Masaji Nambu

A randomized trial of intrahepatic arterial infusion of 4′-epidoxorubicin with Lipiodol versus 4′-epidoxorubicin alone in the treatment of hepatocellular carcinoma

We conducted a prospective randomized trial to evaluate the efficacy of Lipiodol in intrahepatic arterial infusion chemotherapy for patients with hepatocellular carcinoma (HCC). A total of 38 patients with unresectable HCCs and underlying cirrhosis were entered in this trial, and 36 of them were evaluable. Every 4 weeks, 17 patients received 70 mg of 4′-epidoxorubicin (epirubicin) alone (group A), whereas 19 patients received a Lipiodol emulsion containing the same dose of epirubicin (group B) through the hepatic artery. A tumor response (CR+PR) was observed in 12% of group A patients and in 42% of group B patients. The group B patients showed a significantly higher response rate than the group A patients. There was a tendency for an increased duration of survival (P=0.09) in the group B patients. These results suggested that the infusion of the Lipiodol emulsion with epirubicin was more effective than epirubicin alone for the treatment of these patients with HCC.

Hepatic transport of serum bilirubin, bromsulfophthalein, and indocyanine green in patients with congenital non-hemolytic hyperbilirubinemia and patients with constitutional indocyanine green excretory defect.

We carried out a retrospective study of 71 patients with congenital non-hemolytic hyperbilirubinemia who had been treated at our institution over the 25 years from 1965 to 1990. Twenty patients had Gilberts syndrome, 1 had Crigler-Najjar syndrome, 1 had new type unconjugated hyperbilirubinemia, 21 had Dubin-Johnson syndrome, and 28 had Rotors syndrome. We also reviewed 20 patients with constitutional indocyanine green (ICG) excretory defect. The study focused on the hepatic transport of serum bilirubin, bromsulfophthalein (BSP), and ICG. In Dubin-Johnson syndrome, a defect appeared in late-stage transport, while uptake and storage capacity were normal. In Rotors syndrome, defects were found in the early stage, and storage capacity was reduced, while excretion into bile was slightly suppressed. A secondary rise in serum ICG was seen in 5 of the 10 patients with Dubin-Johnson syndrome. The transport defect in Gilberts syndrome was unclear. It could not be considered to be homogeneous, but it may exist at multiple sites, from the conjugation with serum proteins to excretion into bile. Following phenobarbital administration, the ICG secondary rise in the 5 patients with Dubin-Johnson syndrome disappeared, and ICG was rapidly cleared from blood. However, in patients with Dubin-Johnson syndrome, BSP clearance in serum did not show any change before and after phenobarbital administration. ICG excretion in patients with constitutional ICG excretory defect was due only to the impairment o ICG transport, and the defect was suggested to be hepatic uptake. These results indicate that studies of the hepatic transport of bilirubin, BSP, and ICG are useful for determining the etiological factors involved in congenital hyperbilirubinemia and constitutional ICG excretory defect.

Hepatic Dye Transport in Constitutional Hyperbilirubinemia and Constitutional ICG Excretory Defect

体質性黄疸35例,体質性ICG排泄異常症16例の色素移送動態を検討した.Gilbert病とD-J症候群ではビリルビン移送異常が,BSP, ICGより優位であり,Rotor型とICG異常症ではBSPとICG移送異常がビリルビンより優位であった.Gilbert病のBSP消失曲線は,初期消失遅延型と後期消失遅延型の2群に,ICGは,後期消失が正常,遅延,中間の3群に分けられた.D-J症候群で,BSP消失曲線の再上昇は全例にみられ,いずれも一定のパターンを示したが,ICGの再上昇は7例中4例で認め,そのパターンは不定であった.Rotor型は排泄障害のほかに摂取障害が著しく,D-Jの移送障害とは異なり,また,ICG異常症の消失曲線はRotor型に似ているが,20～25分のステップ形成が特異的で,Rotor型の様な肝から胆汁中への色素排泄障害は認めなかった.フェノバルビタールによる影響も,色素と疾患により様々で,各疾患は,ビリルビン,BSP, ICGを軸とした3次元の空間にそれぞれ独自の位置を占めていた.

