Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow,plasma and blood cell binding,and the hepatocellular enzymatic activity on hepatic drug clearance

Two commonly used models of hepatic drug clearance are examined. The “well-stirred” model (model I) views the liver as a well-stirred compartment with concentration of drug in the liver in equilibrium with that in the emergent blood. The “parallel tube” model (model II) regards the liver as a series of parallel tubes with enzymes distributed evenly around the tubes and the concentration of drug declines along the length of the tube. Both models are examined under steady-state considerations in the absence of diffusional limitations (cell membranes do not limit the movement of drug molecules). Equations involving the determinants of hepatic drug clearance (hepatic blood flow, fraction of drug in blood unbound, and the hepatocellular enzymatic activity) and various pharmacokinetic parameters are derived. Similarities and differences between the models are explored. Although both models predict similar hepatic drug clearances under a variety of conditions, marked differences between them become apparent in their predictions of the influence of changes in the determinants of drug clearance on various pharmacokinetic parameters.     

The role of HMGB-1 on the development of necrosis during hepatic ischemia and hepatic ischemia/reperfusion injury in mice

BACKGROUND: High-mobility group 1 (HMGB-1) is a late mediator of endotoxin lethality in mice. The release of HMGB-1 is delayed compared to other proinflammatory cytokines that mediate shock and tissue injury. The purpose of this study was to investigate the role of HMGB-1 levels in response to hepatic ischemia, hepatic I/R injury, and the relationship between changes in HMGB-1 and other cytokines. MATERIALS AND METHODS: Three murine models were employed: our robust model of segmental hepatic warm ischemia (SHWI), a model of partial hepatic ischemia/reperfusion injury (PHIRI), and a model of total hepatic ischemia/reperfusion injury (THIRI). Over a 48-h period following ischemic insult and reperfusion using these models, serum HMGB-1 concentrations, concentrations of HMGB-1 in ischemic and nonischemic lobes, and serum concentrations of TNF-alpha and IL-6 levels were determined in mice. An anti-HMGB-1 antibody treatment was used in SHWI and THIRI to evaluate what aspects of response to ischemia and reperfusion were potentially mediated by HMGB-1. RESULTS: Hepatic HMGB-1 tissue concentrations exhibited biphasic changes in SHWI mice, which were increased in the ischemic lobes relative to nonischemic lobes at 12 h but decreased relative to nonischemic lobes at 24 h after ischemic insult. These results suggested that HMGB-1 was released into the systemic circulation by necrotic cells over the first 12 h but this process may be complete by 24 h postischemia. By 6 to 12 h after SHWI, serum TNF-alpha began to increase significantly and continued to increase for 18 h, followed by a sudden decline. Similarly, serum IL-6 increased over 1-3 h after SHWI and then decreased over the next 6 h. Treatment with an anti-HMGB-1 antibody significantly prolonged survival time in SHWI and THIRI. CONCLUSIONS: HMGB-1 plays a significant role in the response to hepatic ischemia and hepatic ischemia/reperfusion injury. The present study demonstrated a time-dependent production of HMGB-1 following hepatic warm ischemia in mice. The inherent HMGB-1 in ischemic areas was exhausted and HMGB-1 may be released by necrotic cells. HMGB-1 activation is involved in immediate proinflammatory stress response to I/R and anti-HMGB-1 antibody treatment remarkably improved survival. We demonstrated that systemic HMGB-1 accumulation was measured at an earlier phase of the hepatic ischemia and ischemia/reperfusion injury model than LPS-induced endotoxemia.     

Successful management of concomitant omphalocele, accessory hepatic lobe, and biliary atresia in a 44-day-old boy

We report the second case in literature of a boy with the association of large omphalocele, accessory hepatic lobe, and biliary atresia, and the first successful treatment. The patient was submitted to a surgical treatment at 44 days of life, including Kasai procedure, correction of the remnant abdominal wall defect, and removal of a hepatic accessory lobe. The boy evolved with normalization of hepatic function tests. After 15 years of follow-up, the patient is completely healthy, weights 45 kg, and is 1.64 m tall.     

Ciliated hepatic foregut cyst in a young child

Ciliated hepatic foregut cysts are a rare entity usually found in adults. We present a case of a 3-year-old boy incidentally noted to have a radiographically complex liver cyst on computed tomographic scan. Given the complex appearance, the cyst was excised. Pathology revealed a ciliated hepatic foregut cyst. This is the second child and youngest patient affected with this lesion reported in the literature. The etiology of the lesion and an argument for surgical removal in pediatric patients are presented.     

Controlled study of inline radiofrequency ablation (ILRFA) assisted transection of ovine liver

BACKGROUND: Liver resection is now a standard treatment for primary and secondary hepatic tumors around the world. Intra-operative blood loss during liver resection is a major factor associated with morbidity and mortality. We have developed a new instrument using radiofrequency energy (ILRFA), which is intended to achieve coagulative ablation in a plane. This plane can then be cut through with a scalpel, ultrasonic dissector, or diathermy with minimal blood loss. MATERIALS AND METHODS: Five sheep were used in this non-recovery experiment. In these sheep we performed five liver resections with the ILRFA and five similar resections using diathermy and suturing as control. Blood loss was measured by determining the difference in the weights of dry sponges and blood stained sponges after resection. RESULTS: ILRFA was successful in achieving coagulative ablation in all cases to a width of 1 cm. The mean blood loss in ILRFA was 43.2 g (SD36) and 221.8 g (SD147) in the control group. The bleeding was significantly reduced in ILRFA group with a P value of 0.005. CONCLUSIONS: Bleeding remains an important complication of liver resection. To reduce bleeding during liver surgery, different techniques have been used. In this study, we have demonstrated that by using ILRFA we can perform liver resections in sheep with minimal blood loss.     

