Liver Cirrhosis Hepatocellular Carcinoma Research Articles

Qualitative and Quantitative Evaluation of Hepatocellular Carcinoma and Cirrhotic Liver Enhancement Using Gd-EOB-DTPA

The objective of our study was to prospectively evaluate quantitatively and qualitatively the enhancement patterns of cirrhotic liver tissue and hepatocellular carcinoma (HCC) after administration of the hepatocyte-specific contrast agent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) on dynamic MRI and to determine the time point of maximum liver-to-lesion contrast. Twenty-five patients with HCC in liver cirrhosis underwent 1.5-T MRI. T2-weighted turbo spin-echo and T1-weighted 3D gradient-echo sequences before and between 15 seconds and 20 minutes after the injection of 10 mL of Gd-EOB-DTPA were performed. Signal-to-noise ratios (SNRs) of liver parenchyma and liver-to-lesion contrast-to-noise ratios (CNRs) were calculated and plotted over time. Enhancement patterns of HCC were characterized qualitatively by two radiologists. The SNR of liver parenchyma increased significantly at 15 seconds and 60 seconds after contrast injection and remained stable thereafter. HCC showed positive CNR during the arterial phase and increasingly negative CNR during the further time course (p < 0.05). The maximum absolute CNR was found at 20 minutes after contrast injection. There was no correlation between the degree of enhancement at any time point and tumor grade. On qualitative evaluation, 16 HCCs showed arterial enhancement with early washout, and five showed arterial enhancement with late washout. In the remaining four HCCs, enhancement persisted until 20 minutes. Lesion conspicuity at 20 minutes after contrast injection was at least equal to or higher than it was on the remaining sequences in 19 of the 25 patients. After Gd-EOB-DTPA injection, most HCCs showed typical arterial enhancement with early washout. Liver-to-lesion contrast was best at 20 minutes.

Combined analysis of interferon-γ and interleukin-10 gene polymorphisms and chronic hepatitis C severity

Today there is increasing evidence concerning the contribution of pro-/anti-inflammatory cytokine balance and genetic factors in hepatitis C pathogenesis and interindividual heterogeneity of disease outcome. In the current study, we investigated the influence of functionally described single nucleotide polymorphisms (SNPs) present in interferon-γ (IFNγ) and interleukin-10 (IL-10) genes, on chronic hepatitis C severity. IFNγ (+874T/A) and IL-10 (−1082G/A) genotypes were determined in 100 hepatitis C patients with different disease severities (chronic hepatitis, n = 42, liver cirrhosis [LC], and hepatocellular carcinoma in liver cirrhosis [HCC], n = 58) and 103 healthy controls using allele-specific polymerase chain reaction. No statistical differences in allele or genotype distributions of IFNγ and IL-10 genes were observed between patients and controls. However, some significant differences in IFNγ genotype frequencies were observed between the two groups of patients. IFNγ high producer genotypes TT and TA were significantly more common in patients with LC and HCC (odds ratio = 2.65; p = 0.019). Although IL-10 genotypic frequencies were comparable between the different clinical forms of the disease, the combination of IFNγ low producer and IL-10 high producer genotypes was significantly associated with a lower risk of LC and HCC (odds ratio = 0.21; p = 0.015). In conclusion, our findings suggest that the imbalance between the pro-inflammatory and anti-inflammatory responses mediated by polymorphisms in the IFNγ and IL-10 genes may influence the outcome of chronic HCV infection.

Current status of liver diseases in Korea: Toxic and alcoholic liver diseases

The study of the epidemiology of toxic liver injury has been limited in Korea. The number of hospitalizations for toxic liver injury has been estimated to be 2,400 persons per year. About 30~40% of fulminant hepatitis was attributed to toxic hepatitis. The frequent causative agents of toxic hepatitis in Korea are herbal medicines (34-40%), folk remedies (23-34%), and prescribed medicines (24-55%). However, the most common agents causing severe liver injury including fulminant hepatitis are herbal medicine and folk remedies. Antituberculosis drugs and acetaminophen are two common causes of fulminant hepatitis among prescribed drugs. Alcohol is one of the leading causes of chronic liver disease in Korea. No nationwide study on the epidemiology of alcoholic liver disease (ALD) has been carried out, but 7-31% of cirrhosis has been reported to be alcoholic in a few single-center studies. Alcohol could be a risk factor for the development of hepatocellular carcinoma (HCC) in chronic viral hepatitis. Several studies have shown that alcohol increased the risk of HCC in liver cirrhosis with HBsAg or anti-HCV. Furthermore, alcoholic cirrhosis with occult hepatitis B virus infection increased the risk of HCC.

