Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma.

The purpose of this Phase II study was to determine the response rate, the toxicity, and the effect on survival of the combination of cisplatin, doxorubicin, 5-fluorouracil, and alpha-IFN (PIAF) in advanced unresectable hepatocellular carcinoma. Fifty patients with either unresectable or metastatic disease were treated with PIAF: cisplatin (20 mg/m2 i.v., days 1-4), doxorubicin (40 mg/m2 i.v., day 1), 5-fluorouracil (400 mg/m2 i.v., days 1-4), and alpha-IFN (5 MU/m2 s.c., days 1-4). Treatment was repeated every 3 weeks to a maximum of six cycles. All patients were evaluable for response, toxicity, and survival. As assessed by conventional imaging criteria, there were no complete responses, but 13 patients (26%) had a partial response. Among the 36 patients who had an initially high alpha-fetoprotein level (>500 ng/ml), 15 (42%) had a >50% fall after therapy. Nine patients underwent surgical resection after achieving partial response and, in 4 of these patients, histological examination of the resected specimens revealed no viable tumor cells. All these nine patients are alive, and eight patients remain in complete remission at between 7.6 and 25.8 months at the time of analysis. The overall median survival was 8.9 months. Toxicity was mainly myelosuppression and mucositis. There were two treatment-related deaths due to neutropenic sepsis. PIAF is active in hepatocellular carcinoma despite considerable hematological toxicity. Complete pathological remission is possible with this systemic combination. Apparently, persistent radiological lesions may still represent complete pathological resolution of active disease.

Measuring lung shunting in hepatocellular carcinoma with intrahepatic-arterial technetium-99m macroaggregated albumin.

UNLABELLED: With increased use of intraarterial administration of chemotherapeutic and radioactive particulate agents, it is necessary to assess agent delivery in the lung. METHODS: Technetium-99m-labeled macroaggregated albumin (99mTc-MAA) delivered through the hepatic artery was used to determine the degree of lung shunting in 125 patients with hepatocellular carcinoma (HCC). RESULTS: The percentage of lung shunting varied among patients and it ranged from less than 1% to 67.2%, with a median of 8.1%. The degree of shunting depended on the vascularity of the tumors but not on the tumor size. The effect of angiotensin II on lung shunting was tested on six patients and there was no significant difference found between those patients who were pre-treated with angiotensin II and those who were not. One patient who underwent a liver resection, had a significant decrease in lung shunting from 28.5% to less than 1% after surgery. CONCLUSION: The lack of effect of angiotensin II together with the almost complete ablation of lung shunting by tumor resection suggested neoplastic blood vessels were responsible for the shunting.

Increased oxidative metabolism of paracetamol in patients with hepatocellular carcinoma.

Oxidative metabolism (OM) of paracetamol was studied in 19 patients with hepatocellular carcinoma (HCC), 39 with chronic hepatitis B virus infection (CHBV) and 26 healthy controls. Paracetamol (1.5 g) was given and the subsequent 24 h urine collection assayed for paracetamol and its metabolites by HPLC. HCC patients showed greatly increased OM, as reflected by the combined fractional recoveries of mercapturic acid and cysteine conjugates (22%), in comparison with controls (7%) and CHBV patients (10%). As the cytochrome P-450 dependent OM of xenobiotics has been implicated in carcinogenesis, it is interesting that two CHBV patients also had increased OM.

Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine-resistant mutants.

