Kensho Sanjo

Direct evidence for the intact hepatocyte theory in patients with liver cirrhosis

An attempt was made to compare various morphometric parameters, including total hepatocyte number, with the in vivo clearances of aminopyrine and antipyrine in 26 cirrhotic and 14 noncirrhotic patients to evaluate the intact hepatocyte theory. Morphometric analysis was performed with a newly developed method using a computer-aided color image analyzer. Aminopyrine clearance was significantly correlated with liver volume (r = 0.434; P less than 0.05), parenchymal cell volume (r = 0.574; P less than 0.001), and most strongly with total hepatocyte number (r = 0.614; P less than 0.001) in all patients. Significant correlations were also observed between these three parameters and antipyrine clearance (r = 0.367, P less than 0.05; r = 0.663, P less than 0.001; and r = 0.807, P less than 0.001, respectively). The mean aminopyrine clearance per individual hepatocyte showed no significant difference between cirrhotic and noncirrhotic patients (3.52 +/- 1.60 x 10(-10) mL/min vs. 3.65 +/- 1.50 x 10(-10) mL/min, respectively; P greater than 0.10). Similar results were obtained for antipyrine clearance per hepatocyte (7.35 +/- 2.27 x 10(-11) mL/min for cirrhotics vs. 6.16 +/- 1.07 x 10(-11) mL/min for noncirrhotics; P greater than 0.10). Thus, the intrinsic clearances of drugs per individual hepatocyte, as originally proposed in the intact cell hypothesis, were directly evaluated for the first time, lending strong support to the intact hepatocyte theory.

Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases

Blood clearance of antipyrine, indocyanine green, and galactose were measured to evaluate the alterations of effective hepatic blood flow and hepatic intrinsic clearances in chronic liver diseases. Galactose blood clearance, which may be taken as effective hepatic blood flow, decreased by approximately 30% in patients with cirrhosis (12.49 ± 0.76 ml/min/kg; mean ± SE; n = 17) compared with normal subjects (18.17 ± 1.03 ml/min/kg; n = 5). In patients with cirrhosis, intrinsic clearances of antipyrine (0.178 ± 0.014 ml/min/kg; n = 17) and indocyanine green (6.19 ± 1.38 ml/min/kg; n = 7) showed 61% and 85% reduction, respectively, compared with those of normal subjects (0.462 ± 0.048 ml/min/kg; n = 5; 41.72 ± 7.75 ml/min/kg; n = 5). Considering that indocyanine green and antipyrine are eliminated by different hepatic mechanisms, these mechanisms may not be equally sensitive to decrements in hepatic function. In addition, fractional reductions of intrinsic clearances for these compounds are thus much greater than that of effective hepatic blood flow.

Long-term effects of intrasplenically transplanted adult hepatocytes and fetal liver in hyperbilirubinemic Gunn rats

We performed adult hepatocyte transplantation (HCTx) and fetal liver transplantation (FLTx) into the spleens of hyperbilirubinemic Gunn rats in congenic combination and we compared the long-term effects of these procedures for as long as 12 months. Proliferative activity of intrasplenic hepatocytes was evaluated using antiproliferating cell nuclear antigen (PCNA) immunohistochemical staining. The serum total bilirubin levels (T. Bil) significantly decreased from 7.16±0.25 mg/dl to 4.38±0.60 mg/dl 2 months after HCTx and gradually decreased thereafter until 12 months after transplantation (3.23±0.37 mg/dl, P<0.05 vs preoperative value). The T. Bil change after FLTx was similar to that of HCTx: 7.22±0.24 mg/dl before FLTx, and 4.92±0.24 and 3.06±0.47 mg/dl, 2 and 12 months after FLTx (P<0.05), respectively. Bilirubin glucuronides, which were not detectable in the bile from untreated Gunn rats, appeared in considerable amounts 4 months after HCTx and FLTx (27.5% and 36.0% of total bile, respectively). PCNA labeling indices of intrasplenic hepatocytes (4.9%±0.9% and 3.7%±0.7%, 6 months after HCTx and FLTx, respectively) were slightly higher than those of normal hepatocytes (1.0%±0.1%) in the host liver. In conclusion, both adult and fetal rat hepatocytes transplanted into the spleen in congenic combination functioned for at least a year in terms of bilirubin glucuronidation. The spleen is considered to be one of the optimal grafting sites for hepatocytes, with nearly lifelong significant function and proliferative activity.

Functional capacity of the liver after two-thirds partial hepatectomy in the rat

BACKGROUND Liver cell proliferation after partial hepatectomy in rats has been thoroughly investigated. Although DNA synthesis and morphologic restoration have been studied in this rat model, the functional capacity of the remnant liver during regeneration has not been elucidated. METHODS We measured the indocyanine green disappearance rate (ICG-k) and serum aminopyrine (CLamp) in rats at various intervals after two-thirds hepatectomy. Morphologic restoration of the liver after hepatectomy was evaluated on the basis of remnant liver weight, proliferating cell nuclear antigen labeling index, and the DNA content of the regenerating liver. Serial changes in ICG-k and CLamp after two-thirds hepatectomy were compared with the degree of morphologic restoration. RESULTS ICG-k and CLamp were reduced by one third in rats after two-thirds hepatectomy. Although the rate of restoration of remnant liver weight was steady after hepatectomy, ICG-k and CLamp were lowest about 36 hours after hepatectomy. The restoration of ICG-k was comparable to that of liver weight, but the restoration of CLamp was delayed. CONCLUSIONS Functional liver capacity was minimal during parenchymal cell mitosis in the regenerating liver. Functional restoration after two-thirds hepatectomy was delayed in comparison with morphologic restoration in rat.