Laparoscopic US-Guided Radiofrequency Ablation of Unresectable Hepatocellular Carcinoma in Liver Cirrhosis: Feasibility and Clinical Outcome

Radiofrequency ablation (RFA) is a safe, effective treatment in patients with unresectable primary liver malignancies. The laparoscopic approach to RFA (LRFA) has proved to be superior to the percutaneous approach in lesions that are difficult or impossible to be treated in such a way or in severe liver disease. Recent advances in laparoscopic ultrasound (LUS) have greatly improved the accuracy in detecting intrahepatic hepatocellular carcinoma (HCC) nodules, many of which were missed by computed tomography (CT) or magnetic resonance imaging (MRI). Our aim was to assess the feasibility, clinical outcome, and efficacy of laparoscopic RFA under LUS guidance. Between February 2006 and May 2007, 24 consecutive patients (male/female, 20/4) with unresectable HCC in liver cirrhosis were treated with LRFA under LUS guidance. Most patients were in Child-Pugh class A (54.1%). Mean age of the patients was 61.79 +/- 7.74 years (range, 45-76; median, 60). LRFA procedure was completed in all patients and a thermoablation of 62 HCC nodules was achieved. LUS identified 13 new malignant lesions (20%) undetected by preoperative imaging. Mean length of surgery was 148 minutes (range, 60-315). Six procedures were associated in 5 patients: adhesiolysis (3), liver resection (1), partial splenectomy (1), and cholecystectomy (1). A pneumothorax needing immediate drainage during the procedure occurred in 1 case. One patient died 4 weeks after surgery because of liver failure. Mean hospital stay was 6.9 days and postoperative morbidity rate was 4 of 24 (16.6%). A complete tumor necrosis was observed in 56 of the 62 thermoablated nodules (90.3%) through spiral CT 1 month after treatment. LRFA is a safe, feasible treatment modality to achieve tumor destruction in selected patients with unresectable HCC that are not treatable with the percutaneous approach. Further, LUS demonstrated great accuracy during the procedure permitting to detect new HCC nodules missed at preoperative imaging.

Laparoscopic radiofrequency of hepatocellular carcinoma using ultrasound-guided selective intrahepatic vascular occlusion

The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. The authors aimed to assess a novel operative combination of laparoscopic radiofrequency (LRF) with a selective intrahepatic vascular occlusion (SIHVO) to obtain an increased rate of total necrosis and a reduced rate of local HCC recurrences. For this study, 37 patients with HCC in liver cirrhosis were submitted to LRF with SIHVO. An LRF was indicated for patients not amenable to liver resection who evidenced at least one of the following criteria: severe impairment of the coagulation tests, large tumors (but <5 cm) or multiple lesions requiring repeated punctures, superficial lesions adjacent to visceral structures, deep-sited lesions with a very difficult or impossible percutaneous approach, and short-term recurrence of HCC after percutaneous loco-regional therapies. Laparoscopic ultrasound identified seven new malignant lesions (19%) undetected by preoperative imaging. There was no operative mortality. Of the 37 patients, 31 experienced no complications (84%). Computed tomography (CT) evaluation 1 month after treatment showed that a complete response with 100% necrosis had been achieved for all the patients (100%). During the follow-up period (mean, 11.8 +/- 8.2 months), new malignant nodules developed in 14 patients (42%), and 36% of these recurrences were located in the same treated segment of the HCC. The combined LRF and SIHVO procedure proved to be a safe and effective technique at least in the short and mid term. In fact, it permitted the treatment of lesions not treatable using the percutaneous approach with a complete clearance, and it had a low morbidity rate.

