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Background: Liver transplantation for nonresectable liver metastases from colorectal cancer was abandoned in 1994 on account of high recurrence rates. The aim of this study was to investigate whether the genetic detection of micrometastases in histologically negative lymph nodes of the primary colon cancer could be applied to select patients for liver transplantation., Methods: We analyzed 21 patients with colorectal cancer who had undergone liver transplantation between 1983 and 1994 for liver metastases. Eleven patients were histologically lymph node negative at the time of surgery; ten patients with lymph node metastases served as control group. DNA sequencing was used to screen tumor material for p53 and K-ras mutations. Mutant allele-specific amplification (MASA) was then used to search for micrometastases in DNA from regional lymph nodes of the primary colorectal cancer., Results: p53 and K-ras mutations were detected in 12 (57%) and 3 (14%) of 21 patients in the colorectal cancer, respectively. The mutations were confirmed in the corresponding liver metastases. Of 11 patients with histologically negative lymph nodes, nine were eligible for MASA due to presence of p53 or K-ras mutation. MASA revealed six of nine patients to be genetically positive for micrometastases. Three patients were both genetically and histologically negative. These three patients showed a significantly longer overall survival (P = 0.011) of 4, 5, and 20 years, respectively., Conclusions: We conclude that the genetic detection of micrometastases by MASA could be a powerful prognostic indicator for selecting patients with colorectal liver metastases who could benefit from liver transplantation.

Background: Oral ingestion of potassium dichromate produces a complex spectrum of complications. It has an extremely poor prognosis and usually leads to rapid death., Methods: We report the case of a 16-year-old male patient who was admitted to hospital after oral ingestion of potassium dichromate with suicidal intention., Results: The patient's condition deteriorated, and he became comatose within 5 days in spite of immediate attempts at detoxification. Because of irreversible liver failure, which occurred within 2 days after admission, and because of cerebral edema, the decision to perform a liver transplantation was made. On day 6 after admission, a compatible donor liver was transplanted. The course of liver transplantation and the patient's subsequent recovery were uneventful., Conclusion: The rationale for the delayed transplantation was to avoid damage of the new organ because of high serum chromium levels. Despite severe organ damage, the chromium content of the liver was increased. To the authors' knowledge, this is the first case report of acute toxic liver failure, caused by potassium dichromate poisoning, treated successfully by means of liver transplantation.

Background: The release of liver arginase after orthotopic liver transplantation (OLT) causes a deficiency of L-arginine and nitrite in the plasma. This deficiency is possibly related to pulmonary hypertension and reduced hepatic blood flow, which are commonly observed in the immediate reperfusion period. The aim of this study was to evaluate the impact of L-arginine supplementation on metabolic and hemodynamic parameters during liver reperfusion after OLT in pigs., Methods: Thirteen pig OLTs (control group, n=6; arginine group, n=7) were performed by a standard technique. Cold ischemic time was 20 hr. L-Arginine was infused at a dosage of 500 mg/kg body weight into the donor pigs (30 min before liver explantation) and also into the recipients (over a period of 3 hr from the beginning of the reperfusion period). At the end of the experimental study, the pigs were killed with an overdose of potassium., Results: In the control group, liver revascularization increased plasma arginase concentrations (+615%) and reduced plasma levels of L-arginine (-87%), nitrite (-82%), and nitrate (-53%). Infusion of L-arginine increased plasma levels of L-arginine from 94+/-21 micromol/L to 1674+/-252 micromol/L (P<0.001), L-ornithine from 46+/-8 micromol/L to 2215+/-465 micromol/L (P<0.001), and L-citrulline from 58+/-8 micromol/L to 116+/-34 micromol/L (P<0.001), but had no effect on plasma levels of nitrite and nitrate. Administration of L-arginine in the donor pigs did not produce any systemic or organ-specific hemodynamic alterations. Infusion of L-arginine into the recipient pigs improved cardiac performance (increase in heart rate [+61%, P=0.017] and cardiac index [+53%, P=0.005], reduction in pulmonary capillary wedge pressure [-54%, P=0.014]). Moreover L-arginine infusion increased oxygen consumption (+65%, P=0.003), reduced pulmonary vascular resistance index (P=0.001), stimulated portal venous blood flow (P=0.014), and elevated body temperature during the reperfusion period (P=0.007)., Conclusions: From these data, we conclude that the infusion of L-arginine during OLT improves the hemodynamic performance of the heart, lung, and liver.

