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To study the sonographic evolution of hepatocellular carcinoma (HCC) in its early stage, 26 HCCs in 24 patients were observed regularly with real-time ultrasound for a period of 90 to 691 days. In the beginning, 21 tumors were hypoechoic, two isoechoic, and three diffusely hyperechoic. On follow-up, two of the 21 initially hypoechoic HCCs remained the same echodensity, 12 increased in internal echoes but were still hypoechoic, one became isoechoic, four changed to hyperechoic, and the remaining two shifted from hypoechoic to isoechoic and then to hyperechoic. The two initially isoechoic HCCs also gained echogenicity and became hyperechoic. By contrast, the three initially hyperechoic HCCs kept the same echo patterns. The "acquired" hyperechoic HCCs were inhomogeneous in echodensity and larger in size whereas the three originally hyperechoic HCCs were homogeneous and smaller. It is concluded that most small HCCs evolve progressively from hypoechoic to isoechoic and then to inhomogeneously hyperechoic patterns as they grow; a few HCCs have diffusely high echogenicity from the beginning and retain the same features thereafter.

Summary The evolutions of serum hepatitis B virus (HBV)-DNA, liver histology and intrahepatic expressions of HBV antigens were longitudinally investigated in 24 serum HBeAg + /HBV-DNA + chronic hepatitis B patients who subsequently seroconverted to anti-HBe. After HBeAg conversion, serum HBV-DNA still persisted in 10 patients, and liver HBcAg in 7 of them. Of the 24 patients, 3 subgroups with diverse prognoses were identified. Ten patients progressed from chronic active hepatitis to cirrhosis, and in 7 of them HBV-DNA and/or HBcAg persisted. Eight patients with undetectable HBV-DNA and HBcAg recovered. In the remaining 6 patients, chronic liver diseases persisted; in 3 of them, HBV-DNA and in one HBcAg. These findings indicate that continued viral replication is present in a significant number of patients after HBeAg seroconversion in Taiwan, and is responsible for disease progression. In addition to HBcAg and HBV-DNA, the severity of underlying liver histology, when HBeAg seroconversion occurred, was critical for the outcome of the disease. Another remarkable finding was that clusters of ground-glass hepatocytes, well correlated with the marginal expression of HBsAg, were demonstrated in 14 of 16 biopsies with serum anti-HBe + /HBV-DNA − , but found in only 4 of 44 biopsies with positive serum HBV-DNA, indicating a strong association of the expressions of liver histology and hepatocyte HBsAg with the status of viral replication.

To clarify the natural history of hepatitis B virus (HBV)-associated liver cirrhosis, the clinical, laboratory and histological features of 174 untreated hepatitis B surface antigen (HBsAg)-positive cirrhotics were analysed, with a mean follow-up period of 34 months (range 8–135 months) after liver biopsy. Male patients were predominant (86.8%) and the mean age of the whole group was 45 years, s.d. = 12 (range 15–82 years). Serum HBeAg and HBV-DNA positivity were 38.9% and 31.8%, respectively. The calculated annual rate of spontaneous HBeAg seroconversion was 6.4% which was significantly lower than that (12%) of patients with HBeAg-positive chronic active hepatitis (CAH). Superinfection by δ-agent was rare, and anti-δ antibody was detected in only 1.7% of them. The occurrence rate of hepatocellular carcinoma in the whole group was 5.7%/year which was not higher than that of HBsAg-negative cirrhotics (6.2%/year). Serial liver biopsy showed that in the late evolution of cirrhosis, hepatitic activity tended to decline. Active cirrhosis may represent the intermediate stage between CAH and inactive liver cirrhosis. The 5-year survival probability rate of the patients belonging to Child's functional classes A, B and C was 83.4% (s.d. = 5.7), 79.2% (s.d. = 9.4) and 30.9% (s.d. = 14.3), respectively. Most patients were in a well-compensated state on entry into the study and remained stable for several years after diagnosis. Major causes of death include massive variceal bleeding, hepatic failure and/or hepatorenal syndrome, infection and hepatocellular carcinoma.

