Kai-Chah Tan

Hepatitis B virus reinfection after orthotopic liver transplantation: Serological and clinical implications

The implications of hepatitis B virus (HBV) reinfection after liver transplantation were studied in 29 patients followed for 1.7-15 years. Of 20 patients with HBV infection alone, nine were HBeAg and HBV DNA seronegative and 11 had evidence of HBV replication as measured by HBeAg or HBV DNA seropositivity. Nine patients had co-existing HBV and delta virus (HDV) infection. Five patients became HBsAg seronegative after transplantation (four immediately and one after an hepatitic episode). Of the 20 patients with HBV infection alone, 17 had evidence of viral replication after transplantation with markedly increased HBV DNA levels. Five patients with HDV infection had HBV DNA in serum, but in significantly lower amounts than in those with HBV infection alone. Twenty-five episodes of graft dysfunction attributed to recurrent HBV infection occurred in 19 patients (65.5%). Thirteen episodes (in 12 patients) were self-resolving acute hepatitic illnesses. Six patients had a rapidly progressive illness leading to graft loss within 6 weeks, with the distinctive histological features termed fibrosing cholestatic hepatitis (FCH). Liver function tests in these patients showed markedly abnormal serum bilirubin and prothrombin times, but only modest increases in serum transaminase levels. An additional six patients lost their graft as a consequence of HBV recurrence through various pathogenetic mechanisms including possible (but unproven) FCH, chronic active hepatitis or late-onset hepatic failure. Co-existing HDV infection appeared to confer some medium-term protection from graft loss.

Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome

Liver transplantation for primary hepatocellular carcinoma (HCC) has in general been complicated by high recurrence rates. In the present study results from experience of 87 patients were analyzed [56 cirrhotic, 31 non-cirrhotic, 6 with the fibrolamellar (FL) variant] in relation to curative potential. Sixty-two survived > 90 days and form the study cohort. Fifty-six had non-fibrolamellar HCC and, of these, 39 had discrete lesions, measuring 0.8-21 cm (median 5.0 cm) including 4 in whom the diagnosis was made after examination of the explanted liver; 23 had multifocal lesions (> 2 tumor masses). There was no tumor recurrence in the group of 14 cases with single dominant lesions measuring < 4 cm, whereas in the 15 cases with lesions of 4-8 cm the recurrence rate was 40%, and 78% in those > 8 cm and the multifocal lesions (n = 27, P = 0.0001). Five-year actuarial survival figures were 57.1%, 44.4% and 11.1% (P < 0.003) respectively. The mean survival times in patients who died of recurrence were: 4-8 cm, 3.3 years (range 10 months to 6.3 years); > 8 cm or multifocal, 13 months (3-25 months). Reduction of serum alpha-fetoprotein (AFP) to normal levels does not exclude a later recurrence (7 of 17 cases) and this was documented after maintenance of normal AFP levels for up to 29 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver transplantation after paracetamol overdose.

OBJECTIVE--To evaluate the role of liver transplantation after paracetamol overdose. DESIGN--Prospective study of consecutive candidates for transplantation and performance of transplantation over 18 months. SETTING--Liver unit, Kings College Hospital, London. MAIN OUTCOME MEASURES--Fulfilment of indicators of poor prognosis, selection for transplantation, transplantation, survival. RESULTS--30 of 37 patients considered to have a reasonable prognosis with intensive medical care survived. Of 14 of 29 patients considered to have a very poor prognosis and registered for urgent liver transplantation, six received liver transplants, four of whom survived, while seven died and one survived without a transplant. Three of 15 patients with poor prognostic indicators but not selected for transplantation survived. CONCLUSION--Liver transplantation will have a definite but limited role in the management of fulminant hepatic failure induced by paracetamol.

NITRIC OXIDE GENERATION : A PREDICTIVE PARAMETER OF ACUTE ALLOGRAFT REJECTION

The L-arginine:nitric oxide (NO) biosynthetic pathway has been proposed as an important mediator in host defense mechanisms and may therefore play a role in the acute allograft response. We have studied NO generation in liver allograft rejection and determined its value in immunological monitoring. Stable end products of this pathway have been determined serially in 50 primary liver recipients and compared with 2 known mediators and markers of acute allograft rejection (IL-2R positive lymphocytes and circulating TNF alpha). Plasma concentrations of acid-labile nitrosocompounds (NOx), which increased during acute allograft rejection (P < 0.0001), correlated with rejection severity and were reduced after administration of supplemental high dose glucocorticoids. Concentrations were significantly lower in nonrejection graft complications but were elevated during episodes of sepsis. Correlations between plasma NOx levels and circulating TNF-alpha (r = 0.451, P < 0.001) and IL-2R-positive lymphocytes in peripheral blood (r = 0.781, P < 0.001) were demonstrated. In a logistic analysis of these variables, plasma NOx was the most predictive parameter of an episode of acute cellular rejection. Nitric oxide generation in FK506-treated patients was lower compared with patients receiving a CsA-based immunosuppression regimen and was associated with a reduced frequency of acute rejection in the FK506 group. These data are consistent with a role for NO in the cellular alloantigen immune response and indicate that monitoring of plasma levels of NOx may be useful in the detection of acute allograft rejection.

Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression

We report two cases of recurrence of primary biliary cirrhosis (PBC) in the transplanted liver whilst maintained on a FK506-based immunosuppressive regime, the first to be described. One patient experienced symptoms in association with the development of cholestasis. In both there was a persistence of serological markers of PBC and liver histology revealed florid bile duct destruction and a granulomatous reaction.