Indocyanine green (ICG) test before and after exercise in patients with chronic liver diseases

SummaryThe indocyanine green (ICG) test (serum disappearance rate: K and 15 min. retention rate: R15) was performed in 15 patients with chronic hepatitis (CH) and 22 patients with liver cirrhosis (LC) before and after exercise (Master’s two step method for three min.). In LC, ICG K was 0.063±0.026 (mean±SD) before exercise and 0.083±0.028 after exercise. ICG R15 was 31.6± 15.6% and 23.3± 15.3%, respectively. In CH, ICG R15 before exercise was 8.2±4.0%, as compared with that (5.7±3.6%) after exercise. Namely, the ICG test significantly (P<0.05) improved after exercise in chronic liver diseases. Excretion of ICG into bile after exercise increased both in gallstone patients without abnormal liver function and LC, and it markedly increased in patients with decompensated LC. There was no significant difference in ICG excreted into urine before and after exercise. These results suggest that hepatic blood flow increases through moderate exercise in chronic liver diseases.

Compartmenal analysis of indocyanine green transport in normal subjects and patients with hepatic dysfunction

SummaryThe plasma disappearance curve following a single intravenous injection of Indocyanine Green (ICG) was analyzed by an established technique and ICG kinetics evaluated for 12 normal control subjects and 57 patients with various hepatic disorders. The two-compartment model was used in this analysis. Three fractional transport rates were determined for the two-pool system: (1) fractional hepatic removal rate; (2) fractional hepatic plasma reflux rate; (3) fractional biliary secretory rate. The mean values and their standard deviation for the three respective rate in normal subjects are: (1) 0.2168 ±0.0199 min-1; (2) 0.0136 ±0.0089 min-1; (3) 0.0642 ±0.0327 min-1. The respective mean rates for 25 patients with biopsy proved hepatic cirrhosis are: (1) 0.0777 ±0.0388 min-1; (2) 0.0127 ±0.0081 min-1; (3) 0.0434 ±0.0188 min-1. The respective means for 7 patients in the acute phase of acute viral hepatitis are: (1) 0.1066 ±0.0498 min-1; (2) 0.0078 ±0.0046 min-1; (3) 0.0218 ±0.0141 min-1. The respective means for 6 patient with almost complete biliary obstruction are: (1) 0.0503 ±0.0211min-1; (2) 0.0717 ±0.0103 min-1; (3) 0.0422 ±0.0190 min-1. Changes in these parameters were dtermined in acute phase and convalescent phase of acute viral hepatitis. This kinetic approach was compared with previous evaluation of sulfobromophthalein (BSP) transport in man and similar results were obtained for the two dyes in normal subjects and in cirrhotic patients.

The constitutional conjugated hyperbilirubinemia

SummaryPlasma clearance studies with Indocyanine Green (ICG) and Bromsulfophthalein (BSP) were performed on four patients with chronic conjugated hyperbilirubinemia with or without apparent brown pigments in the liver cells, and free from structural hepatic diseases.An abnormal clearance pattern, characterized by reduced hepatic ICG and BSP clearances, was observed in one case with Rotor’s type of hyperbilirubinemia (R). In the other three cases of Dubin-Johnson syndrome (DJ), an abnormal disappearance curve with a secondary rise of serum BSP 60 and 120 minutes after intravenous administration, was observed, although the hepatic disappearance rates of both ICG and BSP were normal. A two-compartmental analysis revealed that the depressed hepatic dye clearance in R might be due to defects both in the uptake and in the excretion of dye by the liver, and there seems to be an excretory defect of the dye in DJ.The studies on the transport maximum (Tm) and the relative storage capacity (S) of ICG demonstrated the reduction of Tm and S in R, while decreased Tm and normal S in DJ. These results suggest that the current diagnostic criteria for DJ and R would be based upon the dye transport distinction in patients with the same basic hyperbilirubinemia.

