive likelihood ratio. Determination of both markers in parallel significantly increased the AUC (0.91) and diagnostic accuracy (92.2 %), with a high sensitivity (86.7 %), specificity (97.8 %), positive predictive value (PPV; 97.5 %), and moderate positive likelihood ratio (PLR; 39.4). Among 31 cirrhotic HCC with AFP?≤?20 ng/ml, the calculated AUC for TGFα was 0.79, with a sensitivity of 64.5 %, specificity of 96.7 %, PPV of 87.0 %, and PLR of 19.5. In conclusion, urinary TGFα and serum AFP are complementary tumor markers for detection of HCC with low AFP production.     

Plasma abnormal prothrombin (des-gamma-carboxy prothrombin) as a marker of hepatocellular carcinoma

Des-gamma-carboxy prothrombin [DCP], a protein induced by vitamin K absence or antagonist-II and also abbreviated PIVKA-II, was evaluated as a serologic marker for hepatocellular carcinoma (HCC). Its plasma levels were measured by enzyme immunoassay (E-1023) using an anti-DCP monoclonal antibody in 514 patients with various diseases. Of 120 patients with HCC, 76 (63%) had abnormal DCP levels greater than 0.1 arbitrary unit (AU)/ml and 58 (48%) showed levels greater than 0.3 AU/ml. When a diagnostic minimum level of 0.3 AU/ml was applied for DCP, false-positive cases of HCC were virtually eliminated. In some patients with HCC, plasma DCP levels normalized after surgical resection of the tumor. However, they rose again later with recurrence of the disease. The sensitivity of DCP in the diagnosis and monitoring of HCC was increased by serial and simultaneous determinations of alpha-fetoprotein (AFP), because high DCP levels were observed more often in low AFP-producing HCC patients. Elevated plasma DCP levels were not related to low vitamin K concentration in the serum. In fact, in many patients vitamin K administration resulted in only a moderate reduction of DCP levels. These results suggested strongly that DCP was synthesized by the hepatoma cells.     

The fucosylation index of alpha-fetoprotein and its usefulness in the early diagnosis of hepatocellular carcinoma

The serum concentration and degree of fucosylation (fucosylation index) of alpha-fetoprotein (AFP) were determined in serum samples from 258 patients with hepatocellular carcinoma (HCC) and 114 patients with benign liver diseases. When the serum AFP concentration was below 1000 ng/ml, it could not be used as a measure to distinguish between HCC and benign liver diseases. However, the fucosylation index of AFP proved useful for such a purpose. The sensitivity of the analysis using the fucosylation index in total patients with HCC was 69%; the specificity was 96% in benign liver diseases, and the accuracy of this test was 77%. When HCC patients who were grouped according to tumor size (5 cm, 3 cm, and 2 cm in diameter) were analyzed, they all had a fucosylation index significantly higher than that in benign liver disease patients. The mean fucosylation index in 28 patients with a serum AFP concentration below 1000 ng/ml and a tumor diameter less than 3 cm was 26 +/- 30%. Corresponding values for 16 patients with an AFP concentration below 400 ng/ml and a tumor size less than 3 cm and for 8 patients with a concentration below 400 ng/ml and a tumor size less than 2 cm were 32 +/- 31% and 27 +/- 27%, respectively. These values were higher, with statistical significance, than those in patients with benign liver diseases. These data indicate that the measurement of the fucosylation index of AFP is useful for the early diagnosis of HCC.     

Serum insulin-like growth factor-II and alpha-fetoprotein as tumor markers of hepatocellular carcinoma.

To evaluate the diagnostic application of serum insulin-like growth factor-II (IGF-II) and alpha-fetoprotein (AFP) levels in hepatocellular carcinoma (HCC), IGF-II and AFP were determined in 100 cirrhotic patients with HCC, 100 sex- and age-matched patients with cirrhosis alone and 50 healthy controls. The results indicated that IGF-II and AFP levels in patients with HCC were higher than in those with cirrhosis alone (p = 0.0001). There is an inverse correlation between IGF-II and (log)AFP (r = -0.410, p = 0.0001) in patients with HCC. Multivariate analysis indicated that IGF-II and AFP were closely associated, in a dose-related fashion, with the presence of HCC. Receiver operating characteristic curves were used to determine the optimal cutoff values of IGF-II (4.5 mg/g prealbumin) and AFP (100 ng/ml), respectively. Both IGF-II and AFP show a high specificity and positive likelihood ratio. The sensitivity was 42.0% for IGF-II and 73.0% for AFP. Determination of both markers in parallel significantly increased the diagnostic accuracy (96.5%) and sensitivity (97.9%), with a high specificity (95.1%) and positive likelihood ratio (19.9). In conclusion, IGF-II and AFP may be used as complementary tumor markers to discriminate HCC from cirrhosis.     

Serum CA 19-9 and alpha-fetoprotein levels in primary hepatocellular carcinoma and liver cirrhosis.