Epidermal Growth Factor Gene Functional Polymorphism and the Risk of Hepatocellular Carcinoma in Patients With Cirrhosis

Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma in animal models. Polymorphisms in the EGF gene modulate EGF levels. To assess the relationship among human EGF gene single-nucleotide polymorphism, EGF expression, and risk of hepatocellular carcinoma. Molecular mechanisms linking the 61*G allele polymorphism to EGF expression were examined in human hepatocellular carcinoma cell lines and human liver tissue. A case-control study involving 207 patients with cirrhosis was conducted at the Massachusetts General Hospital (1999-2006) and a validation case-control study involving 121 patients with cirrhosis was conducted at Hôpital Paul Brousse (1993-2006). Restriction fragment-length polymorphism was used to determine the EGF gene polymorphism genotype. Logistic regression analysis was used to assess the association between the EGF polymorphism and hepatocellular carcinoma risk. Mechanisms by which the EGF gene polymorphism modulates EGF levels and associations among EGF gene polymorphism, EGF levels, and hepatocellular carcinoma. Transcripts from the EGF 61*G allele exhibited more than a 2-fold longer half-life than those from the 61*A allele, and EGF secretion was 2.3-fold higher in G/G hepatocellular carcinoma cell lines than A/A cell lines. Serum EGF levels were 1.8-fold higher in G/G patients than A/A patients, and liver EGF levels were 2.4-fold higher in G/G patients than A/A patients. Among the 207 patients with cirrhosis in the Massachusetts study population, 59 also had hepatocellular carcinoma. Analysis of the distribution of allelic frequencies revealed that there was a 4-fold odds of hepatocellular carcinoma in G/G patients compared with A/A patients in the Massachusetts study population (odds ratio, 4.0; 95% confidence interval [CI], 1.6-9.6; P = .002). Logistic regression analysis demonstrated that the number of copies of G was significantly associated with hepatocellular carcinoma after adjusting for age, sex, race, etiology, and severity of cirrhosis (G/G or A/G vs A/A; hazard ratio, 3.49; 95% CI, 1.29-9.44; P = .01). The significant association was validated in the French patients with alcoholic cirrhosis and hepatocellular carcinoma. The EGF gene polymorphism genotype is associated with risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels.

High circulating D-dimers are associated with ascites and hepatocellular carcinoma in liver cirrhosis

To measure plasma D-dimer levels in cirrhotic patients with and without ascites, assessing the effect of ascites resolution in D-dimer concentration. Seventy consecutive cirrhotic patients (M = 44, F = 26, mean age 65 years, SD +/- 13), observed from October 2005 to March 2006 were enrolled. Circulating D-dimer levels were measured using a latex-enhanced, immunoturbidimetric test. In patients with ascites (n = 42) the test was repeated after ascites resolution. Ascites was present in 42 patients (group A) and absent in 28 (group B). Group A patients had more advanced liver disease. Hepatocellular carcinoma (HCC) was diagnosed in 14 patients and was more frequent in group B. Above normal range D-dimers were found in 45/70 patients. High D-dimers were more frequent in group A than in group B (P = 0.001). High D-dimers were associated with presence of HCC (P = 0.048) only in group B. After ascites resolution, obtained in all patients, mean D-dimer values decreased in those 34 patients with high basal levels (P = 0.007), returning to normal in 17. In patients with liver cirrhosis, ascites and HCC are the main factors associated with increased fibrinolytic activity.

Contrast-Enhanced Intraoperative Ultrasonography During Surgery for Hepatocellular Carcinoma in Liver Cirrhosis

Ultrasound Quarterly: June 2007 - Volume 23 - Issue 2 - p 156 doi: 10.1097/01.ruq.0000277034.74585.b0

Contrast-Enhanced Intraoperative Ultrasonography During Surgery for Hepatocellular Carcinoma in Liver Cirrhosis: Is It Useful or Useless? A Prospective Cohort Study of Our Experience