Based on observations of a limited number of patients, delta (δ) infection has been reported to be infrequent in Taiwan. To further evaluate the role of δ-infection in patients with hepatitis B virus (HBV) infection, serum samples of 493 subjects with acute and chronic HBV infections collected in 1976–85 were studied for anti-δ by radioimmunoassay. Intrahepatic δ-antigen was also studied by immunofluorescence in 12 anti-δ-positive patients. The overall prevalence of δ-infection was 4.7%, consistent with previous studies. δ-Infection had an even yearly distribution in the last decade. However, there were four groups with significantly higher frequencies: (i) 24% of 41 anti-HBe-positive patients with chronic active hepatitis (CAH); (ii) 21% of 14 HBsAg carriers with prominent lobular hepatitis; (iii) two of three HBsAg carriers with intravenous drug abuse; and (iv) two of seven with fulminant hepatitis. On the other hand, δ-infection was uncommon in patients with chronic persistent hepatitis, cirrhosis, hepatocellular carcinoma, classical type B hepatitis, submassive necrosis and asymptomatic HBsAg carriers. δ-Antigen was found in only two patients with CAH; one progressed to cirrhosis, and the other had disease regression on follow-up. Overall, at least half of the δ-superinfected HBsAg-positive patients had a non-progressive course on follow-up. It was concluded that δ-agent was introduced to Taiwan before 1976. Although it has played a role in some clinical settings of HBV infections, it is generally infrequent in Taiwan. The δ-superinfection apparent in half the patients studied seems to have a non-progressive course.

The growth rate of 31 asymptomatic hepatocellular carcinomas (diameter less than or equal to 5 cm) discovered in 28 patients by a prospective screening program was determined by real-time ultrasonography over 36-860 days. Except for one tumor that shrank on follow-up, the doubling time ranged from 29 to 398 days, with a median of 117 days, an arithmetic mean of 136 days, and a geometric mean of 110 days. In 17 tumors with more than two measurements, the growth rate remained exponential in nine, declined in growth in seven, and showed an initial lag period in one. Doubling time correlated with initial tumor diameter but was independent of the patient's age, sex, hepatitis B surface antigen status, tumor location, liver function tests, stage of liver cirrhosis, histologic type, or grade of malignancy. Although initial alpha-fetoprotein levels did not correlate well with growth rate, in 14 patients with an exponential increase of serum alpha-fetoprotein, the alpha-fetoprotein doubling time was closely related to the tumor doubling time. Based on the above data, the median detectable subclinical period of hepatocellular carcinoma was deduced to be 3.2 yr, and the suitable screening interval for its early detection in our area was 4-5 mo.

For early detection of hepatocellular carcinoma (HCC), real-time ultrasonography (US) was performed prospectively in 528 patients, including 236 with cirrhosis, 81 with chronic hepatitis, 168 asymptomatic hepatitis B surface antigen carriers, and 43 with a family history of HCC. Simultaneous measurement of serum alpha-fetoprotein (AFP) level was also done. In addition, 233 patients had regular controls at 3- to 6-month intervals, with an average follow-up period of 1.4 years. On initial screening, a total of 17 patients were found to have HCC: 13 in the cirrhotic group, 3 in the HCC family group, and 1 in the asymptomatic carriers. Of these HCCs, 7 were smaller than 3 cm, 6 were between 3 to 5 cm, and 4 were larger than 5 cm. In patients with tumors smaller than 5 cm, the AFP levels were normal in 46.2%, between 20 to 400 ng/ml in another 46.2%, and only 7.6% were over 400 ng/ml. On follow-up, another seven patients, all in the cirrhotic group, were found to have HCCs varying from 1.6 to 4.7 cm; three of them had normal serum AFP level. The authors conclude that real-time US is more sensitive than AFP assay in early detection of HCC, and the high-risk subjects should receive this procedure at regular intervals.

A 28-yr-old man had pleural effusions coinciding with two separate episodes of acute exacerbation of chronic type B hepatitis. In both episodes, the pleural effusion was exudative with lymphocyte predominance, and there was no ascites. Hypocomplementemia was evident in the second episode when the complement level was determined, but immune complexes were not detected in the serum. The hepatitis itself was thought to be directly responsible for the pleural effusions because of meticulous exclusion of other causes and the fact that, without specific treatment, the effusions resolved completely as the hepatitis subsided.