BACKGROUND: The efficacy of lamivudine therapy in chronic hepatitis B is well established. However, drug-resistant YMDD mutants emerge with extended therapy. This may result in the resurgence of viral replication, the return of hepatitis and histological deterioration. AIM: To study the safety of stopping lamivudine when the drug is no longer effective. METHODS: In the 5-year Asian Lamivudine Study, 34 patients from a single centre were included in this study. They had harboured YMDD mutants for at least 2 years. Lamivudine was discontinued and they were followed up at regular intervals. Clinical symptoms, liver biochemistry and viral serology were monitored. RESULTS: In a median follow-up of 20 months after stopping lamivudine (range, 7-39 months), 20 of the 34 patients (58.8%) had elevated alanine aminotransferase (ALT), 13 patients (38.2%) had elevated ALT one to five times the upper limit of normal and seven patients (20.6%) had an ALT flare (ALT more than five times the upper limit of normal with detectable hepatitis B virus DNA). There was no liver decompensation. ALT flare could be predicted by ALT over twice the upper limit of normal at the time of stopping lamivudine (P = 0.037). CONCLUSIONS: It is relatively safe to stop lamivudine after YMDD mutants have emerged. ALT levels greater than or equal to twice the upper limit of normal at the time of stopping lamivudine have a higher risk for ALT flare.

Lamivudine treatment for fulminant hepatic failure due to acute exacerbation of chronic hepatitis B infection.

BACKGROUND: Exacerbation of chronic hepatitis B infection can lead to fulminant hepatic failure with a mortality of up to 90%. AIM: To evaluate the efficacy of lamivudine in the treatment of this subgroup of patients. METHODS: Twenty-four patients with exacerbation of chronic hepatitis B infection and fulminant hepatic failure were treated with lamivudine, 100 mg daily. Hepatitis A, C, D and human immunodeficiency virus co-infections and hepatocellular carcinoma were excluded. RESULTS: The median age was 53 years (range, 24-77 years) with a male predominance of 20:4. Seventeen patients were hepatitis B e antigen positive. Mean hepatitis B virus DNA was 2079 Meq/mL. Eight patients (33%) survived (group A). Thirteen patients died and three patients received liver transplantation (67%) (group B). Baseline laboratory results were comparable between the two groups, including serum albumin, bilirubin, alanine aminotransferase, prothrombin time and creatinine. Group B patients had significantly more comorbid illnesses at baseline and more complications, including sepsis and renal failure, compared with group A patients. Six out of eight survivors (75%) had full hepatitis B e antigen seroconversion, but this was not sustained in four patients. CONCLUSIONS: Lamivudine may be useful in treating patients with fulminant hepatic failure due to exacerbation of chronic hepatitis B. Hepatitis B e antigen seroconversion was less durable in this subgroup of patients and long-term therapy may be required.

Expression of cyclooxygenase-2 in chronic hepatitis B and the effects of anti-viral therapy.

BACKGROUND: Cyclooxygenase-2 may play a role in the development of hepatocellular carcinoma, but the relationship between cyclooxygenase-2 and chronic hepatitis B is unknown. AIM: To investigate the expression and cellular localization of cyclooxygenase-2 in chronic hepatitis B patients and the effects of anti-viral therapy. METHODS: Using immunohistochemistry, in situ hybridization, Western blot and reverse transcription polymerase chain reaction, protein and messenger RNA expression and cellular localization of cyclooxygenase-2 in 35 chronic hepatitis B patients were assessed. Fourteen histologically normal and non-viral-infected livers were used as controls. The cyclooxygenase-2 immunoreactivities of paired liver biopsies from 12 patients receiving anti-viral therapy were compared. RESULTS: Immunohistochemistry and in situ hybridization revealed that cyclooxygenase-2 expression was confined to hepatocytes. Patients with chronic hepatitis B had significantly higher cyclooxygenase-2 expression compared with controls. The cyclooxygenase-2 expression of hepatitis B e antigen-positive and -negative chronic hepatitis B patients was not significantly different, although the necro-inflammatory activity of the latter group was significantly lower. Over-expression of cyclooxygenase-2 in patients with chronic hepatitis B was further confirmed by Western blot and reverse transcription polymerase chain reaction. Twelve hepatitis B e antigen-positive chronic hepatitis B patients received anti-viral therapy: lamivudine in seven and interferon in five. Despite hepatitis B e antigen seroconversion, disappearance of hepatitis B virus DNA in serum, normalization of liver enzymes and a significant reduction in necro-inflammatory activity in all 12 patients, no significant change in cyclooxygenase-2 expression was found. CONCLUSIONS: Chronic hepatitis B is associated with elevated cyclooxygenase-2 levels in hepatocytes, and the over-expression of this enzyme does not reflect inflammatory activity. Up-regulation of cyclooxygenase-2 persists after successful anti-viral therapy.