The use of percutaneous transluminal angioplasty in hepatic artery stenosis after transplantation.

Graft ischemia following liver transplantation is associated with a high incidence of morbidity and mortality. The present report concerns a group of seven patients in whom an anastomotic stenosis of the hepatic artery was identified. Three patients had unexplained allograft dysfunction at a median time of 28 days (range 13-64 days), and 3 had a biliary leak at a median time of 42 days after liver transplantation (range 35-270 days). In one patient the stenosis was diagnosed by routine Doppler ultrasound one week after transplant. Management was by percutaneous transluminal angioplasty at a median time of 35 days (range 13-270 days) after transplantation. After angioplasty there was a marked improvement in clinical appearance, liver function, and liver histology in 5 of the 7 patients. Those patients who had a biliary leak subsequently developed strictures that eventually required biliary tract reconstruction (hepaticojejunostomy) in two and retransplantation in one. Percutaneous transluminal angioplasty is an effective way of improving arterial blood flow in cases of anastomotic stenosis, reducing the likelihood of complete occlusion by thrombosis. If recognized early and treated promptly ischemic changes in the graft can resolve and the development of biliary strictures may be avoided.

ORTHOTOPIC LIVER TRANSPLANTATION IN PATIENTS OVER 60 YEARS OLD

A retrospective examination was performed, including a case control study, of 40 patients aged 60 years and over who underwent liver transplantation at Kings College Hospital, London, UK, between 1988 and September 1993. There was no significant difference between elderly patients and younger patients in preoperative condition, intraoperative interventions, or outcome assessed by survival, complication rate, and duration of stay on the intensive care unit. The only significant difference between age groups was the median length of hospital stay, which was 24 days for the elderly versus 20 days for younger patients. We conclude that age up to 70 years should not be a barrier to liver transplantation.

Ethnic variations in patient and graft survival after liver transplantation : identification of a new risk factor for chronic allograft rejection

The ethnic origin of renal graft recipients is recognized as an important determinant of graft survival. In liver transplantation, the effect of racial origin has been studied in black American recipients and has suggested a trend toward inferior graft survival in this group. In this study, we have analyzed outcome of transplantation in a large multiethnic liver transplant program. Non-Caucasoid recipients had an inferior patient survival compared with Caucasoids and, in particular, European Caucasoids at 1, 3, and 5 years after transplantation (46.7% vs. 60.2% at 3 years, P=0.05). Non-European recipients had an inferior graft survival compared with European recipients at 1, 2, and 3 years after transplantation (e.g., north Europeans 53.5%, south Europeans 48.5%, Middle Eastern 40%, and non-Caucasoids 27% at 3 years, P<0.01). Different frequencies of chronic allograft rejection in the ethnic groups contributed to the rates of graft survival, with the non-European recipients developing chronic rejection at over twice the rate of European recipients (12.6% vs. 5.9%, respectively, P=0.002). The findings in this study support the evidence from renal transplant programs that the ethnic origin of recipients is an important determinant of outcome after transplantation, with increasing frequency of chronic rejection in recipients nonindigenous to the donor population contributing to the variations in patient and graft survival rates.

IMPORTANCE OF CONCOMITANT VIRAL INFECTION DURING LATE ACUTE LIVER ALLOGRAFT REJECTION

We have determined accompanying events and reviewed the management and outcome of late acute cellular rejection episodes in 384 consecutive liver recipients. A significant proportion of patients experienced concomitant viral infection (group 1, n = 15 [41%]), with CMV infection comprising the largest group and smaller contributions from other viruses (CMV, 30%; HSV, 5%; EBV, 3%; varicella zoster virus, 3%). Thirteen (35%) patients (group 2) developed late rejection associated with low maintenance immunosuppression, and in a further 10 patients (group 3), no accompanying factor could be identified. Refractory rejection was higher in late compared with early rejection episodes in our series (29% vs. 9.2%, P < 0.05). Antiviral chemotherapy administered in rejection episodes with concomitant viral infection, either as sole treatment in cases with accompanying hepatitis or as adjunctive therapy to further supplemental immunosuppression in episodes of steroid-resistant rejection, controlled the rejection process in all treated patients.

Recurrence of hepatitis C following orthotopic liver transplantation: a polymerase chain reaction and histological study

Hepatitis C virus was sought by nested polymerase chain reaction in the preoperative biopsy or the explanted liver of 100 consecutive adult patients undergoing orthotopic liver transplantation. In those found to be positive preoperatively, polymerase chain reaction was performed on subsequent biopsies. Of the 12 patients in whom HCV-RNA was identified in the liver by polymerase chain reaction preoperatively, viral recurrence was documented in ten of the 11 with posttransplant liver tissues available for study. In the one exception, hepatitis C virus was undetectable in the liver graft despite repeated co-amplification of albumin mRNA as an internal control, which may indicate viral clearance. In eight of the ten positive cases, HCV-RNA was also detectable in serum postoperatively, while HCV-RNA was undetectable in serum in both the cases in whom HCV-RNA was undetectable in tissue and in the patient who declined post-transplant biopsy. Two of the 12 patients infected with hepatitis C virus preoperatively have died during the follow-up period from causes unrelated to hepatitis C virus infection. While biochemical liver function in seven of those remaining has been excellent, histological evidence of at least mild chronic active hepatitis has been present in all ten cases for whom long-term biopsies are available. Three cases have progressed to severe, symptomatic chronic active hepatitis within 2 years of transplantation. Recurrent hepatitis C is associated with progressive liver disease and appreciable morbidity in a significant proportion of patients.