Preliminary results showed that contrast-enhanced intraoperative ultrasonography (CEIOUS) could provide information not obtainable with conventional IOUS during surgery for hepatocellular carcinoma (HCC). The aim of the study was to prospectively validate the role of CEIOUS on the basis of a larger experience and to establish a new classification that takes into account its findings. Eighty-seven consecutive patients underwent hepatecomies for HCC. Those patients with new lesions at IOUS underwent CEIOUS: for that patients received intravenously 4.8 mL sulphurhexafluoride microbubbles. Pattern of enhancement was classified in 4 categories: A1 (full enhancement in the arterial phase and wash-out in the delayed phases), A2 (intralesional signs of neovascularization during all phases), A3 (no nodular enhancement but detectability during the liver enhancement), and B (undetectability during the liver enhancement). Resection was recommended for A1-3 nodules and no treatment for B nodules. Twenty-nine patients (33%) had 59 new lesions at IOUS and underwent CEIOUS. Twenty-seven nodules showed a B pattern at CEIOUS and were not removed; 32 nodules were classified as A1 in 5 patients, A2 in 11 patients, and A3 in 16 patients. The nodules were removed, and by histology, five A1, nine A2, and six A3 nodules were confirmed to be HCC. CEIOUS modified the operative decision making in 79% of these patients. CEIOUS is useful during surgery for HCC; it complements the accuracy of IOUS and affects the radicalness of the surgical. Specificity of CEIOUS has to be further improved, although intrinsic drawbacks exist in the diagnostic criterion of tumor vascularity.

Extreme elevation of serum alpha fetoprotein in decompensated cirrhosis without HCC: an ominous sign

Three cases of extreme elevation of serum alpha fetoprotein (>10,000 ng/mL) with decompensated cirrhosis without demonstrable hepatocellular carcinoma are reported. While 2 patients died of liver failure, 1 survived after liver transplantation. Extreme elevation of alpha fetoprotein not associated with hepatocellular carcinoma in liver cirrhosis heralds an ominous prognosis necessitating urgent liver transplantation.

Extreme Elevation of Serum Alpha Fetoprotein in Decompensated Cirrhosis without Hcc: an Ominous Sign

Three cases of extreme elevation of serum alpha fetoprotein (&gt;10,000 ng/mL) with decompensated cirrhosis without demonstrable hepatocellular carcinoma are reported. While 2 patients died of liver failure, 1 survived after liver transplantation. Extreme elevation of alpha fetoprotein not associated with hepatocellular carcinoma in liver cirrhosis heralds an ominous prognosis necessitating urgent liver transplantation.

231 CT-Guided brachytherapy of hepatocellular carcinoma in liver cirrhosis — A novel therapeutic approach

231 CT-Guided brachytherapy of hepatocellular carcinoma in liver cirrhosis — A novel therapeutic approach

Survival and intra-hepatic recurrences after laparoscopic radiofrequency of hepatocellular carcinoma in patients with liver cirrhosis

The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. Percutaneous radiofrequency interstitial thermal ablation proved to be effective, too. Our objective was to assess a novel operative combination of laparoscopic ultrasound (LUS) with laparoscopic radiofrequency (LRF) in the treatment of HCC not amenable to liver resection. One hundred and four patients with HCC in liver cirrhosis were submitted to laparoscopic LRF. A LRF was indicated in patients not amenable to liver resection that had at least one of the following criteria: (a) severe impairment of the coagulation tests; (b) large tumors (but <5 cm) or multiple lesions requiring repeated punctures; (c) superficial lesions adjacent to visceral structures; (d) deep-sited lesions with a very difficult or impossible percutaneous approach; (e) short-term recurrence of HCC following percutaneous loco-regional therapies. The LRF procedure was completed in 102 out of 104 patients (98% feasibility rate). LUS identified 26 new malignant lesions (25%) undetected by pre-operative imaging. There was no operative mortality. Seventy-six patients had no complication (73%). At 1-month computed tomography (CT) evaluation, a complete response with a 100% necrosis was achieved in 88 out of 101 patients (87%). During the follow-up (mean follow-up: 22.5 +/- 15.9 months), 55 patients (54%) developed new malignant nodules (42% of these recurrences were localized in the same segment of the HCC treated). LRF of HCC proved to be a safe and effective technique at least in the short and mid-term: in fact it permits to treat lesions not treatable with the per cutaneous approach, to detect 25% of new HCC nodules and it has a low morbidity rate.