Hepatitis with isolated serum antibody to hepatitis B core antigen. A variant of non-A, non-B hepatitis?

Antibody to hepatitis B core antigen (anti-HBc) has previously been recognized to be a sensitive marker of hepatitis B virus (HBV) infection. In addition, anti-HBc has recently been suggested to be a surrogate marker for non-A, non-B hepatitis agents in donated blood. The authors studied prospectively the HBV antigen and antibody status in four patients with chronic hepatitis and persistent presence of isolated anti-HBc in their sera. The serologic and histopathologic findings of these four patients were compared with those of three groups of patients having chronic hepatitis with or without HBV markers. A low concentration of serum HBV DNA was detected in only one of the four patients with hepatitis with isolated anti-HBc and in another patient with previous HBV infection. HBV antigens and HBV DNA were not detected in the sera and liver biopsies from the remaining patients with hepatitis with isolated anti-HBc and other patients with hepatitis with or without serologic markers of previous hepatitis A or HBV infection. In contrast, all patients with chronic HBV-associated hepatitis had detectable HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) in their sera and/or liver biopsies. These findings suggest that chronic hepatitis associated with isolated anti-HBc is a heterogenous pathologic entity. The condition of some of these patients may represent a variant of non-A, non-B hepatitis, whereas the remaining patients are chronic hepatitis B carriers with low serum concentrations of HBV.

Massive, solitary, intrahepatic, extramedullary hematopoietic tumor in thalassemia.

Diffuse compensatory extramedullary hematopoiesis is well known to involve the spleen and liver in certain hematologic disorders. Hematopoietic tumor masses occasionally form and usually occur paraspinally in the posterior mediastinum. A 31-year-old patient with thalassemia is described with a massive, solitary, intrahepatic hematopoietic tumor and a smaller one in the posterior mediastinum. Review of the literature indicates that presentation as a large, focal liver lesion is unique. The implications and differential diagnosis are discussed.

Determination of tumour vascularity using selective hepatic angiography as compared with intrahepatic-arterial technetium-99m macroaggregated albumin scan in hepatocellular carcinoma.

A total of 51 patients with hepatocellular carcinoma (HCC) were studied to determine the tumour vascularity as determined by selective hepatic angiography (HAG) and by intrahepatic-arterial technetium-99m-labeled macroaggregated albumin (Tc99m-MAA) scan. The tumour vascularity was graded on the HAG films by an interventional radiologist using a scale ranging from 1 (hypovascular) to 4 (extremely hypervascular). The grades of vascularity on HAG were grade 1 in 5 patients, grade 2 in 13 patients, grade 3 in 24 patients and grade 4 in 9 patients. The tumour vascularity on scintigraphy was determined by quantifying the count rates over the tumour and normal liver areas by an analog/digital gamma-camera, and the resultant tumour-to-normal ratio (T/N ratio) gave a quantitative measure of the vascularity. The range of the T/N ratio was 0.9 to 11.1, with a median of 3.7. There was no correlation between the tumour vascularity grading on HAG and the T/N ratio on the Tc99m-MAA scan (Wilcoxon rank test, P = 0.83). Thus, we conclude that HAG cannot reveal the true vascularity nor reflect the T/N ratio in HCC.

Light chain ratios of serum immunoglobulins in disease.