Plasma samples from 89 asymptomatic hepatitis B surface antigen (HBsAg) positive volunteer blood donors were titrated for HBsAg by radioimmunoassay using the parallel line method. HBsAg titers ranged widely from 0.01 to 325 micrograms/ml. The titers correlated well with hepatitis B viral DNA (HBV DNA) and hepatitis B e antigen (HBeAg) in the serum. The HBsAg titers in 55 HBV DNA positive carriers were 90.7 +/- 61.7 micrograms/ml (Mean +/- SD) vs. 6.3 +/- 12.2 micrograms/ml in the 34 carriers without HBV DNA in the serum. The titers were 93.9 +/- 59.1 micrograms/ml in 56 carriers with HBeAg, 6.4 +/- 10.1 micrograms/ml in 24 anti-HBe-positive carriers, and 4.9 +/- 4.6 micrograms/ml in 9 HBeAg/anti-HBe-negative carriers. 50 (89.3%) of the 56 HBeAg-positive carriers had HBV DNA, in contrast to four (16.7%) of 24 anti-HBe-positive carriers. The study indicated that high-titered HBsAg carriers were much more likely to be infectious, and confirmed that HBeAg is a practical marker of infectivity. Absence of HBeAg, however, did not exclude infectivity in asymptomatic HBsAg carriers, inasmuch as one-sixth of the carriers had HBV DNA.

To examine the replication of hepatitis D virus (HDV) and its interactions with helper hepatitis B virus (HBV), the RNA of both viruses was analyzed in liver biopsy tissue obtained from six patients with past or present hepatitis. In four of five hepatitis B surface antigen (HBsAg) carriers, the RNA genome of HDV was found in the liver. Further, the complementary RNA species as replication templates of HDV genomes documented in previous animal studies were confirmed. Within the livers of four HBsAg carriers, the transcription of HBV was absent or incomplete, however, in the patient without HDV RNA, the HBV genes expressed accurately and actively. This may account for the previously observed HBV suppression by concomitant HDV infection.

Intratumor injection of absolute ethanol to treat small hepatocellular carcinoma sometimes results in incomplete necrosis of the tumor. Causes of this include inhomogeneous distribution of the ethanol and difficulty in identifying the tumor after previous ethanol injections. To solve these problems, the authors designed a multiple-side-hole needle for ethanol injection and implanted one or more small steel coils into the tumor before treatment to serve as a landmark. Six patients thus treated all showed adequate necrosis on follow-up computed tomography, biopsy, and angiography studies; initially elevated serum alpha-fetoprotein levels present in five patients were decreased. A resected surgical specimen obtained in one patient showed extensive necrosis of the tumor as well as of the surrounding healthy liver; only a small locus of equivocally viable cancer cells remained in the tumor margin.

Recurrence of hepatocellular carcinoma after treatment is frequent. To study the clonal origin of the recurrent tumors, we examined five pairs of hepatocellular carcinomas resected from individual hepatitis B surface antigen carriers. Using integrated hepatitis B virus DNA as a marker, tumor clonality was determined by Southern blot analysis. In 2 cases the second tumor contained the same integrated viral DNA as the first one. In the other 3 cases, the clonality of the second cancer differed. We conclude that recurrent hepatocellular carcinomas originate from the first tumor in some cases but represent de novo neoplasms in others.

To elucidate the biologic significance of hepatocyte HBsAg, its expression patterns were correlated with virus replication and liver pathology in 578 liver biopsies taken from chronic HBsAg carriers aged 1 to 80 years. Five major patterns of hepatocyte HBsAg were identified: homogeneous [intense and discrete, (Pattern A), faint and discrete, (Pattern B) and faint and grouped (Pattern C)]; globular or spotty (Pattern D), and marginal (Pattern E). Pattern A was always associated with viremia and also very frequently with membrane HBsAg expression, but rarely with active liver disease. It occurred most commonly in HBeAg-positive carrier children and young adults, reflecting an early immune tolerance phase with active virus replication. Pattern B was also usually associated with viremia, but very commonly associated with active disease (70%), reflecting active virus replication with enhanced immune response. Pattern E (marginal HBsAg), which was always in group distribution resembling a clonal expansion, predominated the HBeAg-negative phase and was associated with absence of viremia and occurred mostly in older adults with inactive bipolar disease spectrum (normal liver/mild disease or cirrhosis/hepatocellular carcinoma); this reflects a late phase of inactive virus replication or integration. Patterns C and D did not correlate well with viremia, but also tended to have inactive diseases as did Pattern E. These findings suggest that hepatocyte HBsAg expression is closely related to the natural course of chronic hepatitis B virus infection.