Fulminant hepatic failure secondary to neoplastic infiltration of the liver.

Two patients with previously normal liver function, who presented with fulminant hepatic failure (FHF) of unknown etiology despite an extensive evaluation, are described. No etiology for FHF was apparent with initial evaluation. One patient was found to have nearly complete replacement of hepatic parenchyma by metastasis from an occult small cell lung carcinoma identified postmortem. The other patient had lymphomatous infiltration of the liver detected by a liver biopsy. Imaging studies were performed in the patients and did not reveal any evidence of neoplastic infiltration of the liver. Neoplastic involvement of liver should be considered in the differential diagnosis of FHF of unknown etiology. The imaging studies in this setting can be misleading.

Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation.

Many patients who undergo hematopoietic cell transplantation experience liver injury. We examined the association of serum bilirubin levels with nonrelapse mortality by day +200, testing the hypothesis that the duration of jaundice up to a given point in time provides more prognostic information than either the maximum bilirubin value or the value at that point in time. We studied 1,419 consecutive patients transplanted from allogeneic donors. Total serum bilirubin values up to day +100, death, or relapse were retrieved-along with nonrelapse mortality by day +200 as an outcome measure--using Cox regression models with each bilirubin measure modeled as a time-dependent covariate. The bilirubin value at a particular point in time provided the best fit to the model for mortality. With bilirubin at a point in time modeled as an 8th-degree polynomial, an increase in bilirubin from 1 to 3 mg/dL is associated with a mortality hazard ratio of 6.42. An increase from 4 to 6 mg/dL yields a hazard ratio of 2.05, and an increase from 10 to 12 mg/dL yields a hazard ratio of 1.17. Among patients who were deeply jaundiced, survival was related to the absence of multiorgan failure and to higher platelet counts. In conclusion, the value of total serum bilirubin at a particular point in time after transplant carries more informative prognostic information than does the maximum or average value up to that point in time. The increase in mortality for a given increase in bilirubin value is larger when the starting value is lower.

Temporary support for acute liver failure.

GOAL: To review treatment approaches for temporary liver support of patients with acute liver failure (ALF). STUDY A MEDLINE: search of English language reports published between 1960 and 1999 and a manual search of bibliographies of relevant papers were performed. Studies of humans in whom non-orthotopic liver transplant (OLT)-based approaches were used were reviewed, including case reports, case series, review articles describing unpublished cases, and controlled trials. Relevant clinical information was extracted with emphasis on improvement in liver function, successful bridging to OLT, recovery without OLT, and death. There was a lack of more than one controlled trial for each therapy, and most case reports were anecdotal in nature; therefore, no statistical analysis was attempted. Predefined outcomes from individual patients were synthesized collectively into tables. RESULTS: Both cell-based and non-cell-based therapies for ALF appear promising. Preliminary experience has established the safety of these approaches, but current data are inadequate to evaluate efficacy. CONCLUSIONS: Routine use of artificial liver support systems cannot be recommended at this time. However, the established safety of cell- and non-cell-based liver support devices warrants additional prospective (Phase III) controlled trials among patients with ALF. We suggest an algorithm for management of patients with ALF that incorporates recent data.

Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver.

After transplantation, hepatocytes entering liver sinusoids are engrafted, whereas cells entrapped in portal spaces are cleared. We studied whether hepatic sinusoidal dilatation will increase the entry of transplanted cells in the liver lobule, improve cell engraftment, and decrease microcirculatory perturbations. F344 rat hepatocytes were transplanted intrasplenically into syngeneic dipeptidyl peptidase IV (DPPIV)-deficient rats. Animals were treated with adrenergic receptor blockers (phentolamine, labetalol), a calcium channel blocker (nifedipine), and splanchnic vasodilators (nitroglycerine, calcitonin gene-related peptide [CGRP], glucagon). Transplanted cells were localized by histochemistry. The hepatic microcirculation was studied with in vivo videomicroscopy. Changes in cell translocations were analyzed by injection of (99m)Tc-labeled hepatocytes. Pretreatment with phentolamine and nitroglycerine increased transplanted cell entry in liver sinusoids, whereas labetalol, nifedipine, CGRP, and glucagon were ineffective. Increased deposition of transplanted cells in sinusoids resulted in greater cell engraftment. In vivo microscopy showed disruption of sinusoidal blood flow immediately after cell transplantation with circulatory restoration requiring more than 12 to 24 hours after cell transplantation. However, in nitroglycerine-treated animals, sinusoidal blood flow was perturbed less. Nitroglycerine did not meaningfully increase intrapulmonary cell translocations. In conclusion, these findings indicate that hepatic sinusoidal capacitance is regulated by alpha-adrenergic- and nitroglycerine-responsive elements. Sinusoidal vasodilatation benefited intrahepatic distribution of transplanted cells and restored hepatic microcirculation after cell transplantation. This shall facilitate optimization of clinical cell transplantation and offers novel ways to investigate vascular mechanisms regulating hepatic sinusoidal reactivity.

Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy.

Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells expressing the CD33 receptor by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. Treatment of acute myeloid leukemia (AML) with gemtuzumab ozogamicin may result in liver injury. We reviewed the course of 23 patients who were given gemtuzumab ozogamicin for AML that had relapsed after hematopoietic cell transplantation. Liver toxicity was assessed through physical examination, serum tests, histologic examination, and hepatic venous pressure measurements. Liver injury developed in 11 patients after gemtuzumab ozogamicin administration; it was manifested as weight gain, ascites, and jaundice in 7 patients. Seven patients died with persistent liver dysfunction and either multiorgan failure or sepsis at a median of 40 days after gemtuzumab ozogamicin infusion. Portal pressure measurements were elevated in 2 patients. Results of liver histologic examination in 5 patients showed sinusoidal injury with extensive sinusoidal fibrosis, centrilobular congestion, and hepatocyte necrosis. Six patients experienced AML remission that was sustained for at least 60 days after gemtuzumab ozogamicin infusion. In summary, hepatic sinusoidal liver injury developed after gemtuzumab ozogamicin infusion. Histology showed striking deposition of sinusoidal collagen, suggesting that gemtuzumab ozogamicin targets CD33(+) cells residing in hepatic sinusoids as the mechanism for its hepatic toxicity.