Irregularity of Parenchymal Echo Patterns of Liver Analyzed with a Neural Network and Risk of Hepatocellular Carcinoma in Liver Cirrhosis

Objective: In this study, we scored the hepatic parenchymal echo patterns as the coarse score (CS) analyzed with a neural network in cirrhosis patients and calculated the variations in CS as the coefficient of variation, and evaluate their usefulness as predictor of the development of hepatocellular carcinoma (HCC). Methods: The relationship between the degree of variation in CS and histopathological findings was assessed in 10 autopsied livers fixed in formalin. The degree of intrahepatic variation in CS was calculated as the coefficient of variation of CS (CVCS). Irregular regeneration of liver cells in autopsied livers was classified into two categories, slight and severe. A total of 56 cirrhosis patients were prospectively followed to evaluate the predictors of HCC. Results: A significant positive correlation was observed between CVCS and the coefficient of variation of the diameter of the regenerative nodules. Coefficient variation of nodule diameter and CVCS in patients in whom irregular regeneration was severe were significantly higher than those in patients in whom irregular regeneration was mild (p < 0.05). Concerning the relationship between hepatitis virus markers and CS or CVCS, CVCS was significantly higher in those who were hepatitis C virus antibody positive and those who were hepatitis B surface antigen negative (p < 0.01). Using a combination of CS and CVCS, the incidence of HCC, as determined by the Kaplan-Meier method, was significantly higher in patients whose CS was ≧1.5 and CVCS was ≧15%, as compared with that in patients whose CS was <1.5 and CVCS was <15% (p < 0.01) and whose CS was ≧1.5 and CVCS was <15% (p < 0.05). Multivariate analysis of the predictors for HCC using the Cox’s proportional hazards model showed a significant correlation between the risk of development of HCC and CVCS, CS and serum α-fetoprotein level. Conclusions: CVCS and CS can be calculated from liver echo patterns and are useful for identifying a high-risk group for HCC.

Outcome of liver disease in a large cohort of histologically proven chronic hepatitis C: influence of HCV genotype.

To assess the influence of hepatitis C virus (HCV) genotypes on the clinical outcome of liver disease, we analysed 2,307 patients. The most frequently represented genotypes were 1b (40%) and 2 (28.1%). Patients with these genotypes had a median age higher than patients with other genotypes (P< 0.01). The overall survival of subjects with genotype 1b was poorer than the survival of patients with other genotypes (P< 0.01). Liver cirrhosis was found in 280 patients (12.1%), and type 1b was the most represented isolate among them (P< 0.01). Sixty-two patients (22%) developed hepatocellular carcinoma (HCC) during a follow-up of 1481.8 cumulative years (estimated crude incidence rate, 4.1 cases per 100 person-years for all cirrhotics; 5.9 cases for genotype 1a; 4.5 cases for genotype 1b; and 2.8 cases for genotypes non-1). Considering the whole population of 2,307 patients, only genotype 1b was associated significantly with both cirrhosis and the development of HCC. One hundred and nineteen cirrhotic patients underwent treatment with interferon in uncontrolled studies. Interferon therapy was associated with both better survival (P< 0.01) and a lower cumulative hazard for HCC (P< 0.01). Genotype 1b was associated with a poorer prognosis, probably because it leads to cirrhosis and consequently to HCC development. However, our data did not confirm genotype 1b as an independent risk factor for HCC in liver cirrhosis, which plays a major role in carcinogenesis. Interferon should be considered as a useful strategy in cirrhosis for improvement of survival and reduction of HCC risk.

Ultrasound-guided percutaneous ethanol injection: first choice for treatment of hepatocellular carcinoma in the elderly