Transmission of hepatitis C virus among sexually transmitted disease high risk groups

Recently, the modes of transmission of hepatitis C virus (HCV), other than by blood transfusion, have been discussed. We investigated the possibility of the sexual transmission of HCV among sexually transmitted diseases (STD) in high-risk groups. Anti-HCV was examined for 203 female prostitutes (group STD) and, as controls, 270 nurses (group N) and 628 pregnant women (group P). Anti-HCV positive rates for the STD group (3.9646) were significantly (P < 0.05) higher than the N group (0.74%) and the P group (0.95%). All of the six HCV-RNA-positive subjects in the STD group had high values of HCV-RNA over 104.5 copies/μd. Among the four sexual partners examined for HCV-RNA, three partners (75%) were HCV-RNA positive. The HCV genotype of the six subjects in the three couples all matched type 11. The results of the present study indicate that sexual contact is a possible route of HCV transmission, other than by blood transfusion.

Effect of vitamin K1 plus bile acid therapy on hemorrhagic tendency in patients with decompensated liver cirrhosis.

血液凝固能が異常であった非代償性肝硬変患者25例で,VK1 60mg/日に胆汁酸(UDCA 15例,CDCA 10例)300mg/日を併用投与し,HPT値の変化をみた. VK1の単独投与では,HPT値に有意の改善がみられなかったが,胆汁酸,特にUDCA併用(ウルソ群)の1乃至2ヵ月後に,HPT値は有意に改善した.CDCA併用例(ケノ群)では,HPT値に改善傾向がみられたものの,有意ではなかった.25例中11例(ウルソ群5例,ケノ群6例)で,この胆汁酸併用投与が無効であった.11例の内訳は,肝癌合併3例,ICG R15 40%以上の高度肝実質障害例5例,死亡3例で,このことから,胆汁酸併用療法が無効であれば,その予後はきわめて不良であることが示唆された.さらに,非代償性肝硬変の13例で,γ-カルボキシグルタミン酸の尿中排泄を観察した結果,VK1単独投与例よりもUDCA併用例で,この尿中排泄は有意に増加していた.

Sulfobromophthalein and indocyanine green binding by the hepatic cytoplasmic proteins

SummaryThe elution patterns of human and rat liver supernate mixed with BSP or ICG have been demonstrated using G-100 Sephadex gel filtration. The elution pattern in the rat liver remained the same as that shown by Levi et al. In the human liver BSP localized to Y protein could hardly be demonstrated, whereas ICG was detected. This pattern was quite similar in Rotor’s hyperbilirubinemia and in Crigler-Najjar syndrome Type II. These observations suggest that the imparired hepatic transportation of organic anions in congenital hyperbilirubinemias may not be related to cytoplasmic organic anion-binding proteins.

Consideration of hepatic factor influence on drip infusion cholangiography.

SummaryThe plasma disappearance rate (K) and transfer rate constants for the two compartmental system of Indocyanine Green (ICG) were calculated in visualized and nonvisualized cases of the biliary tract with hepatobiliary disease using drip infusion cholangiography (DIC). In nonvisualized cases with hepatocellular disrder K and the fractional hepatic removal rate mainly decreased, and in nonvisualized cases with cholelithiasis the fractional biliary secretory rate significantly decreased by DIC-A, utilizing it as a screening test. Three methods (B, C and D) of drip infusion cholangiography were established according to the result of the ICG test. Through DIC-B, -C or -D in addition to DIC-A the visualization of the biliary tract significantly elevated in patients with hepatocellular disorder and cholelithiasis. These results were confirmed using131I-iodipamide. In some cases the serum transaminase activity elevated, but the elevation was temporary.