Incidence Of Hepatocellular Carcinoma Development Research Articles

Association of PNPLA3 SNP With the Development of HBV-related Hepatocellular Carcinoma.

Concomitant nonalcoholic fatty liver disease (NAFLD)/hepatic steatosis (HS) is suggested to increase the risk of hepatocellular carcinoma (HCC) in hepatitis virus B (HBV)-infected patients. Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 gene single-nucleotide polymorphism (SNP) is well-known to be associated with the development of NAFLD/HS; however, it is still unclear whether this SNP is related to the development of HCC in HBV-infected patients. We investigated a total of 202 HBV-infected patients who received percutaneous liver biopsy, and simultaneously assessed biopsy-proven HS, insulin resistance, and the PNPLA3 SNP status. We further investigated the relationships of these factors with the development of HCC in HBV-infected patients. Most of the enrolled cases (196/202: 97.0%) were non-cirrhotic patients. One hundred seventy-three patients (85.6%) received antiviral therapy. A Kaplan-Meier analysis showed that the incidence of HCC development in patients with HS was higher than that in patients without HS (p<0.01). An increased homeostasis model assessment as an index of insulin resistance (HOMA-IR) value (≥1.6) was associated not only with the presence of HS (p<0.0001) but also with the development of HCC (p<0.01). The PNPLA3 rs738409 SNP was also associated with the presence of HS (p<0.01) and the development of HCC (p<0.05) in HBV-infected patients. In addition to HS and IR, PNPLA3 rs738409 SNP was suggested to be associated with the development of HCC in Japanese patients with HBV infection.

Factors linked to hepatocellular carcinoma development beyond 10 years after viral eradication in patients with hepatitis C virus.

The risk factors for hepatocellular carcinoma (HCC) development in patients whose duration of sustained virological response (SVR) is over 10 years are not fully understood. We compared the incidence of HCC development within and beyond 10 years after SVR. A total of 1384 patients who achieved SVR (714, interferon-based therapy; 670, direct-acting antiviral therapy) were enrolled. Factors associated with HCC development were analysed within and beyond 10 years after SVR by Cox proportional hazards models. The annual incidence rates of HCC development were 0.568% within 10 years after SVR and 0.190% beyond 10 years, and there was a significant difference in the incidence of HCC development between the 2 periods (p=0.0242, log-rank test). Male gender (adjusted hazard ratio [aHR] 2.930; 95% confidence interval [CI] 1.508-5.693, p=0.0015), fibrosis-4 (FIB-4) score &gt; 3.25 (aHR 4.364; 95%CI 2.206-8.633, p &lt; 0.0001) and alpha-fetoprotein ≥5.0ng/ml (aHR 2.381; 95%CI 1.325-4.280, p=0.0037) were independently associated with HCC development within 10 years after SVR. Male gender (aHR 4.702; 95%CI 1.366-16.190, p=0.0141), presence of diabetes mellitus (aHR 2.933; 95%CI 1.240-6.935, p=0.0143) and gamma-glutamyl transpeptidase (GGT) ≥ 56 U/l (aHR 4.157; 95%CI 1.400-12.350, p=0.0103) were independently associated with HCC development beyond 10 years after SVR. The incidence of HCC development beyond 10 years after SVR was very low, and the associated factors were mainly extrahepatic, including DM and elevated GGT. Annual routine check-ups with abdominal ultrasound may be sufficient for such patients. (242 words).

The Impact of Cirrhosis and History of Hepatocellular Carcinoma on All-Cause Mortality After Eradication of Hepatitis C Virus in Patients With Chronic Hepatitis C.