We have determined the individual kappa (kappa)/lambda (lambda) ratios of serum IgG, IgA, and IgM in normal subjects and patients with rheumatoid arthritis, systemic lupus erythematosus, hepatic cirrhosis and IgA nephropathy--40 in each group. Serum samples were first screened by agarose electrophoresis to exclude paraproteinaemia. Concentrations of IgG, IgA, and IgM were determined by enzyme-linked immunosorbent assay (ELISA). The kappa and lambda chain concentrations of each immunoglobulin class were assayed by an ELISA method first developed by us for the determination of kappa/lambda ratios. Our results showed that kappa/lambda ratios of serum IgA and IgM were significantly different from that of IgG in normal subjects and the 4 groups of patients studied (p less than 0.01). The kappa/lambda ratios of individual immunoglobulins in patients with rheumatoid arthritis, systemic lupus erythematosus and liver cirrhosis were similar to those of normal subjects. However, patients with IgA nephropathy displayed a distinctly lower IgA kappa/lambda ratio, suggesting a unique antibody response in the immunopathogenesis of this disease.

Hepatic intra-arterial lipiodol ultrasound guided biopsy in the management of hepatocellular carcinoma.

One hundred and fifty-one consecutive new patients with suspected hepatocellular carcinoma (HCC) were investigated from 1989 to 1990. Ultrasound showed the tumours to be inoperable in 111 patients. Selective hepatic angiography revealed 17 more patients with inoperable HCC. Hepatic intra-arterial lipiodol (HIAL) was injected in the remaining 23 patients. In 16 of them, a clinical decision could be reached basing on the radiological findings. Hepatic intra-arterial lipiodol ultrasound (HIAL/USG) guided biopsy was done in seven patients with suspicious lesions. Histology obtained with this method revealed hyperplastic cirrhotic nodules in four patients (two with suspected HCC and two with suspected secondaries). In another two patients, the suspected lesions were confirmed to be malignant. In the last patient who had received chemotherapy for extensive HCC, HIAL/USG guided biopsy revealed necrotic tissue only. At laparotomy, diffuse infiltrative abnormality was found and repeated biopsy confirmed residual malignancy in the necrotic tumour. We conclude that when there is radiological uncertainty as to the nature and extent of the HCC, HIAL/USG guided biopsy can help the clinician to make important decisions.

Poems syndrome.

A 40 year old Chinese woman presented with anasarca and later developed features of POEMS syndrome. These are peripheral neuropathy (P), organomegaly (O), endocrine dysfunction (E), monoclonal gammopathy (M), and skin changes (S) which are usually associated with plasma cell dyscrasia. In our patient, monoclonal gammopathy was not detected on immunofixation electrophoresis and was revealed only after analysis of kappa/lambda light chain ratio of the raised serum IgA immunoglobulin. Needle liver biopsy of her grossly enlarged liver showed marked accumulation of glycogen and presence of giant mitochondria in the hepatocytes, a feature not previously reported.

Percutaneous biopsy of small hepatic lesions using an 18 gauge automated needle.

This study evaluates the efficacy of ultrasound guided percutaneous biopsy using an 18 gauge automated side-cutting needle in the diagnosis of small (< or = 3 cm) focal hepatic lesions. 137 consecutive percutaneous biopsies of 131 different small (< or = 3 cm) focal hepatic lesions were included. 11 biopsies were performed on lesions of < or = 1 cm in diameter, 56 were on lesions 1.1-2 cm in size and 70 on lesions 2.1-3 cm in size (average 2.3 +/- 0.7 cm; median 2.3 cm; range 0.7-3 cm). The biopsy specimen was sufficient for diagnosis in 135 cases (98.5%). The sensitivity for diagnosing malignancy was 96.4%; specificity was 100%, positive and negative predictive values were 100% and 94.6%, respectively; accuracy was 97.8%. There was no statistically significant difference in the diagnostic efficacy for lesions of different pathology and size. No significant post-biopsy complication occurred. It is concluded that the 18 gauge Temno needle is safe and effective in diagnosing small hepatic lesions.

Diagnostic pharmaco-scintigraphy with hepatic intra-arterial technetium-99m macroaggregated albumin in the determination of tumour to non-tumour uptake ratio in hepatocellular carcinoma.