Serum CA 19-9 and alpha-fetoprotein (AFP) levels were determined in 211 patients with liver cirrhosis and 27 with primary hepatocellular carcinoma (HCC) associated with liver cirrhosis. This was done to determine the usefulness of CA 19-9 level with respect to AFP level in distinguishing between these two illnesses, and to assess the influence of some clinical and biochemical variables on these tests in patients with liver cirrhosis with or without primary HCC. Pathologic AFP values were found in 23 of 27 (sensitivity, 85%) patients with HCC; CA 19-9 levels increased in only 12 of 27 (sensitivity, 44%) HCC patients, the values being comparable with those of patients with liver cirrhosis. In liver cirrhosis a substantial number of false-positive values was found for both markers, although they were higher for CA 19-9 (50 of 211 versus 39 of 211). In liver cirrhosis correlations were found between AFP level and alanine amino-transferase level; and between CA 19-9 level and (1) total bilirubin value, (2) alkaline phosphatase level, and (3) pseudocholinesterase level. The authors conclude that CA 19-9 level is a poor biochemical marker, inferior to AFP level, in the detection of a carcinomatous transformation of liver cirrhosis. The finding of false-positive AFP values in liver cirrhosis seems mainly attributable to cellular proliferation and necrosis. Cholestasis seems to greatly affect serum CA 19-9 level variations, probably by reducing its liver metabolism.     

Cytokeratin-18 in Diagnosis of HCC in Patients with Liver Cirrhosis

Background: Hepatocellular carcinoma (HCC) is a common malignancy that occurs secondary to viral hepatitis B and C cirrhosis under the influence of environmental factors. In early stages, clinical diagnosis is often difficult and distinguishing HCC from cirrhosis and other hepatic masses by conventional tests is frequently not feasible. Physicians usually depend on measuring serum alpha-fetoprotein (AFP), but this marker has low sensitivity and specificity. The aim of this research was to determine any role of serum cytokeratin-18(Ck-18) as a marker for diagnosis of HCC in patients with liver cirrhosis. Patients and methods: We used ELISA to measure the serum levels of AFP and CK 18 in 60 Egyptian patients (30 cirrhotic and 30 with HCC) and 30 controls. Results: The Ck-18 level was significantly elevated in the HCC group (1247.8± 105.3U/L) when compared to the liver cirrhosis (834.1± 38.8 U/L) and control groups (265.2±83.1U/L). Ck-18 as a marker showed 95.6% sensitivity, 93.3% specificity and 98.8% accuracy. The mean serum AFP was 4901.4±2185.8ng/ml in the HCC group, 100.7±71.7 ng/ml in the cirrhotic group, and 4.0±1.2ng/ ml in controls. AFP showed 55. 7% sensitivity, 97. 7% specificity and 84.4% accuracy. Combined use of both Ck-18 and AFP improved the sensitivity to 98%. Conclusion: Serum cytokeratin-18 level can be used as a diagnostic biomarker for HCC with a higher sensitivity than AFP.     

Clinical evaluation of serum alpha-fetoprotein and circulating immune complexes as tumour markers of hepatocellular carcinoma.

To evaluate the diagnostic application of serum alpha-fetoprotein (AFP) and circulating immune complexes (CICs), AFP, 3% polyethylene glycol (PEG)-CICs, 4% PEG-CICs, and C1q-CICs were determined in 101 patients with cirrhosis alone, 101 sex-matched and age-matched cirrhotic patients with hepatocellular carcinoma (HCC) and 54 healthy controls. Multivariate analysis indicated that AFP (odds ratio 1.014; 95% confidence interval 1.004-1.024) and 3% PEG-CICs (odds ratio 1.011; 95% confidence interval 1.005-1.017) are associated, in a dose-related fashion, with an increased risk for HCC. A receiver operative characteristic (ROC) curve was used to determine the optimal cut-off values of AFP (120 ng ml-1) and 3% PEG-CICs (310 micrograms aggregated IgG equivalent ml-1). The area under ROC curve was 0.875 for AFP and 0.812 for 3% PEG-CIC. Both AFP and 3% PEG-CICs show a high specificity (100%) and positive likelihood ratio. The sensitivity was 65.3% for 3% PEG-CICs and 67.3% for AFP. Determination of both markers in parallel significantly increase the diagnostic accuracy (92.1%) and sensitivity (84%), with a high specificity (100%) and positive likelihood ratio (> 84). In conclusion, both 3% PEG-CICs and AFP are independent risk factors of HCC, and may be used as complementary tumour markers to discriminate HCC from cirrhosis. Determination of 3% PEG-CICs should be performed in cirrhotics negative for AFP to improve detection of HCC.     

Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3

Current surveillance strategies for hepatocellular carcinoma (HCC) are applied uniformly in patients with cirrhosis, regardless of their cancer risk. The aim of this study was to compare the performance characteristics of the biomarkers alpha-fetoprotein (AFP), des-gamma carboxyprothrombin (DCP), and lectin-bound AFP (AFP-L3) in the diagnosis of HCC, and to determine the effect of risk factors for HCC on test performance. Eighty-four patients with HCC and 169 patients with cirrhosis were enrolled and their serum analyzed for total AFP, AFP-L3 and DCP. Receiver-operating characteristic (ROC) curves were constructed to determine the performance characteristics. DCP was significantly better than total AFP or AFP-L3 in differentiating HCC from cirrhosis, with a sensitivity of 86% and specificity of 93%. When subjects were divided into two groups by their risk for HCC, all 3 markers had a lower sensitivity and area under the ROC curve in the high-risk group compared to the low-risk group. In conclusion, DCP has the best performance characteristics of all 3 serum markers for the diagnosis of HCC. Serum biomarkers may be less sensitive and specific in the highest risk patients.