Shio Miyoshi

Papillary-cystic neoplasm of the pancreas with multiple hepatic metastases: A case report

SummaryWe report a case of papillary-cystic neoplasm (PCN) of the pancreas in a 42-yr-old woman. Because of complication with multiple hepatic metastases, the patient could not receive radical operation, and was treated palliatively. The right hepatic tumors decreased in volume by an average of 28% (range: 13–54%) following intra-arterial infusion of doxorubicin and gelatine sponge—i.e. chemoembolization therapy. On the other hand, the left lobe tumor increased by 15% in volume following intra-arterial infusion of doxorubicin alone without selective embolization. A subsequent systemic combination chemotherapy (combinations of 5-fluorouracil, doxorubicin and mitomycin-C) was less effective for both the primary and metastatic sites of PCN of the pancreas. Intra-arterial chemoembolization proved useful—as expected—as a palliative measure.Papillary-cystic neoplasm of the pancreas accompanied by hepatic metastasis is very rare. We present herein its clinical behavior and response to the above treatment as documented by CT scan.

“Nonalcoholic steatohepatitis” induced by massive doses of synthetic estrogen

SummaryWe have noticed that functional disorders of the liver characterized by hepatomegaly and an increase in serum gamma-glutamyl transpeptidase develop in patients with prostatic cancer who are placed under longterm therapy with massive doses of estrogen after castration. We performed laparoscopy in six cases of prostatic cancer with hepatomegaly so that we could study the morphology of the liver. Our findings were as follows. In five, the histological features of the liver biopsies were very similar to those seen in alcoholic hepatitis. In spite of this fact, two of the five had no history of alcohol consumption. Furthermore, in one other case, liver damage resembling alcoholic hepatitis developed during abstinence. The findings in these three cases suggested that long-term, massive doses of synthetic estrogen may lead to liver injury similar to alcoholic hepatitis in nonalcoholics. The ultrastructural findings of the liver cells were also suggestive of the adverse effect of treatment. All cases were negative for hepatitis B surface antigen. Recent reports have demonstrated some nonalcoholics with histological features of the liver indicative of alcoholic hepatitis. This particular condition was termed “nonalcoholic steatohepatitis” by Ludwig et al. It is quite likely that synthetic estrogen is also responsible for “nonalcoholic steatohepatitis” when it is used in massive doses.

Changes in hepatic functional reserve after transcatheter embolization of hepatocellular carcinoma Assessment by maximal removal rate of indocyanine green

To clarify the influence of transcatheter arterial embolization (TAE) on hepatic function, the maximal removal rate of indocyanine green (ICG-Rmax), which represents the hepatic functional reserve, and the plasma disappearance rate of indocyanine green (k-ICG) were measured serially before and after 15 TAE procedures performed on 13 hepatocellular carcinoma (HCC) patients with underlying hepatic diseases. Compared to the values before TAE, ICG-Rmax values did not change or gradually decreased during 4 weeks in seven of the 13 patients but markedly decreased in the remaining six by as much as 50% during the first week. k-ICG values remained almost unchanged at any time after TAE. Albumin and prothrombin time were serially measured before and after 24 TAE procedures performed on 21 HCC patients with underlying hepatic diseases in whom no plasma products had been used for therapy. Albumin decreased by up to 75% in one of the 21 patients during the first week but did not change or gradually decreased in 20 of the 21 patients. Prothrombin time showed no obvious changes. This study showed that prominent changes occurred in ICG-Rmax, i.e., in the hepatic functional reserve, after TAE.

Effect of cholestyramine on bile acid metabolism in conventional rats.

Effects of cholestyramine on biliary secretion of cholesterol, phospholipids and bile acids and fecal excretion of sterols and bile acids were examined in Wistar male rats. Six rats were fed a basal diet, and the other six were fed a basal diet supplemented with 5% cholestyramine for eight days. Bile flow and biliary secretion of bile acids and phospholipids (per hour per rat) decreased with cholestyramine treatment, while biliary cholesterol secretion (per hour per rat) remained unchanged. In the biliary bile acid composition, a marked increase of chenodeoxycholic acid with a concomitant decrease of β-muricholic acid was observed in cholestyramine-treated rats. Fecal excretion of total sterols and bile acids increased about three-and four-fold, respectively, after cholestyramine treatment. The increase of fecal bile acids derived from cholic acid was more predominant than that derived from chenodeoxylcholic acid, resulting in an increase of the cholic acid group/chenodeoxycholic acid group ratio.

Selective reduction of hepatic cytochrome P450 content in patients with intrahepatic cholestasis

Alteration of the components of the mixed-function oxidase system, including cytochrome P450, cytochrome b5, cytochrome P450 reductase, and cytochrome b5 reductase, was examined in liver microsomes prepared from needle biopsy samples of 12 patients with intrahepatic cholestasis. The rate of p-nitroanisole O-demethylation in the microsomes was also measured as the activity of cytochrome P450-dependent drug oxidation. The cytochrome P450 content (0.29 +/- 0.05 nmol/mg microsomal protein) in the patients was significantly lower than that in the 11 control subjects (0.41 +/- 0.09). The rate of p-nitroanisole O-demethylation was also significantly lower in the patients. However, the cytochrome b5 content and the activities of the reduced forms of nicotinamide adenine dinucleotide phosphate- and nicotinamide adenine dinucleotide-cytochrome c reductases did not differ between the two groups. Thus, selective reduction of cytochrome P450 seems to play a major role in the impairment of microsomal drug oxidation during intrahepatic cholestasis. Moreover, the reduction of cytochrome P450 was correlated with the serum concentrations of total bilirubin and bile acid but not with the serum glutamic oxaloacetic transaminase value. These observations suggest that the reduction of cytochrome P450 might be related to the severity of cholestasis.

Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma

SummaryThe pharmacokinetics of l-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a biexponential function (C= Ae-αt Be-βt), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups.The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 ± 0.05 μmol/g liver protein/30 min) and four of those without it (0.13 ±0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 × g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction. The soluble fraction-catalyzed rates per gram of liver protein in the two patients (58 and 67 nmol/g liver protein/30 min) were approximately twice the microsomal fraction-catalyzed rates (28.1 and 34.0), while the former rates in the controls (73 and 76) were very similar to the latter (72.5 and 84.9). These findings suggest that the soluble fraction accounts for a major portion of the capacity for converting FT to FUra in the liver of HCC patients.

Transcatheter arterial chemo-embolization for humoral hypercalcemia of hepatocellular carcinoma

SummaryA 50-year-old male with unresectable hepatocellular carcinoma (HCC) had a hypercalcemic crisis with a serum calcium concentration of 7.8 mEq/ℓ, without any evidence for bone metastases or parathyroid lesions. The hypercalcemia was thought to be due to increased renal reabsorption of calcium and increased bone resorption, which was probably caused by humoral factors derived from the HCC, some being parathyroid hormone-like factors. Since conservative therapy for hypercalcemia was not sufficiently effective and was accompanied by progressive exacerbation of ascites and leg edema, transcatheter arterial chemo-embolization (TACE) was performed. On the following day, serum calcium concentration decreased from 6.3 mEq/ℓ to the normal range, although serum α-fetoprotein levels decreased only slightly. Thereafter hypercalcemia did not develop for about 4 weeks. The results demonstrated that TACE can be effective for humoral hypercalcemia of HCC.

Effect of high doses of synthetic estrogen on lipid metabolism in castrated male rats

The mechanism by which high doses of estrogen influences lipid metabolism was studied with a microtubular blocking agent. Castrated male rats received oral injection daily for 14 days of 3 mg hexestrol in olive oil, or oil alone as controls. About half of the animals in each group were injected intraperitoneally with 4 mg/100 g body weight colchicine 3 hr before they were killed. Hexestrol treatment caused an accumulation of esterified cholesterol in the liver while it decreased those in serum. Triglyceride concentrations slightly decreased in the liver but were unaffected in serum. On polyacrylamide-gel disc electrophoresis, the peaks of high density lipoproteins (HDL) and low density lipoproteins (LDL) were decreased remarkably. Electron microsopic examination of hepatocytes revealed electron-lucent lipid droplets in the cytoplasm.After a colchicine treatment of the control animals, concentrations of esterified cholesterol and triglycerides markedly increased in the liver, while those in serum decreased. Electron microscopic examination of hepatocytes revealed numerous secretory vesicles filled with nascent VLDL. In hexestrol-treated animals, the colchicine treatment was associated with marked decreases in serumesterified cholesterol and triglyceride as seen in the controls. However, there were no further increases of esterified cholesterol in the liver, and the increase of triglycerides was slight. Electron microscopic examination showed less secretory droplets than in the controls.These data suggest that very low density lipoproteins (VLDL) synthesis in the liver of hexestrol treated rats was inhibited. An accumulation of esterified cholesterol with a marked decrease in serum could not be accounted for by the inhibition of lipoproteins secretion, but rather by their enhanced entry into the liver.

The inhibitory effect of forskolin on antibody-dependent cell-mediated cytotoxicity using Chang liver cells as target cells.

The effect of forskolin, a unique adenylate cyclase activator, on antibody-dependent cell-mediated cytotoxicity (ADCC) was examined. ADCC was assayed using Chang liver cells as the target cells, immuned rabbit serum as the antibody and healthy human peripheral blood mononuclear cells (PBMNC) as the effector cells. Forskolin at concentrations ranging from 1 to 20 microM significantly inhibited ADCC in a dose-dependent manner. By the addition of forskolin, cyclic AMP levels did not change in Chang liver cells but increased in PBMNC. Therefore, it appears that forskolin exerted an inhibitory effect on ADCC by increasing the intracellular cyclic AMP levels in PBMNC, the effector cells.

Antipyrine clearance per unit liver volume in cirrhotics with and without hepatocellular carcinoma indicating a correlation with histological change of the liver

SummaryThe antipyrine metabolizing capacity was studied in 12 patients with cirrhosis of the liver and 12 with cirrhosis and hepatocellular carcinoma (HCC). Antipyrine clearance (Cl) and liver volume (LV) were measured and the antipyrine clearance per unit liver volume (Cl/LV) was calculated. The patients with HCC showed a significantly lower Cl value than those without HCC but there was no significant difference in Cl/LV between the two groups. This suggested that the lower Cl values in the HCC patients resulted from a decrease in residual liver mass. Cl/LV showed positive correlation with % parenchymal cell mass as an indicator of residual parenchymal cell mass per unit volume of liver. This result showed a correlation of Cl/LV with histological change of the liver in cirrhotics.