Immediately after hepatic reperfusion in human orthotopic liver transplantation, high amounts of arginase are released from the graft, thereby influencing nitric oxide metabolism. This metabolic alteration may be one component of the ischemia-reperfusion syndrome in OLT with its hemodynamic disturbances (e.g., systemic hypotension, pulmonary hypertension). The aim of this study was to compare hemodynamic and metabolic changes following OLT in the pigs with those obtained under arginase infusions in catheterized, anesthetized pigs. Following liver revascularization in the pigs, plasma arginase concentrations increased from 48 +/- 19 IU/L to 2613 +/- 944 IU/L, resulting in a drop in plasma levels of L-arginine (-87%) and in a drop in nitrite (-82%) and nitrate (-53%) concentrations. Of the measured organ-specific hemodynamic alterations, the mean pulmonary arterial pressure increased from 17 +/- 2 mmHg to 30 +/- 5 mmHg, whereas the flow/pressure index of the portal vein decreased about 60%. A primed continuous infusion of arginase (25,000 IU) increased plasma arginase levels to a maximum of 3,690 +/- 962 IU and evoked a decrease of L-arginine, but did not alter plasma nitrite or nitrate levels. The administration of arginase in healthy pigs did not influence cardiac output, mean arterial pressure, heart rate, or total peripheral resistance, but led to an increase of mean pulmonary arterial pressure from 19 +/- 3 to 48 +/- 5 mmHg and to a reduction of arterial hepatic blood flow from 229 +/- 65 ml/min to 154 +/- 41 ml/min. From this we conclude that high levels of liver arginase cause hemodynamic alterations in the lung and the liver. We hypothesize that the pulmonary hypertension and the reduced hepatic blood flow found during the immediate reperfusion period after OLT are possibly related to the increased arginase release due to the hepatic damage of the graft.

Several studies have shown that the postoperative course of cytokines such as TNF-alpha or IL-6 is predictive of rejection and infection after human orthotopic liver transplantation (OLT). The aim of this prospective clinical trial was to evaluate the impact of transhepatic metabolism of endotoxin (ET), tumor necrosis-factor-alpha (TNF-alpha), and interleukin-6 (IL-6) after hepatic ischemia/reperfusion on the postoperative graft function. In 13 consecutive elective adult OLT patients with primary grafts, we determined concentrations of ET, TNF-alpha, and IL-6 in the radial artery, portal vein, and right hepatic vein at 1, 4, 7, 10, and 13 min after reperfusion. Of the 13 patients, four had ET levels below the detection limit (< 10 ng/L), and one patient had extremely high ET concentrations (151 ng/L in the hepatic vein). In the remaining patients the mean ET levels were 26 +/- 14, 26 +/- 15, and 24 +/- 14 ng/L in the portal vein, hepatic vein, and in the radial artery, respectively. These values indicate that in patients with a moderately elevated ET level, no transhepatic concentration differences of ET exist. However, in the patient with severe endotoxemia, the liver was apparently an ET-producing organ (HV-P: 29 +/- 13 ng/L). TNF-alpha levels were not measurable in four patients, and varied between 15 and 72 pg/ml (portal vein) in the remaining patients. The transhepatic concentration differences (HV-P and HV-A, respectively) of patients with PNF or dysfunction were higher than in those with "good" or "excellent" graft function (HV-P: 160 +/- 122 pg/ml vs. 7.3 +/- 9.7 pg/ml; P < 0.01 and HV-A: 137 +/- 101 pg/ml vs. 3.9 +/- 12 pg/ml; P < 0.01, respectively). Arterial IL-6 levels were below 88 pg/ml (mean value: 31 +/- 20 pg/ml) at the beginning of the operation, and increased considerably in three patients during the anhepatic phase and after reperfusion. No clinical correlation was found with the transhepatic concentration differences of IL-6. We conclude that in OLT patients without infection no transhepatic ET exchange was documented. However, a stimulated hepatic TNF-alpha release seems to be predictive of the beginning of liver dysfunction.

L-Arginine plays an important role in protecting animals against ammonia intoxication, enhances immune function, stimulates wound healing, and is the precursor for the endothelium-derived relaxing factor, recently recognized as nitric oxide (NO). In this study, we investigated the influence of hepatic reperfusion on amino acid metabolism after human OLT. After 10 sec of reperfusion, the arterial plasma levels of L-arginine dropped from 105 +/- 12 mumol/L to 3.8 +/- 0.6 mumol/L (P < 0.001), whereas plasma ornithine increased from 40 +/- 5.5 mumol/L to 129 +/- 15 mumol/L (P < 0.001). The reduced L-arginine levels remained subnormal for several hours after OLT. This drop in plasma L-arginine was due to an arginase release from the implanted graft. Immediately after reperfusion, the plasma concentrations of arginase increased from pretransplantation values of 18 +/- 13 IU/L to 2384 +/- 1456 IU/L (P < 0.01). Measurement of plasma nitrite (NO2-) and nitrate (NO3-), which are the stable end products of NO, revealed that NO2- decreased about 50% after reperfusion (from 1.64 +/- 0.32 mumol/L to 0.80 +/- 0.17 mumol/L; P < 0.001), whereas NO3- levels remained unchanged (76 +/- 23 mumol/L vs. 63 +/- 8 mumol/L). We conclude that hepatic reperfusion causes L-arginine deficiency by liberating high amounts of arginase from the implanted graft. This L-arginine depletion may influence the NO synthesis in patients after OLT.