Between October 1990 and March 1993, 124 patients who had hepatocellular carcinoma (HCC) underwent diagnostic pharmaco-scintigraphy with hepatic intraarterial technetium-99m macroaggregated albumin (TcMAA) to determine the tumourous to non-tumourous liver tissue uptake ratio (T/N ratio). There were 110 males and 14 females. Ages ranged from 16 to 73 with a median of 55 years. The range of T/N ratio was 0.7 to 19.3 with a median of 3.8. 12 patients with inoperable HCC were subsequently selected by predetermined criteria to undergo treatment with hepatic intraarterial yttrium-90 microspheres and the T/N ratios in these patients were validated by beta probe dosimetry and liquid scintillation count of multiple liver biopsies. The T/N ratio determined by preoperative diagnostic TcMAA scan correlated well with intraoperative beta probe dosimetry, with coefficient of correlation r = 0.82. Preoperative TcMAA scan also correlated well with liquid scintillation count of biopsy specimens, with r = 0.96. We conclude that TcMAA scan can be used to determine the T/N ratio in patients with HCC, thus allowing better selection of patients with inoperable tumours for loco-regional therapy.

Disposition of epirubicin in an oily contrast medium after intravenous and intrahepato-arterial administration in liver cancer: a preliminary report.

The present study reports findings on the disposition of epirubicin after an intrahepato-arterial administration of the Lipiodol-drug complex, prepared by mixing the drug-aqueous phase with the iodized oil by ultra-sonification, in 14 patients with histologically proven hepatoma or hepatomegaly with serum alpha-fetoprotein level above 500 micrograms.l-1. The volume of Lipiodol used was 5 ml and the epirubicin dose was 50 mg.m-2. Blood samples were obtained at various time intervals up to 72 h post-dose. Serum concentrations of epirubicin were measured by liquid chromatography with fluorometric detection. The area under serum concentration-time curve (AUCinfinity0) was higher in the Lipiodol-epirubicin group (n = 8) while the clearance was faster and elimination t1/2 and mean residence time shorter in the plain epirubicin group (n = 3). However, interindividual variation in metabolism of epirubicin would affect serum level of the drug. In three patients who were given intravenous and intrahepato-arterial injections (90 mg.m-2) of plain epirubicin and Lipiodol-drug complex, the relative bioavailability of Lipiodol-epirubicin complex (F = 0.76 and 0.45) was lower than that of plain epirubicin (F = 0.80 and 0.73) in two patients while it was approximately 100% (F = 1.06 and 1.20) in one patient. It is likely that liver function of the patients might be modified by the disease state over a period of 3 months in the cross-over study. Further studies with larger patient samples are required to confirm if there is a targeting effect of the Lipiodol-drug complex toward hepatoma using a better formulation of the drug in Lipiodol.

Patterns of viral hepatitis in Hong Kong.

Viral hepatitis is the most common form of acute or chronic hepatitis in Hong Kong. This article outlines current patterns of viral hepatitis in Hong Kong, and discusses the diagnosis, prevention and treatment of the different forms of the disease.

Palmitic acid oxidation and incorporation into triglyceride by needle liver biopsy specimens from control subjects and patients with alcoholic fatty liver disease.

A micro-technique was developed to measure fatty acid oxidation in vitro and to investigate its possible derangement in alcoholic fatty liver disease. Percutaneous liver biopsy specimens were obtained from nine control subjects and 28 alcoholic patients with mild to severe fatty liver. Fresh tissue (10-15 mg) was incubated at 37 degrees C for 90 min in a sealed reaction flask containing 1.92 mmol/l [1-14C]palmitic acid (1-2 microCi) and 1% essentially fatty acid free albumin in Krebs-Henseleit buffer, pH 7.4. Radiolabelled CO2 and perchloric acid-soluble ketone bodies were isolated and counted. CO2 production was markedly reduced in alcoholic patients with mild and severe fatty liver compared with controls. This depression was reversed by the addition of malate to the reaction flask but not by carnitine or coenzyme A. Ketone body production was similar in controls and patients with mild and severe fatty liver. After the incubation in vitro, the tissue was extracted with chloroform/methanol and the triglyceride fraction isolated by thin layer chromatography and counted for radioactivity. The rate of palmitic acid incorporation into triglyceride was higher in alcoholic patients, particularly those with severe fatty infiltration, compared with controls. It is suggested that alcoholic fatty liver is accompanied by a progressive reduction in palmitic acid oxidation with the major defect occurring in the tricarboxylic acid cycle. In contrast, the rate of palmitic acid esterification into triglyceride is enhanced.