Cirrhosis and hepatocellular carcinoma (HCC) are potentially fatal complications of chronic hepatitis C virus (HCV) infection. We investigated how compensated cirrhosis and a history of curatively treated HCC influenced patient mortality after HCV eradication, that is, sustained virologic response (SVR). We studied 5458 patients with confirmed SVR who were prospectively followed up for more than 1 year after SVR achieved with direct-acting antivirals. Mortality and the incidence of HCC development after SVR were analyzed based on the presence or absence of compensated cirrhosis or a history of curatively treated HCC before the start of therapy. Mortality and the incidence of post-SVR HCC were significantly higher in patients with compensated cirrhosis and those with a history of curatively treated HCC than in those without these complications. Multivariate analysis showed that a history of HCC was associated with high mortality after SVR. In patients with no history of HCC, cirrhosis was associated with high mortality. Although both liver-related and nonliver-related mortality rates were significantly higher in patients with a history of HCC or cirrhosis, nonliver-related mortality did not differ based on HCC history, and liver-related and nonliver-related mortality were comparable regardless of cirrhosis after propensity score matching with age, gender, alcohol intake, and comorbidities. Mortality after SVR was significantly higher in patients with compensated cirrhosis or a history of HCC. While a history of HCC significantly increased mortality after SVR, even following curative treatment, the impact of pre-SVR compensated cirrhosis on post-SVR mortality was modest.

The Role of Non-Selective β-Blockers in Compensated Cirrhotic Patients without Major Complications.

Background and Objectives: Non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in cirrhotic patients with clinically significant portal hypertension (CSPH), but remained uncertain for compensated cirrhotic patients without major complications. We aimed to compare the clinical outcomes between propranolol users and non-users of a CC group without major complications. Material and Methods: We conducted this population-based cohort study by using the Taiwanese Longitudinal Health Insurance Database 2000. Propranolol users (classified as cumulative defined daily dose (cDDD)) and non-PPL users were matched with a 1:1 propensity score in both cohorts. Results: This study comprised 6896 propranolol users and 6896 non-propranolol users. There was no significant impact on the development of spontaneous bacterial peritonitis between the two groups (aHR: 1.24, 95% confidence interval (CI): 0.88~1.75; p = 0.2111). Male gender, aged condition, and non-liver related diseases (peripheral vascular disease, cerebrovascular disease, dementia, pulmonary disease, and renal disease) were the independent risk factors of mortality. PPL users had significantly lower incidence of HCC development than non-users (aHR: 0.81, p = 0.0580; aHR: 0.80, p = 0.1588; and aHR: 0.49, p < 0.0001 in the groups of 1–28, 29–90, and >90 cDDD, respectively). Conclusion: The current study suggested that high cumulative doses of propranolol could decrease the risk of hepatocellular carcinoma among compensated cirrhotic patients without major complications. Further large-scale prospective studies are still required to confirm the findings in this study. Results: It remained uncertain whether non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in compensatory cirrhotic patients without major complications. This study aimed to compare the clinical outcomes between propranolol users and non-users of the CC group without major complications.

Assessing the risk of hepatocellular carcinoma by combining liver stiffness and the controlled attenuation parameter

Ultrasound technology can now be used for liver stiffness measurement (LSM) and for evaluating the amount of hepatic fat quantitatively known as the controlled attenuation parameter (CAP). This study aimed to determine the applicable cut-off values of LSM and the CAP for primary hepatocellular carcinoma (HCC), and to investigate their clinical usefulness for assessing HCC risk in patients with chronic liver disease. A total of 1054 patients (88 with primary HCC and 966 without HCC) whose LSM and the CAP were measured by transient elastography with clinically evident hepatitisC virus (419 patients), hepatitisB virus (377 patients), and non-alcoholic fatty liver disease (258 patients) were enrolled in this study. Subsequently, a total of 966 patients who did not have HCC initially were followed, and the usefulness of the cut-off values of LSM and CAP for HCC development were evaluated. In hepatitisC virus patients, the incidence of HCC development was significantly higher among those with a combination of LSM ≥8.0kPa and CAP ≤221dB/m than among those with other values (log-rank test 0.0239, hazard ratio 2.66, 95%CI 1.07-6.47, P= 0.0362). In non-alcoholic fatty liver disease patients, the incidence of HCC development was significantly higher among those with a combination of LSM ≥5.4kPa and CAP ≤265dB/m than among others (log-rank test 0.0040, hazard ratio 8.91, 95% CI 1.47-67.97, P= 0.0192). In the hepatitisC virus and non-alcoholic fatty liver disease groups, a combination of LSM and the CAP cut-off values would be useful for screening to identify the high-risk group for primary HCC development.

Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study

While achieving sustained virological response (SVR) following interferon-based or direct-acting antiviral agent (DAA) treatments reduces the incidence of hepatocellular carcinoma (HCC), an increase in unexpected early occurrence or recurrence of HCC after hepatitis C virus elimination by DAA treatments has been reported. We prospectively investigated the incidence and risk factors of HCC after DAA treatment in a large multicenter cohort in Japan. Patients with chronic hepatitis C with or without cirrhosis who were treated with DAAs and obtained SVR were enrolled. DAAs were administered for 3 or 6months. A total of 2552 patients were enrolled. Of these, 70 patients (2.7%) developed HCC. The 12-, 24-, and 36-month cumulative HCC incidences were 1.3%, 2.9%, and 4.9% in all patients; 2.5%, 5.2%, and 10.0% in those with cirrhosis; and 0.9%, 2.1%, and 2.9% in those without cirrhosis, respectively. Multivariate analysis revealed age, sex, gamma-glutamyl transpeptidase level, and fibrosis-4 index to be independent factors associated with HCC. Patients with these four factors had an approximately six-to-sevenfold increased risk for HCC development. Five patients with large and early tumor occurrence did not receive contrast imaging examinations before treatment. Although the results of our prospective study suggested that achieving SVR by DAA treatment reduces the incidence of HCC, HCC development still occurs. Careful follow-up is important in patients with risk factors.

Tenofovir disoproxil fumarate reduce incidence of HCC development in CHB-patients with compensated cirrhosis

BackgroundThe impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.MethodsTwo hundred forty-two CHB-related compensated cirrhosis patients were attributed into groups regarding their anti-virus regimens containing tenofovir disoproxil fumarate (TDF) or not. The results of two groups were reviewed and investigated. The probability of hepatocellular carcinoma (HCC) development among each group were analyzed and compared.ResultsTwo hundred forty-two CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study. One hundred twenty-seven patients received anti-virus regimen containing TDF and 115 patients received anti-virus regimen without TDF. Child-Pugh score, alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg) and serum HBV DNA level were compared between groups. The cumulative probability of HCC development in TDF-contained group were significantly lower than it in non-TDF-contained group (p < 0.05). Multi-variant analysis indicated that TDF-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07–0.45, p < 0.05).ConclusionAnti-virus regimen containing TDF benefits for the prognosis of CHB-related liver cirrhosis patients.

Comparison of anti-HBV regimen with or without adefovir on hepatocellular carcinoma development of Chronic hepatitis B patients with compensated cirrhosis: a retrospective cohort study

BackgroundThe impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.Methods242 CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study and attributed into groups based on their anti-virus regimens containing adefovir (ADV) or not. The clinical parameters and virological response between ADV-containing regimen group and non-ADV containing regimen groups were reviewed and compared. The risk of hepatocellular carcinoma (HCC) development were analyzed and compared between two groups.Results127 patients received anti-virus regimen containing ADV and 115 patients received anti-virus regimen without ADV. The cumulative risk of HCC development among patients treated with ADV-contained therapy was significantly lower than that observed in patients with non-ADV-contained therapy (p<0.05). Multivariate analysis indicated that ADV-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07-0.45, p<0.05).ConclusionBoth anti-virus regimens were effective in reducing serum HBV DNA. Regimen containing ADV decreased the incidence of HCC development in CHB patients with compensated cirrhosis.

Molecular analysis of Hepatitis B virus sub-genotypes and incidence of preS1/preS2 region mutations in HBV-infected Egyptian patients from Mansoura.