Percutaneous ethanol injection (PEI) under ultrasound guidance has recently been proposed as a new therapeutic approach for patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). HCC is more frequently observed in elderly subjects. We treated 59 patients (44 males and 15 females, mean age 66 years, age-range 54-77 years). Forty-six patients were in Child A, 12 in Child B and 1 in Child C class. Thirty-nine patients had a single lesion up to 5 cm size; 2 had a single lesion larger than 5 cm, and 18 had 2 or 3 lesions, each smaller than 4 cm. The survival rates after 1, 2, 3 and 4 years for all patients were 92, 73, 54 and 54%, respectively; while for those with only a single lesion amounted to 94, 85, 63, and 63%, for the same years. In this latter group, the survival rates at 1 and 2 years were significantly higher in subjects in the Child A class, than in those who were in Child B and C classes (100 and 95%, against 79 and 63%, respectively, p < 0.05). In the group of patients with multiple lesions the survival rates were 89, 57 and 42% at 1, 2 and 3 years, respectively. We did not have any lethal complications during the procedure of PEI, and only minor complications occurred in 6 patients. During the follow-up, 21 patients developed new lesions, and 6 patients had small local recurrences which were possibly retreated. In conclusion, PEI is a safe and efficient alternative therapy for the management of HCC in LC in elderly subjects.

Do CA 19-9 and TPA Play a Minor Role as Compared to AFP in Diagnosing Primary Hepatocellular Carcinoma?

This study was undertaken in order to compare the ability of 4 tumour markers to discriminate between liver cirrhosis patients with or without hepatocellular carcinoma (HCC). Serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA 19-9 and tissue polypeptide antigen (TPA) were determined in 63 patients with liver cirrhosis and in 25 patients with HCC in liver cirrhosis. All 4 serum markers were found to be increased in a number of liver cirrhosis patients, regardless of the presence of HCC. AFP was found to be more elevated in HCC patients as compared to the other group; no difference was observed for CA 19-9, CEA and TPA. A significant correlation was detected in HCC patients between AFP and TPA. Significant correlation were detected in all except HCC patients between liver function tests and TPA. We can conclude that AFP determination remains as yet the only suitable marker able to detect HCC in liver cirrhosis. The newly introduced serum marker CA 19-9 is, as previously reported, unhelpful for CEA. TPA can in some instances (i.e. in the absence of an important hepatic cell necrosis or cholestasis) provide a clue to neoplastic growth.

Pattern Analysis of Serum alpha-fetoprotein in the Early Diagnosis of Hepatocellular Carcinoma in Liver Cirrhosis

In a surveillance program for hepatocellular carcinoma (HCC), serum alpha-fetoprotein (AFP) was determined every 4 months in 164 patients with liver cirrhosis. Ultrasonography (US) was performed yearly or as dictated by abnormal AFP levels. During a follow-up of 32.5 +/- 20.8 months HCC was identified by US in 16 patients. In 9 of them the AFP levels rose steadily over 4 months, increasing 7, 8 and 12 months in 3 cases before the lesion became detectable by US. In 4 patients tumors developed despite persistently normal AFP levels. Nine more patients showed abnormal fluctuations of AFP but HCC was not detected. AFP sensitivity was higher at a low cut-off point (40 ng/ml) while specificity of the test appeared higher at the 200 ng/ml cut-off point. An AFP value rising steeply over a few months appeared more reliable than a fixed preset threshold in indicating carcinomatous transformation. Screening for AFP can be expected to uncover about 3/4 of HCC developing in cirrhotics with few false-positive reactions. The test may have a unique role in identifying a subset of liver tumors whose early expression is AFP production.

Diagnostic accuracy of fibronectin in the differential diagnosis of ascites.

To evaluate the diagnostic accuracy of fibronectin levels in ascites to differentiate malignant from non-malignant ascites, the authors studied 30 patients with sterile uncomplicated ascites in chronic liver disease, 18 patients with malignant ascites and four patients with spontaneous bacterial peritonitis. Fibronectin concentration was significantly higher in malignant ascites than in sterile ascites (P less than 0.001). High values (greater than 85 mg/l) were found in four of six cases of hepatocellular carcinoma in liver cirrhosis with negative cytologic examination, and in six of seven peritoneal carcinomatoses. Low values (less than 85 mg/l) were found in four patients with liver metastases and in one patient with intrahepatic biliary duct carcinoma in cirrhosis. In four patients with infected ascites, the fibronectin level was low. Among all other parameters (total protein concentration, lactate dehydrogenase, gamma-glutamyl-transpeptidase, pH, amylase, triglycerides, leukocyte count, and cytologic examination), fibronectin yielded the best degree of discrimination (diagnostic accuracy, 79%).