Liver volume measurement by ultrasonography in normal subjects and alcoholic patients.

Computer-assisted ultrasonic planimetry was used to determine hepatic volumes in normal subjects and patients with alcoholic liver disease. Normal subjects showed a diurnal variation in liver volume with a minimum between 12.00 and 14.00 h. Studies indicated that this was related to hydration and liver glycogen content. Using data obtained from nonfasted ambulant subjects correlations were found between liver volume and body weight, height and surface area, with body weight showing the closest correlation. The normal range for adults was 18.1 +/- 0.5 (SE) ml/kg body weight. Patients with alcoholic fatty liver showed increased hepatic volumes correlating with degree of fatty change as judged histologically. Patients who continued to abuse alcohol showed a persistent increase in hepatic volume. Those who moderated, and particularly those who abstained, showed a significant decrease in hepatic volume. Serial measurements of liver volume are useful in assessing hepatic changes in alcohol abusers.

Fatty acid synthesis in vitro by liver tissue from control subjects and patients with alcoholic liver disease.

Percutaneous liver biopsy specimens were obtained from 11 control subjects, 24 alcoholic patients and six diabetic patients with mild to severe fatty liver and incubated in Krebs-Henseleit buffer containing 3H2O. The incorporation of 3H into fatty acid was measured and the absolute rate of fatty acid synthesis calculated. Fatty acid synthesis rates were significantly lower in alcoholic fatty liver than in controls. Fatty acid synthesis rates were similar in controls and patients with diabetic fatty livers. Addition of 50 mmol/l ethanol did not alter the fatty acid synthesis rates in vitro. It is concluded that enhanced lipogenesis is not the major cause of fatty liver in patients with alcoholic fatty liver.

Nephrogenous cyclic AMP in primary hepatocellular carcinoma patients with or without hypercalcaemia.

OBJECTIVE: To study the relationship between the excretion of nephrogenous cyclic AMP (NcAMP) and other blood and urine parameters as an index of PTH-like activity in patients with primary hepatocellular carcinoma. DESIGN: After overnight fast, a double voided urine and a blood sample were collected from each subject for determination of various analytes and results compared between various groups. PATIENTS: Fifty-five consecutive untreated patients with primary hepatocellular carcinoma, 14 healthy controls and eight patients with cirrhosis only. MEASUREMENTS: Serum calcium, phosphate, alkaline phosphatase, albumin, creatinine and urinary calcium, creatinine and hydroxyproline were measured by routine methods. cAMP was measured in plasma and urine by a radioimmunoassay (Diagnostic Products Corporation) and PTH measured in serum by an immunoradiometric assay (Nichols Institute). TmP/GFR, NcAMP etc. were calculated according to various published methods. RESULTS: Four out of 55 patients (7%) with primary hepatocellular carcinoma had hypercalcaemia. These four patients had significantly lower (P less than 0.05) phosphate, PTH and TmP/GFR and elevated NcAMP (P less than 0.001) compared with normocalcaemic hepatocellular carcinoma and cirrhotic patients, and healthy controls. The excretion of hydroxyproline and calcium was significantly elevated (P less than 0.001) in the hypercalcaemic patients. Bone resorption was found to be the major cause of hypercalcaemia in three of the four hypercalcaemic patients. Fifteen hepatocellular carcinoma patients (29%) with normocalcaemia had suppressed PTH. CONCLUSION: We conclude that a PTH-like humoral factor such as PTH related peptide is the cause of hypercalcaemia in patients with primary hepatocellular carcinoma, and that in some normocalcaemic patients with this tumour PTH is suppressed.