Hepatitis B virus (HBV) is one of the major causes of viral hepatitis worldwide. Despite the prevalence of HBV infection in Egypt, few studies have focused on sub-genotyping of the virus. Moreover, no studies are available regarding the mutational analysis of the preS1/preS2 region of the viral genome, or its impact on hepatocellular carcinoma (HCC) development in Egypt. In this study, we have analyzed the sub-genotypes and incidence of mutations in the preS1/preS2 region of HBV present in HBV-infected patients, from Mansoura city (located in the center of Nile Delta region of Egypt), via partial sequencing of this specific region. Moreover, we have investigated the impact of these mutations on HCC development by measuring serum alpha fetoprotein (AFP) level and abdominal ultrasound examination of the HBV-infected patients. According to our results, all samples were genotype D in which sub-genotype D1 was predominant. In addition, the results revealed mutations in the preS1/preS2 region, which could result in either immature preS1 protein or completely inhibit the translation of the preS2 protein. However, there was no incidence of HCC development in patients infected with mutated HBV in the preS1/preS2 region. In summary, for the first time our work has proved the predominance of sub-genotype D1 among HBV-infected Egyptian patients in Mansoura city, Nile Delta region, Egypt, and incidence of mutations in the preS1/preS2 region of HBV genome. This current study opens up research opportunities to discuss the impact of HBV mutations on the development of HCC in Egypt.

Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C

Objective: Treatment for chronic hepatitis C has recently developed in a very rapid manner. In Japan, in September 2014, IFN-free asunaprevir (ASV) and daclatasvir (DCV) became available for combination therapy. We report the treatment outcomes achieved at our hospital using this combination therapy. Methods: Sustained virological response (SVR) 24 could be evaluated in 120 of 125 patients with chronic liver disease type C who visited our hospital and were treated with ASV/DCV after September 2014, and these patients were analyzed. Results: SVR24 was achieved in 106 patients (88%). End-of-treatment response was not achieved in 10 patients (8.3%). Five of them carried multiple-resistant NS3/4A or NS5A region, and administration was discontinued early in 4 patients due to adverse effects. After ASV/DCV treatment, hepatocellular carcinoma (HCC) developed in 2 patients (1.7%) and recurred in 5 (4.2%). Conclusions: ASV/DCV treatment achieved favorable SVR in elderly and hepatic cirrhosis patients and patients in whom HCC was cured. However, an increase in the incidence of HCC development in patients who markedly respond to direct-acting antivirals treatment is expected and surveillance of HCC becomes more important.

An indeterminate nodule in the cirrhotic liver discovered by surveillance imaging is a prelude to malignancy.

Surveillance imaging often shows indeterminate lesions in the cirrhotic liver, which may represent early hepatocellular carcinoma (HCC), dysplastic or regenerative nodules, or vascular shunts. The risk of HCC after identification of an indeterminate nodule is not well described. We identified 252 patients with cirrhosis and at least one indeterminate nodule discovered on surveillance imaging over a 4-year period. The incidence of HCC development within 2 years of nodule identification was measured along with baseline risk factors associated with developing HCC. The incidence of HCC in this population was 21% (53 of 252), and risk factors associated with HCC included chronic viral hepatitis, male gender, and low platelet count. The median time from identification of an indeterminate nodule to diagnosis of HCC was 2.7 months. Patients with indeterminate nodules who developed HCC were more likely have to have an indeterminate nodule with arterial enhancement. The 2-year incidence of HCC in the setting of cirrhosis and an indeterminate nodule discovered by surveillance imaging may be as high as one in five persons. Early follow-up imaging, biopsy, or empiric treatment should be considered for those at higher risk. Further, this population is well suited for early detection biomarker and chemoprevention studies.

A comparison of efficacy and safety of 2-year telbivudine and entecavir treatment in patients with chronic hepatitis B: a match–control study

There are limited data comparing the clinical outcomes between telbivudine and entecavir. We consecutively enrolled 115 telbivudine-naive and 115 entecavir-naive chronic hepatitis B patients, who were matched for age, sex, hepatitis B e antigen (HBeAg) status and cirrhosis, and treated for at least 2 years or less than 2 years but had developed resistance. Except for the rate of HBeAg seroconversion, which was similar, patients in the entecavir group had better clinical outcomes than those in the telbivudine group for alanine aminotransferase normalization (85.2% vs 78.4%, p <0.048), undetectable HBV DNA (96.5% vs 74.8%, p <0.001), and viral resistance (0.9% vs 21.7%, p <0.001) after 2 years of treatment, After applying roadmap or super-responders concepts, entecavir still had better outcomes than telbivudine in undetectable HBV DNA and viral resistance. The cumulative incidence of hepatocellular carcinoma development was similar between telbivudine-naive and entecavir-naive patients (p 0.565). In renal function analysis, there were significantly more patients with estimated glomerular filtration rate (eGFR) category improvement in both the telbivudine and entecavir groups at year 1 (p 0.006 and p 0.047, respectively). The rate of virological improvement was significantly higher with entecavir than with telbivudine after 2 years of treatment, whether applying the concepts of roadmap or super-responders. The incidence of hepatocellular carcinoma was similar between telbivudine and entecavir. Both telbivudine and entecavir were associated with eGFR improvement, especially in patients with renal insufficiency.

Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C

Assessment of the risk of hepatocellular carcinoma (HCC) development is essential for formulating personalized surveillance or antiviral treatment plan for chronic hepatitis C. We aimed to build a simple model for the identification of patients at high risk of developing HCC. Chronic hepatitis C patients followed for at least 5 years (n=1003) were analyzed by data mining to build a predictive model for HCC development. The model was externally validated using a cohort of 1072 patients (472 with sustained virological response (SVR) and 600 with nonSVR to PEG-interferon plus ribavirin therapy). On the basis of factors such as age, platelet, albumin, and aspartate aminotransferase, the HCC risk prediction model identified subgroups with high-, intermediate-, and low-risk of HCC with a 5-year HCC development rate of 20.9%, 6.3-7.3%, and 0-1.5%, respectively. The reproducibility of the model was confirmed through external validation (r(2)=0.981). The 10-year HCC development rate was also significantly higher in the high-and intermediate-risk group than in the low-risk group (24.5% vs. 4.8%; p<0.0001). In the high-and intermediate-risk group, the incidence of HCC development was significantly reduced in patients with SVR compared to those with nonSVR (5-year rate, 9.5% vs. 4.5%; p=0.040). The HCC risk prediction model uses simple and readily available factors and identifies patients at a high risk of HCC development. The model allows physicians to identify patients requiring HCC surveillance and those who benefit from IFN therapy to prevent HCC.

Chemopreventive Effect of Silymarin on Liver Pathology in HBV X Protein Transgenic Mice

There are currently limited therapeutic regimens available for effective treatment of hepatocellular carcinoma (HCC). Silymarin is a naturally derived polyphenolic antioxidant with hepatoprotective properties and is very widely used in clinical application; however, effect of silymarin on spontaneous HCC has not been studied. Silymarin was evaluated for its efficacy against spontaneous carcinogenesis using the HBV X protein (HBx) transgenic model. Silymarin was p.o. given to the HBx transgenic mice from 4 to 6 weeks of age. Our data indicated that silymarin has therapeutic effects on the early stages of liver damage, reversing fatty changes and recovering liver histopathology in a dose-dependent manner. To study the chemopreventive effects on the later stages of carcinogenesis, the mice at 13 months were split into a precancerous group and a group with significant liver carcinogenesis. After silymarin was given to the precancerous mice from 13 to 16 months of age, in contrast to an 80% incidence of HCC development in the untreated transgenic mice, no HCC was detected in any of these mice. Nonetheless, small hyperplastic nodules were detected in 86% of these precancerous mice. In the second group with notable HCC, silymarin was unable to block cancer progression. Although silymarin did not affect HBx expression, intracellular reactive oxygen species levels were decreased, cell proliferation was stimulated, and hepatocyte ultrastructure was found to significantly recover. In conclusion, silymarin exerts beneficial effects on the early stages of liver pathogenesis, preventing and delaying liver carcinogenesis. This drug should be considered as a potential chemopreventive agent for HBV-related hepatocarcinogenesis.