Effects of nonshunting operations on portal venous pressure and hepatic blood flow

A comparative analysis has been presented of the effect of the nonshunting operation on portal venous pressure and effective hepatic blood flow in patients with liver cirrhosis and idiopathic portal hypertension. A reduction of portal pressure after splenectomy with esophagogastric devascularization in 17 patients with idiopathic portal hypertension was significantly greater than that in 79 patients with liver cirrhosis (-21 +/- 4.1 percent versus -8.9 +/- 1.6 percent, p less than 0.01). Clearance of galactose from the blood, which approximates effective hepatic blood flow, was decreased after the nonshunting operation by 6.7 percent in five patients with liver cirrhosis (p value not significant). On the other hand, there was a 19.4 percent reduction (statistically significant) in galactose clearance in four patients with idiopathic portal hypertension (p less than 0.05). Based on these data, we suggest that in patients with idiopathic portal hypertension, the splenic circuit largely contributes to the portal hypertension, the effective hepatic blood flow, or both. We recommend a nonshunting operation for the treatment of esophageal varices from the hemodynamic viewpoint in cirrhotic patients.

Comparison between wedge and needle biopsies for evaluating the degree of cirrhosis

To examine whether the biopsy method could affect histological evaluation, the volumetric ratio of human liver parenchyma was estimated in specimens from subcapsular and intralobar areas, and also in specimens obtained by needle biopsy (Tru-Cut needle). A new method of morphometric analysis was performed using a computer-aided color image analyzer. Eighteen cirrhotic, 7 fibrotic, and 4 normal liver biopsies were taken during hepatic resection and analyzed. The parenchymal cell volume ratio in the intralobar area was significantly correlated with that in the subcapsular area, and less significantly with needle biopsy samples (r = 0.844, p < 0.001; r = 0.577, p < 0.01, respectively). Both showed one-to-one correspondence. These results suggest that both wedged and needle biopsy samples are appropriate for assessing the degree of fibrosis or cirrhosis, although the sampling variability of the latter is greater than the former.

Current strategy for esophageal varices in Japan

Management of bleeding esophageal varices in Japan includes tamponade, sclerotherapy, devascularization, and shunt procedures. Sclerotherapy is the most widely used treatment in both acute and chronic management. The Japanese Research Society for Sclerotherapy of Esophageal Varices monitors and surveys this treatment method at 152 institutions. Extensive devascularization operations now include a thoracotomy less frequently than previously, and they have a 6.6% rebleeding rate in elective patients. Shunt operations are applied in 20% of cases of bleeding esophageal varices in Japan. Effective medical and surgical treatments have led to changes in management strategy and to diversity in treatment during the last decade. The timing of treatment, the nature of the disease, the patients liver function, and the distribution of collaterals should all be considered in selecting treatment.

Reduced gastric surface mucus layer in experimental portal hypertension

The pathogenesis of portal hypertensive gastropathy has not yet been thoroughly elucidated. Changes in the gastric surface mucus layer in prehepatic portal hypertensive and cirrhotic rat models were studied by observing frozen sections fixed with formaldehyde vapor and stained with hematoxylin and eosin. We produced prehepatic portal hypertensive rats by partial ligation of the portal vein, and cirrhotic rats by prolonged administration of carbon tetrachloride (CCl4) and phenobarbital sodium. The thickness of the corporal and antral gastric surface mucus was significantly reduced in prehepatic portal hypertensive and cirrhotic rats compared with the values obtained in control rats for portal hypertension (subjected to sham operation) and control rats for cirrhosis (treated with phenobarbital but not CCl4). These results indicate that the hemodynamic changes associated with portal hypertension reduce the thickness of the gastric surface mucus layer and may be one of the causes of the gastropathy associated with portal hypertension.

Morphometry of sinusoids and portal hypertension in non-alcoholic cirrhosis

To examine whether structural changes in hepatocytes and/or sinusoidal areas contribute to the portal hypertensive state in non-alcoholic cirrhosis, a new method of morphometric analysis using a computer-aided color image analyzer was performed in 16 patients with non-alcoholic cirrhosis, which allowed quantitative evaluation of various morphometric parameters of sinusoids and hepatocytes. The sinusoidal pressure gradient was estimated theoretically with these and clearance parameters using Poiseulles equation and compared with the hepatic venous pressure gradient measure by hepatic vein cannulation. A significant relationship was found between the hepatic venous pressure gradient and sinusoidal volumetric ratio (r = -0.598, p < 0.05), but not between mean hepatocyte volume and sinusoidal volumetric ratio (r = 0.416, NS), or the hepatic venous pressure gradient (r = 0.371, NS). The estimated sinusoidal pressure gradient showed a significant relationship with the hepatic venous pressure gradient (r = 0.637, p < 0.01). However, the absolute values of the former were much lower than those of the latter. Therefore, in non-alcoholic cirrhosis, although sinusoidal stenosis not caused by hepatocyte swelling may lead to increased vascular resistance, other factors must also play a significant role.

Experimental transcatheter hepatic subsegmentectomy using absolute ethanol in dogs

In this study, we evaluate the effect of an intraportal injection of absolute ethanol in the canine liver and discuss how to introduce it in clinical application. The intraportal injection of ten millitiers of ethanol using a balloon occlusion catheter created an evident and well-demarcated necrotic lesion in the right central lobe. Histological examination showed a typical coagulation necrosis with fibrous bands, which became thicker day by day. The weight of the necroses ranged from 5 to 55 grams with an average of 26.0±5.5 grams (mean±SE), which was approximately 20 to 40 per cent of the right central lobe. Complications resulting from the ethanol injection were minimal and although more studies need to be done to clearly establish its safety for cirrhotic patients with hepatoma, this technique may be an easier and less invasive substitute for operative hepatic subsegmentectomy.