Peritumoral fat-spared area is well correlated with the presence of temporal peritumoral enhancement in hepatic hemangioma in fatty liver

PURPOSE: To assess the relationship between temporal peritumoral enhancement and peritumoral focal fat sparing adjacent to hepatic hemangiomas. MATERIALS AND METHODS: On the basis of MRI and sonographic imaging follow-up, 51 hepatic hemangiomas were identified in 37 patients, who had both hepatic hemangiomas and focal fat-sparing areas in fatty liver. Among them, 36 tumors were associated with peritumoral focal fat spares. The association between the temporal peritumoral enhancement in the early arterial phase of dynamic MRI and peritumoral fat sparing in the same hemangioma was investigated. Furthermore, the configuration of the temporal peritumoral enhancement was correlated with that of the peritumoral focal fat-sparing area. We used Chi square and Fisher's exact test for statistic analysis. RESULTS: A total of 31 out of 36 hemangiomas (86.1%) showed both peritumoral focal fat spares and temporal peritumoral enhancement. The presence of temporal peritumoral enhancement is significantly related to that of peritumoral focal fat-sparing (P < 0.001). A total of 21 of the 31 tumors (67.7%) presented with similar configuration of the peritumoral focal fat-sparing area and temporal peritumoral enhancement area with respect to size and shape. The remaining 10 hemangiomas showed similar shape but slightly different size in these two imaging characteristics. CONCLUSION: Temporal peritumoral enhancement seen in hepatic hemangioma might be related to focal fatty sparing adjacent to the hemangiomas.     

Nonspecificity of the fat-sparing ring surrounding focal liver lesion at MR imaging

RATIONALE AND OBJECTIVES: The presence of a fat-sparing ring surrounding focal liver lesions in patients with steatosis has been described only in malignant lesions. Our purpose is to evaluate whether this fat-sparing ring peripheral to tumors is a specific marker of malignancy. MATERIALS AND METHODS: From 300 magnetic resonance examinations of focal liver lesions, 132 patients with a confirmed nature of the lesions were selected. There were 24 patients (18.2%) with lesions having a perilesional fat-sparing ring in the opposed-phase spoiled T1-weighted gradient echo images. All these livers had steatosis. RESULTS: Perilesional fat-sparing rings were observed in 19 (21.6%) malignant and 5 (11.4%) benign lesions. Size of the lesion was not related to the presence of the fat-sparing ring (P=.6), neither was type of lesion (malignant versus benign) statistically related to the presence of the perilesional fat-sparing ring in the opposed-phase gradient echo magnetic resonance images (chi-square, P=.15). Fat-sparing rings were mainly seen in metastases (51.4% of metastases), but seldom in primary malignant tumors (1.9% of hepatocellular carcinomas). Hemangiomas also presented this finding (18.5% of hemangiomas). CONCLUSIONS: We believe that the presence of this bright rim surrounding lesions on oppose-phase images in patients with steatosis mainly represent decrease portal flow, either because of compressed and atrophic hepatocyte cords with sinusoidal congestion in expanding metastatic lesions or the presence of arterioportal perfusion abnormalities in vascularized hemangiomas.     

Isolated Hepatic Perfusion for the Treatment of Patients With Colorectal Cancer Liver Metastases After Irinotecan-Based Therapy

Background Irinotecan given with 5-fluorouracil and leucovorin is currently used as first-line therapy for patients with metastatic colorectal cancer (CRC). However, the response duration is <1 year, and second-line systemic chemotherapy has limited efficacy. We analyzed the efficacy of isolated hepatic perfusion (IHP) for patients with progressive CRC liver metastases after irinotecan.Methods Between March 1993 and February 2003, 124 patients with CRC liver metastases underwent IHP on institutional review board–approved protocols. The overall treatment mortality was 4% (5 of 124). Twenty-five patients (10 women and 15 men; mean age, 53 years) were identified who had progressive liver metastases by carcinoembryonic antigen, imaging studies, or both after irinotecan. A 1-hour hyperthermic IHP (mean hepatic temperature, 40.0°C) with melphalan 1.5 mg/kg (mean total dose, 100 mg) was administered via laparotomy. Perfusion with an oxygenated extracorporeal circuit was established with inflow via a cannula in the gastroduodenal artery and common hepatic artery inflow occlusion. Outflow was via a cannula in an isolated segment of the inferior vena cava. During IHP, portal and inferior vena caval flow were shunted to the axillary vein. Patients were assessed for radiographical response, recurrence pattern, and survival.Results The mean number of prior irinotecan cycles in 25 patients was 6 (range, 2–14), and it was given primarily as second-line therapy. The median number of liver metastases before IHP was 10 (range, 1–50), and the median percentage of hepatic replacement by tumor was 25%. The mean operative time was 9 hours (range, 6–12 hours), and the median hospital stay was 11 days (range, 8–76 days). There was 1 complete response and there were 14 partial responses in 25 patients (60%), with a median duration of 12 months (range, 5–35 months). Disease progressed systemically in 13 of 25 patients at a median of 5 months (range, 3–16 months). The median overall survival was 12 months (range, 1–47 months), and the 2-year survival was 28%.Conclusions For patients with progressive CRC liver metastases after irinotecan, IHP has good efficacy in terms of response rate and duration. Continued evaluation of IHP with melphalan as second-line therapy in this clinical setting is justified.     

Drainage of hepatic hydatid cyst with a surgiport

This article describes the safe and effective technique of hepatic hydatid cyst drainage.