Reduction therapy of ALT levels and prevention of HCC development in patients with HCV-associated cirrhosis

1529 Background: Approximately 30 million people worldwide are estimated to have liver cirrhosis (LC) associated with hepatitis C virus (HCV). In addition, patients with HCV-associated liver cirrhosis (HCV-LC) have a high risk of developing hepatocellular carcinoma (HCC). Namely, 60–80% of the patients may develop HCC in 10 years. So, preventing these patients from developing HCC is an urgent problem to be solved. To find a way to prevent the development of hepatocellular carcinoma (HCC) from hepatitis C-virus associated liver cirrhosis (HCV-LC), an analysis of the HCV-LC patients who had reduction therapy of ALT levels was performed. Patients and Methods: Seventy-four consecutive HCV-LC patients of Child Stage A were followed for &gt; 10 years for the development of HCC. They were divided into two groups: In group A, the reduction therapy for ALT levels is aggressively performed and in group B, the reduction therapy was not performed aggressively. Results: Initial ALT was higher in group A than in group B, but there was no significance. After reduction therapy, ALT level was significantly high in group A in the first year. However, there were no significant differences between ALT levels in groups A and B of after the second year. In total, 39 patients out of 74 (52.7%) developed HCC within 13 years from the beginning of the study and 35 patients did not developed HCC in the same observation period. The incidence of HCC development in group B [65.7% (23/35)] was significantly higher than in group A [41.0% (16/39)] (p=0.039). The median HCC developing time in group A (12.8 years) was significantly longer than in group B (3.8 years) (p=0.0013). Multivariate analysis demonstrated that reduction therapy and ALT levels were the significant factors affecting HCC development. The incidence of HCC development in group B was 5.8 times higher than in group A. The high and unclassified ALT groups were 4.6 times and 2.2 times higher than in the low ALT group. Conclusion: The chances of surviving for more than 10 years without developing HCC in the HCV-LC patients of Child Stage A were far more favorable in group A than in group B. These results suggest that aggressive reduction therapy for ALT levels in HCV-LC patients could significantly prevent HCC development. No significant financial relationships to disclose.

Prospective study of α-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma

The usefulness of measurements of serum alpha-fetoprotein elevation for diagnosis of the development of hepatocellular carcinoma was evaluated by a prospective study of 260 patients with cirrhosis. Hepatocellular carcinoma was found in 55 patients during the 5-yr follow-up, excluding 7 found to have hepatocellular carcinoma in the first 6 mo. The cumulative incidence of hepatocellular carcinoma was 26% in the 185 patients who had alpha-fetoprotein levels below 20 ng/ml at the time of entry and 46% in the 68 patients who had alpha-fetoprotein levels of 20 ng/ml or more but below 200 ng/ml. In 169 of the patients, serum levels of alpha-fetoprotein were assayed regularly for at least 2 yr. The incidence of hepatocellular carcinoma development in the 36 patients who had repeated transient increases in alpha-fetoprotein to above 100 ng/ml was 36%. This was significantly higher than the incidence in the 99 patients who had alpha-fetoprotein levels consistently below 20 ng/ml. Thus patients who had alpha-fetoprotein levels of 20 ng/ml or more, who had transient increases in alpha-fetoprotein or who had both should be treated as being in a super-high-risk group for hepatocellular carcinoma. Frequent and careful examination by ultrasonography of such patients is recommended.

Prospective study of α-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma

The usefulness of measurements of serum α-fetoprotein elevation for diagnosis of the development of hepatocellular carcinoma was evaluated by a prospective study of 260 patients with cirrhosis. Hepatocellular carcinoma was found in 55 patients during the 5-yr follow-up, excluding 7 found to have hepatocellular carcinoma in the first 6 mo. The cumulative incidence of hepatocellular carcinoma was 26 in the 185 patients who had α-fetoprotein levels below 20 ng/ml at the time of entry and 46 in the 68 patients who had α-fetoprotein levels of 20 ng/ml or more but below 200 ng/ml. In 169 of the patients, serum levels of α-fetoprotein were assayed regularly for at least 2 yr. The incidence of hepatocellular carcinoma development in the 36 patients who had repeated transient increases in α-fetoprotein to above 100 ng/ml was 36. This was significantly higher than the incidence in the 99 patients who had α-fetoprotein levels consistently below 20 ng/ml. Thus patients who had α-fetoprotein levels of 20 ng/ml or more, who had transient increases in α-fetoprotein or who had both should be treated as being in a super-high-risk group for hepatocellular carcinoma. Frequent and careful examination by ultrasonography of such patients is recommended. (Hepatology 1994;19:61–66).